Textbook of Cosmetic Dermatology 6th

SERIES IN COSMETIC AND LASER THERAPY
SIXTH EDITION
Textbook of
Cosmetic
Dermatology
EDITED BY
Robert Baran and Howard I. Maibach
CRC Press
Taylor & Francis Group
Textbook of Cosmetic Dermatology
This text documents the science that lies behind the expanding field of cosmetic dermatology so that clinicians can practice with
confidence and researchers can be fully aware of the clinical implications of their work. New chapters have been added to this
edition on skin bioengineering, skin imaging, sunscreens, gel nail polish, management of hair loss, cosmetics and moisturizers
in acne management, cryolipolysis, and radiofrequency for minimally invasive body contouring, amongst others, and chapters
have been updated throughout to keep this at the forefront of work and practice.
The Series in Cosmetic and Laser Therapy is published in association with the Journal of Cosmetic and Laser Therapy.
Robert Baran, MD, is formerly Head of the Nail Disease Centre and of the Dermatology Unit, Cannes General Hospital, and
Honorary Professor of the University of Franche-Comté, France. He is also the editor of Baran and Dawber’s Diseases of the
Nails and Their Management 5E, Fungal Infections of the Nail and Scalp 3E, and Nail Therapies 2E, amongst many others.
Howard I. Maibach, MD, is Professor of Dermatology at the University of California School of Medicine, San Francisco,
California, USA. He is also the editor of Dermatotoxicology 8E, Handbook of Cosmetic Science and Technology 4E, and
Handbook of Systemic Drug Treatment in Dermatology 3E, amongst many others.
Series in Cosmetic and Laser Therapy
About the Series

The world of cosmetic and aesthetic medicine and surgery has grown greatly in size and complexity over recent years, and the
series in Cosmetic and Laser Therapy keeps readers up to date with the latest clinical therapies to improve and rejuvenate the
appearance of skin, hair, and nails. Published in association with the Journal of Cosmetic and Laser Therapy, each volume in
the series is prepared separately and typically focuses on a topical theme. Volumes are published on an occasional basis,
according to the emergence of new developments.
Textbook of Chemical Peels: Superficial, Medium, and Deep Peels in Cosmetic Practice, Second Edition
Philippe Deprez
Textbook of Cosmetic Dermatology, Fifth Edition

Robert Baran, Howard I. Maibach
Disorders of Fat and Cellulite: Advances in Diagnosis and Treatment

David J. Goldberg, Alexander L. Berlin
Botulinum Toxins in Clinical Aesthetic Practice 3E: Two Volume Set

Anthony V. Benedetto
Botulinum Toxins in Clinical Aesthetic Practice 3E, Volume One: Clinical Adaptations
Botulinum Toxins in Clinical Aesthetic Practice 3E, Volume Two: Functional Anatomy and Injection Techniques
Aesthetic Rejuvenation Challenges and Solutions: A World Perspective

Paul J. Carniol, Gary D. Monheit
Illustrated Manual of Injectable Fillers, Second Edition

Neil S. Sadick
Adapting Dermal Fillers in Clinical Practice

Yates Yen-Yu Chao, Sebastian Cotofana
Cosmeceutical Science in Clinical Practice, Second Edition

Neil S. Sadick, Mary P. Lupo, and Zoe Diana Draelos
Chemical Peels in Clinical Practice: A Practical Guide to Superficial, Medium, and Deep Peels
Xavier G. Goodarzian
Textbook of Cosmetic Dermatology, Sixth Edition

For more information about this series please visit: https://www.crcpress.com/Series-in-Cosmetic-and-Laser-Therapy/book-

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Textbook of Cosmetic Dermatology
Sixth Edition
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ISBN: 978-1-032-27067-8 (hbk)
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DOI: 10.1201/b22897
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Contents
Contributors��viii
1. Skin Physiology and Gender�� 1

Ethel Tur
2. Climatic Influence on Cosmetic Skin Parameters�� 15

Mathias Rohr and Andreas Schrader
3. Transepidermal Water Loss�� 27

Jan Kottner
4. Nail Penetration�� 32
Xiaoying Hui and Howard I. Maibach
5. Advances in Skin Bioengineering�� 44

Enzo Berardesca and Norma Cameli
6. Advances in Skin Imaging in Cosmetology and Aesthetic Dermatology�� 48

Ferial Fanian
7. Sensitive Skin: New Findings Yield New Insights�� 56

Miranda A. Farage and Howard I. Maibach
8. Organic Acids with Novel Functions: Hydroxy, Bionic, N-Acetylamino Acids, N-Acylpeptide, and Creatine
Derivatives�� 69
Ruey J. Yu and Eugene J. Van Scott
9. Retinyl Propionate and Related Retinoids�� 87

John E. Oblong
10. Antioxidants�� 92
Frank Dreher
11. Topical Retinol: An Efficacious Solution for Improvement of Main Photodamage Signs��101
Christiane Bertin, Thierry Oddos, and Georgios N. Stamatas
12. Urokinase and Plasmin in Dry Skin, Skin Aging, and Skin Pigmentation�� 106
Yuji Katsuta
13. 4-Hexyl-1,3-Phenylenediol, a NF-κB Inhibitor, Improves Clinical Signs of Aging��113

Cécilia Brun, Simarna Kaur, Michael D. Southall, Christiane Bertin, Thierry Oddos, and Georgios N. Stamatas
14. Perfumes��119
Jeanne Duus Johansen
15. Alternative and Natural Treatments in Dermatology�� 125

Conor Palleschi and Cheryl Levin
16. Sunless Tanning Products�� 146

Stanley B. Levy
v
vi Contents
17. Percutaneous Penetration: Sunscreens��151

Uli Osterwalder
18. Photodamage: Protection and Reversal with Topical Antioxidants��167

Karen E. Burke
19. Actinic Keratosis�� 188

Brigitte Dréno
20. Gel Nail Polish and Its Side Effects�� 195

Noureddine Litaiem
21. Nail Cosmetics�� 202

Robert Baran, Nilton Gioia Di Chiacchio, Christel Scheers, Josette André, and Douglas Schoon
22. Nail Cosmetics for Abnormal and Pathological Nails�� 212

Douglas Schoon, Nilton Gioia Di Chiacchio, Christel Scheers, and Josette André
23. Treatment of Nail Fragility in Males and Females�� 225

Bianca Maria Piraccini and Luca Rapparini
24. Nail Prostheses�� 228

Shari Lipner and Kelita Waterton
25. Assessing the Efficacy of Moisturizers�� 234

Whitney Hannon
26. Anticellulite Products and Therapies�� 259

Enzo Berardesca
27. Therapy of Telangiectasia and Varicose Veins and Their Complications�� 264
Charles M. Weddington, Christian R. Halvorson, Robert A. Weiss, and Margaret A. Weiss
28. Management of Hair Loss�� 274

Ömer Kutlu and Uwe Wollina
29. Pigmentation: Dyschromia�� 286

Thierry Passeron and Jean-Paul Ortonne
30. Treatment of Keloids�� 306

Joshua E. Lane and Tanda N. Lane
31. Keratolytic Treatment of Acne��317

Brigitte Dréno
32. Cosmetics and Moisturizers in Acne Management�� 326

Uwe Wollina and Ömer Kutlu
33. Ethnic Cosmetics�� 333

Enzo Berardesca
34. Changes in Female Hair with Aging: New Understanding and Measures�� 340
Paradi Mirmirani, R. Scott Youngquist, and Thomas L. Dawson Jr.
35. Menopause: Skin and Cosmetology�� 352

Rashmi Sarkar, Preethi B. Nayak, and Vivek M. Pai
36. Microneedles and Cosmetic Uses�� 357

Klaus Fritz, Carmen Salavastru, and George Sorin Tiplica
Contents vii
37. Cosmetic Cryotherapy�� 368

Rodney Sinclair
38. Botulinum Toxins�� 378

Doris Hexsel and Ana Carolina Krum dos Santos
39. Soft Tissue Augmentation�� 393

Joanna Dong and C. William Hanke
40. Chemical Peels�� 403

Philippe Deprez
41. Lasers and Light Sources for Vascular and Pigmented Components of Photoaging��416
Shealinna Ge, Anne Marie Mahoney, and Robert A. Weiss
42. Nonablative Laser Rejuvenation�� 425

Shealinna Ge, Karen L. Beasley, Christian R. Halvorson, and Robert A. Weiss
43. Cryolipolysis for Nonsurgical Fat Reduction�� 444

Alain Michon
44. Radiofrequency for Minimally Invasive Body Contouring�� 457

Yu-Ching Weng
45. Minimally Invasive Upper Arm Contouring in Esthetic Medicine�� 466

Uwe Wollina, Alberto Goldman, and Ömer Kutlu
Index�� 472
Contributors
Josette André Frank Dreher

CHU St Pierre, CHU Brugmann TOPALIX LLC
and Queen Fabiola Children’s Hospital San Francisco, California, USA
Brussels, Belgium
Brigitte Dréno
Karen L. Beasley Nantes University Hospital
University of Maryland School of Medicine Nantes, France
and Maryland Laser, Skin, & Vein Institute
Hunt Valley, Maryland, USA Ferial Fanian
Laboratoires FILLMED
Enzo Berardesca Paris, France
Dr Phillip Frost Department of Dermatology
University of Miami Miranda A. Farage
Miami, Florida, USA R&D, Procter & Gamble
Cincinnati, Ohio, USA
Christiane Bertin
Johnson & Johnson Santé Beauté France Klaus Fritz
Issy-les-Moulineaux, France Dermatology and Laser Consulting
Center
Cécilia Brun Landau, Germany
Johnson & Johnson Santé Beauté France
Shealinna Ge
Issy-les-Moulineaux, France
Maryland Laser, Skin, & Vein Institute
Hunt Valley, Maryland, USA
Karen E. Burke
Mt Sinai Icahn School of Medicine
Alberto Goldman
New York, New York, USA
Hospital São Lucas da PUCRS
Porto Alegre, Brazil
Norma Cameli
San Gallicano Dermatological Institute Christian R. Halvorson
Rome, Italy Maryland Laser, Skin, & Vein Institute
Karlijn Clarysse
Department of Dermatology C. William Hanke
University Hospital Brussels Laser and Skin Surgery
Brussels, Belgium Center of Indiana
Indianapolis, Indiana, USA
Thomas L. Dawson Jr.
A-STAR Skin Research Labs Whitney Hannon
Skin Research Institute Dermatology
Singapore Alachua, Florida, USA
Philippe Deprez Doris Hexsel

Skin Tech Pharma Group and Clinica Hera Hexsel Dermatologic Clinics
Empuriabrava, Spain Porto Alegre, Brazil
Nilton Gioia Di Chiacchio Xiaoying Hui

Dermatology Department University of California, San Francisco
Hospital do Servidor Publico Municipal de Sao Paulo San Francisco, California, USA
Sao Paulo, Brazil
Joanna Dong Gentofte Hospital
Laser and Skin Surgery Center of Indiana University of Copenhagen
Indianapolis, Indiana, USA Copenhagen, Denmark
viii
Contributors ix
Yuji Katsuta Preethi B. Nayak

MIRAI Technology Institute Experia Advanced Skin & Hair Clinic
Osaka, Japan Karnataka, India
Simarna Kaur John E. Oblong

Johnson & Johnson Santé Beauté R&D, The Procter & Gamble Company
France Cincinnati, Ohio, USA
Issy-les-Moulineaux, France
Thierry Oddos
Jan Kottner Johnson & Johnson Santé Beauté France
Charité-Universitätsmedizin Issy-les-Moulineaux, France
Berlin, Germany
†Jean-Paul Ortonne
Ana Carolina Krum dos Santos
Hexsel Dermatologic Clinics Uli Osterwalder
Porto Alegre, Brazil Sun Protection Facilitator GmbH
Switzerland
Ömer Kutlu
Tokat Gaziosmanpasa University Vivek M. Pai
Tokat, Türkiye AK Clinics
Indiranagar, Bangalore, India
Joshua E. Lane
Conor Palleschi
Mercer University School of Medicine
Kuchnir Dermatology
Macon, Georgia, USA
Milford, Massachusetts, USA
Tanda N. Lane
Thierry Passeron
Emory University
Dermatology
Atlanta, Georgia, USA
Université Côte d’Azur
Nice, France
Cheryl Levin
Harvard Medical School
Eshini Perera
and Levin Dermatology
Mowbray Park Medical & Dermatology
Newton, Massachusetts, USA
East Brisbane, Australia
Stanley B. Levy Bianca Maria Piraccini
Duke University School of Medicine IRCCS Azienda Ospedaliero–Universitaria di Bologna
Durham, North Carolina, USA Bologna, Italy
Shari Lipner Luca Rapparini
Weill Cornell Medical College Department of Medical and Surgical Sciences
Cornell University University of Bologna
Ithaca, New York, USA Bologna, Italy
Noureddine Litaiem Mathias Rohr
Charles Nicolle Hospital Institute Dr Schrader
and University of Tunis El Manar Holzminden, Germany
Tunis, Tunisia
Carmen Salavastru
Anne Marie Mahoney Colentina Clinical Hospital
Maryland Laser, Skin, & “Carol Davila” University of Medicine and Pharmacy
Vein Institute Bucharest, Romania
Rashmi Sarkar
Alain Michon Lady Hardinge Medical College and Hospital
Ottawa Skin Clinic New Delhi, India
Ottawa, Ontario, Canada
Christel Scheers
Paradi Mirmirani CHU St Pierre
Dermatology Clinic at Mount Zion CHU Brugmann and Queen Fabiola Children’s Hospital
San Francisco, California, USA Brussels, Belgium
x Contributors
Douglas Schoon Poorna Weerasinghe

Schoon Scientific Department of Dermatology
Dana Point, California, USA University of Melbourne
Melbourne, Australia
Andreas Schrader
Institute Dr Schrader Robert A. Weiss
Holzminden, Germany University of Maryland School of Medicine
Baltimore, Maryland, USA
Rodney Sinclair
Sinclair Dermatology Margaret A. Weiss
Melbourne, Australia Department of Dermatology
University of Maryland School of Medicine
Michael D. Southall Baltimore, Maryland
Johnson & Johnson Skin Research Center and
Johnson & Johnson Consumer Inc. Laser, Skin, & Vein Institute
Skillman, New Jersey, USA Hunt Valley, Maryland, USA
Georgios N. Stamatas Yu-Ching Weng

Johnson & Johnson Santé Beauté Taichung Veterans General Hospital
Issy-les-Moulineaux, France Taichung, Taiwan
Graduate Institute of Clinical Medical Sciences
George Sorin Tiplica National Yang Ming Chiao Tung University College of
Colentina Clinical Hospital Medicine
“Carol Davila” University of Medicine and Pharmacy Taipei, Taiwan
Bucharest, Romania
Uwe Wollina
Ethel Tur Städtisches Klinikum Dresden
Tel Aviv University Dresden, Germany
Tel Aviv, Israel
R. Scott Youngquist
Eugene J. Van Scott The Procter & Gamble Company
Private Practice Mason, Ohio, USA
Abington, Pennsylvania, USA
Ruey J. Yu
Kelita Waterton Private Practice
SUNY Downstate College of Medicine Chalfont, Pennsylvania, USA
Brooklyn, New York, USA
Charles M. Weddington
University of Marland
Baltimore, Maryland, USA
1
Skin Physiology and Gender
Ethel Tur
the fifth decade, after which it decreased with age. The male
Introduction forearm skin contained more collagen at all ages in the range
15–93 years. In both sexes there was a linear decrease in skin
Numerous characteristics of the body are reflected in the collagen with age. Collagen density calculated as the ratio of
skin, gender being a prominent one. Genetic and hormonal skin collagen to thickness was lower in women at all ages. The
differences affect skin structure and function, resulting in rate of collagen loss was similar in both sexes. Women start
variations between women and men and causing these gen- with lower collagen content; as a result, they seem to age ear-
der variations to change with age. In addition, exogenous lier than men. Collagen density, representing the packing of
factors differ according to differences in lifestyle between fibrils in the dermis, is lower in women than in men. This may
the sexes. be due to androgen, as skin collagen density is increased in
Methodologies used in dermatological research have patients with virilism.
improved substantially in the last few decades, providing Forearm skinfold thickness, as measured by a caliper,
means of objective evaluation of skin function and charac- decreases starting at age 35 for women and 45 for men. Starting
teristics. Studies addressing various aspects of differences at age 35, it is thinner in women than in men.12 In younger sub-
between women and men were conducted in the last few years, jects: 17–24 years, forearm, thigh, and calf skinfold thickness
along with the growing interest in studying gender related dif- in women is lower than in men.13
ferences of physiological and disease processes.1,2 However, Heel pad thickness, an indicator of soft tissue thickness
the subject has not yet been systematically studied, so much in the body, was thicker in Ethiopian men than in women.14
of the data are by-products of studies with a different focus. Skinfold compressibility in Japanese students was greater
This chapter outlines the various aspects of physiological dif- in women than in men at the pectoral site, and smaller at
ferences between the skin of women and men, based on the nuchal, submental, biceps, thigh, suprapatellar and medial
available data. calf sites.7 The changes in the distribution of fat between
the ages of 6 to 18 years were studied in 2300 subjects.15
Up to 12 years of age, there was no difference between the
Structural and Anatomical two sexes: the mass of the subcutaneous fat increased more
than threefold, while that of the internal mass increased
Characteristics (Table 1.1)
less than twice. After the age of 12, the relative mass of
The skin of female frogs is thicker than that of males in all the subcutaneous fat continued to increase in girls but not
body regions3 (whereas the opposite is true for rat skin4). In in boys.
humans, skin thickness (epidermis and dermis) is greater in The distribution of fat over the body is different in men
men than in women,5 up to 1.428 times,6 whereas the subcu- and women.16 In men, an increase in fat tends to accumulate
taneous fat thickness is greater in women.7 The skin of men is in the abdominal region and upper parts of the body, whereas
thicker across the entire age range of 5–90 years.8 Hormonal in women it is in the lower body, particularly in the gluteal
influence on skin thickness was demonstrated when conjugated and femoral regions. In addition, the proportion of body fat
estrogens were given to postmenopausal women.9 Following is higher in non-obese women than in non-obese men. The
12 months therapy, the dermis was significantly thicker, and characteristic difference in body fat distribution between
histologic improvement in the previously atrophic epidermis the sexes exists both in non-obese subjects and obese ones.
was noted. Epidermal thickness alone, as measured by opti- Lipoprotein lipase activity and mRNA levels were higher in
cal coherence tomography, does not differ between men and women both in the gluteal and in the abdominal regions. In
women, except for the forehead epidermis which is thinner in women, higher enzyme activity was found in the gluteus than
women.10 in the abdomen, whereas in men it was higher in the abdo-
Skin collagen and collagen density were measured in addi- men. These regional and sex differences in lipoprotein lipase
tion to dermal thickness.11 The skin of men demonstrated a activity might underlie the difference in fat distribution and
gradual thinning with advancing age (12–93 years), whereas total fat content. Variation is both at the mRNA level and
the thickness of women’s skin remained constant up until post-translational level.
DOI: 10.1201/b22897-1 1
2 Textbook of Cosmetic Dermatology
TABLE 1.1
Structural and Anatomical Characteristics
Ref. Finding Obtained by Subjects Conclusions
(a) Significant differences
10 Forehead epidermis thinner in women Optical coherence 83 Caucasians
Other sites: Epidermal thickness does not tomography Young: 20-40 y
differ between men and women Old: 60–80 y
5 Skin thickness in humans greater in Echographic evaluation 24 women; 24 men
men than in women, except for lower half 27–31 y, half 60–90 y
back in young subjects
8 Men’s skin thicker than women’s Ultrasonic echography: 69 women; 54 men
across the entire age range of 5–90 y Forearm 5–90 y
6 Men’s skin thicker than women’s, up to 12.0-MHz- in B-mode 112 healthy
1.438 times 43 women; 69 men: 19–28 years
24 sites
9 Thickening of dermis following Conjugated estrogen 28 estrogen, Estrogens affect skin thickness
12 months estrogen therapy therapy: 26 placebo
ultrasound women: 51–71 y
measurement
11 Men: gradual thinning of skin with Skin collagen, skin Collagen: 80 women; Rate of collagen loss same in
advancing age. Women: thickness thickness and collagen 79 men: 15–93 y men and women, although total
constant up to 5th decade, then density, measured Thickness: 107 women; 90 men skin collagen content is less in
decreasing with age chemically and 12–93 y; Density: 26 women; women than men at all ages
histologically 27 men: 15–93 y
12 Forearm skinfold thickness decreases Caliper: 145 women and men
starting at age 35 for women and 45 for Forearm 8–89 y
men. Starting at age 35 it is thinner in
women than in men
13 Skinfold thickness lower in women Caliper: 42 women; 37 men
Forearm, thigh and calf 17–24 y
7 Subcutaneous fat thickness greater in Caliper and ultrasound 45 women; 41 men
women Japanese: 18–22 y
14 Heel pad thickness thicker in men than in Ankle X-ray 113 women; 125 men
women; correlation with body weight Ethiopian: 10–70 y
7 Skinfold compression in women is Caliper and ultrasound 45 women; 41 men
greater in the trunk and lower in the Japanese: 18–22 y
limbs
15 Up to 12 years of age no difference Caliper 1292 women; 1008 men
between the sexes. Subcutaneous fat ages 6, 8, 10, 18
increases more than threefold, while
internal fat mass increases less than
twice. After 12 y, the relative mass of
the subcutaneous fat increased in girls
but not in boys
16 Lipoprotein lipase activity higher in Lipoprotein lipase 8 women; 11 men Regional and sex differences in
women. Women: higher values in activity and mRNA 37 ± 4 y lipoprotein lipase activity might
gluteus than abdomen. Men: higher in levels measured; underlie the difference in fat
abdomen hybridization, distribution and total fat content.
Northern blot Variation is both at mRNA and
post-translational levels
(b) No significant differences
15 Up to 12 y: the mass of the subcutaneous Caliper 1292 women; 1008 men
fat increases more than threefold, while ages 6, 8, 10, 18
that of the internal mass increases less
than twice in both sexes
significant increase in ceramide 1 and 2 accompanied by

Biochemical Composition (Table 1.2) a decrease in ceramide 3 and 6. After maturity there was a
decrease in ceramide 2 and an increase in ceramide 3. These
Significant age-related differences in the stratum corneum findings indicate an influence of female hormones on the com-
sphingolipid composition were found in women, but not position of stratum corneum sphingolipids. These lipids play
in men.17 From prepubertal age to adulthood there was a an important role in the water permeability barrier function of
Skin Physiology and Gender 3
TABLE 1.2
Biochemical Composition
Significant differences
17 Stratum corneum sphingolipid Ethanolic extracts; 27 women; 26 men Female hormones influence the
composition differs with age in women biochemical methods 10–79 y composition of stratum corneum
but not in men of lipid identification sphingolipids
19 Women: higher concentrations of metals Liquid chromatography; 60 women; 72 men
in hair. Concentrations of copper did not trace metal 6–40 y
differ with age in men, whereas in determination
women they increased with age
the human epidermis, and thus endocrinological factors may women, in both young and old subjects.25,26 In addition, tran-
influence this barrier. sepidermal water loss showed no difference between the two
Human tissue kallikreins are a family of 15 trypsin or sexes. In contrast, another study27 found lower basal transepi-
chymotrypsin-like secreted serine proteases (hK1–hK15).
dermal water loss values in women compared with men aged
hK5, hK6, hK7, hK8, and hK13 have been identified in the 18–39 years.
stratum corneum (SC), stratum granulosum, and skin append- The adhesion of the stratum corneum, measured in vitro in
ages. hK6 and hK14 were significantly lower in women skin biopsy samples, did not differ between men and women
between 20 and 59 y.18 in several body regions.28 But age (and probably hormonal)
Differences in the metal content of human hair were found related differences were demonstrated in vivo by measuring
between men and women: higher concentrations of metals the speed of dermal–epidermal separation utilizing the time
were noted in women. Concentrations of copper did not differ required for blisters to form by controlled suction.29 From 15
with age in men, whereas an increase with increased age was up to 69 years of age, women exhibited longer blistering times
noted in women.19 than men in both antecubital and abdominal sites. The differ-
ence was more pronounced in the age range 15–39 years than
40–69 years and disappeared in older ages.
Skin elasticity did not differ between the sexes, as measured
Mechanical Properties (Table 1.3) utilizing two suction cup methods.24, 31 Similarly, torsional
Clinical assessment, as well as objective measurements of extensibility of the skin, as measured by a twistomenter, did
stratum corneum hydration, and grading of scaling (by adhe- not differ between the sexes.8
sive tape stripping followed by densitometry readings) showed Cutaneous extensibility was identical in men and women,
no differences between men and women.20 A positive effect but after hydration it increased only in women.30 Hydration
of estrogens on stratum corneum hydration and wrinkles was changes the properties of the stratum corneum, softening
demonstrated when estriol or estradiol cream was applied on it, and thus allowing the difference in dermal thickness to
the face of perimenopausal women.21 express itself as a difference in extensibility. Since the dermis
The degree of facial wrinkling is affected by gender. In men, is thinner in women, elimination of the stratum corneum fac-
forehead wrinkles were increased in men in all age groups as tor allows a rapid extensibility of the skin in women.
compared with women. However, no gender-dependent differ- Plasticity was found to be greater in women than in men in
ences were found in upper eyelid wrinkles. Other facial wrin- 3 sites of the foot in one study.31
kles were greater in men than in women in all except the oldest
group (65–75 years), in which wrinkles in women were greater
than or equal to those in men.22
Functional Differences (Table 1.4)
Photographs and dermal elasticity measurement by cutom-
eter showed that the morphology, areas of sagging and elas- Following pilocarpine iontophoresis sweat secretion rates
ticity in male cheeks are similar to those in females, but were higher in men than in women in both healthy and chronic
sagging at the lower eyelid is more severe in males after renal failure subjects.26
middle age.23 Body sweat distribution over the upper body in nine clothed
Epidermal hydration affects the friction between the skin male and female runners of equal fitness while running at 65%
and textiles. Friction of women showed higher moisture sensi- and subsequent 15-min rest in a moderate climate (25°C, 53%
tivity than men, when measured at different hydration states, rh) was investigated using technical absorbent materials to col-
when forearm skin was rubbed with dry to completely wet lect the sweat produced. Local sweat rates were higher in men
textile. Higher skin hydration caused gender specific changes for the mid-front, sides, and mid-lateral back as compared to
in its mechanical properties and surface properties, leading to women. Both sexes showed similar sweat distribution patterns
softening and increased contact area.24 over the upper body with some exceptions. Men showed higher
Other studies showed no difference of frictional properties relative (local to overall) sweat rates than women for the mid-
of the skin, or stratum corneum hydration, between men and lateral back, while it was lower for the upper arm, lateral lower
TABLE 1.3
Mechanical Properties
30 From 15 y to 69 y of age women Measuring the speed of 178 women, 15–101 y
exhibited longer blistering times than dermal–epidermal 209 men, 16–96 y
men. The difference was more separation utilizing the
pronounced in the age range 15–39 y time required for
than 40–69 y, and disappeared in older blisters to form by
ages controlled suction.
antecubital and
abdominal sites
24 Friction of women showed higher Corneometry; 11 women, 11 men Higher skin hydration causes
moisture sensitivity than men Forearm skin. gender specific changes in its
Rubbing with various mechanical properties, leading
hydration states, dry to to softening and increased
wet textile contact area
22 Men: increased forehead wrinkles Photographs. Replicas 173 Japanese men and women Men tend to have more severe
compared with women. No differences from five facial sites wrinkles than women. This
in upper eyelid wrinkles. Other facial used to measure tendency disappeared or was
wrinkles were greater in men than in surface roughness reversed in some regions of the
women in all except the oldest group face and in individuals more
(age, 65–75 years), in which wrinkles in than 60 y old
women were greater than or equal to
those in men
23 Sagging in male faces: similar to females photograph-based 98 Japanese men, 108 women Dermal elasticity of male facial
in the cheek, but sagging at the lower grading, Cutometer 20–60 y old skin decreased with age similar
eyelid is more severe in males after to that of females, except for the
middle age lower eyelids

20 Stratum corneum hydration, and grading Clinical assessment and 50 women; 22 men
of scaling showed no differences bioengineering 21–61 y
between men and women measurement
21 A positive effect of estrogens on facial Stratum corneum 18 women (8 applied estriol, Topical treatment with estrogen
skin: moisture increased; wrinkles hydration and 10 estradiol): 46–66 y seems promising
decreased wrinkles—
profilometry of skin
replicas
25 No difference between men and women Bioengineering 7 women, 25 y (mean); 7 men,
in friction, moisture, transepidermal measurement 29 y; 7 women, 75 y; 8 men,
water loss 74 y
26 No difference in moisture Bioengineering; healthy Healthy: 24 women, 21 men.
and chronic renal Patients: 30 women, 50 men
failure subjects
31 Skin elasticity did not differ between the In vivo suction device Young: 8 women (26 y); 8 men
sexes, as measured by suction devices (bioengineering) (28 y)
Old: 9 women (75 y); 8 men (75 y)
24 Skin viscoelasticity comparable for Suction chamber 11 women, 11 men
women and men Forearm skin
Rubbing with various
hydration states, dry to
wet textile
8 Torsional extensibility did not differ Twistometer 69 women; 54 men
between men and women 5–90 y
29 The adhesion of the stratum corneum did Biopsy; in vitro 9–34 women and men (number
not differ between men and women measurement of the varied with site studied); 20–40 y
force needed to
separate cells
back, and upper central back. Sweating in both sexes was high- Increases in sweating as a function of increasing concentra-
est along the spine, and higher on the back as a whole than tion of acetylcholine significantly differed between males and
the chest as a whole. Upper arm sweat rate was lowest. Men females. Maximum values were lower in females in response
showed a higher ratio of highest to lowest local sweat rates.32 to acetylcholine.33
TABLE 1.4
Functional Differences
26 Men sweat more than women Pilocarpine Healthy: 24 women; 21 men
iontophoresis—healthy CRF Patients: 30 women;
and chronic renal 50 men: 18–75 y
failure subjects
34 Local sweat rates higher in men for the Technical absorbent 9 clothed male and female
mid-front, sides, and mid-lateral back. materials to collect the runners while running at 65%
Men showed higher relative (local to sweat produced in a and subsequent 15-min rest
overall) sweat rates than women for the moderate climate
mid-lateral back, while it was lower for (25°C, 53% rh)
the upper arm, lateral lower back, and
upper central back
32 Cutaneous extensibility increased only in Bioengineering methods 15 women; 14 men Hydration allows the effect of
women after hydration 23–49 y and 60–93 y thinner dermis in women to be
reflected in extensibility
35 Increases in sweating with increasing Intradermal 12 women, 12 men peripheral modulation of
concentration of acetylcholine microdialysis sudomotor activity in females
significantly differed between men and
women. Maximum values were lower in
women in response to acetylcholine
The fatty acid composition of sebum is affected by andro- assessed. Changes during the menstrual cycle, however, were
gens in both sexes.34 demonstrated by measuring baseline transepidermal water
Sex-related differences in the metabolism in the skin of topi- loss.39
cally applied compounds were found in guinea pig skin.35
Cutaneous Microvasculature (Table 1.6)

Differences in Response to Irritants (Table 1.5)
Hormonal factors affect the skin blood flow: differences
The incidence of irritant dermatitis is higher in women than between men and women were found during the reproductive
in men, but experimental irritant dermatitis does not differ years, and differences were found within different phases of
between men and women.36,37 Occupational factors leading the menstrual cycle.40 Moreover, vasospastic diseases, such as
to a greater exposure to irritants by women may provide an Raynaud’s phenomenon, are more common in women, more
explanation of this discrepancy. In a study of skin irritabil- prevalent in the reproductive years, and improve during preg-
ity by sodium lauryl sulfate, women showed lower baseline nancy, suggesting an influence of female sex hormones.43 Skin
transepidermal water loss compared with men, but after irri- circulation varied during the menstrual cycle. There might be
tation both sexes gave similar transepidermal water loss val- a direct influence of sex hormones on the blood vessel wall,
ues.28 The importance of interpretation of the results, and the or an indirect systemic hormonal action causing a cyclic pat-
lack of a standardized way of analyzing them, is illustrated in tern in women. Estrogens influence the sympathetic nervous
the latter study. The authors define an irritation index as the system, inducing an upregulation of (vasoconstrictive) α2-
ratio of the difference between the values for irritated and non adrenoceptors. Thus, blood flow measurements utilizing laser
irritated skin to the value for non irritated skin. Although the Doppler flowmetry revealed a reduction of basal cutaneous
value for irritated skin did not differ between men and women, blood flow in women compared with men,41–42 but these differ-
this index was higher in women, since the value for non irri- ences existed only in young women and not in women over 50
tated skin was lower in men, and so the authors conclude that years.43 This reduction was due to a basal increase in sympa-
women’s skin is more irritable. A review article considering thetic tone rather than to a local structural or functional differ-
the absolute values following irritation interpreted the same ence in the cutaneous circulation.
results as indicating no sex-related differences in sodium The vasodilatation induced by local heating occurred at a
lauryl sulfate irritation.38 Until a universal way of interpret- lower skin temperature in women.44 However, the maximum
ing the results is established, contradictory conclusions may skin blood flow following heating of the skin was not different
be reached by different analyses of the same set of data. In between men and women, and neither was the postocclusive
another study baseline transepidermal water loss did not differ reactive hyperemia response in a study including a group of
between men and women.38 This study found no significant women aged 20–59 years.43 In contrast, in a study that divided
differences between men and women in developing cumula- women according to age, the reactive hyperemia response was
tive irritant dermatitis, when visual scoring, transepidermal lower in young women compared both with women over 50
water loss, skin blood flow, and dielectric water content were years and with young men.46 The latter study also measured
TABLE 1.5
Irritants
38 Incidence of irritant dermatitis higher in Occupational factors
women than in men
28 Lower baseline transepidermal water loss Sodium lauryl sulfate 15 women; 23 men Comparing the irritation index
in women compared with men, but after irritation; evaporimeter 18–39 y (the difference between irritated
irritation similar values in both sexes and unirritated values over
unirritated): female skin more
irritable
41 Higher on the day of minimal estrogen/ Back and forearm sites 9 women: Barrier function is less complete
progesterone secretion compared with Baseline transepidermal 19–46 y (mean 32) just prior to the onset of menses
the day of maximal secretion. Also water loss; compared with the days just
higher on the day of maximal evaporimeter prior to ovulation
progesterone secretion compared with
the day of maximal estrogen secretion

39 No significant differences between men Irritation tested for 11 21 women; 21 men No tendency to stronger reactions
and women with or without hand irritants at several with hand eczema; 21 women; in either sex. Speculation:
eczema concentrations 21 men without hand eczema women’s occupations lead to a
20–60 y greater exposure to irritants
40 No significant differences between men Repeated once-daily 7 women; 7 men: No sex-related susceptibility to
and women in developing cumulative application of 3 16–65 y develop cumulative irritant
irritant dermatitis concentrations of dermatitis. Speculation:
irritant (SLS), 5 days, women’s occupational and
followed by a patch domestic duties lead to a greater
test; upper back; exposure to irritants
bioengineering
measurements
the response to cooling, which was prolonged in young women might be explained by the thinner epidermis of women. Age-
compared with the other two groups. related sex differences were noted in measuring transcutane-
Skin microvascular response to vasodilators was evaluated ous oxygen pressure during postocclusive reactive hyperemia.
by laser Doppler perfusion imager, an instrument that maps Greater values were found in adult women than in men, but no
the skin blood perfusion. The substances used were: acetylcho- differences between boys and girls.49
line, an endothelium-dependent vasodilator, and nitroprusside The contribution of endothelin-B receptors to resting cuta-
and isoprenaline—two endothelium-independent vasodilators neous vascular tone differs between men and women. In men,
with different modes of action. The substances were ionto- endothelin-B receptors mediate vasoconstriction, whereas,
phorized into the skin. The response to nitroprusside, and to in women, endothelin-B receptors mediate vasodilation.
a lesser extent to acetylcholine, was higher in women before Blockade of endothelin-B receptors by a competitive antago-
menopause than after,45 reflecting functional and structural nist (BQ-788) in men caused skin vasodilation consistent with
changes in skin vasculature with aging. removal of a tonic vasoconstrictor effect of endothelin-B. In
The cutaneous blood flow response to topical and intrader- women, it caused a vasoconstriction, demonstrating release of
mal administration of histamine was comparable in men and tonic vasodilator activity.50
women at three anatomical sites: the back, volar side of the
forearm, and ankle.46 These observations indicate that there
are no functional differences between men and women in the Sensory Functions (Table 1.7)
skin microvascular response to histamine. On the other hand,
Thermoregulatory Response
histamine administered by iontophoresis produced bigger
wheals in women, as measured by laser Doppler flowmetry.44 Studies of human thermoregulation were conducted by expos-
The bigger wheals were attributed to differences in the stratum ing subjects to various thermal environments. The importance
corneum layer, which is the main obstacle to penetration. of considering all the possible variables is demonstrated in
Transcutaneous oxygen pressure is a method that measures studies of the physiological responses to heat stress:51 data
changes in oxygen pressure at the skin surface that are mainly showed differences between women and men. But when tak-
determined by changes in skin blood flow. During skin suring into account the differences in the percentage of fat in the
face measurement, significantly higher values of transcutane- body and the ratio between the body surface and mass, the
ous oxygen pressure were noted in women.47,48 The difference effect of gender disappeared.
TABLE 1.6
Cutaneous Microcirculation
(a1) Significant differences
43 Reduction in basal skin blood flow in Bioengineering 56 women; 44 men
women measurement 20–59 y
45 Reduction in facial basal skin blood flow Laser Doppler 5 women; 5 men
in women 25–52 y
44 Reduction in basal skin blood flow in Bioengineering 26 women; 23 men Sympathetic tone is Increased,
women measurement; cooling 23–38 y not a structural or functional
and warming to difference in the cutaneous
change sympathetic circulation
tone
42 Skin circulation varied during menstrual Bioengineering 31 women: 15–45 y Skin blood flow and its response
cycle: basal flow lowest in the luteal measurements at 4 to cold varies during the
phase, highest in the pre-ovulatory times during the menstrual cycle
phase. Greatest cold-induced menstrual cycle
constriction and lowest recovery in the
luteal phase
46 Reactive hyperemia response lower in Bioengineering 12 women, 19–39 y; Hormonal factors might explain
young women as compared to both measurement; 13 women, 51–67 y; the differences. Different
women over 50 y or young men. The postocclusive reactive 13 men, 22–47 y dressing habits may also
response to cooling prolonged in young hyperemia and direct contribute
women compared with the other two and indirect cooling
groups
47 Vasodilatation induced by local heating Bioengineering 9 women; 6 men
occurs at a lower skin temperature in measurement age not specified
women
48 Response to nitroprusside higher in Laser Doppler perfusion 21 women; 13 men Indicating functional and
women before menopause than after imager; iontophoresis 18–80 y structural changes in skin
vasculature of women with
aging
4 Histamine produced bigger wheals in Histamine administered 33 women; 38 men Differences in the stratum
women by iontophoresis 15–52 y corneum layer
53 Endothelin-B receptors mediate Laser Doppler, 11 women; 11 men Resting tone is different in
vasoconstriction in men and microdialysis 33± 3 women, 30± 3 men women and men
vasodilatation in women
(a2) Significant differences: Transcutaneous oxygen pressure

50 Significantly higher values of Bioengineering; 18 women; 42 men
transcutaneous oxygen pressure in anterior chest, forearm 22–88 y
women
51 Significantly higher values of Bioengineering; 23 sites 7 women; 12 men Might be explained by women’s
transcutaneous oxygen pressure in on face, extremities 21–63 y thinner epidermis
women and trunk
52 Transcutaneous oxygen pressure during Bioengineering Adults: 30 women; 37 men: Hormonal influence is indicated
postocclusive reactive hyperemia measurement; forearm; 22–60 y
greater in adult women than in men, but postocclusive reactive Children before puberty: 34
did not differ between boys and girls hyperemia, 35–37°C

49 No difference in cutaneous blood flow Topical and intradermal 10 women; 10 men
response to histamine administration; 24–34 y
bioengineering
methods
43 No difference in postocclusive reactive Bioengineering methods 56 women; 44 men
hyperemia and maximum skin blood 20–59 y
flow following heating
In contrast to these results of heat stress, the response to superior to men’s, whereas no significant differences between
cold stress of Japanese young subjects differed with gender, the sexes were found in the summer. The differences in cold
although body surface area-to-mass ratios were similar.52 tolerance may be caused by differences in the distribution
Subjects were exposed to cold (12°C) for 1 hour at rest in sum- of fat over the body, even though body surface area-to-mass
mer and in winter. In winter women’s tolerance to cold was ratios were similar in the two sexes.
TABLE 1.7
Sensory Function
61 Women more sensitive to small Marstock method—quantitative 67 women; 83 men
temperature changes and to pain 10–73 y
caused by either heat or cold
62 Lower threshold values in women Pricking pain sensation to heat; 93 women; 165
than in men threshold determination, volar men: 18–28 y 132
forearm women; 135 men:
50–90 y
63 Women more sensitive than men: Pressure threshold 68 women; 68 men
palm and sole, but not on the measurement; palm, sole, 17–30 y
forearm forearm
64 Neonate girls: significantly higher Skin conductance (autonomic 20 women; 20 men These differences may represent
conductance than boys function) Neonates: 60–110 h differences in maturation. Very
young: no effect yet of training
and different behavior accorded
the sexes
55 Women’s tolerance to cold superior Exposed to cold (12°C) for 1 h 7 women; 8 men Differences in fat distribution over
to men’s in winter at rest in summer and in Japanese: 18–26 y the body, even though body
winter; skin and body surface area-to-mass ratios were
temperature similar in the two sexes, might
have contributed to the
differences in cold tolerance
59 Greater decrease in women in finger Auditory stimulation, music; 60 women; 60 men; Possible explanation: difference in
temperature as a response to skin temperature, index finger young students vascular autonomic sensitivity to
musical stimulus music
60 Men: more asymmetry between Auditory stimulus. Magnitude 15 women; 15 men Possible hemispheric differences
hands, larger skin conductance and frequency of skin 19–27 y in response to auditory stimuli
responses on the left hand. Women: conductance responses right-handed
less asymmetry, larger skin
conductance responses on right
hand
65 Acute muscle or skin pain: skin Skin sympathetic nerve Awake human subjects
blood flow increased in women, activity. Hypertonic saline
whereas in men it decreased injected into tibialis anterior
muscle or into skin.
Skin blood flow measurements
54 Physiological responses to heat Heat stress; ergometer; oxygen 12 women; 12 men Differences between women and
stress differ with gender, but uptake; body and skin 20–28 y men disappeared when
depend on fat content and body temperature; sweat rate differences in the percentage of
surface area fat in the body and the ratio
between body surface and mass
were considered
The thermal sensitivity distribution (topographical map- response (at a site remote from the cooling site) were mea-
ping) over the glabrous skin of the hand in men and in women sured.54 The women were tested twice, once in the follicular
was assessed by measuring warm and cold thresholds in 25 and once in the luteal phase of the menstrual cycle. Blood flow
healthy volunteers (12 women, 13 men), applying a multi-site was measured before and during local cooling of one hand at
test of 23 locations on the volar part of the hand. The palm 15°C. Local cooling evoked a significantly greater decrease in
area was more sensitive than the fingers to both warm and cold cutaneous blood flow in women than in men in direct as well
stimuli. On the palm itself, the proximal part was the most as in indirect response conditions. Direct response to local
sensitive. Women were more sensitive than men to both warm cooling was significantly greater in the luteal phase than in
and cold sensations.53 the follicular phase. In contrast, there was no menstrual cycle-
Cold-induced vasomotor response was measured by laser dependent difference in the indirect response to cold. Thus,
Doppler flowmetry in 12 healthy men and 12 healthy women. sympathetic neural reactivity, as assessed by way of an indi-
Both direct response (at the site of cooling) and indirect rect response to a cold stimulus, significantly contributes to
gender differences in the response to local cooling. In contrast, Unlike the forearm lower pricking pain sensation threshold in
the variation in microvascular responsiveness to cold exposure women, pressure threshold was lower in women than men on
due to the menstrual cycle is most probably caused by local the palm and on the sole, but not on the forearm.60
vascular mechanisms rather than by variation in sympathetic
neural reactivity to local cooling.
Sex-related differences in thermoregulatory responses
while wearing protective clothing were found.55 Women were
Autonomic Function
at a thermoregulatory disadvantage compared with men when Skin conductance measures one aspect of the autonomic func-
wearing protective clothing and exercising in a hot environ- tion. Neonate girls manifested a significantly higher conduc-
ment. This disadvantage can be attributed to the lower specific tance than boys.61 These differences may represent differences
heat of adipose versus non-adipose tissue and higher percent- in maturation.
age body fatness. Both acute muscle and skin pain evoked a measurable sym-
pathetic activity in human subjects who were awake. Sweat
release was increased to the same level in men and in women,
but dissimilar changes in skin blood flow were recorded: skin
Thermal Response to Stimulation blood flow increased in women, whereas in men it decreased.62
The decrease in finger temperature as a response to musical
stimulus was greater in women.56 This may be due to differ-
ences between men and women in vascular autonomic sen- Skin Color (Table 1.8)
sitivity to music, or to differences in sensitivity or density of
peripheral vascular adrenergic receptors. An article by Tegner63 gives several examples of artists depict-
Electrodermal responses: Electrodermal asymmetry has ing their female models as lighter skinned than males. Such
been considered as an index of hemispheric specialization. differences were indeed found utilizing spectrophotometric
A study recorded the magnitude and frequency of the skin measurements, in various ethnic populations. A lighter skin in
conductance responses when subjects listened to tones.57 women was demonstrated in studies from Iran,64 India,65 and
Subjects were right-handed in order to control the effects of Australia.66 In addition to hormonal influences, differences in
handedness. Men displayed more asymmetry between hands, melanin, hemoglobin, and carotene might be involved, as well
with larger skin conductance responses on the left hand. In as differences in sun exposure. Skin reflectance spectroscopy
women, asymmetry was less marked, and larger skin conduc- was measured in 10 anatomical sites in 20 healthy Caucasian
tance responses were found on the right hand. These results babies (mean age 5 months, range 1 to 10 months). The level of
indicate a possible hemispheric difference in response to audi- skin pigmentation was the same in all the 10 measured sites,
tory stimuli. and there were no gender differences in pigmentation for any
site.67 In general, both sexes darken as age increases.69 But
the changes are more intricate68: from the end of infancy to
the onset of puberty there is a progressive skin darkening in
Thermal and Pain Sensation, both sexes. During adolescence they both lighten, but women
Pressure Sensitivity lighten more. Simple hormonal effects cannot explain this dif-
ference since both testosterone and estrogen provoke darken-
Sensation in the skin can be studied in relation to pain. Pain ing rather than lightening of the skin. These changes might be
can be induced mechanically, electrically, by chemical stimu- partly attributed to differences in exposure to sunlight since
lus or by thermal stimulus. Pain sensation is best determined UV irradiation increases the number of melanocytes in both
by the threshold at which pain begins, and the stimulus exposed and unexposed skin. Another study assessed skin
required to produce it can be quantified. Thermal and pain color in adolescents.68 The forehead (sun-exposed) pigmenta-
sensations are mediated by cutaneous receptors and travel tion of boys was darker than that of girls. But the medial upper
through myelinated (Aδ) and unmyelinated (C) nerve fibers. arm (less sun exposure) pigmentation varied among the differ-
Women were more sensitive to small temperature changes ent phases of adolescence: girls were darker than boys during
and to pain caused by either heat or cold.58 Another study early adolescence, during middle adolescence the pigmenta-
measured the threshold of the pricking sensation provoked by tion was similar in the two sexes, and during late adolescence
heat projected to the skin from a lamp.59 The pricking pain girls were significantly lighter than boys.
threshold increased with age in both sexes. In addition, the The lighter skin color of women was attributed to differ-
threshold of women was lower at all ages in the range 18–90 ences in melanin, hemoglobin (variations in vascularity), and
years. Possible explanations to the difference between the carotene.69 Natural selection might explain the overall visual
sexes are: effect of lighter skin. In addition, women are more homog-
enous in color than men since regional variations in reflec-
(i) anatomical differences in skin thickness tance spectrophotomery were smaller in women than in
(ii) differences in blood flow and blood vessels that men.72 Colorimetric measurements revealed a darker and red-
absorb part of the heat transmitted to the skin der skin in elderly men (65–88 years) compared with elderly
(iii) differences in nervous structure or function women, but such differences were not found in young subjects
TABLE 1.8
Skin Color
19 Women’s skin lighter Spectrophotometry Review article Not a simple hormonal effect.
Differences in melanin,
hemoglobin, and carotene
67 Women’s skin lighter Spectrophotometry 33 women; 68 men Differential tanning; vascularity
8–24 y variations
68 Women’s skin lighter Spectrophotometry; 566 women; 578 men During puberty, males darken,
upper inner arm 1–50 y females lighten.
Different levels of MSH.
Hereditary and environmental
factors
71 Forehead: boys darker than girls. Skin color, measured by 105 women, 10–16 y Physiologic changes during
Medial upper arm: girls darker than reflectance of forehead and 105 men, 12–18 y adolescence may cause these
boys during early adolescence, not medial upper arm, in sex differences
different from boys during middle adolescents
adolescence, and during late
adolescence girls lighter than boys
69 Women’s skin lighter. Spectrophotometry; inner 461 women; 346 men Different levels of MSH.
Both sexes darken with age upper arms, lateral forearms, 20–69 y Difference in sun exposure
back of hands (tanning and thickening of skin)
73 In the elderly: skin of men darker and Colorimetric measurements 8 women, 5 men:
redder compared with women, but of forehead (sun-exposed) 65–88 y; 9 women,
not in the young and forearm (protected) 4 men: 18–26 y
74 No difference between men and 5 mm paraffin embedded 38 skin samples of
women in epidermal melanocytes sections men and women of
counts different ages; DOPA
reagent.
73 In Caucasian babies: pigmentation Colorimetric measurements 10 women, 10 men
same for men and women of 10 sites 1–10 mo
(18–26 years).70 Another study of 461 women and 346 men associated with loss in skin collagen content. Collagen con-
aged 20–69 years found that both sexes darken with age.69 Yet tent increased with hormone replacement therapy by 48%
another study did not find difference between men and women compared with non-treated subjects.73 Moreover, the ratio of
in epidermal melanocytes counts.71 type III to type I collagen in the skin is reduced with age.
Postmenopausal women receiving hormone replacement ther-
apy showed an increased proportion of type III collagen in
the skin.74 In the future, further hormonal manipulation might
Hormonal Influence (Table 1.9)
change the skin of both men and women in ways we cannot
Any of the aforementioned differences between women and yet predict.
men might be related to hormonal effects. Some evidence for
hormonal influence on the skin has already been previously
mentioned, like the increase of skin thickness following con-
Pilosebaceous Unit (Table 1.10)
jugated estrogens treatment of postmenopausal women,9 or
the positive effect of estrogens on stratum corneum hydration The sebaceous glands are hormone dependent. The increase in
and wrinkles of the face of perimenopausal women,21 or the their activity during puberty can be stimulated by the admin-
changes during the menstrual cycle demonstrated by measur- istration of the appropriate hormone. Androgenic steroids,
ing baseline transepidermal water loss41 and skin blood flow.42 of either gonadal or adrenal origin, have a direct stimulatory
Hormone replacement therapy for menopause had an effect effect on sebaceous gland activity. Most of the hormones (TSH,
on skin extensibility:72 in untreated women a steep increase ACTH, FSH, LH) act indirectly by stimulating their respective
in skin extensibility was evidenced during the menopause. endocrine tissues. In other cases, the hormones (for instance
Hormone replacement treatment limited this age-related GH) act synergistically with another hormone to which the
increase in skin extensibility, thus having a preventive effect sebaceous gland is sensitive. Average values for sebum secre-
on skin slackness. Other parameters of skin viscoelasticity tion were significantly higher in men than in women for age
were not affected. After menopause the skin becomes thinner, ranges 20 to over 69, but not for 15–19 years.75 This difference
TABLE 1.9
Hormonal Influence
75 Hormone replacement treatment Computerized suction device Women: 43 nonmenopausal Hormone replacement therapy has a
limited the age-related increase measuring skin (19–50 y); 25 menopausal not preventive effect on skin slackness
in skin extensibility. Other deformability and treated (46–76 y); 46 on
parameters of skin viscoelasticity; inner hormone replacement therapy
viscoelasticity were not affected forearm since onset of menopause
(38–73 y)
76 Collagen content increased by Hydroxyproline and collagen Postmenopausal women Estrogen or testosterone, or both,
48% with hormone replacement content; biopsies of right (35–62 y); 29 untreated; 26 prevent the decrease in skin
therapy compared with thigh below the greater estradiol + testosterone collagen content that occurs with
nontreated subjects trochanter aging
77 Increased proportion of type III Analysis of collagen types; Postmenopausal women The clinical improvement in the skin
collagen in the skin of biopsies of lateral thigh (41–66 y); 14 untreated; 11 following hormone replacement
postmenopausal women estradiol + testosterone therapy is due not only to increase
receiving hormone replacement in total collagen but also to changes
therapy in the ratio of type III to type I
TABLE 1.10
Pilosebaceous Unit
79 During January women’s hair was denser and the percentage Phototrichogram; hair count after 7 women, 29–49 y
of telogen hair lower compared with men washing 7 men, 25–47 y
78 Higher sebum secretion in men than in women for age ranges Sebum production 330 women; 458 men
20 to over 69, but not for the 15–19 age range. In the 50–70 15 y to over 69 y
age range the secretion in men remains unaltered, whereas in
women there is a significant decrease in sebum output,
probably as a result of decreased ovarian activity
78 No correlation between sebum production and plasma Sebum production and plasma 8 women; 28 men
testosterone androgen levels
in sebaceous gland activity becomes more apparent in the The effect of androgens on hair growth varies according to
50–70 age range, when the secretion in men remains unaltered body site, and may be opposite, like transforming vellus hair
whereas in women there is a significant decrease in sebum out- on the face to terminal beard hair at puberty and the reverse
put, probably a result of decreased ovarian activity. on the scalp. The face, scalp, beard, axilla, and pubic hair folli-
Beginning in young adulthood there is an age-related cles are targets for androgens. Androgen affects different cells
decline in wax ester secretion—thus hormones also affect the in the dermal papilla, which is also affected by melanocyte-
composition of sebum. stimulating hormone (MSH), prolactin, thyroid hormones,
Obviously, the distribution of hair over the body differs pregnancy, and nutritional state.78 In addition to higher serum
between men and women. The hair follicles possess individual levels of testosterone, female facial hirsutism correlated with
mechanisms controlling the evolution and triggering of suc- obesity and age.79
cessive phases, but systemic factors like hormones and exter- Despite exposure to the same circulatory hormones, the
nal factors also play a significant part. The season of the year activity of hair follicles depends on the body site, varying
influences hair growth and hair shedding. From data given in a from no effect on the eyelashes to stimulation in many other
study concerning this seasonal effect,76 we calculated sex dif- areas. High levels of testosterone inhibit the hair papilla cells
ferences, which were not discussed in the study. The data refer and outer root sheath keratinocytes and have a lesser effect on
to the month of January. Women’s hair was denser and the per- fibroblasts and interfollicular keratinocytes, while low levels
centage of telogen hair lower compared with men. of testosterone have no effect. The opposite was found with
The diversity of male and female hair patterns is determined estrogen and cyproterone.80
by a difference in the transformation of vellus to terminal hair, The effect of estrogens (17-β-estradiol, E2) on estrogen
stimulated by androgens, but also by racial and genetic fac- receptor (ER) expression and gene regulation of human scalp
tors. In Koreans, women had a significantly higher number of hair follicles was studied in vitro. The distribution pattern of
terminal hairs than men.77 ERbeta and TGF-β2-immunoreactivity differed between men
and women hair follicles after 48 h culture. Of 1300 genes 13 Davies BN, Greenwood EJ, Jones SR, Gender differences in
tested, several genes were regulated sex differently as relates the relationship of performance in the handgrip and stand-
to gender. Thus, substantial sex-dependent differences were ing long jump tests to lean limb volume in young adults.
found in the response of frontotemporal human scalp hair fol- Eur J Appl Physiol 1988; 58: 315–20.
licles to E2.81 14 Tilahun M, Atnafu A, Heel pad thickness of adult Ethiopian
patients in Tikur Anbessa Hospital, Addis Abeba. Ethiop
Med J 1994; 32: 181–7.
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2
Climatic Influence on Cosmetic Skin Parameters
Mathias Rohr and Andreas Schrader
measured continuously at a station by a computer (CAN sys-

Introduction tem, Lufft Company, Fellbach, Germany). Capturing the data
by computer ensures that the climate is recorded day and night.
In addition to good compatibility, which should be a matter of Let us take climatic changes in Holzminden (longitude 9.27 east
course for cosmetic products, the physiologic effectiveness, in and latitude 51.49 north; Middle Germany) over a year as an
particular moisture and smoothing effects on the skin, is the main example. As Figure 2.1 shows, temperature fluctuates between
interest for cosmetic products. Techniques such as fast optical values of about −10 and 25°C in a year. Relative humidity is
in vivo topometry of human skin (FOITS) (1, 2) and corneom- about 50% in summer and 90% in winter.
etry are used to investigate their effectiveness. A high degree of
standardization is required to quantify the effects of cosmetics
(3, 4). To obtain reproducible and statistically significant results, Positive and Negative Standards
experimental conditions, such as test panel–controlled climatic
Tests have been carried out with the same products repeatedly
conditions and a test design including a positive and a nega-
over a period of several years, and these will serve to demon-
tive standard, are the basic starting tools. Nevertheless, as the
strate the effect of climatic conditions on skin physiology. The
following discussion will show, it is not only the normal stan-
positive standard is a well-accepted former brand product that
dardization procedures, such as acclimatization of volunteers
is currently unavailable on the European market. However, we
in special air-conditioned laboratories, which have to be taken
have been making it at a constant quality level for years using
into consideration when interpreting objective and subjective
the known formulation. This product, referred to hereafter as
cosmetic parameters, but also the effect of the actual climate
“standard L” (Table 2.1), is tolerated very well by the skin and
during the application phase and especially during the days of
demonstrates a moisture-retaining and skin-smoothing effect
measurement. The influence of the indoor climate in the labora-
that can be easily classified in terms of physiologic effective-
tory as well as the outdoor climate will be analyzed. What will
ness. This makes it an ideal standard because other products
happen to the level of skin moisture during the preconditioning
can be classified as better or worse with respect to their effec-
phase or what will happen at different seasons of the year? Will
tiveness. Another aspect of demonstrating the effectiveness of
it be influenced by the level of relative room humidity and/or the
products on skin physiology relates to negative effects that, for
actual climate conditions? Will the influence vary for different
instance, can be induced by aggressive surfactants. Here, too,
kinds of products? Will the influence on skin moisture and skin
we have been using the same standard product for years. This
structure be comparable? Will the influence change for different
is sodium dodecyl sulfate (SDS), which is referred to as the
types of volunteers? What is the best time for preconditioning?
“negative standard” from now on.
Could the regeneration of the stratum corneum be influenced
by the climate? Will effects felt subjectively (washing the bend
of the elbow) be equally dependent on climatic conditions as Laser Profilometry
objectively rated parameters?
The laser profilometry technique is used to investigate the
A summary of individual results and averages of thousands
antiwrinkle effect. Skin replicas are taken from the test areas
of volunteers will be given. Both a positive standard (in the
on the volar forearms by means of a white pigmented silicone
sense of increasing moisture and smoothness) and a negative
substance (two components, Optosil, Bayer, Inc., Germany)
standard (in the sense of increasing dehydration, roughness or
before the first application and 12 hours after the last appli-
side effects) are used to present the effect of climatic condi-
cation. A round impression having a diameter of 18 mm is
tions on skin physiology tests.
made using a label especially designed for this purpose. While
the impressions are being made the volunteers are seated on
chairs with adjustable armrests so that the angle between the
Materials and Methods upper arm and the forearm can be adjusted to 90°. Fixing
the forearms in this way ensures that no factitious smooth-
Climatic Data
ing or roughening effects, due to stretching of the arms when
To be able to correlate climate data with skin physiology the impressions are taken after application, are evaluated and
parameters, the relative humidity and outside temperature are included in the documentation.
DOI: 10.1201/b22897-2 15
FIGURE 2.1 Climatic outdoor conditions at Holzminden, Germany,

from August 2001 to 2002.
TABLE 2.1
Declaration of Positive “Standard L” According to the
International Nomenclature of Cosmetic Ingredients
Ingredients
• Water
• Liquid paraffin
• Caprylic/capric triglyceride
• Hydrogenated coco-glycerides
• Glycerine
FIGURE 2.2 Definition of DIN parameters Ra (a) and Rz (b) according
• Myristyl alcohol to DIN 4768/1.
• Isohexadecane
• Glyceryl stearate
• Cetyl alcohol
Ra Parameter
• Proprietary composition The Deutsche Industrie Norm (DIN) parameter Ra represents
• 4-Methylbenzylidene camphor the mean roughness index according to DIN 4768. Ra indi-
• Tocopheryl acetate cates the arithmetic mean of the absolute values of the skin
• Butyl methoxydibenzoylmethane profile’s deviations from the center line over the total distance.
• Aloe barbadensis If the overall structure of the profile remains unchanged
• Isopropyl myristate
(Rz constant) but the fine structure of the profile changes, then
the Ra parameter will indicate smoothing or roughening by a
• Methylparaben
reduced or increased value, respectively (7, 8).
• Polyaminopropyl biguanide
• Bisabolol
• Soluble collagen Rz Parameter
• Simethicone
The Rz parameter represents a mean peak-to-valley height
• Sodium hydroxide
according to DIN 4768/1. If, in the two-dimensional case,
• Ethylenediaminetetraacetic acid a profile line is divided into five equal parts and the Rmax
parameter is calculated for each part, Rz will be the arithme-
An automated laser scanner with an optical autofocus sen- tic mean of these five individual values. The Rz parameter
sor is used for contactless scanning of the skin replicas (UBM, will indicate roughening of the skin profile by a significantly
optical measuring system Microfocus, UBM RC14, Karlsruhe, increased value if the profile is changed by the influence of a
Germany) (5). The measuring range of the laser scanner is ±500 product (Figure 2.2).
mm at a resolution less than 0.01% of the measuring range. The
measuring spot (focus of the laser diode) has a diameter of about
1 mm. The z resolution is increased to ±25 mm by an additional
shift of the z-axis if necessary. The resolution in the x- and
Fast Optical In Vivo Topometry of Human Skin
y-directions is identical to be independent of any predominant
direction of wrinkles. The skin replica taken from the volar After a successful validation phase, the new FOITS technol-
forearm of a volunteer is scanned over an area of 8 mm × 8 mm ogy was introduced in 1997 (1). In comparison to the replica-
in the x- and y-directions at a resolution of 25 points/mm. Thus driven technique during the previous decade, the touch-free
40,000 individual measurements are available, permitting an technique of fringe projection became state-of-the-art to
exact three-dimensional reconstruction of the skin surface (5, 6). investigate skin surface (2, 9–11). Because of many technical
Climatic Influence on Cosmetic Skin Parameters 17
advancements (for example, improved camera resolution, the side parameters is shown in Figure 2.3, from the first experi-
use of blue LED lighting systems, or laser-supported and comments up to the current time (Figure 2.4).
puter-optimized overlaying procedures), an easy-to-operate Starting with analysis of the inner side of the forearm, the
system has been realized recently. As there has always been a crow’s feet area eventually became the area of most inter-
great deal of scientific interest on the mechanisms of wrinkle est. Increasing the power of FOITS technique as described in
evaluation, the technical developments led to a tool of high Figure 2.3, more areas could be investigated such as the cheek,
scientific standard (12–15). glabella area, under the eye, nasolabial area, lips, or all body
FOITS is a touch-free optical technique with a history of areas such as the décolleté and legs. The latest technique com-
more than a decade of investigating skin surface structures bines the fastest data measurement with the best superimposi-
in a direct three-dimensional measurement by fringe projection technique to guarantee a perfect comparison of baseline
tion (16). The fringe-projection technique used is a combina- and end-value data. Superimposition is realized in a combi-
tion of gray-code and phase-shift technique (7). In less than nation of laser-aided mechanical alignment of the subject in
a few hundred milliseconds, the absolute space coordinates a first step followed by a software-driven rotation and shift-
of all object points in the selected image area are measured ing procedure of measured data/pictures to find the optimum
with great precision. The FOITS measurement system con- superimposition.
sists of a projection unit and a CCD camera. Both are fixed
under the triangulation angle. In the gray-code method,
Parameter of Analysis
grids with a rectangular brightness distribution by differ-
ent numbers of lines are projected. The number of lines is Bringing into focus the periorbital wrinkle area (crow’s feet),
doubled at each new projection. This gives a clearly defined the morphological structure of this test area has to be taken
hierarchy of lines for each image point. In the phase-shift into account if wrinkles are investigated. Having this in mind,
technique, only one grid with a sinus-like intensity distribu- analysis is carried out perpendicular to the main wrinkle
tion is projected several times with different phase positions. direction based on the Rz parameter (according to DIN 4668
The FOITS technique is able to realize a depth sharpness [12]) or the frequency distribution of depth (FDD) analysis.
area of ±10 mm on an inspection area of 30 mm × 40 mm. Starting close to the eye, 50 separate lines with a distance of
The resolution in the vertical z-direction with 0.2% of the 400 mm are analyzed. The resulting roughness is shown as
measured area leads to an effective resolution of 4 mm in a function of line number (Figure 2.5). Ten successive lines
the z-direction. A CCD camera with horizontal and vertical are averaged, resulting in five areas of evaluation. Separating
resolution in x- and y-directions of about 30 mm is used. The the area of analysis into these five subareas (areas 1 to 5, see
resolution in the z-direction is not limited by 256 gray steps Figure 2.5), the area close to the eye, called area 1, represents
of the CCD camera. The high resolution in the vertical direc- the deepest structures, while with area 5 smaller structures are
tion is achieved by analysis of the intensity and phase dis- quantified. An example of this analysis is given in Figure 2.4.
placement of the projected grids. The surface structure of the In comparison, analysis of the lip area is shown. Because of
analyzed area causes a deviation of the intensity and phase the smaller test area, only four areas are defined with 40 sepa-
information of the projected grid structures from the theo- rate lines with a distance of 250 mm. As shown by Figure 2.1,
retical model structure of a plane surface. With correspond- correlation of line number and Rz results in a more flat link for
ing mathematical algorithms, the absolute three-dimensional the lip area in comparison to the crow’s feet area.
coordinates of the inspected area can be calculated of these To document the surface structure by a global parameter,
deviations. A synopsis of the most important experimental the frequency distribution of all depths is used. The FDD
FOITS 1995 1998 2003 2006

Gray-code and phase-shift technique
Technique Contact free direct skin measurement in vivo
Halogen light Blue LED technique
Superimposition Mechanically aided by online overlay procedure LASER aided Software aided on top
mechanically of all
Measurement area Inner side of the forearm Crow’s feet, under the eye, cheek, glabella, lips, nasolabial, dé colleté,
forearm, leg
Area of inspection 875 mm2 (25 mm × 35 mm) 1200 mm2 (30 mm × 40 mm)
Area of analysis 20 mm × 20 mm 20 mm × 20 mm (or as needed)
Resolution x-direction ~40 mm ~30 mm
y-direction ~30 mm
z-direction 4 mm
Time to digitize the fine ~320 msec ~260 msec
structure
FIGURE 2.3 Synopsis of the technical side parameters of FOITS.

FIGURE 2.4 Presentation of various FOITS systems from 1995 to today; example of FOITS data presentation on an individual subject. 3-DIM data
presentation of the crow’s feet area before and after 4 weeks of product application.
is calculated in the range from −600 mm to 600 mm (after Corneometer

polynomial correction) by using interval steps of 5 mm. The
defined evaluation area is equivalent to a surface of 2 cm × 2 Water differs markedly from most substances as far as its
cm and according to the technical resolution of the camera dielectric constant is concerned. A quantitative proof of
represents 640,000 single points. Therefore, a calculated FDD changes to the water content of the skin can thus be achieved
parameter is based on a rearrangement within these 640,000 in a noninvasive manner by means of capacity measurements
values of depth. (17, 18).
Working with a distribution function, the zero level has to be A Corneometer (Courage + Khazaka Co., Köln, Germany)
kept in mind. Thus, the zero level of each volunteer is defined as is used to measure the water content (Table 2.2). A measuring
the first plane representing a level of about 0.1% of all single val- capacitor reacts to the samples in the volume to be measured
ues (about 600 counts). This plane is set as zero and all further by way of capacitance changes (depending on water content).
calculations are done with these resulting standardized values. Those capacitance changes registered by the measuring head
From the surface structure, a frequency distribution of all depths capacitor are processed fully automatically by the equip-
is obtained, as shown exemplarily in Figure 2.6 (left curve). ment to form a digital measured value. There is no conduc-
According to the selected zero level, a classification of depth tive (galvanic) connection between the object measured and
is made as follows: the measuring equipment. Consequently, almost no electricity
flows through the object measured. Properties such as ionic
conductivity and polarization effects have no influence on the
• 0 to 50 mm ® Microstructure (about 5%)
measurement result. The fact that the electronics adapt to the
• 55 to 170 mm ® Fine structure (about 65%) moisture circumstances almost without inertia means that the
• <170 mm ® Rough structure (about 30%) measuring process is very fast and that it is possible, to a con-
siderable extent, to eliminate effects on the results caused by
The given proportion will give a rough estimation of structure involuntary movements or moisture accumulation during the
ranges found in the crow’s feet area of women with distinct measuring process.
wrinkles and Caucasian skin. Taking into account a product’s All tests mentioned in this discussion were carried out in
smoothing effect, the green FDD curve as shown in Figure 2.4 an electronically controlled air-conditioned laboratory that
can be expected. Consequently, an improvement of skin struc- ensures that room temperature and air humidity are kept
ture is defined by a shift of maximum and a change of width of constant. The volunteers were kept seated in this laboratory
the distribution function. A reduction of rough structures can at 22°C (±1) and 60% or 50% (±5%) relative humidity for 45
be expected, while for fine and micro structures an increase is minutes before the test and during the complete standard test
obtained in the case of structural improvements. procedure.
FIGURE 2.5 Definition of subarea of analysis. Rz as a function of subarea lines of an individual example in the crow’s feet area and lip area.
investigation. In a second series of measurements, five differ-

ent brands and five different formulations with an increasing
amount of glycerine (3%–25%) as an active ingredient were
investigated in a short time test design up to 4 hours after prod-
uct application. To quantify the influence of the indoor climate
on the product rating, the second test series was carried out
twice. In a first run, the relative humidity was set at 60%; in a
second run the relative humidity was reduced to 50%.
Transient individual side effects that may have an influence
on the skin are standardized in this way. However, this pro-
cedure does not compensate for climatic conditions such as
winter or summer.
Regeneration
FIGURE 2.6 Histogram of depth of a surface profile (crow’s feet area), Dihydroxyacetone (DHA) is a substance that is tolerated very
classification of structural regions as well as visualization of smoothing
effect/age effect–baseline: 65-year-old subject, end value: 15-year-old well and is approved in the cosmetics industry as a suntan
subject. substance. It tans by means of the Maillard reaction, forming
combinations with amino acids in the skin that do not wash
To quantify the influence of this procedure of standard- off. The color disappears within approximately 3 weeks as a
ization, frequent measurements were carried out immedi- result of desquamation of the colored horny cells. The tan of
ately after the volunteers arrived at the institute and for up to the skin decreases accordingly.
5 hours. To show the basic influence of the indoor climate, For this investigation the desquamation effect, and conse-
no product application was performed during the time of the quently the rate of regeneration, is measured in the laboratory
TABLE 2.2 Further statistical treatment is described in detail in Refs. 3

Summary of Experimental Conditions for the Various Skin and 9.
Physiology Tests
Investigation brief description: Corneometer 20–30 volunteers 2–3 wk of Washing Test on the Bend of the Elbow
application; twice a day
To assess the skin tolerance, the cleansing effect, and the
Baseline measurement on the forearm
acceptance of surfactant products, we carry out the washing
Final value 12 h after the last application
test on the bend of the elbow. In a practical test, the bend of the
Statistical analysis of data
elbow is washed under intensive conditions. Twenty volunteers
Corneometer kinetic frequent measurements up to 5 h
take part in this test. In each application, the bend of one elbow
Laser profilometry 30 volunteers
is lathered vigorously with the first sample and washed for 2
3 wk of application; twice a day
minutes by hand. After being rinsed with lukewarm water, this
Silicone replica of the forearm (baseline)
bend of the elbow is again lathered and washed for 2 minutes.
Silicone replica 12 h after the last application (final value)
This is followed by a period of drying also lasting 2 minutes.
Robot-controlled laser profilometry
After the second rinsing with lukewarm water, the area is care-
Analysis of Ra and Rz
FOITS frequent measurements up to 4 h
fully dabbed dry with a towel, ensuring that there is no rub-
No replica
bing. The bend of the other elbow is treated in exactly the same
Analysis of Ra and Rz
way with the negative standard SDS (21, 22).
Washing test on the bend of the elbow 20 volunteers 5 days of application
To determine any side effects induced by the test prod-
Twice a day, 2 × 1 min of washing
ucts, the volunteers are asked at the end of the test about any
Subjective rating of side effects in a direct comparison
reactions they noticed directly after washing. The following
Reddening/stinging/skin tautness/itchiness
parameters are ascertained: reddening, stinging, skin tautness,
Skin roughness/dull feeling/bad skin feeling
itchiness, skin roughness, dull feeling, and dehydrated skin
Statistical analysis of reaction points
feeling. The ratings are given on the basis of a coded volunteer
DHA decoloring 20 volunteers, aged >50 years
questionnaire.
Measurement of skin color by chromameter (baseline)
Application of DHA to inner side of forearm
Application of test product twice a day for 18 days Results and Discussion
Measurement of skin color every day
Analysis of decay curves Outdoor Climate
Abbreviation: DHA, dihydroxyacetone. One of the major factors in cosmetic skin physiology is the
moisture-retaining effect of a product. Figure 2.7 shows a
color room by measuring the decoloring with a Minolta summary of this for 1992–1995. The data have been summa-
Chromameter CR 300 (L-a-b color room). The yellow value b rized on a monthly basis in each case. The percentage increase
differentiates best, and this is used to establish the color decay in moisture induced by the positive standard L after correc-
curves (19, 20). tion for changes in the corresponding untreated area is shown.
The region that is tested is again the volar forearm. Areas The recorded averages are based on at least 100 volunteers a
of 4 cm × 4 cm in the middle of the region of application are month.
colored with DHA after a defined washing procedure to stan-
dardize the baseline conditions. In the coloring process, a
special emulsion with 10% DHA is applied to the area to be
tested. The amount applied is 6 mg/cm2. In addition, an adhe-
sive bandage saturated with DHA emulsion is applied for 24
hours. Over the next 18 days, the volunteers continue to use the
products twice a day. The forearms are permitted to be washed
only twice a day with warm water. Surfactants and abrasive
cleansing agents are not allowed to be used. Measurements are
taken directly before DHA coloring, and then every day over
the next 18 days with the exception of weekends. For each time
and area of measurement, three values are recorded at differ-
ent places in the measurement area and averaged. The b-values
of all 30 volunteers per product are averaged, and the standard
deviations, percentage changes, and percentage differences
standardized to the coloring are calculated. The color decay
curves can be described under normal conditions with the fol-
lowing exponential function:
FIGURE 2.7 Percentage increase in moisture, after correction for the
untreated area, of positive standard L monthly summary (12 hours after
b = a1e – a2t + a3 last application, 4460 volunteers, 1992–1999).
Methods” section. Figure 2.9 shows clearly how important

this prior treatment is. Whereas the Ra and Rz parameters for
the positive standard fluctuate between −6% and −8% from
January to October 1994 to 1996 without showing a definite
trend, these parameters fall noticeably for the untreated area
from January to August, followed by a rise in September and
October. After allowing for the untreated area, the profilom-
etry tests result in the dependency that is shown in Figure 2.10.
Again, the positive standard L was found to be less effective on
average in the summer months of June, July, and August than
in the other months.
The data clearly show that the seasonal dependency was
based on both the reduced positive effectiveness of standard
FIGURE 2.8 Standardized differences of moisture for the positive L in the summer and the reduced negative sensitivity of the
standard L after correction for the untreated area (12 hours after the last
application, 3100 volunteers, 1992–1995). untreated area (prior treatment with a surfactant of all areas
tested). External climatic conditions thus have a distinct influ-
ence on the cosmetic effects that can be achieved. The basic
Calculations led to an average moisture increase of approxi- level of the skin is increased in the summer months to such an
mately 12.7% for all data recorded. To make it easier to com- extent that, first, skin moisture and smoothing can be increased
pare seasonal dependency of the achievable moisture increase, further by cosmetics to only a limited degree and, second, that
Figure 2.8 shows the difference from the overall average after the deliberate use of substances that are detrimental to the skin
the data have been standardized on the basis of the overall also has a limited negative effect. This leads to an apparent
average. A change of 0% corresponds to the aforementioned reduction of cosmetic effectiveness.
overall average of approximately 12.7% moisture increase. In addition to these objective skin physiology parameters,
A bar in the positive direction thus shows an increase in subjective information gained from volunteers’ answers to
moisture that is higher than the average, whereas a bar in the questions indicates a comparable dependency on external cli-
negative direction indicates a reduced level of effectiveness. matic conditions. Figure 2.11 shows the total negative reac-
Figure 2.8 shows that from November to February, there was tion points that volunteers gave for reddening, stinging, skin
about 15% above the average moisture increase, whereas in the tension, itchiness, skin roughness, dull feeling, and bad skin
summer months of June, July, and August, the level of effec- feeling in the elbow washing test. The negative reaction points
tiveness was approximately 50% below the average achievable for the negative standard fluctuated between 11 and 18 in May,
moisture increase. depending on the comparative product. Since the comparative
Figure 2.9 shows the relative change of the laser profilom- product is of crucial importance in rating effects subjectively,
etry parameters Ra and Rz both for the positive standard L and the same test setup was repeated in November with the same
for the untreated area in a way that is comparable to Figure 2.7. comparative products. Here, the average total negative reaction
The area referred to as “untreated” has not been treated with points for the comparative product SDS were distinctly higher
a cosmetic but has been subjected to a washing procedure in all four groups taking part in the test. Whereas the average
to obtain better results, as described in the “Materials and for May was approximately 15 negative reaction points, this
FIGURE 2.9 Percentage of differences for the DIN parameters Ra and Rz for the positive standard L and the untreated area in a summary of laser
profilometry data (1000 volunteers in general, 12 hours after the last application, 1994–1996).
FIGURE 2.10 Differences of the DIN parameters Ra and RzDIN after correction for the untreated area in laser profilometry (12 hours after last
application, 1994–1996).
Both before and after this sudden change, the curve is in keep-
ing with theoretical expectations. When all potential technical
sources of error had been eliminated, the solution to this prob-
lem was found in the temperature and relative humidity data
for the days of measurement, as shown in Figure 2.13. As the
curves show, relative humidity fell from about 90% to about
60%, whereas the temperature rose from about 0 to 68°C over
the same period of just a few hours, and then fell to 18°C after
a short time. Since temperature/humidity fluctuations were far
less extreme in the rest of the test period, it seems reasonable to
suppose that the strong fluctuations of temperature and humid-
ity correlate with the recorded inconsistency in the DHA color
decay curves. This inconsistency induced by extreme climatic
fluctuations made it necessary to repeat the test because it was
FIGURE 2.11 Negative reaction points in a subjective rating system no longer possible to carry out an exponential analysis of the
for four individual comparisons of the negative standard sodium dodecyl
sulfate (SDS) to four different products in a washing test on the bend of decay curves.
the elbow (20 volunteers in each comparison). As the measured curve was constant before and after day
8 but higher humidity fluctuations accompanied by lower
temperature fluctuations were recorded on day 7, it can be
rose to approximately 23 reaction points in November under assumed that humidity is of greater importance in examining
otherwise identical conditions as far as the volunteers’ subjec- the regeneration of the stratum corneum and that the outside
tive feelings were concerned. These data, based on 80 volun- temperature plays only a subordinate part in the quality of this
teers, clearly show that it is possible and necessary to correlate skin physiology investigation.
information derived from volunteers’ subjective ratings with
climatic conditions and to consider this along with the objec-
tively demonstrable parameters for skin physiology.
Indoor Climate
Another example of how external climatic conditions make
it almost impossible to evaluate the results of skin physiol- Figure 2.14a presents the results of the “no-product Corneo‑
ogy investigations is the turnover of the stratum corneum on meter kinetic” (i.e., without application of a product). The
the basis of DHA decoloring tests. When the stratum corneum kinetic measurements were carried out on four different test
has been colored with DHA, it can generally be expected that areas (forearm—lower, middle, and upper—and upper arm).
there will be a constant exponential reduction of skin coloring In Figure 2.14b, the forearm data are summarized on the basis
of both the untreated area and the areas that have been treated of the first measured value. The first group had starting val-
with the test products (19). Figure 2.12 shows average curves ues below 40 Corneometer units (CU), the second group sum-
that have been standardized to the maximum coloring, on the marized the volunteers between 40 and 55 CU, and the third
basis of 20 volunteers for two test products (A and B) contain- group was based on starting values above 55 CU.
ing a-hydroxy acids and one untreated area. The observation Analyzing the data of different test areas resulted in a
period was 18 days. In contrast to theoretical expectations and decrease of about 2 CU for the upper forearm and a little less
preliminary experiments, this investigation revealed a reduc- for the other test areas independent of the absolute level, which
tion in skin coloring from about 70% to about 30% on day 8. was different for each test site (lower forearm < middle forearm
FIGURE 2.12 Exponential decay curves of the dihydroxyacetone (DHA) decoloring test standardized to the maximum coloring characterized by
changing of the b-value of the L-a-b color room.
FIGURE 2.13 Climatic data of temperature (grey) and relative humidity (black) from day 6 to day 8 during the dihydroxyacetone (DHA) investigation.
< upper forearm = upper arm). These data were calculated The data describing the skin surface are given in
without taking into account the individual skin type of the Figure 2.15b. No significant changes occurred during the
volunteers. Figure 2.14b reflects this, showing the individual 4-hour kinetic investigation. Differences between lower and
starting conditions. As can be seen from the differences from upper forearm were comparable to the Corneometer measure-
baseline, the group with 40 to 55 CU did not show any changes ments. Summing up the Rz and Ra values for up to 4 hours, no
above about 1% during 5 hours of investigation. The group trend in the changes was observed. Consequently, the influence
below 40 CU showed a constant increase of approximately 2%, of the indoor climate seems to be of minor impact if compared
whereas for the group with high starting values above 55 CU, to skin moisture. In any case, changes of the skin structure are
a decrease of up to 10% was obtained. Independent of the test obviously on a much slower time scale if the producing event
site, the preconditioning phase seems to be most effective for is as indirect as the indoor climate.
a high skin moisture level at the beginning of the study. A dry Changing the kinetic view to more static analysis, the
skin might be less influenced by the indoor climate. The data data of five different brands are summarized in Figure 2.16.
to determine the optimal time of preconditioning to generate Figure 2.16a shows the difference between baseline and end
stable skin conditions are represented in Figure 2.15. value 4 hours after unique product application in absolute
As shown in Figure 2.15a, the difference from baseline CU. The dark gray bars represent the data at an indoor cli-
(–D– curve: mean overall) became stabilized at 30 minutes and mate of 60% relative humidity, whereas the light gray bars are
remained constant from 60 minutes on. Thus, 45 minutes of obtained at 50% relative humidity.
acclimatization seems to be the best choice—a time not too short With the exception of product no. 1, no difference occurred
for “moist” skin and not too long to reflect a reliable test design. from changing the indoor humidity. For product no. 1, a
FIGURE 2.14 (a) Kinetic Corneometer—data summarized for different test areas, without any product application (n = 120). (b) Kinetic Corneometer—
difference from baseline; data summarized for different volunteers, without any product application (n = 120).
tendency was calculated for the comparison of both measure- the elbow-washing test, clearly show that such tests are influ-
ments. Taking product no. 1 as a hint that an influence might enced considerably by climatic conditions. Differences, such
be possible, a second run of five formulations with an increas- as between summer and winter, cannot be compensated for
ing amount of glycerine was carried out under the same condi- by acclimatization in air-conditioned laboratories. Alongside
tions. In this case, significant changes occurred for the first two standardized measurement conditions, it is therefore essential
low-glycerine concentrations (concentration below saturation). to record the quality of the test panel not only by including an
At 50% relative humidity, the level of measured absolute units untreated area but also by means of a positive or negative con-
decreased significantly. Thus, the selectivity became better if trol. Only in this way is it possible to establish a classification
the relative humidity was reduced and the product contained system for test products that is not dependent on a particular
hygroscopic active ingredients. The hygroscopic ingredient season and allows the quality of cosmetic products to be rated
seems to pick up the air humidity like a sponge as long as it is in objectively.
the upper stratum corneum. Nevertheless, the origin of moisture As demonstrated by the obtained results, the indoor climate
should be irrelevant for the skin, but in the case of ranking and also plays an important part in cosmetic efficacy testing. In
differentiating products as quickly as possible after the prod- addition to the outdoor climate, which might have an effect on
uct application, it might be helpful to measure at 50% relative a long-term basis, the indoor climate (especially the time of
humidity. preconditioning) is decisive for short-term and kinetic inves-
tigations. While the influence of the moisture level is strongly
dependent on the starting value, the changes of the skin topom-
etry seem to be not so marked. On the basis of the Corneometer
Conclusion
kinetic data, 45 minutes of preconditioning appears to be an
The data recorded, from both objective skin physiology param- optimal compromise between effect, standardization, and
eters such as moisture and smoothness and subjective factors in costs. The laboratory conditions (relative humidity) may also
FIGURE 2.15 (a) Kinetic Corneometer—difference from baseline; data summarized for different volunteers up to 90 minutes, without any product
application (n = 120). (b) Kinetic FOITS and Corneometer—difference from baseline mean overall up to 240 minutes, without any product application
(n = 120/40).

FIGURE 2.16 (a) Corneometer for brands 1–5. Difference from baseline after correction by untreated. (b) Corneometer for increasing concentration
of glycerine (bar 1, 3% increasing to bar 5, 25%). Difference from baseline after correction by the untreated test area. **, significant difference; –, no
significant difference.
be of great influence. Depending on the active ingredients image triangulation using a digital micro-mirror device.
(hygroscopic or not), a ranking of products might be of greater Skin Res Technol 1999; 5:196–207.
selectivity if a lower level of relative humidity is used. 11 Ferraq Y., Black D., Lagarde J.M., et al. Use of 3-D imag-
The data presented underline the importance of a standard- ing technique for non-invasive monitoring of the depth of
ized procedure to investigate cosmetic effects on a statistical experimentally induced wounds. Skin Res Technol 2007;
and reproducible level. 13:399–405.
12 Rohr M., Schrader A. FOITS (Fast Optical in vivo
Topometry of Human Skin)—A classical method in mod-
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Skin Imaging, Vienna, 1997. populations—a pilot study. J Dermatol Sci 2005; 40(3):
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3 Rohr M., Schrader A. FOITS (fast optical in vivo topom- cosmetic products differentiated by FOITS, a statement of
etry of human skin)—A classical method in modern effi- effectiveness, age and ethnic background. IFSCC Congress,
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SÖFW-J 2009; Jahrgang; 135(8):2–10. 15 Rohr M., Brandt M., Schrader A. Skin surface—Claim sup-
4 Jaspers S., Hoperman H., Sauermann G., et al., Rapid in port by FOITS. SÖFW-J 2000; 126(8):2–11.
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3
Transepidermal Water Loss
Jan Kottner
In theory, water molecules may take two routes through

Introduction the SC: diffusion via the transcellular route through the cor-
neocytes or intercellular penetration (Figure 3.1). Because the
The physician Santorio Sanctorius (1561–1636) who lived more water diffusion coefficient of the intercellular lipids is con-
than 400 years ago in Italy is considered to be the first person sidered to be ten times higher compared to the corneocytes,
to work systematically on the phenomenon called perspiratio the intercellular water flux might also be higher (13). At the
insensibilis, the invisible loss of water from the human body. same time, the structure and order of these lipids is considered
Since then, it was widely agreed that water gets lost via the most important for water barrier function (8, 14), and they are
respiratory system and via sweating, but alternative passages widely considered to be the major barriers for perpendicular
of water through the skin were less clear (1). In 1911 Loewy water transport (6, 9, 15). The composition of the intercellular
and Wechselmann proposed for the first time that besides matrix, however, is complex and includes lipophilic, but also
sweating there is the possibility of passive water diffusion hydrophilic subcompartments. Although hardly detectable
through the skin (2). Why and how this water penetrates and under normal conditions or on tissue sections, studies suggest
leaves the skin was another issue of debate for the following that such aqueous regions can be expanded to tube-like struc-
40 years (3, 4). Irrespective of these discussions, the American tures, e.g., by means of sonophoresis, which enable entry of
dermatologist Stephen Rothman introduced the term transepi- large molecules (16). Such phenomena are further supported
dermal water loss (TEWL) in 1955, characterizing continuous by work that focuses on pathways of deformable carrier sys-
water loss through the epidermis excluding sweat secretion (5). tems across intact skin (17).
Today, TEWL plays an important role in characterizing the Finite element and microscopic transport models increas-
skin barrier function in physiological and pathological condi- ingly support the importance of the transcellular permeation
tions. This chapter gives a brief overview about the structural pathway for hydrophilic chemicals, including water (6, 13, 15).
and functional determinants of TEWL, how it can be mea- The surface area of the corneocytes is also much larger com-
sured, and what this parameter means. pared to the intercellular lipids and therefore the total amount
of transcellular water transport and the subsequent evapora-
tion are major determinants of TEWL in healthy skin under
Biological Background physiological conditions (13).
Without effective protection of the “moist inside” of the human

body, life in the dry environment on land would be impossible.
The main anatomical barrier limiting the amount of water loss
Measurement of Transepidermal Water Loss
is in the stratum corneum (SC). At most skin areas the SC
consists of 15 to 20 stacked layers of flat, terminally differenti- The flux of water through the SC cannot be observed directly.
ated keratinocytes connected by desmosomes embedded in a Today the established method of measuring TEWL is by plac-
matrix of lipid bilayers. Depending on the hydration state the ing a measurement probe on the skin and recording the amount
diameter of the corneocytes is approximately 20 to 50 μm, and of water that evaporates from the skin surface. The measured
the thickness is approximately 1 to a maximum of 3 μm if fully water flux density is expressed in g/m2/h. In order to infer
hydrated (6, 7). The thickness of the intercellular lipid bilayer that this amount of evaporated water per area and time equals
is up to 0.1 μm (Figure 3.1) (8–10). This paper-thin but dense the water flux within the SC several assumptions need to be
and compact structure separates the outermost boundary, the met: two of the most important are that sweat gland activity is
skin surface, from the living epidermal cells underneath. From reduced as much as possible and that the water flux within the
the deeper highly hydrated tissue there is a constant flux of SC is in a steady state. In clinical and research practice this
water molecules to the skin surface where it evaporates, result- is accomplished by standardizing the measurement conditions
ing in equilibrium between the ongoing process of water loss and procedures, but total control of these variables is impos-
at the surface and replenishment from beneath. Under physi- sible (18).
ological conditions the water concentration underneath and in Several TEWL measurement devices are commercially avail-
the innermost layer of the SC is approximately 70%, and it is able. They can be classified as open-chamber, semi-open and
approximately 10% to 30% in the outermost layer of the SC closed-chamber instruments (12, 19, 20). Open-chamber instru-
depending on environmental conditions (7, 11, 12). ments consist of a small hollow cylinder that is placed onto the
DOI: 10.1201/b22897-3 27
FIGURE 3.1 Two-dimensional model of the human stratum corneum and possible inside-out diffusion pathways of water.
skin. In still environmental conditions the water vapor from the • A calibration according to the manufacturer’s
skin surface diffuses through the lower end of the chamber to instructions must be conducted regularly and/or
the upper end into the ambient atmosphere. The steady-state before a larger set of measurements.
humidity gradient between the skin surface and the ambient • If the “baseline” or “normal” TEWL is the param-
air is the physical basis for the water flux measurement. Using eter of interest, no cleansing procedures, leave-on
these types of devices continuous measurements are possible, products, or similar applications must be used before
but their accuracy depends on the ambient conditions. measurement.
Closed-chamber instruments have only one orifice. The • Neither too much nor too little pressure must be
open end is placed onto the skin surface, and the water vapor applied when placing the probe head onto the skin
diffuses into the closed chamber. The change of the constantly surface. It must be ensured that no gaps arise between
increasing water concentration inside the closed-chamber is the lower orifice and the skin.
used for TEWL estimation. The accuracy of the TEWL esti-
• The probe head should be placed vertically onto the
mates is much more independent from ambient conditions, but
horizontal skin surface.
continuous measurements are not possible. The probe needs
to be dried between measurements. The condenser-chamber
In research or clinical settings these and other details are
method also uses a closed-chamber but the water vapor inside
usually specified in standard operating procedures. These
the chamber is controlled. Water vapor diffuses from the
protocols are especially important when measurements are
skin surface toward a condenser, creating a humidity gradi-
conducted by many different persons, at multiple centers,
ent which, comparable to the open-chamber method, is used
and over long durations. Empirical evidence suggests that as
to TEWL estimation. Continuous measurements are possible.
long as measurement protocols are followed, TEWL estimates
Based on the different measurement principles, technical
are reliable, but the limits of agreement may vary widely. To
specifications, measurement ranges, and degree of precision,
increase reproducibility it is recommended to perform at least
different instruments produce slightly different results (21,
two measurements independently and to use the mean value
22). Even placing a probe onto the skin surface will influence
from these (22, 28, 29).
the TEWL because the water flux density on uncovered skin
is different from the flux density within small measurement
chambers (12, 23). However, available method comparison
studies indicate that TEWL estimates seem to be comparable What Do Transepidermal Water Loss
and are highly correlated (22, 24). Values Really Tell Us about the Skin?
In order to achieve valid and reliable TEWL estimates, mea-
TEWL is considered one of the most important parameters
surement guidelines have been proposed (18, 25–27). Selected
indicating the state and integrity of the epidermal (water) bar-
key recommendations are:
rier. It is elevated in a large range of dermatological conditions
(e.g., atopic dermatitis), and TEWL decreases indicate barrier
• An acclimatization period prior to TEWL measure- restoration and skin health (18, 25). This parameter is also
ment is required. During this time the skin areas that very sensitive and can indicate functional changes before clini-
will be measured must be uncovered by any material cal signs become obvious (30, 31). On the other hand, there are
(e.g., clothing). Recommended durations vary, but numerous non-pathologic factors influencing the TEWL. In
they should not be shorter than 15 minutes. addition to measurement instruments and measurement condi-
• Acclimatization and measurements should be con- tions, TEWL may be dependent on many factors, including
ducted under standardized ambient conditions. age, skin area, skin temperature, circadian rhythm, season,
Room temperatures should be lower than 22°C, and menstrual cycle, or cigarette smoking (25, 27, 32). Because of
the relative humidity should be around 50% or lower. this complexity and interdependence of the various factors it is
Transepidermal Water Loss 29
strongly recommended that TEWL values be interpreted very location, the method and number of measurements, and ambi-
cautiously, and not necessarily in absolute terms (14, 33, 34). ent measurement conditions (22, 25). Irrespective of the sub-
Hundreds of descriptive and experimental studies measuring sequent statistical analysis, TEWL values must be reported at
TEWL have been conducted, and larger scale studies report- least using arithmetic means and standard deviations (24).
ing skin barrier characteristics of hundreds of persons are now In clinical controlled intervention studies, randomization
available (35, 36). Two systematic reviews and meta-analyses is a key design element to reduce bias. Because the TEWL
have been conducted to summarize the available evidence is strongly dependent on the anatomical location, baseline
about TEWL in adults of 18+ years (24) and infants from 0 comparability even between adjacent skin areas is limited.
to 24 months (37). Despite large variations, these reviews pro- For instance, available evidence indicates increasing TEWL
vide reference TEWL values for more than 50 skin areas in from proximal to distal on the volar forearm skin (24, 48, 49).
healthy individuals. These reference values are useful for study Consequently, randomization even within small skin areas
planning and for comparison with existing data, but neverthe- is complicated. Contralateral skin areas are very well com-
less it must be emphasized that a “normal” TEWL seems to be parable, and randomization should be preferred in so-called
unknown so far (24, 25, 34). Consequently, cutoff values or pos- within-person or “split-body designs”.
sible TEWL thresholds are also arbitrary. According to Menon
and Kligman there is no single optimal TEWL value for the
entire skin and that what is important is not how “tight” a bar-
Conclusion
rier is but rather when the barrier is good enough to allow for
survival and subserve other biological functions. (p. 180) (38) TEWL is a valuable, straightforward parameter to measure the
SC integrity and the inside-out water barrier. Highly standard-
ized settings are required to yield accurate and reliable data.
Transepidermal Water Loss as a This parameter is extremely sensitive to environmental fac-
tors as well as intra-individual variations among body regions.
Parameter in Skin Research
TEWL is only one parameter to characterize the skin barrier
In clinical research changes (delta) of TEWL over time, e.g., function. Other techniques might be used in addition to obtain a
during the course of disease, during artificial irritation tests, comprehensive picture of the skin barrier structure and function.
or during cosmetic treatments, are much better parameters
for measuring skin barrier changes or effects of treatments
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4
Nail Penetration
Xiaoying Hui and Howard I. Maibach
and intermediate layers derived from the matrix, and the ven-
Introduction tral layer from the nail bed (9, 10). The upper (dorsal) layer is
only a few cell layers thick and consists of hard keratin. It con-
Human nail, equivalent to claws and hooves in other mam- stitutes a main barrier to drug diffusion into and through the
mals, acts as a protective covering for the delicate tips of the nail plate. The intermediate layer constitutes three-quarters of
fingers and toes against trauma, enhances the sensation of fine the whole nail thickness and consists of soft keratin. Below the
touch, and enables one to retrieve and manipulate objects. The intermediate layer is the ventral layer of soft keratin—a few
nail is also used for scratching and grooming, as a cosmetic cells thick—that connects to the underlying nail bed, in which
organ, and, by some, to communicate social status. The nail many pathological changes occur. Thus, in the treatment of
plate appears as a thin, hard, yet slightly elastic, translucent, nail diseases, achieving an effective drug concentration in the
convex structure (1). ventral nail plate is of great importance. The nail bed consists
Disorders of the nail resulting from conditions such as of non-cornified soft tissue under the nail plate. It is highly
infections or physical-chemical damage can result in painful vascularized. Beneath the nail bed is the nail matrix, which is
and debilitating states and often change the nail plate’s appear- a heavily vascularized thick layer of highly proliferative epi-
ance. Onychomycosis, the most common nail plate disorder (2) thelial tissue that forms the nail plate.
thickens the nail, makes it white and opaque, and in the toe- The human nail is approximately 100 times thicker than
nails, it may cause pain while wearing shoes. Onychomycosis the stratum corneum, and both are rich in keratin. However,
is a fungal infection of the nail plate—usually caused by the they exhibit some physical and chemical differences (11,
species Epidermophyton, Microsporum and Trichophyton— 12). The nail possesses high sulphur content (cystine) in its
and affects 14% of the human population. Aging increases the hard keratin domain, whereas the stratum corneum does not.
incidence significantly, with the rate estimated at 48% in per- The total lipid content of the nail ranges from 0.1% to 1%,
sons 70 years of age (3). as opposed to approximately 10% for the stratum corneum.
To cure the infection, the patient is obliged to take oral sys- This suggests that the role of the lipid pathway in the nail
temic medication for an extended period, generally months, plate is probably of much less importance than that in the
or undergo surgical nail removal (4). These treatments have stratum corneum. The human nail acts like a hydrophilic gel
adverse effects such as pain (surgery) and systemic side effects membrane, while the stratum corneum acts like a lipophilic
(oral treatment). Thus, topical therapy is a desirable approach, partition membrane.
but has met with limited success. Topical therapy is limited by Under average conditions, the nail contains 7%–12% water,
the infection’s deep-seated nature and by the ineffective pen- in comparison to 25% in the stratum corneum. At 100% rela-
etration of the deep nail plate by topically applied drugs (5, 6). tive humidity, the maximal water content in the nail is approx-
How can topical drugs be delivered effectively into the nail? imately 25%, in sharp contrast to the stratum corneum that can
And, perhaps as importantly, how can the drug content in the increase its water content to 200%–300%. The rate of chemi-
human nail be assessed in order to validate nail drug delivery? cal penetration into/through the human nail depends upon its
Our challenge was to develop a system to assay drug content in water solubility (11) and its molecular size (12).
the inner nail bed in which infection often resides. We developed Topical therapy for onychomycosis has been largely ineffec-
a micrometer-controlled drilling instrument that removes and tive, and this failure may be due to minimal drug penetration
collects from the inner nail bed a powder sample from which— into the nail plate (5). The nail’s unique properties, particu-
by mass balance recovery—we assay the amount of penetrated larly its thickness and relatively compact construction, make
radio-labeled drug. With this procedure, the effectiveness of it a formidable barrier to the entry of topically applied agents
topical nail drug delivery can be assessed (7, 8). This chapter (6). The concentration of an applied drug across the nail drops
reviews the results of studies undertaken with drilling system. about 1000-fold from the outer to the inner surface (13). As
a result, the drug concentration presumably does not reach a
therapeutically effective level in the inner ventral layer. The
Review of Nail Physical and Chemical existing clinical evidence suggests that a key to successful
treatment of onychomycosis by a topical antifungal prod-
Properties That Affect Topical Penetration
uct lies in effectively overcoming the nail barrier. Currently
The human nail anatomy consists of nail plate, nail bed, and available topical treatments have limited effectiveness, possi-
nail matrix. The nail plate consists of three layers: the dorsal bly because they cannot sufficiently penetrate the nail plate
32 DOI: 10.1201/b22897-4
Nail Penetration 33
to transport a therapeutically sufficient quantity of antifungal 4 Correlation of in vitro onychopharmacokinetics assays

drug to the target sites (14) and eradicate the infection. and the in vivo onychopharmacokietics studies: The
To achieve an effective chemical concentration into/through in vitro data obtained with the use of modified dif-
the human nail plate, penetration enhancers that tend to pro- fusion requires comparison to human in vivo data
mote diffusion through the skin’s horny layer have been stud- with the use of radioisotopes and possibly attenu-
ied. However, these studies were conducted on a few limited ated mass spectroscopy. Until these correlations are
nail penetration models that may not provide an intimate con- defined and until we enhance our understanding of
tact between the receptor compartment and the nail surface, the pathophysiology of the disease, biological inter-
and the nail plate can be easily hydrated beyond normal levels pretation remains tenuous (19). Additional references
(6, 11, 12, 14, 15). Moreover, nail samples prepared with scal- are found in Murdan 2002 and 2008 (1, 20).
pel or sandpaper are time consuming and may not accurately
represent the three nail compartment structures (10, 16).
Advances in Nail Permeation
Testing and Sampling
Challenges in Overcoming the Nail topical therapy has been a challenge for scientists due to
Nail Permeation Barrier the minimally permeable nature of the nail plate; thus much
interest has been directed toward finding a more efficient and
Overcoming low ungual permeability to xenobiotics can robust screening method.
be achieved by several approaches and is an active field of As mentioned earlier, Hui et al. modified the conven-
research. Their effectiveness and applicability will vary from tional Franz diffusion cell by using a Teflon one-chamber
drug to drug depending on the physicochemical nature of diffusion cell (Permegear, Inc., Hellertown, PA) along with
the compound. A drug absorbed topically must partition into a cotton ball soaked in normal saline in order to maintain
the nail bed and maintain concentration higher than the cor- the nail at physiological levels of temperature and humid-
responding minimum inhibitory concentration (MIC) to be ity. A novel sampling technique developed by Hui et al.
effective. enables the determination of drug concentration within the
A hypothesized quantitative structure–activity relation- plate, where fungi reside. This method relies on a drill-
ship (QSPR) model was developed based on the available in ing system which samples the nail core without disturbing
vitro data set for eight drugs studied in the laboratory, listed its surface. This is achieved by the use of a micrometer-
in Table 4.2, later in the chapter (17). This small sample size precision nail sampling instrument that enables finely con-
weakens the predictive power of the model, and a larger sam- trolled drilling into the nail as well as the collection of the
ple is needed to improve predictability. As this model has been powder created by the drilling process. Drilling of the nail
derived from data in one laboratory where the study design and occurs through the ventral surface. The dorsal surface and
methodology of the nail study and nail sampling have been the ventrally accessed nail core can be assayed separately. The
same with similar sensitivity, precision, and robustness of the core from the ventral side provides drug measurement at
analytical method using radioactivity; thus, one main factor the site of disease while the dorsal surface sample contains
contributing to a variation in ungual drug delivery in vitro has residual drug. This method allows for drug measurement in
been eliminated. the intermediate nail plate, which was previously impos-
sible (21, 22).
Murthy et al. developed the TranScreen-N™ method, based
on a simple and rapid technique for screening that uses a sim-
Limitations of Current Ungual ple microwell plate based high throughput (23).
Drug Permeability Studies (18) A novel model of infected nail plate made of human
hair keratin for testing the efficacy of topical antimicro-
1 Animal hooves: May not provide a representative bial formulation was recently developed by Luisiana and
model for nail penetration in which diffusion through Muller-Goymann (24). This was subsequently infected by
the human nail can be evaluated. Trichophton rubrum, the common causative agent of onycho-
2 Nail clippings: May not provide a complete represen- mycosis. The infected keratin films were treated with selected
tative model for nail permeation studies as they are topical formulations—cream, gel, and nail laquer—and com-
not connected to the nail bed. pared to bovine hoof. They demonstrated that the keratin film
3 Hydration-controlled method: Modified diffusion model was comparable to the bovine hoof, as both gave an
cells are a commonly used in vitro method in ungual equivalent response to the tested antifungal. The gel formu-
drug permeation. These assays super hydrate the lations were superior to the cream. Thus this model may be
nail and possibly alter the physical property and nail able to differentiate between efficacies of different topical
permeability. Hui et al. modified the conventional antifungal formulations based on their activities against T.
modified diffusion cells commonly used for in vitro rubrum.
studies by using a cotton ball soaked in saline to pro- Infrared (IR) and impedance microscopy (IS) tools have
vide moisture (but not saturation) and hydrating the been studied to show their usefulness in the development and
nail throughout the experiment. optimization of topical drug delivery systems in treating nail
diseases. The authors used IR and IS to characterize the effects Methodology

of drug transport enhancement techniques such as hydration,
iontophoresis, and N-acetyl-L-cysteine on human nail plate. Chemicals/Formulations
The findings utilized nail clippings of healthy human volun- [14C]-Urea (specific activity 55 mCi/mmol, 99% purity),
teers; further testing will be needed to characterize the spec- [7-14C]-salicylic acid (specific activity 55 mCi/mmol,
troscopic properties of diseased nail and the extent to which 99% purity), and [3H(G)]-ketoconazole (specific activ-
they are modified by the drug transport enhancement tech- ity 5 Ci/mmol, 99% purity) were purchased from American
nique used in the study (25). Radiolabeled Chemicals, Inc. (ARC, St. Louis, MO). [14C]-
AN2690 was synthesized by Amersham Biosciences UK
Limited (Buckinghamshire, UK). [14C]-Econazole [chlo-
Advances in Methods of Identification rophenyl benzyl-14C]-(D,L)-econazole (chemical name:
1-[2-[(4-chlorophenyl)-methoxy]-2-(2,4-dichlorophenyl)ethyl]-
of the Fungal Elements in the Nail 1H-imidazole), [14C]-ciclopirox (pyridinone-6-(14C)-ciclopirox)
The conventional method for the identification of a fungus is was obtained from Perkin-Elmer Life Sciences, Inc. (Boston,
the use of KOH preparation of nail samples with consecutive MA). [14C]-Terbinafine freebase and [14C]-terbinafine hydro-
culture of the nail samples on agarose plates as well as histo- gen malate were obtained from Novartis Pharma AG (Basel,
logical examination of the nail plate (26). These methods are Switzerland). The radiochemical purities and specific activities
known to produce false negative results ranging from 20% to of all chemicals were >98% and >98%, respectively. Penlac1
40%. If false negative results are obtained in a clinically evi- nail lacquer (ciclopirox 8% topical solution) was manufactured
dent onychomycosis case, an invasive nail plate punch biopsy by Dermik (Berwyn, PA). 2-n-nonyl-1,3-Dioxolane (SEPA), a
for giemsa staining may be performed. penetration enhancer, and all necessary lacquer components
were provided by MacroChem Corp. (Lexington, MA).
Emerging Noninvasive Diagnostic Formulations

Tools for Onychomycosis Nails have a high content of disulfide bonds (10.6% versus
1.2% for human skin), which make the nails both strong and
Optical Coherence Tomography
impenetrable. To deliver a therapeutically sufficient quantity
This method allows for noninvasive cross-sectional imaging of of an antifungal drug to fungally infected sites, such as nail
the nail plate. Abuzahra et al. conducted a pilot study to com- plate, bed, and matrix, a suitable carrier is needed to enhance
pare optical coherence tomography (OCT) with conventional drug penetration through the nail barrier. In the case of urea,
methods. They examined the potential of OCT as a noninva- ketoconazole, and salicylic acid, a lotion (Pennsaid lotion,
sive tool for the diagnosis of onychomycosis. The authors were Dimethaid Research Inc., Markham, Ontario, Canada) con-
able to demonstrate a reliable pattern for identifying onycho- taining the penetration enhancer dimethylsulfoxide (DMSO)
mycosis using OCT where it detected fungal elements in all had previously been shown to enhance skin penetration (7, 8,
histologically positive specimens, and no false-positive results 29). To test these three drugs, we prepared three formulations
were seen in their controls (27). In contrast to Abuzahra’s find- with [14C]-urea, [3H]-ketoconazole and [14C]-salicylic acid at
ings, Rothmund et al. conducted a study to evaluate the use of 0.002%, 0.1%, and 0.07%, respectively, and corresponding
confocal laser scanning microscopy (CLSM) and OCT as a saline controls with each drug at the same concentrations (7).
noninvasive diagnostic tool and compare them to established For the antifungal drugs econazole, terbinafine free base,
techniques. Rothmund et al. had a very low specificity and and terbinafine salt, we used a nail lacquer formulation, which
a high number of false positive results with the use of OCT, is a popular choice for topical antifungal treatment. Nail lac-
possibly due to the lower resolution, which may not allow a quer contains a film-forming agent and a solvent, in addition to
clear-cut differentiation between hyphae/spores and other nail the antifungal drug, and possibly a penetration enhancer. Once
creases/artifacts, like trapped air, that may appear similarly the lacquer is applied, it forms a thin, water-insoluble film
(28). Contradictions are an indication for further, larger, and containing the supersaturated antifungal drug. This provides
more detailed investigations. a chemical gradient to drive drug flux as the drug is released.
Thus, a lacquer formulation is suitable for topical treatment of
nail diseases. We selected a commercial lacquer formulation,
Confocal Laser Scanning Microscopy
EcoNail™ (MacroChem Corp). The components of this lac-
CLSM is regarded as a helpful noninvasive tool in the diagno- quer formulation include econazole with penetration enhancer,
sis of skin lesions of the human skin, primarily for pigmented 2-n-1,3-nonyl-dioxolane (18%) and were assembled into a test
lesions, as well as other skin tumors and diseases. It has been formulation in the lab prior to use (8). The control is the same
investigated as a noninvasive tool in diagnosis of onychomy- formulation minus 2-n-1,3-nonyl-dioxolane.
cosis possibly offering higher precision and faster results com- [14C]-Ketoconazole was mixed with a filming solution, Time
pared with KOH preparations. The study by Rothmund et al. Off Nail (Neutrogena Corporation, Los Angeles, CA) to be a
showed that CLSM had the best specificity superior to KOH final 2% nail lacquer formulation. 2% [14C]-Ketoconazole com-
preparations, culture, and OCT (28). One major drawback to mercial cream was purchased from TEVA Pharmaceuticals
this technique is the cost. USA (Sellersville, PA) and used for control.
Nail Penetration 35
AN2690 (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole)
was obtained from Anacor Pharmaceuticals, Inc. (Palo Alto,
CA). Trace amount of [14C]-AN2690 was mixed with propylene
glycol/ethanol (1:4, v/v) to a final 10% (w/v) test formulation
(30). Penlac® nail lacquer (ciclopirox 8% topical solution) was
manufactured by Dermik (Berwyn, PA) (31). Trace amount of
[14C]-ciclopirox was mixed with the lacquer to be a control.
Human Fingernail Plates FIGURE 4.1 Nail support and incubation system in a Teflon one
chamber diffusion cell. The cotton ball prevented the over hydration of
Nail plates were collected from adult human cadavers and a liquid interface. Cotton is a hydrophilic fiber which can contain a high
degree of moisture content and absorbs watersoluble substances. It also
stored in a closed container at 0°C. Before each experiment, absorbs lipophilic substances, which can fill the lumen and lie between
nail samples were gently washed with normal saline to remove the numerous internal layers of the cotton (32). Thus the cotton ball is an
ideal receiving medium for in vitro transungual delivery.
any contamination, then rehydrated by placing them for 3
hours on a cloth wetted with normal saline. Nail samples were
randomly selected and allocated to test groups. Nail thickness water-soluble substances. It also absorbs lipophilic substances,
was measured by a Sony microdigital meter (Sony Magnescale which can fill the lumen and lie between the numerous internal
Inc., Japan) before testing to determine the drilling depth for layers of the cotton (32). Thus the cotton ball is an ideal receiv-
each nail. Five nails were used for each formulation tested. ing medium for in vitro transungual delivery.
Dosing and Surface Washing Procedures Nail Sampling

A 10-μl dosing aliquot of each of the test formulations was The objective was to determine drug concentration within
applied to the surface of a nail plate with a micro-syringe. the nail where the disease resides. Treatment is applied
Topical application was usually conducted in the morning. For to the nail surface. The drilling system samples the inner
twice-daily dosing, a second one was done in the evening, 8 core of the nail without disturbing the nail surface. The two
hours after morning application. Surface washing to remove parts (surface and inner core) can be assayed separately.
the residue dose was done in the morning, 24 hours after the The surface contains only residual drug after washing. The
previous morning application, and 10 minutes prior to the next drilled-out core (from the ventral side) is thus a true drug
one if necessary. The nail was washed with cotton tip swabs measurement at the target site where the disease resides
in a cycle as follows to simulate daily bathing: a dry swab, (Figure 4.2). Drug penetration into the nail was sampled by a
then a swab wetted with 50% Ivory liquid soap (Procter & unique micrometer-controlled nail sampling instrument that
Gamble, Cincinnati, OH), then a swab wetted with distilled enabled finely controlled drilling into the nail and collec-
water, then another swab wetted with distilled water, then a tion of the powder created by the drilling process (7, 8). The
final dry swab. The nails treated with lacquer also received an nail sampling instrument (Figure 4.3) has two parts, a nail
alcohol wash to remove residual lacquer that was insoluble in sample stage and a drill. The nail sampling stage consists of
soap and water. The samples from each cycle from each nail a copper nail holder, three adjustments, and a nail powder
were pooled and collected by breaking off the cotton swab capture. The three adjustments control vertical movement.
into scintillation glass vials. An aliquot of 5.0 ml methanol The first coarse adjustment (on the top) is for changing the
was added to each vial to extract the test material. The radio- copper cell and taking powder samples from the capture.
activity of each sample was measured in a liquid scintillation The other two adjustments (lower) are used in sampling.
counter. The second coarse adjustment allows movement of 25 mm
while the fine adjustment provides movement of 0.20 mm.
Nail Incubation The nail powder capture is located between the copper cell
and the cutter. The inner shape of the capture is an inverted
To keep the nail at physiological levels of temperature and
humidity, we incubated it in a Teflon one-chamber diffusion
cell (PermeGear, Inc., Hellertown, PA). The nail surface (top
center) was open to air and the inner surface contacted a small
cotton ball acting as a nail supporting bed (Figure 4.1). The
cotton ball was wetted with normal saline. The incubation
period started 24 hours prior to the first dose and ended 24
hours after the final dose. A small cotton ball wetted with 0.1
mL normal saline was placed in the chamber beneath the nail
plate to serve as a “nail bed” and provide moisture for the nail
plate, and hydration was monitored and controlled during the
experiment (7, 8). This cotton ball method prevented overhy-
dration of a liquid interface. Cotton is a hydrophilic fiber, which
can contain a high degree of moisture content and absorbs FIGURE 4.2 Nail and nail drilling tip. (From Ref. 41, with permission.)
collected was measured by the difference in weight of the

plate before and after drilling (7, 8).
Results
Nail Incubation Conditions
Table 4.1 shows that the average hydration of the wetted cot-
ton balls, 109 ± 6.2 AU, resembles the average hydration of a
human nail bed, 99.9 ± 8.9 AU, measured from fresh human
cadavers. During the experiment, the holding tank temperature
was 25 ± 2°C and relative humidity was 44 ± 8%. Thus, there
was no statistical difference between hydration conditions for
nails treated with either the test formulation or the saline con-
trol. This incubation device is nonocclusive and hydration con-
trolled, and approximate normal physical condition is reached.
FIGURE 4.3 The nail sampling system. The instrument has two parts: Here AU represents arbitrary units—a digital expression of
a stage and a drill. The stage consists of a copper nail holder, three capacitance when using a Corneometer to estimate our body
adjustments, and a nail powder capture. During drilling, the vacuum
draws the powder debris onto the filter paper so it can be collected and surface membrane hydration such as the stratum corneum
measured and increase total collection for mass balance determination. (SC) or nail. Agache et al. (33) used a sorption–desorption test
(From Ref 41, with permission.) to assess the water content of SC. They correlated the results
measured with the Corneometer CM 820 as AU unit and
funnel with the end connected to a vacuum pump. By plac- TEWL (g.m–2.h–1) measured with an evaporimeter and found
ing a filter paper inside the funnel, nail powder samples can that water retained in the SC(μg.cm–2) = In(AC/3.8)/0.0436.
be captured on the filter paper during sampling. The nail is
fastened in a cutting holder below the cutter and surrounded
by a funnel containing a filter paper. The funnel is attached Accuracy of Nail Sampling Processes
to a vacuum pump. During drilling, the vacuum draws the The advantage of the micrometer-controlled drilling and
powder debris onto the filter paper so it can be collected nail powder removal system is the accuracy of the sampling
and measured and increase total collection for mass balance process. The sampling instrument allowed well-controlled,
determination. accurate, and reproducible sampling of the inside of the nail.
After completion of the dosing and incubation phase, the Table 4.2 shows that the average depth of nail sampling from
nail plate was transferred from the diffusion cell to a clean the inner center surface was well controlled at 0.26 ± 0.05
cutting holder for sampling. The nail plate was secured in mm, which was close to the expected depth of 0.24 mm. The
position so that the ventral surface faced the cutter and the weight of the nail samples collected was consistent for all
dorsal-dosed surface faced the holder. The cutting holder was experiments.
moved to bring the plate surface just barely in contact with the
cutter tip. The drill was then turned on and a fine adjustment
TABLE 4.1
moved the stage toward the cutter tip, removing a powder
sample from the nail. In this way, a hole approximately 0.3– Hydration of Nail Plate and Nail Bed
0.4 mm in depth and 7.9 mm in diameter was drilled in each Measurement* Hydration (AU)**
nail, enabling the harvest of powder sample from the center
Source N Time Nail plate Nail bed
of each nail’s ventral surface. We refer to these samples as
Human cadavers 6 24-hr postmortem 7.6 ± 0.9 99.9 ± 8.9
having been taken from the “ventral/intermediate nail plate.”
Diffusion cells 8 Twice/day for 7 days 8.5 ± 2.4 109.9 ± 6.2
After the nail had delivered its ventral/intermediate nail
plate powder samples, it was removed from the sampling Notes: During the experiment, the holding tank temperature was 25 ± 2°C
instrument. The nail outside the dosing area was cut away and relative humidity was 44 ± 8%. The importance of this con-
trolled temperature and humidity is to mimic normal physiological
and discarded. The nail within the dosing area but outside condition of the human nail to prevent over hydration which was
the sampling area was trimmed away and saved; we refer easily occurred in nail in vitro studies.
to this as the “remainder nail plate.” It surrounds the dor- * Hydration of the nail plate and the supporting cotton bed was measured
sal layer above the sampling area where the powder samples with a Corneometer CM 820 (Courage & Khazaka, Cologne, Germany).
were taken; we refer to this as the “sampling area dorsal nail ** AU is Arbitrary Units, a digital expression of capacitance. Thus, the
plate.” The ventral/intermediate nail plate powdered sam- CM820 Corneometer gives only an estimate of the nail (or other mem-
brane such as stratum corneum) hydration. Agache et al. (21) used a
ples, the sampling area dorsal nail plate, and the remainder
sorption–desorption test to assess the water content of the stratum cor-
nail plate were individually collected into a glass scintilla- neum. They correlated the results measured with the CM820
tion vial and weighed. The nail samples were then dissolved Corneometer (as AU unit) and TEWL (g/m2.hr) measured with an evap-
by adding 5.0 mL of Packard’s Soluene®-350 (Packard orimeter and found that water was retained.
Instrument Company, Meriden, CT). The total mass of nail Source: From Ref. 41, with permission.
Nail Penetration 37
TABLE 4.2
Nail Core Sampled from the Ventral (Inner) Surface Center of the Human Nail Plate*
Whole nail thickness % Whole nail Total core sample Powder sample
Test chemicals (mm) Depth of core (mm) thickness removed (mg) collected (mg)
Urea 0.65 0.25 39.52 16.4 5.2
(control) ± 0.09 ± 0.03 ± 8.05 ± 4.3 ± 0.8
Urea 0.71 0.27 37.97 17.6 6.4
(test) ± 0.07 ± 0.03 ± 2.69 ± 4.3 ± 1.3
Ketoconazole (control) 0.68 0.28 41.88 14.3 6.7
± 0.05 ± 0.03 ± 1.16 ± 6.7 ± 2.6
Ketoconazole (test) 0.73 0.28 38.62 14.1 4.3
± 0.03 ± 0.02 ± 2.69 ± 5.1 ± 1.6
Salicylic acid (control) 0.77 0.25 32.62 12.1 6.0
± 0.07 ± 0.08 ± 9.38 ± 2.4 ± 0.5
Salicylic acid 0.60 0.21 35.03 23.4 4.7
(test) ± 0.12 ± 0.06 ± 6.45 ± 8.3 ± 0.8
Average 0.69 0.26 37.61 16.3 5.5
± 0.09 ± 0.05 ± 6.20 ± 6.2 ± 1.6
* Nail sample, approximately 0.24 mm in depth and 7.9 mm in diameter, was drilled from the center of the ventral surface of the nail. The amount of nail
sample removed was measured by difference in weight and depth of the drilled area before and after sampling. Each number represents mean (± S.D.)
of 5 samples. The data demonstrated the repeatability and accuracy of the nail sampling system.
Source: From Ref. 7, with permission.
TABLE 4.3
Mass Balance Recovery of Econazole following 14-Day Human Nail Treatment with a Test Formulation Containing a Penetration
Enhancer and a Control without a Penetration Enhancer
Carbon-14 recovery as percent of dose
Test formulation Control formulation
Dorsal/intermediate nail plate 11.4 ± 3.6 20.1 ± 2.9
Ventral/intermediate nail plate (powdered
1.3 ± 1.1 0.22 ± 2.9
samples)
Remainder nail plate 5.6 ± 3.9 3.2 ± 2.3
Supporting bed (cotton ball) 0.7 ± 0.3 0.0 ± 0.0
Surface washes 71.7 ± 12.5 72.8 ± 5.1
Total 90.8 ± 16.4 96.4 ± 7.3
Note: The data represent the mean (SD) of each group (n = 5). The test formulation group contains 18% 2-n-nonyl-1,3-dioxolane and the control formula-
tion contains no 2-n-nonyl-1,3-dioxolane. The data demonstrated not only the importance of the penetration enhancer but the high recovery rate of
two groups when using the nail sampling system.
Mass Balance of Radioactivity Recovery is greater for both the ventral/intermediate nail plate and
the supporting bed, which is an effect of the drug delivery
Table 4.3 summarizes the econazole mass balance recov- enhancer. At the sampling area dorsal nail plate, there is
ery following the 14-day nail treatment. Overall recovery of more econazole from the saline control because the dose
applied dose was 90.8 ± 16.4% for the test formulation and remained on the nail surface.
96.4 ± 7.3% for the saline control, indicating that essentially
the entire dose was accounted for.
Effects of Dosing and Washing Frequency
Table 4.3 also indicates what happens to chemicals
applied to the nail. Approximately 72% was washed from Figures 4.4 and 4.5 show the weight normalized of 14C econ-
the surface. The dose absorbed from the surface of the nail azole equivalent in different layers of the nail plate and cumu-
penetrated to the sampling area dorsal nail plate (11.4%), lative 14C econazole equivalent collected in the cotton ball
the ventral/intermediate nail plate (1.4%), and the support- supporting bed following different frequency of topical dosing
ing bed (0.7%), which is the cotton ball upon which the nail or surface washing treatments. As expected, after twice-daily
rested. Note that econazole recovery in the test formulation application (and surface washing once daily) for 14 days, the
FIGURE 4.4 Nail penetration profile of 14C-econzaole following a 14-day treatment/incubation period in vitro. Each bar represents the mean (SD) of
six samples. The frequency of topical dosing was different, but the surface wash was the same, once daily. * The group that received twice-daily topical
doses was statistically significantly higher than the one treated with a once-daily dose (p < 0.05). (From Ref. 41, with permission.)
enhancer. In each case the test formulation enhanced drug

delivery (p < 0.05). Table 4.5 compares antifungal efficacy
of econazole, terbinafine base, and terbinafine salt follow-
ing topical applications (34). Each test antifungal agent con-
tains 18% 2-n-nonyl-1,3-dioxolane (SEPA), a skin penetration
enhancer, and the control (no 18% 2-n-nonyl-1,3-dioxolane).
All test formulations show the antifungal efficacy coefficient
(E) was significantly higher than that of corresponding con-
trol (p < 0.05).
Topical Formulation Comparison

Table 4.6 compares [14C]-ciclopirox penetration into/through
nail plate in vitro from three topical formulations: market gel,
experimental gel, and lacquer. The order of deeper penetra-
FIGURE 4.5 Nail penetration profile of 14C-econzaole following a tion, amount detected in the ventral/intermediate nail center,
14-day treatment/incubation period in vitro. Each bar represents the
mean (SD) of six samples/group. Each group received oncedaily topical and cotton ball supporting bed samples was from the highest
application for 14 days. The frequency of surface washing for each group to the lowest market gel, lacquer, and experimental gel, respec-
was different. The group that received daily washing was not statistically
significant from the corresponding bar from the once-weekly washing tively. Figure 4.6, however, shows that the deeper penetration
group (p > 0.05). (From Ref. 41, with permission.) of a lacquer formulation of ketoconazole was greater than that
of cream when comparing their antifungal efficacy coefficient
(p < 0.05).
14C econazole content in all nail and cotton ball samples was
significantly higher than that in the dosing and washing once-
daily group (p < 0.05). Comparison of the once-daily dosing Determination of Nail Penetration,
and washing treatment group and the once-daily dosing and Distribution, and Transungual Delivery
once-weekly washing group did not show significant differ-
ence for all collected samples (p > 0.05). This in vitro nail study model exams test formulation effect
on the penetration of [¹⁴C]-labeled substance into each nail
layers, particularly the deeper layer and the nail bed tissue,
Enhancer Effects
and to determine the flux rate and kinetics of [¹⁴C]-substance.
Table 4.4 summarizes the penetration of ketoconazole, urea, Table 4.7 provided information that may help to understand
and salicylic acid into the human inner nail plate. Each test permeation character and rate of panthenol in each layer of the
formulation contained a drug delivery enhancer (7, 8) and was human nail and to design an optimum transungual delivery
compared to a control formulation without any penetration system (35).
Nail Penetration 39
TABLE 4.4
Radiolabelled Drug Penetration into Human Nail from a Test Formulation Containing DMSO, a Penetration Enhancer, versus a
Control without a Penetration Enhancer
Radioactivity content in ventral/intermediate
center layer of the nail plate
Significant
Test chemicals Penetration enhancer* Unit** Test formulation Control formulation (p < 0.05)
Ketoconazole Dimethylsulfoxide Mg Eq/g 53.9 34.0 Yes
± 10.6 ± 15.9
Urea Dimethylsulfoxide Mg Eq/g 0.3 0.2 Yes
± 0.1 ± 0.1
Salicylic acid Dimethylsulfoxide μg Eq/g 10.2 7.0 Yes
± 0.6 ± 1.1
Note: The data represent the mean (SD) of five samples per formulation group. The nail sample drilled as powder from ventral/intermediate layer of
human nail plate.
* Dimethylsulfoxide (DMSO) is a transdermal delivery enhancer. The enhancement mechanism of transungual delivery is not clear. However, it did
enhance the nail penetration of the test chemicals.
** μg Eq/g = microgram equivalents drug per gram of nail sample. Because radioactivity is used, the drug mass is referred to as “equivalents” because
radioactivity was measured, not the drug itself.
TABLE 4.5
Comparison of Econazole Concentration and Relative Antifungal Efficacy with a Test Formulation Containing 2-N-Nonyl-1,3-
Dioxolane, a Penetration Enhancer and a Control
Test Control Significant
Parameter* formulation formulation (p < 0.05)
Econazole in the deeper layer (μg/cm3) 14,830 ± 341 2,371 ± 426 Yes
ED (MICD = 1 μg/mL) 14,830 2,371 Yes
EY (MICY = 100 μg/mL) 148 23.7 Yes
Terbinafine salt in the deeper layer (μg/cm3) 5946 ± 1029 463 ± 271 Yes
ED (MICD = 0.04 μg/mL) 5946 463 Yes
EY (MICY = 1.77 μg/mL) 134 10 Yes
Terbinafine base in the deeper layer (μg/cm3) 727 ± 372 407 ± 106 Yes
ED (MICD = 0.04 μg/mL) 1527 156 Yes
EY (MICY = 1.77 μg/mL) 34 3 Yes
The data represent the mean (SD) of each group (n = 5). The test formulation group contains 18% 2-n-nonyl-1,3-dioxolane and the control formulation
contains no 2-n-nonyl-1,3-dioxolane.
Abbreviations: E, antifungal efficacy coefficient; MIC, minimum inhibitory concentration (of the tested antifungal agent); D, dermatophytes; Y, yeast (8).
* The deeper layer is the center of the ventral/intermediate layer of the nail plate. The data represent the amount of drug in the sample after a 14-day
dosing period. The amount of antifungal agents in the tested nail layer (μg/cm3) was computed from the average of the cumulative amount of the test
agent permeated into the area (area × thickness) of the deeper layer of the nail (dorsal/intermediate layer).
TABLE 4.6
Summary of Weight Normalized 14C-Ciclopirox Equivalent in the Nail and Supporting Bed Samples after 14-Day Treatment
Normalized 14C-Ciclopirox Equivalent
Significant
Items (Unit) Marketed gel Experimental gel Lacquer (p < 0.05)
Dorsal/intermediate center within surface 72 ± 17 103 ± 38 2162 ± 526 Lacquer vs experimental gel
of nail (μg eq/mg) Lacquer vs marketed gel
Marketed gel vs lacquer
Ventral/intermediate center within 0.6 ± 0.3 0.2 ± 0.1 0.3 ± 0.1 Marketed gel vs experimental gel
infection-prone area (μg eq/mg) Experimental gel vs lacquer
Marketed gel vs lacquer
Penetration through the nail into the 46 ± 4 6±1 16 ± 3 Marketed gel vs Experimental gel
supporting bed cotton ball (μg eq/sample) Experimental gel vs lacquer
Note: The data represents the mean (SD) of each group (n = 5).
supersaturated antifungal drug. This film provides a chemical

gradient to drive drug flux as the drug is released. For exam-
ple, 14C-ketoconazole lacquer yields a significantly higher
antifungal efficacy coefficient than that in cream (p < 0.05;
Figure 4.6). However, the deeper penetration of [14C]-ciclopirox
from the commercially available formulation, Penlac nail lac-
quer (ciclopirox 8% topical solution), was statistically lower
than that of market gel formulation (ciclopirox 0.77 % topical
solution) (Table 4.6) (31). When compared with other antifun-
gal topical formulations, such as [14C]-AN2690, 10% (w/v) in
propylene glycol/ethanol solution, it decreased (p < 0.05) the
deeper nail layer penetration rate (Figure 4.7) (30).
To design an effect topical antifungal formulation, it is
important to detect if there is significant drug concentration
to reach the nail layer, particularly in deep diseased tissues.
Human nail behaves like a hydrophilic gel membrane in that
FIGURE 4.6 Comparison of antifungal efficacy coefficient of two
ketoconazole formulations, lacquer, and cream. Each bar represents the flux of a substance across each nail layers is dependent
the mean (SD) of five samples/group. Each group received a once-daily upon its solubility and permeability in dorsal, intermediate,
topical dose and washing for a 7-day treatment. The lacquer group shows
that the antifungal efficacy coefficient was statistically significantly and dorsal, and nail bed layers. Figure 4.8 gives an example of
higher than that of the cream group (p < 0.05). (From Ref. 41, with panthenol distributions and concentrations in the dorsal sur-
permission.) face, interior (by drilling and removal), and in the supporting
bed (beneath the nail plate) following a daily topical applica-
tion for 7 days. A significant linear increase of panthenol levels
with daily doses was found in the dorsal nail (R2 = 0.87; p <
Discussion 0.001), nail interior (R2 = 0.94; p < 0.001), and nail supporting
bed groups (R2 = 0.79; p < 0.003). The slope of the panthenol
Topical therapy for onychomycosis is not yet maximally effec- concentration versus time curve of the dorsal layer is higher
tive, and this failure may be due to inadequate penetration of than that of the interior layer, which was higher than that for
drugs into the nail plate. The nail’s unique properties, particu- the supporting bed cotton ball. The results suggested the main
larly its thickness and relatively compact construction, make barrier to drug permeation in the human nail plate may be the
it a formidable barrier to the entry of topically applied agents. low diffusivity of drugs in the dorsal layer (10) as the highest
The concentration of an applied drug across the nail drops of panthenol affinity to the dorsal nail plate (35).
about 1000-fold from the outer surface to the inner surface (6). The variation in the diffusion rate of panthenol as a function
As a result, the drug concentration presumably does not reach of location within the nail plate is like the diffusion behavior
a therapeutically effective level in the ventral/intermediate lay- of 5-fluorouracil, another small water-soluble molecule into
ers. To optimize the nail penetration of topical treatments, it human nail plate, which was explored in an in vitro study con-
is important to consider the nail’s unique barrier properties ducted by Kobayashei et al. (10). They concluded that the drug
and develop an antifungal drug formulation that has matching permeation characteristics of the layers of the human nail plate
physicochemical properties. are as follows: the dorsal layer is characterized by low dif-
Nail lacquer formulations, a popular choice for topical fusivity to substances; the intermediate layer is characterized
antifungal treatment, typically contain a film-forming agent, by low lipophilicity and higher diffusion rates of hydrophilic
solvent, antifungal drug, and possibly a penetration enhancer. molecules; and the ventral layer is characterized by high lipo-
Once the lacquer is applied, it forms a thin film containing a philicity and diffusion rates that can be lower than that of the
TABLE 4.7
Flux of Panthenol into/through the Human Nail Plate from the Nail Treatment
Flux (μg equivalent panthenol/cm2/hr)*
Nail layers 0–24 hrs 0–48 hrs 0–72 hrs 0–96 hrs 0–120 hrs 0–144 hrs 0–168 hrs Average
Interior (nail 12 8.2 7.2 8.3 13 13 14 10.3
core) ± 2.6 ± 0.5 ± 1.7 ± 0.8 ± 0.4 ± 1.8 ± 4.8 ± 2.8
Supporting bed 0.5 2.3 1.6 1.4 1.2 1.8 3.0 1.5
cotton ball ± 0.2 ± 0.9 ± 0.6 ± 0.3 ± 0.2 ± 0.7 ± 1.2 ± 0.8
* Each value represents the mean (SD) of three samples.
Note: The average flux in the interior nail plate was 10.3 ± 2.8 g equivalent panthenol cm–2 h–1 and in the nail supporting cotton bed (completely through
the nail) was 1.5 ± 0.8 g cm–2 h–1.
Nail Penetration 41
FIGURE 4.7 Cumulative amounts of AN 2690 and ciclopirox (mg FIGURE 4.9 Time profile of terbinafine HCl flux rate (µg/day) in cotton
equivalent) in cotton ball supporting bed samples following a 14-day pad/nail supporting bed samples. After the first dose application, the
treatment. The test was dosed daily, and the dose residue was washed amount terbinafine HCl quickly penetrated through the nail plate and the
24 hours later and 10 minutes prior to the next application. Each bar concentration in the cotton pad increased linearly until day 5 (after 96
represents the mean (SD) of six samples/group. Each bar of the AN2690 hours) and then kept constantly. (From Ref. 36, with permission.)
group was statistically higher than the corresponding one from the
ciclopirox group (p < 0.05). (From Ref. 41, with permission.)
nail plate and the concentration in the cotton pad increased lin-
early until day 5 (after 96 hours) and then remained constant.
The volume of the receiving chamber of the inline diffusion
cell used is approximately 1 ml. Therefore, daily terbinafine
HCl penetrating through the nail plate into the wetted cotton
pad sample (as nail bed model) can express as 1.9 ± 0.6 µg/cm3
in average (± SD) or as total cumulative amount for 14 days 27
± 1.2 µg/cm3 (36).
DMSO and 2-n-nonyl-1,3-dioxolane, two transungual deliv-
ery enhancers were tested for enhancement of the deeper nail
penetration of [14C]-ketoconazole (Table 4.3), [14C]-econazole,
[14C]-terbinafine salt, [14C]-terbinafine base (Table 4.5) sig-
nificantly compared to the controls (p < 0.05). DMSO has
been previously reported to facilitate the penetration of some
topical antimycotics (15, 35). The enhancement function of
FIGURE 4.8 Panthenol concentration as a function of time (0–168 2-n-nonyl-1,3-dioxolane has not previously been determined.
hours). The cumulative panthenol concentration (mg eq.g–1, expressed as
y) in and through the nail layers increased linearly with time (0–168 hrs, The mechanism of 2-n-nonyl-1,3-dioxolane in skin penetration
as x) and can be mathematically expressed as y = mx +b, here the m was suggested to reversibly fluidize the stratum corneum lipids
expresses as the slope. The results of each nail layer were predicted as and alter barrier function (37). However, [14C]-dioxolane, the
follows. (From Ref. 35, with permission.)
radiolabeled 2-n-nonyl-1,3-dioxolane, had minimal penetra-
• Dorsal Nail: y = 0.054*hrs–0.20, R² = 0.94, P < 0.001.
• Interior Nail: y = 0.021*hrs–0.29, R² = 0.87, P < 0.001. tion to and through the human nail plate in vitro (8). 2-n-nonyl-
• Nail supporting bed cotton ball: y = 0.004*hrs–0.07, R² = 0.79 P = 0.003. 1,3-dioxolane can function as an adhesion promoter and a
plasticizer for the film-forming polymer of the nail lacquer
(38, 39). The enhancement function of 2-n-nonyl-1,3-dioxo-
intermediate layer. These researchers found that the diffusion lane for the tested antifungal agents was possibly to soften the
rates of their probe molecules were faster in the interior of the lacquer film to increase releasing per-unit time (8). As shown
nail plate than the dorsal or ventral layers. Our observed pan- in Table 4.5, the amounts of [14C]-econazole, [14C]-terbinafine
thenol kinetic data is consistent with these findings. free base, and [14C]-terbinafine salt detected from the deeper
Since the deep nail plate, especial the nail bed tissues are layer, ventral/intermediate nail layer in the test groups, which
mainly infected with fungus, this in vitro nail penetration the lacquer formulation contains 18% 2-n-nonyl-1,3-dioxolane
model is interested in the concentration of testing drug per- were significantly greater than that in the controls (p < 0.05).
meating into the nail supporting bed samples to determine The results suggest that the enhanced level of these antifungal
the penetration rate and kinetics. Figure 4.9 shows the time agents in the ventral/intermediate layers and supporting bed
profile of terbinafine HCl flux rate (µg/day) in cotton pad/nail dramatically increased, which exceeds the minimum inhibi-
supporting bed samples. After the first dose application, the tory concentration (MIC) of econazole for most common ony-
amount of terbinafine HCl that quickly penetrated through the chomycosis organisms (Table 4.5).
MIC is a laboratory index in the determination of antifungal 11. Martin D., Lippold B.C. In vitro permeability of the human
potency. Mertin and Lippold (11) introduced an efficacy coef- nail and a keratin membrane from bovine hooves: Influence
ficient E to better estimate and compare the relative efficacy of of the partition coefficient octanol/water and the water solu-
antifungal agents. The efficacy coefficient E is the ratio of the bility of drugs on their permeability and maximum flux.
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5
Advances in Skin Bioengineering
Enzo Berardesca and Norma Cameli
The measurement of skin hydration (in conjunction some- 2. Non-contact dermoscopy: This technique involves
times with TEWL) is still one of the most frequently used the use of a specialized tool that allows the derma-
tests in vivo conducted both in dermatology and cosmetol- tologist to examine the skin without touching it.
ogy to evaluate skin condition and/or to assess the efficacy 3. Polarized dermoscopy: This uses polarized light
of topical products. Many new techniques or refinements to reduce glare and improve visualization of skin
of older techniques have appeared during the last decades structures and in particular of deep structures such
and are used currently in dermatology and skin research in as microcirculation, teleangectasia, and melanin net-
general. work inside a mole.
Among these, skin image analysis techniques have become 4. Multispectral dermoscopy: This technique involves
very important tools in dermatology as they can help derma- using multiple light wavelengths to visualize differ-
tologists diagnose and monitor skin conditions more accu- ent layers of the skin.
rately and efficiently using a “visual” approach. By using these
techniques, dermatologists can provide more effective treat-
ment options and improve patient outcomes. Computer-Aided Diagnosis
Computer-aided diagnosis (CAD) involves the use of algo-
rithms and machine learning techniques to analyze skin images
Systems for Skin Imaging and Analysis and aid in diagnosis. This technique can help dermatologists
detect subtle changes in skin lesions and improve diagnostic
Skin image analysis is an important tool used in dermatology
accuracy. Computer-aided diagnosis is an important tool used
to diagnose and monitor various skin conditions. This section
in dermatology to aid in the diagnosis of skin conditions. Some
highlights are some techniques used in skin image analysis.
examples (among others) of CAD systems used in dermatol-
ogy are VISIA, Visioface, and Newtone Systems (6–10).
Dermoscopy
Dermoscopy involves using a specialized magnifying tool to 1. VISIA is a CAD system developed by Canfield
examine skin lesions and moles in detail. This technique can Scientific, Inc. It uses a high-resolution digital cam-
help dermatologists distinguish between benign and malignant era and specialized software to capture images of
lesions and improve the accuracy of skin cancer diagnosis. the skin and analyze various skin features, includ-
Dermoscopy, also known as dermatoscopy or epilumines- ing wrinkles, pores, texture, and pigmentation. The
cence microscopy, is a noninvasive technique used in derma- system provides quantitative measurements of these
tology to examine skin lesions and moles in detail. It involves features and compares them to a database of normal
using a specialized magnifying tool called a dermatoscope, skin to identify any deviations from normal. VISIA
which has a light source and a magnifying lens, to examine the is particularly useful for monitoring changes in the
skin surface and underlying structures (1–5). skin over time and assessing the effectiveness of var-
Dermoscopy allows the visualization of the features of a ious skincare treatments.
skin lesion in more detail than with the naked eye. This can 2. Visioface (Courage & Khazaka) is a non-invasive
help distinguish between benign and malignant lesions and imaging system used in dermatology and cosmetics
improve diagnostic accuracy. Dermoscopy is particularly use- to analyze the skin’s surface and identify skin prob-
ful in the diagnosis of skin cancers such as melanoma, as it can lems. The system captures high-resolution images of
help detect subtle changes in the color, shape, and structure of the skin and provides a detailed analysis of various
a mole that may indicate malignancy. parameters, such as wrinkles, fine lines, pigmenta-
There are several different types of dermoscopy techniques, tion, and pore size.
including: 3. Newtone Systems is a CAD system developed by
Newtone Technologies, Inc. It uses a combination
1. Contact dermoscopy: This technique involves apply- of computer vision and machine learning techniques
ing a small amount of oil or gel to the skin surface to to analyze skin images and aid in the diagnosis of
improve visualization. skin conditions. The system can analyze various skin
44 DOI: 10.1201/b22897-5
Advances in Skin Bioengineering 45
features, including lesions, moles, and rashes based on Besides these important new tools for investigating skin sur-
the image analysis. The system also includes a data- face and function, measurements of hydration and skin barrier
base of dermatological knowledge and can provide remain the mainstay of skin research; indeed a healthy skin is
recommendations for further testing or treatment. a skin characterized by a normal hydration and a functioning
and efficient barrier.
Optical Coherence Tomography

Optical coherence tomography (OCT) is a non-invasive
imaging technique that uses light waves to produce high-res- Measurements of Hydration and
olution images of the skin. This technique can help derma- Transepidermal Water Loss (TEWL)
tologists visualize the layers of the skin and detect changes From a technical point of view, the basic approach of mea-
in skin thickness and structure. OCT is particularly useful in suring skin water content using electrical methods is still the
the diagnosis and monitoring of skin cancers, as it can pro- main approach used by manufactures of technical devices.
vide detailed images of the skin layers and help differentiate Improvements have been obtained by the evolution of software
between benign and malignant lesions. It can also be used to and data collection and handling. From the previous guide-
visualize the depth and extent of a lesion, which is useful in lines (21, 22) new instruments have appeared on the market
planning surgical procedures. showing good reproducibility and correlation with “older” ver-
OCT is also useful in the evaluation of inflammatory skin sions (23).
conditions, such as psoriasis and atopic dermatitis. It can pro-
vide information on the thickness and morphology of the epi-
dermis and dermis, as well as the presence of inflammation Moisturemeter
and cellular infiltration. In addition to its diagnostic capabili-
ties, OCT can also be used to monitor the efficacy of various By offering a multiple frequency approach one can obtain
treatments, such as topical or systemic therapies for skin con- more easily different depth measurements, useful to differ-
ditions (11–15). entiate water in the different layers of the skin (stratum cor-
neum, epidermis) or even deeper tissues in case of oedema,
lymphedema, or related conditions by measuring the Tissue
Reflectance Confocal Microscopy Dielectric Constant (TDC). TDC values were highly corre-
lated with body composition parameters, and the magnitude
Reflectance confocal microscopy (RCM) is a non-invasive
of these correlations increased with increasing measurement
imaging technique that uses laser light waves to visualize skin
depth. The significant negative correlation between TDC val-
structures at a cellular level. This technique can help dermatol-
ues and total body fat percentage could be consistent with the
ogists detect changes in skin structure and identify abnormal
increased fat percentage as a function of depth.
cell growth (16–20). RCM has various applications in derma-
tology, including:
Mapping of Skin Hydration by Electrical Methods
1. Skin cancer diagnosis: RCM can be used to visual-
ize and differentiate between different types of skin An interesting technique, always based on skin conductance
cancers, such as basal cell carcinoma, squamous allows 2D mapping of skin surface in terms of moisturization
cell carcinoma, and melanoma. It can help identify (24). This allows the visualization of water distribution on
tumor margins, depth of invasion, and response to skin surface: dry skin sometimes can be considered an uneven
treatment. distribution of water in the stratum corneum such appears in
aging. Mapping of moisturization allows a more precise evalu-
2. Diagnosis of inflammatory skin diseases: RCM can
ation of the total water content of the stratum corneum.
be used to visualize and diagnose various inflamma-
tory skin diseases, such as psoriasis, eczema, and
lupus erythematosus. It allows for the assessment of The Moisture Map
disease severity and treatment response.
This is the only commercially available for skin hydration
3. Monitoring of treatment response: RCM can be used mapping based on L’Oreal Skin Chip (25). The sensor mea-
to monitor treatment response in various skin dis- sures the penetration of the electromagnetic field. Conductive
eases, including skin cancers and inflammatory skin material, e.g. water, will reflect the signal making the resulting
diseases. It can help assess the efficacy of topical or pixel darker while non-conductive material will make the sig-
systemic treatments. nal go farther inside, and the resulting pixel will be lighter on a
4. Mohs surgery: RCM can be used to guide Mohs sur- scale of 255 grey levels. Rather than absolute moisture figures
gery for non-melanoma skin cancers by visualizing the Moisture Map indicates the distribution of hydration on
tumor margins and depth of invasion, potentially the skin surface. With a special image analysis software the
reducing the number of surgical stages needed. image can be evaluated in different ways. Together with the
5. Cosmetic dermatology: RCM can be used to visualize Corneometer for quantitative assessment of the hydration level
and assess skin aging and other cosmetic concerns, of the stratum corneum and the Tewameter to measure exactly
such as wrinkles, hyperpigmentation, and scarring. the transepidermal water loss and assess the skin barrier
function, is possible to create a complete “Water Measurement Overall, non-invasive techniques in dermatology have revo-
Center”. In literature the use of such equipment is known for lutionized the way we diagnose and monitor skin diseases,
efficacy testing of cosmetics, pharmaceuticals, and surfac- allowing for earlier detection, more accurate diagnosis, and
tants; skin photoaging; and illustration of skin lesions and better patient outcomes. These techniques have also provided
scars (26). Capacitance imaging has also been used to map the a better understanding of the pathophysiology of skin diseases,
hair moisture distribution (27). leading to the development of more effective treatments.
Transepidermal Water Loss

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In these years many instruments based on closed cham-
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ber methods have been released. Closed chamber methods
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are increasingly used to measure transepidermal water loss
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(TEWL) from the skin because measurements are less influ-
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3. Scope A, Dusza SW, Halpern AC, et al. The “ugly duck-
tum corneum, the outermost layer of the skin. The closed ling” sign: Agreement between observers. Arch Dermatol.
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a defined area of skin, typically on the forearm or the back, 4. Braun RP, Rabinovitz HS, Krischer J, et al. Dermoscopy
and measuring the amount of water that evaporates from the of pigmented seborrheic keratosis: A morphological study.
skin surface into the chamber over a specified period of time. Arch Dermatol. 2002;138(12):1556–1560.
There are several different types of closed chamber methods 5. Zalaudek I, Kittler H, Marghoob AA, et al. Time required
for TEWL measurement, including (28–30): for a complete skin examination with and without dermos-
copy: A prospective, randomized multicenter study. Arch
1. Vapometer: This method involves placing a small, Dermatol. 2008;144(4):509–513.
circular chamber with a defined surface area on 6. Kwon HH, Park SY, Yoon HS, et al. Objective measure-
the skin and measuring the rate of water vapor dif- ment of skin condition using optical skin imaging. Skin Res
fusion through a membrane covering the top of the Technol. 2015;21(1):13–19.
chamber. 7. Helander L, Haftek M, Zanca A, et al. Evaluation of a novel
2. Aquaflux: This method involves placing a small, optical skin diagnostic device in clinical use. Skin Res
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rate of water vapor diffusion through a small hole 8. Ng EW, Cheng SC, Ying SY. Comparison of the Visioface®
in the top of the chamber using a thermistor-based and VISIA® complexion analysis systems for assess-
sensor. ing skin pigmentation. Skin Res Technol. 2015;21(2):
184–191.
9. Lipoff JB, Cobos G, Lee PK, et al. Validation of a com-
Closed chamber methods for TEWL measurement are widely
puter-aided diagnosis system for cutaneous leishmaniasis.
used in clinical and research settings to assess the barrier
JAMA Dermatol. 2018;154(11):1283–1287.
function of the skin, to evaluate the efficacy of topical thera-
10. Khazova M, Molodtsov I, Nikolenko E. Automated skin
pies for various skin conditions, and to investigate the effects
disease recognition and classification using multi-label
of environmental factors, such as temperature and humidity,
classification algorithm. Int J Adv Comput Sci Appl.
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11. Kwon HH, Park SY, Yoon HS, et al. Objective measure-
ment of skin condition using optical skin imaging. Skin Res
Conclusion Technol. 2015;21(1):13–19.
12. Helander L, Haftek M, Zanca A, et al. Evaluation of a novel
In summary, the field of dermatology has seen significant
optical skin diagnostic device in clinical use. Skin Res
advancements in non-invasive techniques for diagnosis and Technol. 2019;25(1):31–39.
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Advances in Skin Bioengineering 47
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6
dvances in Skin Imaging in Cosmetology
A
and Aesthetic Dermatology
Ferial Fanian
Introduction
The human eye can only spot the contours of skin diseases.
Despite the visibility of the skin, essential aspects of skin
diseases remain hidden beneath the variety of structures, the
diversity of patterns and the large varieties of colours (1).
In 1794, the Italian biologist, Lazzaro Spallanzani discov-
ered that the bats use sound rather than sight. This discovery
led to the first experience of medical imaging in November
1895, by Wilhelm Röntgen, who saw the bones of his hand
on a photographic plate on the other side of an electron beam
tube (2).
Since then, there is a huge range of different high resolu- FIGURE 6.1 Resolution versus penetration depth of different skin
imaging techniques.
tion imaging techniques which allow the researchers and
physicians to discover the underneath skin structure without
disturbing the skin surface (3). Their role is very similar to a many new devices designed based on dermoscopy to evalu-
skin biopsy but in a non-invasive manner. Skin imaging plays a ate the signs of the skin aging such as skin roughness, depth
crucial role in dermatology, aiding in the early detection, diag- and volume of the wrinkles, skin pore size and density, skin
nosis and monitoring of various skin conditions and diseases pigmented lesions, skin colour and skin.
and also in cosmetology and aesthetic dermatology in order to The Visioscan® VC 98 device (Courage and Khazaka,
prove the effect of the interventions and treatments. Cologne, Germany) (Figure 6.2) features a black-and-white
There are many types of skin imaging, physically based high-performance digital camera that takes pictures of the skin
on light, sound and electrical perception of the skin or other surface under standardized homogenous ring-shaped ultraviolet
technologies. Some of the most important methods are der- A illumination (340–400 nm, peak 375 nm) (4). Each 640 × 480
moscopy, skin surface analysis, trichoscopy, polarization pixel picture was analysed using dedicated software (Visioscan
speckles, fluorescence and multiphoton microscopy, coherent 2000) and parameters representing pseudo-roughness (R1 [Rt],
Raman scattering microscopy, in vivo and ex vivo reflectance R2 [Rm], and R3 [Rz], indicators of deep wrinkles) and micro-
confocal microscopy, multispectral imaging, OCT, LC-OCT, relief (R4 [Rp] and R5 [Ra], indicators of microrelief). Rz, or
ultrasound imaging, optoacoustic imaging, skin MRI, thermal circular roughness, is the arithmetic average of five measure-
imaging and 3D imaging. ments of the distance between the highest and lowest value,
The resolution could be at 1 micrometer for RCM and referred to as reference length 1, on a selected line.
LC-OCT or more for other techniques, while the penetration
could be limited to some hundreds of micrometers (Figure 6.1).
Trichoscopy
Trichoscopy (or dermoscopy of hair and scalp) is an easy in-
Dermoscopy
office technique that may be performed with a handheld der-
One of the most commonly used skin imaging techniques is moscope or a digital videodermoscopy system (5). These basic
dermoscopy. It is a handheld device called a dermatoscope, structures may be divided into four groups: (1) hair shafts, (2)
which magnifies the skin surface and allows dermatologists hair follicle openings (dots), (3) perifollicular epidermis and
to visualize structures that are not visible to the naked eye. (4) blood vessels. See Figure 6.3.
This technique aids in the identification of skin cancers, such Although trichoscopy is the main method for evaluation
as melanoma, by examining specific patterns, colors and of the hair disease, it is also a reliable method for evalua-
structures within skin lesions. On the other hand, there are tion of the cosmetic hair product, shampoos, conditioners,
48 DOI: 10.1201/b22897-6
Advances in Skin Imaging in Cosmetology and Aesthetic Dermatology 49
FIGURE 6.2 (a) Visioscan camera, (b) measurement of the roughness in two different conditions, (c) measurement of spots and lesions, (d) anisometry
of younger (left) and older (right) skin. (Courtesy of Courage & Khazaka.)
FIGURE 6.3 Trichoscopy of the scalp, normal aspect.
supplementations and also aesthetic and surgical treatments follicular hair density (defined as number of hairs per cm²),
such as mesotherapy, autologous hair graft, PRP, etc. percentage of anagen hair, percentage of telogen hair and den-
In this case, the parameters measured are hair growth sity of terminal and vellus hair (defined as the number of hairs
(defined as the length of hair grown per two days or more), per cm²) (6).
A few years ago, the only available machines were the

High-Frequency Ultrasound very expensive ones which did not allow the physicians and
Imaging of the Skin researchers to integrate it in their pre and post procedure eval-
uation. Nowadays, there are the portable, small and wireless
High-frequency ultrasound (HFUS) imaging is a non-invasive, technologies at a very affordable price which makes ultra-
safe and painless form of non-ionizing acoustic energy that sound increasingly a “must have” item in the aesthetic medi-
uses high-frequency sound waves more than 14 MHz to per- cine offices, particularly for the prevention and treatment of
form real-time skin imaging (7). As a rule, by increasing the the vascular complications in soft tissue fillers.
frequency, the resolution increases while the penetration depth
decreases. The best frequency for evaluation of the skin struc-
tures is around 20 however the most frequent one is between
14 to 22 MHz. The ultra high-frequency ultrasound imaging In Vivo Reflectance Confocal Microscopy
uses the frequencies more than 30 MHz (Figure 6.4). Another emerging imaging technique is reflectance confocal
There are many applications of high-frequency ultrasound microscopy (RCM), which provides real-time, high-resolution
in cosmetic dermatology (8): images of the skin at a cellular level (1 µm). RCM uses a laser
beam of 830 nm to scan the skin and capture images of individual
1. Facial mapping of skin ultrasound parameters in dif- skin cells and their structures. This non-invasive technique is par-
ferent age groups and gender (9) ticularly useful in diagnosing and monitoring skin cancers, as it
2. The effects of the cosmetic products on the skin allows for the visualization of cellular abnormalities without the
quality, thickness and density (10) need for invasive biopsies. The first publication was in 1996 on a
prototype which demonstrated the hydration of the stratum cor-
3. The effects of the oral supplementations on the skin
neum after application of propylene glycol or immersing the hand
thickness (11, 12)
in the water (26). Later, many researchers used this non-invasive
4. Evaluation of the skin aging grade by measuring the and high-resolution method to demonstrate the effect of the cos-
SLEB (subepidermal low echogenic band) induced metic products or injectables as well as the laser treatments.
by both the cumulative effect of ultraviolet (UV) The indications of the in vivo RCM in cosmetology and aes-
radiation and chronological aging (13–15) thetic dermatology are:
5. Tissue effect and the safety of the dermal fillers (16–
20) (Figure 6.5) 1. Effects of the cosmetic products on the stratum cor-
6. Miscellaneous: cellulite (21–23), tattoo reactions neum, dermo-epidermal junction and superficial
(24), hypertrophic scars (8) and acne vulgaris (25) dermis (27)
FIGURE 6.4 Relation between the frequency and the penetration depth of the ultrasound probes in dermatology.
FIGURE 6.5 High-frequency ultrasound pattern regarding different fillers: (A) hyaluronic acid; (B) lipofilling; (C) PLLA or poly lactic acid;
(D) calcium hydroxyapatite, the filler induces a posterior acoustic shadow. ([A] from Ref. 16 with permission; [B–D] from Ref. 19 with permission.)
FIGURE 6.6 (Left) Demodex is observable in almost all sebaceous canals before the treatment. (Right) Two months’ treatment with topical
Ivermectine produced a parasite clearance in sebaceous canals. (Courtesy of Philippe Humbert, CERT, Besançon, France.)
2. Follow-up the pigmentary lesions such as melasma,

post inflammatory hyperpigmentation (28) Optical Coherence Tomography (OCT)
3. Follow-up of the tattoo removal (29) Furthermore, optical coherence tomography (OCT) is a
4. Follow-up of the treatment of rosacea (30) (Figure 6.6) non-invasive optical three-dimensional (3D) morphological
imaging technique that uses near infrared light (1300 nm)

waves to create cross-sectional images of the skin (31). It Line Field Confocal Optical Coherence
provides detailed information about the skin’s layers, thick- Tomography (LC-OCT)
ness and structural changes, making it valuable in diagnosing
and monitoring various skin conditions, including psoriasis, Nowadays, LC-OCT (DEEPLIVE®, DAMAE Medical, France)
eczema and skin tumors. The advantage of this method com- has proven invaluable for diagnosing and monitoring a wide
pared to RCM is the possibility to have the vertical section of range of skin conditions in dermatology, including but not limited
the skin as well as the deeper penetration till around 1.5 mm to melanoma, basal cell carcinoma, squamous cell carcinoma,
beneath the skin surface (Figure 6.7). The disadvantage is the psoriasis, eczema, acne and rosacea. The ability to visualize
lower resolution of 7.5 µm (31). cellular structures, DEJ undulation, melanine content, collagen
With OCT, there is the possibility to measure the skin fibers and blood vessels in real time empowers clinicians to make
roughness before and after skin abrasion or skin repair by cos- accurate and timely diagnoses, facilitating the early detection
metic creams (Figure 6.8). and treatment of potentially serious skin disorders as well as the
FIGURE 6.7 Serial imaging with OCT after one injection of a hyaluronic acid based filler (ART FILLER Universal, FILLMED Laboratories
France). The increased undulation of the DEJ is clearly observable after 6 months (D180). (Courtesy of CPCAD Research Center, Nice, France.)
FIGURE 6.8 OCT 3D imaging before and after six strippings. The biometrological measures indicated that all roughness parameters decreased
significantly. (Courtesy of Vivosight® [Michelson Diagnostics Ltd. Kent, England], CERT, Besançon, France.)
normal conditions and the effect of the antiaging procedures on images reveal a structural organization down to about 0.5 mm
skin aging cellular signs. As technology continues to advance of depth (Figure 6.9). The study of Pedrazzani et al. in 2020
and LC-OCT systems become more accessible, the integration of showed that the measures of superficial papillary dermis with
this imaging modality into routine clinical practice is expected LC-OCT is quite close to the histopathological measures of
to further enhance the standard of skin care, benefiting both this layer (33).
patients and healthcare providers alike. In cosmetology and aesthetic dermatology, LC-OCT pro-
With a resolution of 1 μm, LC-OCT is more accurate than vides a precise possibility to measure the thickness of the dif-
standard optical coherence tomography (OCT) and presents an ferent skin layers, evaluation of the morphology and size of
ideal resolution for nuclei segmentation (32). LC-OCT allows the skin cells (keratinocytes), quantity of the melanin content,
real-time analysis with axial and lateral resolution of 2 μm measurement of the DEJ undulation and elastin fibers density
at an optical wavelength centered at 1300 nm (33). Obtained and orientation (Figure 6.10).
FIGURE 6.9 Dual-mode LC-OCT for ultra high-resolution vertical and horizontal section imaging of human skin in vivo. (Courtesy of DAMAE
Medical Scientific Department.)
FIGURE 6.10 (a) 3D thickness of skin layers and 3D DEJ undulation; (b) precise measures of stratum corneum, stratum spinosum and DEJ undulation
level; (c) precise measurement of keratinocyte diameter and morphology; (d) melanin content of epidermis around the dermal papillae; (e) fiber density
and fiber orientation in dermis. (Courtesy of DAMAE Medical Scientific Department.)
15. Gniadecka M, Gniadecki R, Serup J, et al. Ultrasound

Conclusion structure and digital image analysis of the subepider-
mal low echogenic band in aged human skin: Diurnal
Today, imaging technologies provide opportunities to per- changes and interindividual variability. J Invest Dermatol.
form the most precise diagnosis as well as selecting the most 1994;102(3):362–5.
adapted treatment procedure for preventing or treating the 16. Micheels P, Besse S, Sarazin D, et al. Ultrasound and histo-
signs of skin aging. In addition, it is a suitable way to record logic examination after subcutaneous injection of two volu-
the effect of the treatment modalities in the patient medical mizing hyaluronic acid fillers: A preliminary study. Plast
profile. Unfortunately, the most precise technologies are more Reconstr Surg Glob Open. 2017;5(2):e1222.
expensive, and they are not available for the daily activity of 17. Trevidic P, Andre P, Benadiba L, et al. Objective 18-month
the aesthetic doctors but the companies are trying to deliver comparison of the tolerability of 2 dermal fillers formulated
the more affordable models in the near future. with tri-hyal technology. Plast Reconstr Surg Glob Open.
2020;8(12):e3274.
18. Pérez-Pérez L, García-Gavín J, Wortsman X, et al.
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7
Sensitive Skin
New Findings Yield New Insights
Miranda A. Farage and Howard I. Maibach
have hindered a better understanding of this condition. It is typi-

Introduction cally self-diagnosed (8). Patients may interpret an underlying
dermatological condition as well as any reaction to product use
The goal of product testing is to ensure that consumer products as sensitive skin (9). There are also some psychological disorders
are free of irritant potential and to prevent unexpected con- characterized by similar symptoms (e.g., cosmetic intolerance
sumer reactions to the product once it reaches the marketplace. syndrome, dermatological non-disease) (10). Many people who
It is not uncommon, nonetheless, for post-marketing surveil- profess sensitive skin do not predictably experience visible signs
lance efforts to receive reports of sensory perceptions not pre- of the sensations reported, whereas some who describe them-
dicted by even the most robust methodology (1). These sensory selves as non-sensitive react strongly to tests of objective irritation
perceptions, though often transient and not accompanied by (11). The diversity of methodology approaches employed in sen-
a visual dermatological response in rigorous experimental sitive-skin research has also contributed to interpretive difficul-
testing, strongly influence consumer product preference (1). ties. Further, much of the research to date has been published in
In fact, 78% of consumers who profess sensitive skin report cosmetic journals that are inaccessible through major databases
avoiding some products because of unpleasant sensory effects and may be ignored by leading dermatological publications (5).
associated with their use (2). Irritant testing reveals profound interpersonal variability in
Unpleasant and subjective sensory effects, often unaccom- individual response to specific irritants (12, 13), even among
panied by objective physical signs, define a controversial and chemicals with similar modes of action (14). Some have
still evolving dermatological condition known as sensitive skin. reported sizeable variation within the same individual at dif-
Consumer reports of sensitive skin are typically self-diagnosed ferent anatomic sites (13), and even at the same anatomical site
and may be increasing (3). The concept of sensitive skin arose in on symmetric limbs (15).
the 1970s with the observation that despite the fact that previous The etiology of sensitive skin is unknown, but the disorder
safety evaluations had found no evidence of toxicity, some patients is believed to be the product of multiple etiologies with mul-
reported stinging sensations upon using a particular sunscreen tiple components, including deficiencies in barrier function,
that contained a derivative of P-aminobenzoic acid (4). Growing neurosensory dysfunction, compound-specific irritancy, and
consumer awareness of the potential for irritation from common cultural influences (16).
products fueled a huge increase in products marketed for the sup- Deficiencies in barrier function have been shown to be a criti-
posedly rare individual with susceptibility to components of every- cal component of skin discomfort (17). Increased permeability
day products, particularly since no requirement for proof of safety is believed to be the result of a functional compromise of barrier
and efficacy for such products has existed (5). The initial concep- function in the sensitive-skin patient (18). Lipid content of the
tualization of sensitive skin as a minority complaint has not been stratum corneum has been shown to be a more accurate predic-
borne out by epidemiological surveys, which consistently find a tor of skin permeability than stratum corneum thickness or cell
high prevalence of sensitive skin across the world (Table 7.1). number (13). The permeability barrier in the stratum corneum
Sensitive skin syndrome (SSS) is a term whose definition requires the presence of well-organized intracellular lipids (8,
continues to be refined and sometimes described as hyper- 17) and depends highly on lipid composition (13). Increased neu-
active and hyper-sensitive skin conditions. SSS is now gener- tral lipids and decreased sphingolipids are associated with supe-
ally agreed to describe unpleasant subjective sensory reactions rior barrier properties (13). A weak barrier inadequately protects
(such as prickling, burning, tingling, or pain) in response to nerve endings and facilitates access to antigen presenting cells, a
common external factors (such as ultraviolet light, heat, cold, mechanism which would support an association with atopic con-
wind, cosmetics, cleaning products, etc.) and intrinsic stress- ditions (17). Irritation results from the abnormal penetration in
ors (such as stress or hormones) (6, 7). Sensory effects are only skin of potentially irritating substances and a resulting decrease
occasionally accompanied by erythema or other demonstrable in the skin tolerance threshold (8). Alterations in barrier func-
irritation or immunological responses (6). tion in sensitive-skin patients have been observed (19, 20).
Although sensitive skin is now generally accepted as a real Alterations of baseline capacitance values imply barrier impair-
physiological disorder, there is still no consensus regarding its ment and support the view that hyperreactivity to water-soluble
etiology, classification, or criteria for diagnosis. Several issues
56 DOI: 10.1201/b22897-7
Sensitive Skin 57
TABLE 7.1
Prevalence of Sensitive-Skin Perception in Various Geographies
Percentage of people who
Population(s) studied* Population characteristics Definition of sensitive skin claimed sensitive skin Reference(s)
France (2000) 319 women, conducted by Cutaneous discomfort in the 90% (23% very sensitive skin) 4
interviews absence of clinical and
histological evidence of skin
lesions
France (2005) 1006 men and women, Sensitive skin 59% women, 44% men 25
identified by questionnaire
France (2006) 8522 men and women, Sensitive skin 61% women, 32% men 26
identified by questionnaire
France (2008) 1004 men and women, Sensitive scalp 44.2% (47.4% women, 40.8% 27
opinion poll survey men)
France (2008) 18 women, identified by Sensitive skin 50% (facial skin, specifically) 28
questionnaire
France (2008) 400 identified by Sensitive skin 85% (facial skin, specifically) 6
questionnaire
Germany (2001) 420 men and women Sensitive skin 75% (48% severe) 29
England (2001) 3300 men and women, Intolerance to cosmetics and 51.4% men (5.8% very sensitive 30
conducted by mailed toiletries, including both skin)
questionnaire sensory and visible signs 38.2% women (10% very
sensitive skin)
Italy (2005) 1870 women Sensitive skin 56.50% 31
Greece (2008) 25 women, identified by Sensitive skin 64% 32
questionnaire
Greece (2008) 25 women with atopic Sensitive skin 100% 32
dermatitis
USA (San Francisco) 800 women, conducted by Sensitive facial skin 52% 2
(2002) telephone interview
USA (Cincinnati) (2009) 1039 men and women Sensitive skin 68.4% reported some degree of 3
surveyed by questionnaire sensitivity (“slight”–“very”)
(69.0% women, 64.4% men)
USA (Cincinnati) (2006) 29 women with light Sensitive skin 83% reported some degree of 33
incontinence sensitivity (“slight”–“very”)
USA (2011) 994 subjects by phone survey Rate their skin as: “very 44.6% reported “very sensitive” 34
(495 men and 499 women) sensitive,” “sensitive,” or “sensitive” (38.2% men,
“slightly sensitive,” or “not 50.9% women)
sensitive at all”
USA (2013) primarily 89 women by questionnaire Sensitive skin 77.5% reported some degree of 35
rural southern states sensitivity (“slight”–“very”)
Japan, USA, Europe 15 000 men and women, People whose skin reacts to 50% women (25% very sensitive 36
(1992) conducted by questionnaire particular insults more than skin) 30% men
the majority of people
China (2012) 408 women surveyed by Sensitive skin 23% 37
questionnaire
China (urban dwellers) 9154 surveyed by Sensitive skin 13% (8.62% men, 15.93% 38
(2012)* questionnaire (3931 men and women)
5223 women)
Mexico (2013) 246 subjects (78 men and 168 Sensitive skin 36% 39
women)
Dermatologist opinion
survey
USA (2013) 300 dermatologists surveyed Sensitive facial skin 58.3% have noticed an increase in 40
by email questionnaire male patients reporting sensitive
facial skin over the past 5 years
Europe (2013) 1531 dermatologists surveyed Sensitive facial skin 82% have noticed an increase in 40
by questionnaire male patients reporting sensitive
facial skin over the past 5 years
Japan (2011) 1500 subjects (723 men and Sensitive facial skin 52.8% men and 56% women 41
777 women) surveyed by answered have sensitive skin
questionnaire
(Continued)
TABLE 7.1 (Continued)

Prevalence of Sensitive-Skin Perception in Various Geographies
Percentage of people who
Population(s) studied* Population characteristics Definition of sensitive skin claimed sensitive skin Reference(s)
Russia (2014*) 1500 Total men and women Sensitive facial skin 25.4% men and 50.1% women 42
surveyed answered as having “rather
sensitive or very sensitive skin)
Brazil (2014*) 1022 Total men and women Sensitive facial skin 22.3% men and 45.7% women 42
surveyed answered as having “rather
sensitive or very sensitive skin)
India (2019*) 3012 total men and women Sensitive skin 27.9% men and 36.7% women 43
surveyed by interview having “sensitive skin or very
sensitive skin”
* Year of publication, not year of study.
irritants results from increased absorption (21). A derangement another and has not correlated well with evaluation of objec-
of intercellular lipids, specifically, was also associated with a tive signs (46).
decline in barrier function in sensitive skin (22). The pain sensa-
tions, which are the hallmark of the disorder, also imply possible
integration dysfunctions in the central nervous system. Cho et al.
(23) found that individuals were classified into sensitive skin and
Factors in Skin Sensitivity
non-sensitive skin based on a lactic acid sting test performed on Numerous potential host factors (Table 7.2 undoubtedly play a
the face. There were no differences in transepidermal water loss role in experimental variability observed in sensitive skin. To
(TEWL) and erythema index values between the two groups. date, no constitutional factors have been identified (24).
However, the mean value of the quantity of stratum corneum
ceramides on the face was significantly lower in the sensitive
skin group compared to the non-sensitive group.
Gender
The pain and other unpleasant sensations that are the hall- Sensitive skin is self-reported far more often in women than
mark of sensitive skin imply a likely relationship to dysfunc- in men (Table 7.1). There is biological plausibility for greater
tions in the central nervous system, possibly involving several sensitivity, as thickness of the epidermis was observed to be
neuromediators and sensory receptors (24). Of the two studies greater in males than in females (p < 0.0001) (47), and hor-
reviewed that did evaluate the relationship between neurosen- monal differences, which may produce increased inflamma-
sory responses and objective clinical irritation and included only tory sensitivity in females, have also been demonstrated (15,
subjects with demonstrated sensory sensitivity, both showed a 48). Irritant testing, however, generally finds no differences
correlation between sensory and objective signs (19, 20). In a (13). One study, though, found among 1039 subjects a 68.4%
study regarding sensitivity to facial tissue which did not exclude prevalence of self-reported sensitive skin, with no difference
non-sensitive individuals, sensory effects were demonstrated to
be the most reliable measure of product differences (19, 20).
Although no predictive value was demonstrated for any indi- TABLE 7.2
vidual sensitivity when subjects were tested with a seven-irri- Possible Contributors to Sensitive Skin
tant panel, a weak association between tests was demonstrated
Factor Reference(s)
by statistical analysis of binomial probability (14). However,
studies which evaluated the association of barrier function and Female sex 30
Hormonal status 29,49
sensitivity have yielded arguably the most conclusive results. Cultural expectations in technologically advanced 30, 51,52
A high baseline TEWL was associated with increased suscep- countries 44, 51, 52
tibility to numerous cutaneous irritants by numerous studies Fair skin which is susceptible to sunburn 53–55
and a variety of assessment methods (15). Susceptibility to blushing and/or flushing 8, 56, 57
Most methods focused on objective assessment of physical Skin pigmentation 50
effects to skin rather than the sensory effects reported (44), and Thin stratum corneum 8, 58
Decreased hydration of stratum corneum 53
few reports have quantified sensory effects or correlate sen-
Disruption of stratum corneum 59
sory effects to degree of irritation. Most testing has included Increased epidermal innervations 21, 60–64
few subjects, and few have restricted subjects to those with Increased sweat glands 15
demonstrated sensitivity (45). Few have attempted to evaluate Increase neutral lipids and decreased sphingolipids 65
the influence of endogenous hormones or lifestyle factors. Decreased lipids
Ultimately, traditional irritant-testing methodologies High-baseline TEWL
have not proven to be good predictors of consumer response Atopy
(1). Response to one irritant does not predict sensitivity to Abbreviation: TEWL, transepidermal water loss.
Sensitive Skin 59
between men and women (3). It may be that with increased data according to age (66). Those over 50 were more likely
marketing of products for sensitive skin in men it has become to claim sensitive skin than younger adults and more likely
more cultural acceptable for males to define themselves as to perceive genital skin (to the exclusion of other body sites) to
having sensitive skin. be more sensitive (66). Older adults also stated that their skin
had become more sensitive over time (46%) (66). The turnover
rate of the stratum corneum has been reported as longer in
Age
aged skin (50), which may contribute to increased sensitivity.
The physiological changes that occur as skin ages would pre- However, in a large Italian study that performed lactic acid
dict an increased susceptibility to irritants (66). Existing stud- sting tests on more than 100 elderly subjects, the intensity of
ies, however, are ambiguous with regard to the influence of the stinging response was inversely proportional to age (31).
age on skin sensitivity. Clinical assessment of the erythema-
tous response to irritants in older people suggest that suscep-
Ethnicity
tibility generally decreases with age (66). However, objective
signs of irritation often show little correlation with the inten- There are pronounced differences in skin structure depending
sity of subjective complaints (66). A study of sensory percep- on skin type (Table 7.3), and racial differences, with regard
tions of sensitive skin conducted on 1029 individuals in Ohio to skin susceptibility to irritants, are among the fundamental
stratified subjects into four age groups (subjects under 30, in questions in dermatotoxicology (45). Two large epidemiologi-
their 30s, in their 40s, and over 50), and evaluated subjective cal studies reported no observed racial differences in reporting
TABLE 7.3
Comparison of Racial Differences in Functional Skin Properties
Skin property Types Racial differences Reference(s)
Permeability In vitro penetration of fluocinolone acetonide Lower in Blacks than in Caucasians 67
In vitro penetration of water No differences 67,68
Topical application of anesthetic mixture Less efficacy in Blacks than in Caucasians 69
In vivo penetration of C-labeled dipyrithione Lower in Blacks (34%) than in Caucasians 70
Methyl nicotinate-induced vasodilation Time-to-peak response equal 71
Slower in Blacks 72
TEWL Baseline TEWL (in vitro) Higher in Blacks 73
Higher in Blacks (in vitro) 73
TEWL in response to SLS irritation (in vivo) Higher in Blacks and Hispanics 58
Baseline TEWL (in vivo) Blacks > Caucasians > Asians 74
Return to baseline TEWL after tape stripping Blacks faster than Whites 75
Reactivity to SLS (measured by TEWL) Higher in Blacks than Caucasians 73
Skin irritant reactivity Reactivity to dichlorethylsulfide (1%) Lower in Blacks (measured by erythema, 15% 76
versus 58%) than Caucasians
Reactivity to o-chlorobenzylidene malonitrile Lower, longer time to response in Blacks than 77
Caucasians
Reactivity to dinitrochlorobenzene Lower in Blacks, but trend towards equalization 78
after removal of stratum corneum than
Caucasians
Reactivity to octanoic acid, 20% SLS, 100% Asians more reactive than Caucasians (react more 79
decanol, and 10% acetic acid quickly)
Stinging response Stinging response Lower in Blacks than Whites 80
Equal in Blacks and Whites 81
Higher in Asians than Whites 53,82
Skin transparency UV protection factor of stratum corneum Higher in Blacks (about 50% higher) than in 83
Caucasians
UVB transmission in stratum corneum Lower in Blacks (about 50% lower) 83
Spectral emittance Lower in Blacks (above 300 nm: 2–3-fold) 84
UV protection factor of epidermis Higher in Blacks (4-fold) 83
UVA transmission through epidermis Lower in Blacks (almost 4-fold) 83
UVB transmission through epidermis Lower in Blacks (4-fold) 83
Contribution of malpighian layer Black skin: twice as effective in absorbing UVB 83
as white skin
Photoprotection of Skin extensibility on dorsal (sun exposed) and Black skin maintains extensibility on sun- 85
epidermis volar (sun-protected) forearms exposed sites, but Hispanic skin extensibility is
reduced on sun-exposed sites
(Continued)

Comparison of Racial Differences in Functional Skin Properties
Skin property Types Racial differences Reference(s)
Consequence of Elastic recovery Black skin maintains recovery on sun-exposed 85
photoaging sites, white and Hispanic skins reduced
Drying Higher in Caucasian and Asians than in Hispanics 86
and Blacks
Hypertrophic scarring Higher in Asians than Caucasians 87
Response to insult Pigmented dermatoses Higher in Asians than Caucasians 87, 88
Wrinkling Average onset is 10 years later in Asians than 88
Caucasians
Wrinkling Average onset 20 years later in Blacks than 89
Caucasians
Thermal tolerance Blacks have a lower threshold than Whites 90
Somatosensory function Elastic recovery (tested on the cheek) 1.5 times greater in black as compared with white 91,92
subjects
Abbreviations: SLS, sodium lauryl sulfate; TEWL, transepidermal water loss; UV, ultraviolet; UVA, ultraviolet band A; UVB, ultraviolet band B.
product sensitivity (2, 30). Most testing, however, has focused were more likely to report sensitivity in the genital area than
on Caucasian females (45). other groups (p = 0.0008) (3).
Differences have been observed in sensory perceptions, A study of 800 women in San Francisco enrolled 200 sub-
although substantive conclusions are hard to provide. Asians jects in each of four ethnic groups to interview by phone and
have been reported to complain of unpleasant sensory responses found no significant difference in overall prevalence between
more often than Caucasians, supported by the observation that ethnic groups studied. Euro-Americans, however, were found
a higher incidence of dropouts in a Japanese clinical study to have a relatively higher susceptibility to wind than other
withdrew because of adverse skin effects as compared with ethnic groups, Asians had significantly higher sensitivity to
those in Caucasian studies (53). There have also been reports spicy food, and Hispanics had relatively less reactivity to alco-
of an increased sensory response, as well as speed of response hol (2).
in Asian subjects versus Caucasian in sensory testing (53).
Another study, however, found fair-skinned subjects prone
Cultural Factors
to sunburn had higher sensory responses to chemical probes
than those with darker skin tones (54). No racial differences in Cultural factors may play a role. Fastidious cleansing routines
innervation on an architectural or biochemical level have been (with douches, perfumes, medication, antifungal medica-
observed (14). tions, and contraceptives), which often precede irritation (48),
Studies of racial differences with regard to irritants have undoubtedly have some cultural component. Hygiene practices
yielded conflicting evidence. Although black skin was dem- are the most common cause of vulvar irritation (48).
onstrated to have greater potential for irritant susceptibility Confounding lifestyle factors should be considered with
than white skin (13), another study found Blacks to be less regard to some observed differences, as cultural practices may
reactive than Caucasians (12). Asians seemed to be more reac- produce widely different exposures to potential irritants (24).
tive than Caucasians in some studies and less in others, even For example, older women were found to be more likely to
within studies done under the same investigator and protocol report irritation due to incontinence products than younger
(45). Tristimulus colorimeter assessment of skin reflectance women, who were more likely to report irritation due to tam-
observed that skin pigmentation was inversely associated pons (66). Air conditioning is more likely to be reported as a
with susceptibility to irritation (15), supported by the finding trigger for sensitive skin in July than in March (25, 93). These
that irritant susceptibility to sodium lauryl sulfate (SLS) is findings are quite likely to be based on increased levels of
decreased after ultraviolet B (UVB) exposure (tanning) (15). exposure than on actual physiological differences.
Methyl nicotinate assessment of vasoactive response sug-
gests that there may be genuine racial differences in permea-
bility (72). Increased percutaneous absorption of benzoic acid,
Environmental Factors
caffeine, and acetylsalicylic acid was demonstrated in Asians A majority of sensitive-skin sufferers report unpleasant sensory
when compared with Caucasians, and decreased percutaneous responses to cold temperatures, wind, sun, pollution, and heat
absorption was observed in Blacks (53). (2, 8). An increased susceptibility to SLS was observed in the
More studies have observed that, while overall prevalence winter compared with the summer (15). Low temperatures and
of skin sensitivity is similar across skin types and ethnic humidity characteristic of winter cause lower water content in
groups, there are some observable differences with regard to the stratum corneum (15). Large-scale epidemiological testing
what triggers discomfort and how discomfort is experienced. in France conducted phone interviews of over 1000 people each
Caucasians report visual effects more than African Americans, in March and then in July and observed the frequency of sensi-
while African Americans are more likely to report sensory tive skin in women to be significantly higher in summer than in
effects (46). In addition, African Americans of both genders winter (71.2% in July versus 59.39% in March) (25).
Sensitive Skin 61
Numerous other host factors that could influence skin sen- vulva was less responsive to both than was the upper arm
sitivity include unusual occupational or leisure exposures to (100).
chemicals and home climate-control measures (46). Long- Nonkeratinized vulvar skin exhibits clearly increased per-
term or excessive use of personal-care products can also create meability related to the absence of keratin and loosely packed,
sensitivities (8). Daily topical use of corticosteroids has been less structured lipid barrier (11). In addition, the inner epithelia
demonstrated to produce fragile skin (8), and excessive use of are thinner, representing a shorter distance to penetrate (11).
topical medications has been demonstrated to be the source of Buccal tissue is often employed in a surrogate model for vulvar
up to 29% of vulvar dermatitis (94). Drug-induced sensitivity testing, as it has very similar structure and biochemistry (11).
is also possible, although no reports on that issue were uncov- Buccal skin has been demonstrated to be 10 times more per-
ered. Interestingly, the thickness of the epidermis in one study meable than keratinized skin (101).
was demonstrated to be inversely proportional to the number Although the vulvar area may be particularly susceptible
of years that the subject had smoked, with a p = 0.0001 (47). to cutaneous irritation (102), little objective published data
The specific methodologies and conditions involved in exists with regard to sensitive skin (98). Irritant reactions to
the testing of skin sensitivity introduce a significant amount feminine-care products have been reported (94) with a few
of variability into the published results; however, one study feminine products that contain chemicals known to be irritants
reveals that parameters of the testing can themselves induce in certain doses (103). However, the potential for heightened
sensitivity apart from that of the specific irritant employed. vulvar susceptibility to topical agents is not widely reported in
Sahlin et al. (95) evaluated the sting potential of the vehicle literature (11). The contribution to irritation by topical agents,
used in testing the adverse stinging reaction related to lactic though, is substantial (12) and often underestimated (48). In
acid application. The results showed that the ordinary oil- fact, 29% of patients with chronic vulvar irritation were dem-
in-water emulsion induced stinging in and of itself; use of a onstrated to have contact hypersensitivity, and 94% of those
water-in-oil emulsion created less discomfort. It was also were determined to have developed secondary sensitization
observed that decreasing the mineral oil content in the oil- to topical medications (94). Thus, reported sensitivity in the
in-water emulsion resulted in decrease in the degree of sting vulvar area may often be related to underlying contact hyper-
experienced (95). sensitivity because of excessive use of topical hygienic and
medicinal preparations.
Some studies have evaluated skin sensitivity in the vulvar
Anatomic Site
area with regard to sensory responses to consumer products
Differences in skin sensitivity between anatomical regions meant for the vulvar area. It was hypothesized that patients
have been observed. Analysis of structural differences found with erythema related to a previous genital infection may rep-
that stratum corneum density varies tremendously by anatomi- resent a population of sensitive subjects; however, no increase
cal site: palms and soles are the thickest, whereas the genital in sensory effects to exposure to feminine hygiene pads was
area is the thinnest (50). The face is the most common site of observed (98).
skin sensitivity. In a study of 1039 men and women, 77.3% In a similar population, however, in which observed ery-
reported facial sensitivity, compared with 60.7% for the body, thema was evaluated against perceived sensory effects, women
and 56.2% specifically with regard to genital skin (3). Saint- who perceived themselves as particularly susceptible to facial
Martory also found the face to be the most commonly reported erythema were significantly more likely to have medically
site of sensitivity, with hands, scalp, feet, neck, torso, and back diagnosed vulvar erythema, a potential indicator of an under-
also reported, in order of frequency (6). The nasolabial fold lying connected body and biological origin (98).
has been reported to be the most sensitive region (14) of the Interestingly, a separate study evaluated perceptions of sen-
facial area, followed by the malar eminence (14), chin, fore- sitive skin in women with urinary incontinence, expecting to
head, and upper lip (6). Misery et al. (96) found 44.22% of sen- observe an increased sensitivity of genital skin (104). Increased
sitive-skin subjects questioned experienced sensitivity of the sensitivity specific to the genital area was not observed, but
scalp. Factors contributing to facial sensitivity are likely the incontinent women were significantly more likely to assess
number of products used on the face (particularly in women), a themselves as having overall skin sensitivity than continent
thinner barrier in facial skin, and a plentitude of nerve endings subjects (p = 0.014: 86.2% in incontinent subjects versus
as well (10). Individual susceptibility appears to be dependent 68.3% in controls) (104).
on anatomical site (97). Most studies have been conducted in
facial skin because of its sensitivity. Stinging sensations, par-
ticularly, are readily elicited on facial skin (98). Further, the
Sensory Effects and Objective Signs
face is readily accessible for both visual (99) and biophysical
assessments (21). It was observed early on that some subjects report a greater
The vulva is an area of particular interest since it is formed incidence of adverse reactions to certain products because of
partially from embryonic endoderm; it differs from skin at higher sensitivity (2, 30). Some individuals possess exagger-
exposed body sites (11). Differences in irritation seem to be ated sensitivity to specific individual irritants (54). Despite
dependent on relative permeability of the irritant in vulvar the fact, however, that studies have demonstrated that sensi-
skin; vulvar skin is significantly more reactive than forearm tive-skin patients are capable of distinguishing products on
skin to benzalkonium chloride and maleic acid (49) but less the basis of blinded sensory endpoints (14, 44), a clinically
reactive than the forearm to SLS (11). When both venous satisfactory description of observed sensitivities remains out
blood and menses were evaluated for irritant potential, the of reach.
Tantalizing clues to the underlying mechanisms of sensitive erythema is the end result of a complex, multistep physiologi-
skin, however, continue to be reported. If deficits in barrier cal process. Numerous underlying processes (e.g., changes in
function do play a role in skin sensitivity, regular use of mois- blood flow, moisture content, pH) would be expected to occur
turizer should improve sensitivity; patients who completed four before the appearance of visible external changes (1). A goal
daily treatments with moisturizer improved (9). Evaluation of our research has been to increase the ability to predict and
of the potential role of the stratum corneum in sensitive skin quantify these subjective consumer responses. Our approach
using corneosurfametry demonstrated that subjects with dem- has been three-fold: to exaggerate testing conditions to elicit
onstrated sensitivity to detergents had an increased reactiv- corroborating physical findings, to increase the sensitivity of
ity to tested products as compared with the control group. It assessment of physical findings, and to find a way to quantify
may be a specific subgroup of sensitive skin with some sort sensory endpoints (1).
of defect in the stratum corneum that caused weakened resis-
tance to surfactants (19).
Exaggeration of Test Conditions
Local anesthetics block response in lactic acid sting tests;
stingers respond more vigorously to vasodilators (10). An One study evaluated four versions of facial tissues, with and
Italian study compared self-reports of sensitivity with response without coating, with repeated wiping to accentuate irritation
in the lactic acid test as follows: stingers were found at very (103). Affected skin had been compromised by tape strip-
similar prevalence to self-reported sensitivity (56.9% of ping prior to wiping protocol initiation. Erythema as well as
women perceived skin as sensitive, 54.3% revealed to be sting- dryness were evaluated daily by trained graders. In addition,
ers). In addition, those who believe skin to be sensitive were panelists were interviewed about specific aspects of product
revealed to be more likely to be stingers (59%) than among preferences. Statistical analysis revealed that the panelists’
non-stingers (48.9%) (31). subjective product preferences were more consistent in distin-
Simion et al., by exaggerated arm-washing with synthetic guishing between the test products than were either erythema
detergent bars, observed signs that correlated statistically with or dryness.
sensory perceptions (dryness, tightness, and itching). In addi- A second method of accentuating test conditions, devel-
tion, consumers were able to reproducibly distinguish between oped in our laboratories specifically for testing paper such as
test products purely on the basis of sensory effects (105). catamenial products, has proven very effective at accentuating
Another study evaluated specific biophysical parameters irritant response to inherently mild products. The behind-the-
in 32 subjects medically diagnosed with sensitive skin in knee (BTK) protocol uses the popliteal fossa as a test site and
parallel with a non-sensitive skin control group. Patch test- adds a relevant mechanical friction component to old testing
ing, skin hydration, sebum production, alkali resistance test, (106). BTK testing consists of a test product placed behind the
lactic acid sting test, methyl nicotinate 0.5%, methacholine knee and held securely by a knee band. Levels of irritation
chloride 1:1000, pH, dermographism, and measurement produced in BTK testing are consistently higher than those
of total and specific Ig were performed (20). Patch testing achieved with standard patch testing and have proven to be
found that patients with sensitive skin were 10 times more consistently reproducible (106). BTK testing, in conjunction
likely to respond to allergens in the European standard with the other two approaches explained next, has proven use-
series (p < 0.01) and three times more likely to respond to ful in the development of potentially valuable protocols for
cosmetic allergens (p < 0.01) than those without sensitive sensitive-skin testing.
skin. Sensitive subjects also had significantly less sebum
production (p < 0.01) and dryer skin (p < 0.05). Sensitive
patients had a four-fold risk of a decrease of alkali resistance
Quantifying Sensory Responses
(p < 0.05). A study similar to the previously mentioned facial tissue
Vascular reactions to methyl nicotinate and methacholine study tested feminine hygiene products according to four
chloride in sensitive-skin patients were observed to be char- combinations of test conditions (wet/dry, intact/compro-
acterized by a significant hyperreaction of skin blood ves- mised skin). Products tested were inherently non-irritating
sels, with a more intense erythema after methyl nicotinate and were tested in parallel in arm patches and BTK. In
application (20). The risk of an intense vascular reaction to addition, the study evaluated observed erythema grading
methyl nicotinate was 75 times higher in sensitive patients against a patient log of sensory effects. Although no dif-
than in non-sensitive subjects, and nearly one-third of sensi- ferences were observed between any combinations tested, a
tive-skin subjects experienced an abnormal vascular reaction significant correlation of reported sensory discomfort with
(skin blanching) after application of methacholine chloride. mean irritant scores was observed. Skin sites where patients
A strong association of sensitivity with fair skin was also experienced burning, itching, or sticking had consistently
observed. This may relate to well-established differences in higher mean irritant scores (107). Ultimately, eight sepa-
skin structure and permeability across different skin types. rate comparison studies were able to statistically associ-
ate perceived sensory effects with an increase in irritant
scores (106).
Companion papers that utilized only BTK methodology
Sensitive Skin: Zeroing in on Biological Origin
(108) but also evaluated patient diaries in conjunction with the
Part of the reason for the observed breakdown between sensory irritant testing observed correlation between sensory effects
effects and objective signs is the fact that an objective sign like and mean irritant scores as well (107).
Sensitive Skin 63
Increasing Sensitivity of Assessment tape, was applied to skin for 60 seconds and then removed.
of Physical Response Application of the tape to both healthy skin and compromised
skin was followed by extraction of different cytokines from
Several new methodologies were evaluated in the pursuit of an the Sebutape®, which were then quantified. Levels of IL-1a,
increased sensitivity of the evaluation of the physical response. IL-1RA, and IL-8 were evaluated. Compromised skin was
Visual grading of erythema has been relied on for a number associated significantly with increased IL-1a levels, increased
of years; trained graders achieve a high degree of reproduc- IL-8 levels, and increased IL-1RA:IL-1a ratio. This technique
ibility with no specialized equipment (109). A new approach in has not been substantially applied to the problem of sensitive
our laboratories, however, utilized cross-polarized light, which skin yet, but it shows potential (113).
allows visualization of the skin at a depth of 1 mm below the sur-
face (110). Testing was performed with SLS in a standard, 24-h
patch test on the upper arm, and with two different feminine
Links between Sensitive Skin and Immunology
hygiene products (identified as A and B) in the BTK. It had been Evidence for a link between atopy and sensitive skin has accu-
established previously that these two products differed in con- mulated. An assessment of 1039 individuals (83.6% female)
sumer preference, but no discernible difference had been found found that individuals who claimed overall to have sensitive
in objective measures of skin effects (44). With the minor irrita- skin were five times likely to have skin allergies confirmed by
tion produced the SLS patch on the upper arm, both unaided a doctor (p < 0.0001) and more than 3.5 times more likely to
visual scoring and subsurface visualization detected erythema have relatives with sensitive skin (65). In a study in older adults,
associated with irritation. With multiple, shorter exposures (2-h those who claimed sensitive skin had a higher frequency of
and 6-h) to lower concentrations of SLS, the subsurface visual- medically diagnosed skin allergies than younger people who
ization detected erythema earlier than unaided visual scoring. claimed sensitive skin (66). Loffler et al. (29) observed a link
Using the mild feminine hygiene products in BTK-enhanced between sensitive skin and nickel allergy.
visual scoring through subsurface visualization allowed the A study compared 25 Greek women with medically diag-
observation of significant differences in the irritation produced nosed atopic dermatitis with 25 healthy women (32). A sig-
by the two different products, thus establishing a potential link nificant association was found between the clinical diagnosis
between sensory effects and subclinical irritation. of atopic dermatitis and the self-diagnosis of sensitive skin
A second approach evaluated the potential for changes in (p < 0.001). All patients in the atopic dermatitis group
skin temperature related to inflammation to act as a subclinical described themselves as having sensitive skin to at least some
measure of skin irritation. Previous research has demonstrated degree, with 80% claiming either moderately or very sensitive.
a correlation between surface temperature measurements and By contrast, 64% of individuals in the control group described
inflammatory response (111). A high precision, handheld infra- their skin as sensitive to some degree, with only 16% claiming
red thermographic scanner makes it feasible to conveniently either very or moderately sensitive. Patients with atopic der-
measure local changes in skin temperature in situ (112). Two matitis were also significantly more likely to indicate a family
catamenial products were compared in a BTK protocol. Skin history of sensitive skin than were non-sensitive individuals
surface temperature was measured using an infrared thermo- (68%–24%, p = 0.004) 76% of atopic patients who claimed a
graphic scanner. Subjects were also asked to keep a diary of family history identified a parent as having sensitive skin.
skin discomfort experienced at test sites, specifically including Atopic individuals were significantly more likely to report
sticking, chafing, burning, itching, pain, edema, or any other genital sensitivity after contact with hygiene pads, although
issue. Skin temperature changes observed were closely asso- not more likely to experience sensitivity to genital cleans-
ciated with visual scores. In addition, the study incorporated ing products, fragrances, or antiperspirants (32). In addition,
diary-derived data on sensory effects experienced by panelists the study demonstrated a link between clinically diagnosed
as an additional endpoint. The diaries of subjective sensory atopic dermatitis and sensitive skin, with the frequency,
experiences over the course of the exposure made a clear dis- severity, and history of skin sensitivity in patients with atopic
tinction between the two test products that was consistent with dermatitis far more pronounced than in controls. This link
both visual scoring and skin temperatures. A significant t-dif- has substantial biological plausibility, as contact allergy and
ference was also observed between mean visual scores of those skin sensitivity are phenomena that share similar cytokine
who reported specific adverse sensations as compared with inductions (65).
those who did not report negative sensations. Skin temperature Of potential utility for large-scale screening in industry,
means were significantly higher for those who reported the post-market surveillance, and epidemiological testing, a rapid
adverse sensations rubbing and chafing (interestingly, burning algorithm containing only three questions has been developed
sensations were not associated with increase in skin surface to quickly identify atopic individuals (114). Testing indicated
temperature). Conditions in this protocol were optimized for the algorithm was capable of successfully categorizing indi-
using erythema as the primary endpoint; refining the protocol viduals as “atopic” and “non-atopic” with a 90% success rate
to optimize detection of differences in skin surface tempera- (45 out of 50 individuals in the test).
ture would be a logical next step. Skin surface temperatures
correlated well with visual signs of irritation; six of eight sen-
Insight into Neurogenic Causality
sory effects were associated with higher visual scores.
The commercially available technique and product, Sensitive skin is predominantly sensory in nature and thus
Sebutape® (CuDerm Corporation, Dallas, Texas), an absorbent ultimately a neurological disorder. Sensory differences
may be related to innervation (59, 115). Dermal nerve fibers only eight subjects (four with sensitive skin) and should be
extend throughout viable epidermis as free nerve endings, followed up in a larger population.
but the epidermal component of this network is still poorly
characterized (59). Epidermal nerve density variation could
explain the different sensitivity thresholds in various ana-
tomical sites (116). Hyperreactivity of the neural response of Conclusion: A Valid Syndrome
the skin is postulated to play a role. Possible mechanisms for
with Multiple Origins?
neural system hyperreactivity include nerve fibers; endothe-
lin receptors; burn, itch, and heat receptors; cold receptors; Sensitive skin syndrome though now largely recognized as
and neutrophins (24). genuine syndrome of physiological origin, is still a subjective
Neurogenic inflammation probably results from release of complaint with no consistent associations (29), no predictable
neurotransmitters such as substance P, calcitonin gene-related or classical visible signs of irritation, no immunologically ver-
peptide, and vasoactive intestinal peptide, which induce vaso- ifiable response, and no accepted and reproducible diagnostic
dilation and mast cell degranulation. Nonspecific inflamma- test (24). Although it is clear that specific individuals clearly
tion may also be associated with the release of interleukins have heightened sensitivity to different kinds of sensory and
(IL-1, IL-8, prostaglandin E2, prostaglandin F2, and tumor physical irritants, observed reactions are not predictive of
necrosis factor-a) (96). Other studies have evaluated what con- generalized sensitivity, and the relationship between observed
tribution neural dysfunction may play in the development of sensitivities is unclear (26, 44). Evidence suggests that sensi-
sensitive skin. tive skin may not be a single condition, but the product of
Functional magnetic resonance imaging, which measured multiple etiologies with multiple components. Therefore, the
cerebral activation associated with skin discomfort, was used condition may encompass different categories of subjects and
to evaluate neural reaction to application of lactic acid to the sensitivities based on different mechanisms (21). Multiple eti-
face in 18 women, with and without sensitive skin (28). Lactic ologies would not be farfetched, as the nervous system does
acid-induced skin discomfort resulted in increased activity in not act in isolation but is interdependent with both the immune
the primary sensorimotor cortex contralateral to the applica- system and the skin, sharing numerous cellular contacts as
tion site as well as in a bilateral frontoparietal network that well as the same language of cytokines and neurotransmitters.
included the parietal cortex, prefrontal areas around the supe- All three interact to affect cutaneous responses (20).
rior frontal sulcus, and the supplementary motor activity. In There is an urgent necessity to establish methodolo-
addition, in sensitive skin patients only, group activity spread gies with the capacity to accurately identify sensitive skin
into the ipsilateral primary sensorimotor cortex and the bilat- (5), independent of self-assessed reports (24). Methods are
eral periinsular secondary somatosensory area, a phenomenon needed that are capable of detecting very subtle skin benefits
which did not occur in the control group. Subjects with self- or potential for adverse effects. Testing has been done pri-
assessed sensitive skin were also observed to have significantly marily on normal subjects, bringing into question the need to
greater increases in neural activity than those without sensitive focus on examining populations that may be inherently more
skin, demonstrating an increase in neural activity specifically sensitive to irritant effects (11). Some studies did compare the
associated with sensitive skin. irritation potential of products between self-declared sensi-
Another study measured calibrated electrical stimula- tive skin to non-sensitive–skin subjects (118, 119). A sum-
tion of the skin, which stimulates sensory nerve fibers such mary of current methodologies used to identify sensitive skin
as the myelinated A fiber, A delta fiber, and unmyelinated is shown in Table 7.4.
c-fiber independently (117). In subjects with clinically docu- Subclinical irritation may be the key to understanding
mented sensitive skin (lactic acid sting test, cosmetic com- sensitive skin, as sensations elicited by product exposure
patibility tests) versus non-sensitive controls (all subjects are generally discerned long before observable differ-
male), nerve fibers were stimulated by three different current ences (105). One significant advance in the understanding
strengths, and capsaicin (0.075%) was applied to the zygo- of sensitive skin is the development of new, non-invasive
matic arch. Sensory perception was verbalized by the sub- techniques; for example, cross-polarized light-enhanced
ject and recorded. Baseline perception of current revealed no visualization, which has demonstrated good correlation
significant differences between sensitive and non-sensitive with sensory perceptions and the ability to measure sub-
subjects at either 2 kHz or 250 Hz, but at 5 Hz—a current clinical damage (110).
known to selectively stimulate the c-fibers of sensory nerves. An immediate need is to build on what is known with
Sensitive skin subjects displayed a significantly lower percep- improved techniques, carefully crafted protocols that evalu-
tion threshold. In addition, stimulation of the skin by capsa- ate appropriate exposures and study populations, and rigorous
icin, in non-sensitive subjects, had no effect on perception methodological and statistical procedures, bringing the study
of the 5-Hz current, whereas sensitive subjects displayed a of sensitive skin out of the realm of fairy tales and into the
long-lived increase in the sensory perception threshold (still realm of a genuine physiological disorder worthy of focused
in place at last time point of 60 minutes). These findings research. The challenge of the future is to unravel the biologi-
imply that sensory perception in sensitive subjects is easily cal link between subjective clinical signs and their physical
disturbed by weak stimulation, inducing a wide variability of sequelae as a means to develop appropriate diagnostic crite-
response compared with non-sensitive subjects, an effect that ria as well as to understand the etiologies of this still largely
appears to be c-fiber modulated. The study was conducted in multi-factorial syndrome.
Sensitive Skin 65
TABLE 7.4
Some Methodologies Used for Sensitive Skin
Sensory affect Physical effect
Methodology evaluated evaluated Relevant irritants Advantages Disadvantages
Lactic acid (9) Stinging None Cosmetics, other Sensitive for some Does not predict
personal preparations sensitivity to other
meant to be left on irritants
Capsaicin (24) Stinging None Cosmetics, other Sensitive, detection Does not predict
personal preparations threshold well sensitivity to other
meant to be left on correlated (inversely) to irritants
perception of sensitive
skin
Sodium lauryl Burning Erythema Industrial exposures, Cheap, quick, reliable Sensitivity to one irritant
sulfate (15) cleaning products assessment of not predictive of
individual susceptibility general sensitivity,
to specific irritant relationship to sensitive
skin in question
Cross-polarized None Subclinical erythema Any potential irritant Permits detection of Requires specialized
light (110) physical changes not equipment
apparent by standard
visual scoring,
noninvasive
Thermoscan None Temperature increases Any potential irritant Noninvasive, objective, Requires specialized
(112) resulting from quantitative equipment
inflammatory processes
related to skin injury
Sebutape None Measurement of Any potential irritant Noninvasive, objective, Requires training,
(113) cytokines produced by quantitative, potentially specialized equipment;
injured skin very sensitive utility for sensitive skin
still unassessed
Note: Lactic acid test is positive in 90% of women who claim sensitive skin.
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8
Organic Acids with Novel Functions
Hydroxy, Bionic, N-Acetylamino Acids,
N-Acylpeptide, and Creatine Derivatives
Ruey J. Yu and Eugene J. Van Scott
(2–5). AHAs such as glycolic acid and lactic acid are routinely
Introduction used in peel solutions by estheticians and dermatologists. In
dermatological office procedures they are used for topical
Organic acids cover a wide range of organic compounds hav- management and treatment of various skin conditions includ-
ing an acidic group such as carboxyl, sulfonyl, or phosphoryl, ing skin smoothing, acne, and skin changes associated with
which include retinoic acid, salicylic acid, benzoic acid, and its intrinsic and extrinsic aging (6–9). AHAs, on topical applica-
peroxide form, benzoyl peroxide. The present discussion will tion, have been shown to markedly increase biosynthesis of
focus on certain organic carboxylic acids and related deriva- hyaluronic acid and collagen in the papillary dermis, although
tives with unique cosmetic and dermatological effects on the the mechanism of action is unknown (5, 10).
skin. These acids are α-hydroxyacids (AHAs), β-hydroxyacids Polyhydroxy AHAs constitute one of the two major compo-
(BHAs), polyhydroxy acids (PHAs), aldobionic acids (ABAs), nents of hyaluronic acid, chondroitin sulfate, dermatan sulfate,
N-acetylamino acids (NAAs), N-acylpeptides (NAPs), and heparin, and heparan sulfate. In combination with numerous
creatine derivatives (CREs). cosmetic or pharmaceutical agents, hydroxyacids have been
Abnormal keratinization is a principal event associated with found to enhance desirable topical effects and also to reduce
a majority of dermatologic conditions including ichthyosis, or prevent side effects caused by topical agents. Because most
xerosis, eczema, psoriasis, and acne. As a result, we estimate hydroxyacids are nontoxic, natural, and physiological they are
that over 50% of all skin problems are due to or are associated used as primary or secondary ingredients in many cosmetic
with disturbed formation and shedding of the stratum corneum, and pharmaceutical products.
and in part attribute the cosmetic and therapeutic uses of AHAs NAAs and NAPs are derived from amino acids or peptides
on skin to their unique ability to modulate the process of kerati- by substitution at the amino group. N-acetyl-L-cysteine (NAC)
nization and normalize stratum corneum exfoliation. has been shown to be a potent antioxidant. We have found, for
Hydroxyacids and related acids of nonphenolic origin are a example, N-acetyl-L-proline, N-acetyl-L-glutamine, N-acetyl-
group of natural and physiological substances that have profound L-valyl-L-alaninamide, N-acetyl-L-tyrosyl-L-tyrosinamide, and
effects on keratinization and the synthesis of dermal compo- N-acetyl-L-tyrosyl-L-tyrosyl-L-tyrosinamide to be topically
nents. Many hydroxyacids and related acids occur in food, fruits effective for relieving itch and improving lesions associated with
such as sugar cane, tomato, oranges, lemons, grapes, apples, eczema and xerosis. We have also found that NAAs and NAPs
mangos, and body tissues. For many years, cosmetic chemists are effective for topical treatments of aging-related skin changes.
have used lactic acid along with other organic acids to adjust In this chapter we discuss the scientific basis for topical
pH, and citric acid as a chelating and antioxidant stabilizer in effects of certain organic acids in dermatological therapy and
topical formulations. In addition, lactic acid has been used as a in various cosmetic applications.
stabilizer in urea formulations for topical treatment of dry skin.
Creatine is N-methylguanidino acetic acid, which is known to
be a physiological source of energy for muscle movement or
exercise. We have recently discovered that creatine derivatives
Hydroxyacids: Nomenclature and Occurrence
such as N-acetyl creatine ethyl ester have immediate anti-pain
effect on topical administration or subcutaneous injection. Organic hydroxyacids of non-phenolic origin may be clas-
In 1974, the term AHA was first introduced to dermatology sified into the following four groups: AHAs, BHAs, PHAs,
when it was discovered that AHAs substantially improved the and ABAs. For group names, the spellings α-hydroxyacid and
severe hyperkeratotic conditions of ichthyosis (1). AHAs are β-hydroxyacid are preferred instead of α-hydroxy acid and
also beneficial for topical treatment of dry skin, dandruff, cal- β-hydroxy acid because α and β indicate the position of hydroxyl
luses, acne, keratoses, warts, wrinkles, photoaging skin, and group in the hydroxyacid molecule. In contrast, the spelling
for other cosmetic conditions and dermatological purposes polyhydroxy acid is preferred instead of poly-hydroxyacid or
DOI: 10.1201/b22897-8 69
poly-hydroxy acid because in the word, poly indicates many or Polycarboxy AHAs
multiple hydroxyl groups, not the position of hydroxyl group
in the acid (11). AHAS may consist of more than one carboxyl group, as
shown in Table 8.2. Malic acid, occurring in apples, is also
called apple acid, and tartaric acid, present in grapes, has been
called fruit acid in the past. Citric acid, occurring in oranges
α-Hydroxyacids and lemons, has one hydroxyl group and three carboxyl
groups. The α- or β-hydroxyacid refers to the position of a
AHAs are organic carboxylic acids having one hydroxyl group
hydroxyl group as related to a carboxyl group in the hydroxy-
attached directly to the α position of an aliphatic or alicyclic
acid. When a hydroxyacid has more than one carboxyl group
carbon atom, but not to a benzene or other aromatic ring. On
it can be an AHA and BHA at the same time. For example,
a broader scope, AHAs may include those molecules having
malic acid, tartaric acid, and citric acid can be both AHA
additional carboxyl groups (11). Glycolic acid, present in sugar
and BHA.
cane juice, is the smallest molecule of all the hydroxyacids, and
it is a major ingredient in most AHA products on the market.
All other AHAs may be considered derivatives or substituted
glycolic acid. The AHAs may be divided into three subgroups: β-Hydroxyacids
alkyl AHAs, aralkyl AHAs, and polycarboxyl AHAs.
BHAs are organic carboxylic acids having one hydroxyl group
attached to a carbon atom at the β position and are represented
Alkyl AHAs by β-hydroxybutanoic acid and tropic acid. β-hydroxybutanoic
acid, also known as β-hydroxybutyric acid, is excreted in
A radical attached to the α carbon of glycolic acid can be a
amounts as much as 30 grams per day in the urine of dia-
simple hydrocarbon called alkyl group. The smallest alkyl
betic subjects. Salicylic acid, 2-hydroxybenzoic acid, has both
group is a methyl group, and in this case, the AHA is lac-
hydroxyl and carboxyl groups directly attached to a benzene
tic acid (present in tomatoes). Representative alkyl AHAs are
listed in Table 8.1.
TABLE 8.2
Aralkyl AHAs Nomenclature and Occurrence of Polycarboxy α-Hydroxyacids
Systematic name
Aralkyl is an abbreviation of aryl plus alkyl. Aralkyl AHA is
Chemical structure Common name Occurrence
formed when a phenyl group is attached to an alkyl AHA, and
is represented by mandelic acid, benzilic acid, 3-phenyllactic 2-Hydroxypropane-1,3-dioic acid Tartronic acid
acid, and atrolactic acid. Mandelic acid has been used in com- HOOC CHOH COOH
bination as methenamine mandelate for oral administration to 2-Hydroxybutane-1,4-dioic acid Malic acid Apple
HOOC CH2 CHOH COOH
treat urinary tract infections.
2-Methyl-2-hydroxybutane- Citramalic acid
1,4-dioic acid
TABLE 8.1 HOOC CH2 C(CH3)OH COOH
2,3-Dihydroxybutane-1,4-dioic Tartaric acid Grape
Nomenclature and Occurrence of Glycolic Acid and Alkyl acid
α-Hydroxyacids HOOC CHOH CHOH COOH
Systematic name 3-Carboxy-3-hydroxypentane- Citric acid Orange
Chemical structure Common name Occurrence 1,5-dioic acid
C(OH)(COOH) (CH2COOH)2 Lemon
2-Hydroxyethanoic acid Glycolic acid Sugar cane
3-Carboxy-2-hydroxypentane- Isocitric acid
CH2OHCOOH Hydroxyacetic acid
1,5-dioic acid
2-Hydroxypropanoic acid Lactic acid Tomato HOOCCHOH CH(COOH)
CH3CHOHCOOH CH2COOH
2-Methyl Methyllactic acid Mango 3-Carboxy-3-hydroxyhexane- Homocitric acid
2-hydroxypropanoic acid 1,6-dioic acid
(CH3)2COHCOOH HOOCCH2 C(OH)(COOH)
2-Hydroxybutanoic acid α-Hydroxybutyric acid CH2CH2COOH
CH3CH2CHOHCOOH 3-Carboxy-2-hydroxyhexane- Homoisocitric
2-Hydroxyoctanoic acid α-Hydroxycaprylic acid 1,6-dioic acid acid
CH3(CH2)5CHOHCOOH HOOCCHOH CH(COOH)
2-Hydroxyeicosanoic acid α-Hydroxyarachidonic CH2CH2COOH
acid 3-Carboxy-2-n-hexadecyl- Agaricic acid
CH3(CH2)17CHOHCOOH 3-hydroxypentane
1,5-Dioic acid
2-Hydroxytetraeicosanoic Cerebronic acid Skin as ceramide
acid HOOCCH2 C(OH)(COOH) n-Hexadecyl
CH3(CH2)21CHOHCOOH CH(C16H33)COOH citric acid
Organic Acids with Novel Functions 71
ring. It is not chemically a true BHA, but it is erroneously

referred to as a BHA (12) in casual jargon. Aldobionic Acids
ABA, also known as bionic acid, consists of one monosaccha-
ride chemically linked through an ether bond to an aldonic
Polyhydroxy Acids acid, as shown in Table 8.4. An ABA may also be described
as an oxidized form of a disaccharide or dimeric carbohydrate,
PHAs are organic carboxylic acids having multiple hydroxyl
such as lactobionic acid derived from lactose and maltobionic
groups (13). Many PHAs are also AHAs; they are derived
acid from maltose. Lactobionic acid solution is currently used
from carbohydrates and are important intermediates in carbo-
in preservative media for organ transplants.
hydrate metabolism. PHAs may be divided into three groups:
aldonic acid, aldaric acid, and alduronic acid.
Aldonic Acid AHA-Related Compounds

An aldonic acid is a carbohydrate, called aldose, having the An α-ketoacid has a keto instead of hydroxyl group at the
carbon atom at position 1 changed to a carboxyl group, and alpha carbon of an organic carboxylic acid and is related to its
is represented by ribonic acid and gluconic acid, as shown counterpart alpha-hydroxyacid. Pyruvic acid (2-ketopropanoic
in Table 8.3. Vitamin C, L-ascorbic acid, is a 1,4-lactone acid, CH3 CO COOH) and lactic acid have such a biochemical
form of the AHA 2,4,5,6-tetrahydroxy-3-ketohexanoic acid, relationship in that the latter can be converted to the former
a keto PHA with chemical structure: HOCH2 CHOH CHOH when the hydroxyl group is oxidized to keto group by lactate
CO CHOH COOH. The lactone form of vitamin C has two dehydrogenase.
acidic hydroxyl groups at carbon positions 2 and 3 and does
not have an effect on keratinization comparable to that of
α-hydroxy PHAs.
Hydroxyacids: Physicochemical Properties
Stereoisomers
Aldaric Acid
Stereoisomers are formed when a carbon in a hydroxyacid
An aldaric acid is a carbohydrate having two carbon atoms has a stereocenter in the molecule, i.e. the carbon has four
at the end positions changed to carboxyl groups and is rep- non-identical radicals. Whereas glycolic acid, methyllac-
resented by glucaric acid (saccharic acid) and galactaric acid tic acid, and benzilic acid do not have stereoisomers, lactic
(mucic acid). acid and mandelic acid have stereoisomers, D and L forms.
Tartronic acid and citric acid do not have stereoisomers, but
malic acid has D and L, and tartaric acid has D, L, and meso
Alduronic Acid
forms. For PHAs and ABAs, stereoisomers usually result in
An alduronic acid is a carbohydrate having the terminal car- different chemical names, such as ribonic acid and arabinoic
bon changed to a carboxyl group and is represented by gluc- acid, gluconic acid and galatonic acid, lactobionic acid and
uronic acid, which is produced in the body as a detoxifying maltobionic acid, and often retain similar though not identi-
agent, and forms hyaluronic acid with N-acetyl glucosamine. cal functions.
TABLE 8.3
Nomenclature and Occurrence of Aldonic Acids
Systematic name and chemical structure Common name/Stereoisomer name Occurrence
2,3-Dihydroxypropanoic acid Glyceric acid
HOCH2 CHOH COOH
3,3-Dimethyl-2,4-dihydroxybutanoic acid Pantoic acid In vitamin B5
HOCH2 C(CH3)2 CHOH COOH
2,3,4-Trihydroxybutanoic acid Erythronic acid
HOCH2 (CHOH)2 COOH Threonic acid
2,3,4,5-Tetrahydroxypentanoic acid Ribonic acid, arabinoic acid, xylonic acid, lyxonic acid
HOCH2 (CHOH)3 COOH
2,3,4,5,6-Pentahydroxyhexanoic acid Allonic acid, altronic acid, gluconic acid, mannoic acid, gulonic acid, idonic acid, In skin
HOCH2 (CHOH)4 COOH galactonic acid, talonic acid
2,3,4,5,6,7-Hexahydroxyheptanoic acid Alloheptonic acid, altroheptonic acid, glucoheptonic acid, mannoheptonic acid,
guloheptonic acid, idoheptonic acid, galactoheptonic acid, taloheptonic acid
TABLE 8.4 containing 29% water molecules complexed with maltobionic

Nomenclature and Source of Aldobionic Acids molecules. Under the same conditions, lactobionic acid and cel-
lobionic acid can form clear gels containing 14% and 7% water
Common name Chemical structure Source respectively. The gel matrix may add protective, soothing, and
Lactobionic HOH2 C CHOH CHOR(CHOH)2 Lactose healing effects for inflamed skin or in wound healing.
acid COOH
R=galactose;4-O-β-D-Gal-D-
gluconic acid Acid Strength and pK a
Isolactobionic 6-O-β-D-Gal-D-gluconic acid Isolactose The acid strength of an organic hydroxyacid is determined
acid
by its proton dissociation from the carboxyl group in aqueous
Maltobionic HOH2 C CHOH CHOR(CHOH)2 Maltose
acid COOH
solution. After equilibrium is reached, the dissociation con-
R=glucose;4-O-α-D-Glc-D-
stant Ka is defined as hydroxyacid anion multiplied by proton
gluconic acid ion and divided by undissociated hydroxyacid based on molar
Isomaltobionic 6-O-α-D-Glc-D-gluconic acid Isomaltose concentration. The acid strength is expressed as pKa, and the
acid latter is a negative logarithm of the dissociation constant.
Cellobionic acid HOH2 C CHOH CHOR(CHOH)2 Cellobiose The hydroxyacid is a stronger acid if its pKa number is lower
COOH (14). The acid strength of a hydroxyacid may not be related
R=glucose;4-O-β-D-Glc-D- to its topical action on keratinization, although its pKa is cru-
gluconic acid cial to the determination of bioavailability and bioavailable
Gentiobionic ROH2 C (CHOH)4 COOH Gentiobiose concentration.
acid
R=glucose;6-O-β-D-Glc-D-
gluconic acid Antioxidant Property
Kojibionic acid HOH2 C (CHOH)3 CHORCOOH Kojibiose
Oxidation is defined as removal of electrons or reaction with
R=glucose;2-O-α-D-Glc-D-
oxygen. An antioxidant is defined as any substance capable
gluconic acid
of preventing or inhibiting oxidation. In biological systems,
Laminarabionic HOH2 C (CHOH)2 Laminarabiose
acid CHORCHOHCOOH an antioxidant may be described as a substance capable of
R=glucose;3-O-β-D-Glc-D- disposing, scavenging, or suppressing formation or actions
gluconic acid of peroxide, superoxide, or free radicals. There are three
Melibionic acid ROH2 C (CHOH)4COOH Melibiose simple screen methods which are useful to determine antioxi-
R=galactose;6-O-α-D-Gal-D- dant properties: prevention or retardation of air oxidation of
gluconic acid (1) anthralin, (2) hydroquinone, or (3) banana peel. Based on
Nigerobionic 3-O-α-D-Glc-D-gluconic acid Nigerose these three tests, all the PHAs and ABAs we have tested are
acid antioxidants, which include ribonolactone, gluconolactone,
Sophorobionic 2-O-β-D-Glc-D-gluconic acid Sophorose galactonolactone, gulonolactone, glucoheptonolactone, lacto-
acid bionic acid, and maltobionic acid (11, 15, 16). Among AHAs
and BHAs, citric acid, isocitric acid, tartaric acid, and malic
acid are antioxidants.
Lactone Form
In contrast to AHAs and BHAs, many PHAs can form spon-
taneous intramolecular lactones by elimination of water mol- Hydroxyacids: Biochemistry
ecules between the carboxyl and hydroxyl groups, especially Relationship to Amino Acids
when these two functional groups are separated by two or
three carbons. D-Gluconolactone, known as D-gluconic acid Many hydroxyacids are related to or derived from amino acids.
δ-lactone, is formed by eliminating one mole of water between Based on chemical structures, the only difference between an
the carboxyl group and the hydroxyl group at carbon 5 position AHA and an amino acid is the hydroxyl group instead of the
of D-gluconic acid, forming a six-member ring lactone. amino group, as shown in Table 8.5.
Solubility and Gel Matrix Carbohydrate Metabolism and Citrate Cycle

AHAs and BHAs with small molecular weight, and most Many hydroxyacids are intermediate products or end metabo-
PHAs and ABAs, are soluble in water. Certain AHAs and lites in carbohydrate metabolism; these include glyceric acid
BHAs such as methyllactic acid, mandelic acid, malic acid, in glycolysis. In anaerobic glycolysis, D-glucose is converted
phenyllactic acid, atrolactic acid, and tropic acid are also solu- to L-lactic acid as the end product. Gluconic acid and glucono-
ble in alcohol. Some aralkyl AHAs are lipophilic and are more lactone are important intermediates in the pentose phosphate
soluble in alcohol than water, such as benzilic acid. pathway for the synthesis of nucleotides in DNA and RNA.
One unique property of ABAs is their potential to form a gel Gulonic acid and gulonolactone are carbohydrate intermedi-
matrix with water. Maltobionic acid can form a clear gel matrix ates for the synthesis of vitamin C in plants and some animals.
TABLE 8.5 or lactic acid molecules can readily penetrate into the stra-
Biochemical Relationship between Hydroxyacids and Amino tum corneum, the ionized glycolate or lactate anions from the
Acids metallic salt cannot. Although the active form of a hydroxy-
acid may be the anions once inside the skin, a topical formula-
Hydroxyacid and amino acid Chemical structure
tion must contain a bioavailable form which can penetrate into
Glycolic acid CH2OHCOOH and through the stratum corneum.
Glycine CH2NH2COOH
Lactic acid CH3CHOHCOOH
Alanine CH3CHNH2COOH
Partial Neutralization and Buffered Formulation
Isopropylglycolic acid C3H7 CHOHCOOH A topical formulation containing a hydroxyacid without neu-
Valine C3H7 CHNH2COOH tralization has a pH below 2. Since the pH of skin surface is
3-Isopropyllactic acid C3H7 CH2CHOHCOOH approximately 4.2 to 5.6, many commercial products contain-
Leucine C3H7 CH2CHNH2COOH ing glycolic acid or lactic acid are partially neutralized with
3-Methyl-3-ethyl-lactic acid (C2H5)CH(CH3)CHOHCOOH sodium hydroxide or ammonium hydroxide to pH 3.5 to 4.5
Isoleucine (C2H5)CH(CH3)CHNH2COOH and claim to be buffered formulations. A buffered system is
Glyceric acid CH2OHCHOHCOOH designed to control pH changes of a formulation and does not
Serine CH2OHCHNH2COOH effectively reduce or eliminate skin irritation without compro-
3-Methylglyceric acid CH3CHOHCHOHCOOH mising topical efficacy. Therefore, lessened irritation is mainly
Threonine CH3CHOHCHNH2COOH due to decreased penetration of glycolic acid or lactic acid.
Malic acid HOOCCH2CHOHCOOH
Aspartic acid HOOCCH2CHNH2COOH
3-Phenyllactic acid C6H5 CH2CHOHCOOH
Efficacy Potential
Phenylalanine C6H5 CH2CHNH2COOH Cosmetic or therapeutic efficacy of a topical formulation con-
taining a hydroxyacid is proportional to bioavailable concen-
tration of the hydroxyacid in an optimal vehicle (13, 14). The
Citric acid, isocitric acid, and malic acid are important inter- bioavailable concentration is obtained by bioavailability mul-
mediates in the citrate cycle for energy production. tiplied by initial total concentration of the hydroxyacid. The
bioavailability is defined as a ratio or fraction of the undissoci-
ated hydroxyacid because only the free acid, not the anion, can
Glycosaminoglycans
substantially penetrate the stratum corneum. Bioavailability
Glycosaminoglycans (GAGs) are large carbohydrates widely decreases sharply when the pH is raised.
distributed in the body, for example in skin, fibroblasts, mast
cells, cartilage, bones, synovial fluid, cornea, and loose con-
nective tissues. Their physiological roles include formation of
extracellular matrix, specific interactions with collagen and Hydroxyacids: Optimal Release Formulation
elastin, binding of water and ions, facilitating cell migration, Skin Stinging and Irritation
formation of anticoagulants, and facilitating cell adhesion, cell
interaction, and cell receptors. There are six different types A topical formulation containing a hydroxyacid without partial
of GAGs, namely hyaluronic acid, chondroitin sulfate, keratan neutralization usually has pH of below 2. Such formulation,
sulfate I and II, dermatan sulfate, heparin, and heparan sulfate. especially with a small molecular AHA, may provoke sensa-
Each GAG is formed from two major carbohydrate compo- tions of tingling, itching, stinging, or irritation when applied
nents which include PHAs. For example, glucuronic acid is to sensitive, atopic, diseased, or inflamed skin. The undesired
one of the two major components of hyaluronic acid, chondroi- skin reactions may be due to the lower pH of the formulation,
tin sulfate, and heparan sulfate. Iduronic acid is an important or uncontrolled release and fast penetration of hydroxyacid
component of dermatan sulfate and heparin. into the skin. We have found that faster penetration of an AHA
is the major factor in causing skin stinging (17).
Hydroxyacids: Bioavailability and Molecular Complex

Bioavailable Concentration In an amphoteric system, the control-release mechanism is
based on intermolecular attracting forces between a hydroxy-
Stratum Corneum Barrier
acid and an amphoteric substance to form a molecular com-
In normal human skin, the stratum corneum consists of 14 plex. Amino acids are the best amphoteric substances, and the
to 30 layers of corneocytes, including the inner level stratum preferred ones are arginine, lysine, histidine, tryptophan, and
compactum and the outer level stratum dysjunctum. The ker- ornithine. There are three major attracting forces between a
atin-enriched corneocytes in the stratum corneum are embed- hydroxyacid and an amphoteric substance: ionic/ionic, dipolar/
ded in a lipid matrix and are very resistant to penetration by ionic, and dipolar/dipolar (17). The amphoteric formulations
ionic compounds or large molecules with molecular weight are therapeutically effective with minimal or no irritations to
greater than 800 to 1000. While undissociated glycolic acid the skin.
In a non-amphoteric system, the control-release mecha- after discontinuation of topical application. Because of these
nism is also based on intermolecular attracting forces between dermal effects and increased skin thickness, hydroxyacids are
a hydroxyacid and a non-amphoteric substance to form a found to be therapeutically effective for topical treatment of
molecular complex. The non-amphoteric substances are mul- skin changes associated with aging, including wrinkles and
tifunctional organic bases such as amino acid esters, amino photoaging.
acid amides, aminocarbohydrates, aminoalditols, or amino- In contrast, under the same test conditions salicylic acid at
cyclitols. Examples include glycine ethyl ester, glycinamide, 5% concentration has been found to cause a reduction in skin
argininamide, lysinamide, ornithinamide, glucosamine, glu- thickness, as shown in Table 8.7. Forearm skin treated with
camine, meglumine, and streptamine. In contrast to that of an salicylic acid clinically appeared thinner.
amphoteric system, the main attracting force of a non-ampho-
teric system is from ionic/ionic force between a hydroxyacid
Peel Solutions and Skin Peeling
anion and a cation of a non-amphoteric substance such as
glycine ethyl ester ammonium ion. The non-amphoteric for- Certain AHAs can be used in office procedures as peel solu-
mulation is also therapeutically effective with minimal or no tions for topical treatment of various cosmetic and dermato-
irritation to the skin. logical indications, including acne, keratoses, warts, wrinkles,
and photoaging (20, 21). The AHAs adaptable for such include
glycolic acid, lactic acid, citric acid, and mandelic acid. In
wide use is glycolic acid in 20, 35, 50, and 70% aqueous solu-
Hydroxyacids: Topical Actions tions containing small amount of ethanol and propylene glycol
Effects on Keratinization for uniform penetration with pH 1.6, 1.3, 1.2, and 0.6 respec-
tively (7, 8). DL-Lactic acid can be used in the same man-
On topical application, hydroxyacids exert a profound effect ner, and 90% syrupy liquid having pH 0.5 is commercially
on desquamation. At low to moderate concentrations, the available. Citric acid peel can be used as 20, 30, 40, and 50%
hydroxyacid, such as glycolic acid 10% cream, on topical aqueous solution with pH 1.5, 1.4, 1.3, and 1.2 respectively.
application to ichthyotic skin (Figure 8.1), causes initial sepa- DL-mandelic acid 50% in ethanol solution can be used for
ration of stratum corneum at lower levels near stratum com- light desquamatory peeling.
pactum (3, 11). The separation of stratum corneum as a sheet Pyruvic acid, an α-ketoacid, is the most powerful peeling
indicates that topical action of the hydroxyacid is not a dis- agent but is unsuitable for clinical use because of its chemical
persive keratolysis, such as by salicylic acid. A similar event instability. Glycolic acid 70% solution or DL-lactic acid 90%
can also happen to normal skin. For example, DL-mandelic liquid can provoke epidermolysis on the facial skin, generally
acid 10% cream on topical administration twice daily to nor- requiring several minutes of exposure depending on skin type.
mal skin causes sudden separation of stratum corneum as a The clinical sign of epidermolysis is blanching of the skin,
thin sheet after a few days of application. The skin exposed which indicates the threshold between superficial peeling and
after the separation of stratum corneum shows light pinkish deeper peeling. For new patients it is best to begin with 20%
coloration with a shiny smooth surface. With continued appli- or 35% glycolic acid solution and establish a reaction profile
cations such desquamation returns to normal, i.e. cannot be for each subject. In most, cases, the appearance of erythema
perceived. Because of their marked effects on desquamation, is a good indication that the skin will be peeled superficially.
hydroxyacids can be topically effective for various cosmetic The peeling process should be terminated by neutralization
objectives. with sodium bicarbonate solution. The patient may feel mild
stinging, but degrees of discomfort are mild to moderate and
acceptable for the intended end result. Superficial peeling may
Effects on Dermal Components and Skin Thickness
be repeated at intervals of 2 to 3 weeks or longer to provide
Hydroxyacids at concentrations of 10% to 25% on topical appli- beneficial effects in acne, acne-prone skin of younger age,
cation have been shown to increase biosynthesis of glycosami- older skin prone to milia and comedones, post-acne scaring,
noglycans and collagen fibers, and also to improve the quality wrinkle-prone skin, keratosis-prone skin, and photoaging skin.
of photoaged elastic fibers (5, 10, 18, 19). Hydroxyacid 10% to For superficial peeling with milder reactions, glycolic acid
35% creams topically applied twice daily to one forearm and 50% in ethanol may be used. Application of this solution to
control cream to the opposite forearm for 1 to 9 months have facial skin is associated with rapid onset of a burning sensa-
been found to increase skin thickness very substantially (4, 8). tion and erythema. After 1 minute, the skin is rinsed with
The increased skin thickness is mainly due to increased bio- sodium bicarbonate solution to relieve the burning sensation.
synthesis of glycosaminoglycans and collagen fibers as shown In most cases, the erythema fades within 1 to several hours.
by histological analysis (5, 19). The degree of increase in skin Epidermolysis can occur if glycolic acid 50% in ethanol is
thickness is quite variable, as shown in Table 8.6, and seems left on facial skin for several minutes. The erythema may per-
to depend on individual subject and the type of hydroxyacid sist into the next day, with denudation of skin and degrees of
used. In some cases hydroxyacids have been found to increase serous oozing. In some cases, sheet-like separation of stratum
skin thickness by more than 40%. Although epidermal thick- corneum occurs 1 day after the procedure, leaving the skin
ness is also increased, the major part of the increase in thick- light pink in color and smooth without other overt signs of an
ness is the dermis. The increased skin thickness is not due to unwanted reaction. For most cosmetic procedures, superficial
edema formation because it persists for many weeks to months peeling with 50% or 70% glycolic acid is adequate and can be
FIGURE 8.1 Thirteen-year-old girl with lamellar ichthyosis before (a, b) and after (c, d) topical application of 10% glycolic acid in hydrophilic
ointment twice daily for 3 weeks.
TABLE 8.6
Increased Skin Thickness by Topical Application of Hydroxyacids and Related Compounds*
Substance Subject number Age range (years) Duration (months) Percentage increase over control
Benzilic acid 2 68–72 2 22–45
Citric acid 13 50–83 5–9 7–55
Glycolic acid 4 58–77 4–8 11–43
Gluconolactone 6 62–81 2–7 7–19
Lactic acid 4 59–70 5–7 17–42
Lactobionic acid 7 49–76 1–3 5–58
Mandelic acid 2 55–62 1 22–27
Methyllactic acid 3 65–76 1–3 14–20
Pyruvic acid 4 62–82 2 14–27
* 10%–35% concentration twice daily on forearm skin.
TABLE 8.7
Decreased Skin Thickness by Topical Application of 5% Hydroxyacids: Mechanisms of Action
Salicylic Acid Solution Twice Daily on Forearm Skin
Specificity of Chemical Structure
Subject (age and Percentage decrease
gender) Duration (weeks) over control Unique biological and biochemical actions of a hydroxyacid
depend on specific chemical structure of the molecule, although
57F 8 –6
its receptor molecule(s) in the skin has not been identified.
60F 3 –7
Regarding the three attachment or binding sites, the hydroxyl
59F 6 –8
group must be neutral and not acidic in chemical property, like
63F 10 –11
that in alcohol but not like aromatic phenol, which is slightly
61F 2 –12
acidic. The carboxyl group must be attached to a non-aromatic
60F 5 –14
carbon, preferably an alkyl chain carbon. The amide or ester
67F 6 –21
form is substantially less active than the free acid form. The
49F 3 –23
side chain can be H, alkyl, or aryl, but the one preferred is a
73F 7 –32
short chain. In the case of glycolic acid, the three attachment
points or binding sites to a receptor molecule(s) in the skin
are hydroxyl, carboxyl, and one of the two hydrogen atoms
repeated every 2 to 3 weeks. For deeper peeling, glycolic acid attached to the alpha carbon. Among related compounds,
70% in water or 50% in ethanol can be left on the skin for lon- pyruvic acid is the most active and effective α-ketoacid. In
ger periods and can be so used in the treatment of seborrheic contrast with the hydroxyacid, the ester form of pyruvic acid,
keratoses and actinic keratoses. such as methyl pyruvate or ethyl pyruvate, can be topically
active. It has been speculated that the ester form is hydrolyzed
to free pyruvic acid by an esterase enzyme in the skin.
Synergistic Compositions
Associated with the ability of hydroxyacids modulating kerati- Biological Action
nization and inducing biosynthesis of glycosaminoglycans and
collagen fibers is the capability of these natural and physiolog- The precise mechanisms of actions induced by the hydroxyacid
ical substances to enhance or amplify pharmacologic actions are not known. Based on the available laboratory and clinical
of many topical agents. Such topical agents include corticoste- data, hydroxyacids at different concentrations provide the fol-
roids, retinoic acid, hydroquinone, diphenhydramine, 5-fluoro- lowing actions: diminished corneocyte cohesion at lower level
uracil, and antifungal agents (11, 22). The mechanism of this of stratum corneum, near the stratum compactum; a dimin-
synergistic action is not known. It may be because hydroxyac- ished number of desmosomes; reduced epidermal thickness in
ids disrupt skin barriers and promote better binding between a lamellar ichthyosis (Figure 8.2); increased epidermal and der-
topical agent and its receptor molecule, resulting in enhanced mal skin thickness in aging skin; increased synthesis of gly-
topical effect. The enhanced therapeutic effects appear not due cosaminoglycans and collagen fibers; and increased activities
to an increased penetration of the topical agent into the skin. of dermal dendrocytes (3, 5, 24).
Hydroxyacids can also reduce or eliminate tachyphylaxis, as
well as rebound worsening associated with topical cortico- Biochemical Action
steroids. It has been found that certain side effects associated
with topical corticosteroids, such as atrophy, can be reduced or Biological actions are usually due to or caused by biochemi-
avoided with concomitant use of an AHA (23). cal reactions. In normal stratum corneum, extractable lipids

FIGURE 8.2 Two-year-old girl with lamellar ichthyosis, including scaly skin and erythema, before (a) and after (b) twice-daily topical application
of 8% gluconolactone in control-release combination formulation for 4 weeks.
contain by weight approximately 45% to 50% ceramides, 25% ethanol, propylene glycol 40:40:20 ratio containing 5% to
cholesterol, 10% to 15% free fatty acids, and less than 5% each 10% hydroxyacid and applied twice daily is usually quite ben-
of other lipids including cholesterol-3-sulfate, which appears eficial for topical treatment or prevention of early acne. The
to be involved with cell cohesion in the lower layers of stra- hydroxyacids include glycolic acid, lactic acid, methyllactic
tum corneum (25–27). The conversion of cholesterol-3-sulfate acid, mandelic acid, and benzilic acid. In general, improve-
to cholesterol is required for normal desquamation of stratum ment of acne lesions is discernible within a few weeks of
corneum in the upper layers (28). It has been shown in X-linked starting topical treatment.
ichthyosis that the skin is deficient in steroid sulfatase enzyme For moderate to severe acne, hydroxyacids at higher skin
(29). While cholesterol is non-ionic, cholesterol-3-sulfate is an peeling concentrations can be used to cause epidermolysis to
ionic compound which may cause stronger intercorneocyte unroof pustules and beneficially modulate follicular epithe-
binding and cohesion, resulting in retarded desquamation. We lium to the level of sebaceous glands (7, 34). Glycolic acid 50%
might speculate that the hydroxyacid activates steroid sulfatase or 70% aqueous solution containing small amounts of alco-
to enhance hydrolysis of cholesterol-3-sulfate to free choles- hol and propylene glycol can be effectively used as peeling
terol in the stratum compactum of ichthyotic skin. AHAs such solution. The solution is applied to acne-involved areas with
as glycolic acid, lactic acid, and citric acid have been shown to a cotton ball or suitable brush. The patient will feel a mild
activate factor XIIIa transglutaminase enzyme, tumor necrosis to moderate sense of burning as erythema develops over a
factor-α, and to stimulate mast cells, fibroblast cells, and der- period of a few minutes. When skin blanching or perifollicu-
mal dendrocytes. lar edema is detected, the skin is neutralized with 5% sodium
bicarbonate solution to stop further epidermolysis. With this
procedure, most pustules will become unroofed. The proce-
dure may be repeated every 2 to 3 weeks. During intervening
Hydroxyacids: Cosmetic and periods, a low concentration such as 5% to 8% hydroxyacid in
Dermatological Indications gel or solution may be used by the patient once or twice daily
to keep follicles open.
Dry Skin and Skin Smoothing
Rosacea is characterized by vascular dilatation with ery-
Hydroxyacids can modulate keratinization at the levels of thema near the center of the face. The cause is unknown,
the stratum compactum, and such action is desirable for topi- although sunlight may play an important role in the develop-
cal treatment of dry skin conditions. Most cosmetic products ment of rosacea lesions. Rosacea lesions can evolve into telan-
for dry skin contain humectants or moisturizers that tend to giectasia with acneiform papules and pustules, and the skin is
improve water content or prevent water loss from the stra- quite sensitive to many topical agents. Metronidazole 0.75%
tum corneum. Although lactic acid has been claimed to be gel is beneficial for topical treatment of rosacea but has no
a moisturizer, most AHAs are not primary humectants or effect on telangiectasias. Because PHAs and ABAs are anti-
moisturizers. Rather, they modulate keratinization to normal- oxidants and gentle to sensitive skin, substances such as gluco-
ize or improve the quality of stratum corneum so that water nolactone, lactobionic acid, and maltobionic acid at 5% to 10%
loss is minimized. Most AHAs and BHAs, 4% to 10% cream concentrations are beneficial for prophylactic as well as topical
or lotion, are therapeutically effective for topical treatment treatment of rosacea (35).
or prevention of common dry skin or xerosis (30, 31). PHAs
and ABAs 5% to 10% concentration have extra benefits for
Warts (Verrucae Vulgares)
dry skin because of multiple hydroxyl groups in the molecule,
which seem to bind water molecules through hydrogen bond- Hydroxyacids are therapeutically effective for topical treat-
ing. In addition, these hydroxyacids are gentle to sensitive or ment of warts caused by human papillomavirus, which induces
inflamed skin without causing skin stinging. extreme degrees of hyperkeratosis (6). A rational approach
Hydroxyacids such as glycolic acid, lactic acid, and man- to topical treatment includes removing the hyperkeratotic
delic acid at 10% concentration are therapeutically effec- “armor,” destroying the tissue harboring the virus, and intro-
tive for topical treatment of ichthyosis and other severe dry ducing antiviral agent(s).
skin conditions. PHAs and ABAs such as gluconolactone, Much of the hyperkeratotic plate can be removed by scal-
lactobionic acid, and maltobionic acid 10% to 15%, alone or pel paring. Thereupon an AHA in 70% solution or gel can be
in combination with other topical agents, are beneficial and applied under occlusion twice daily by patients for a week or
soothing for topical treatment of eczema and psoriasis (32). more to cause epidermolysis. In most cases, destruction of
Combination of several hydroxyacids seems to be the best for wart tissue occurs by epidermolysis and is sufficient to eradi-
topical treatment of severe dry skin. cate the virus as well as the lesion. However, combined use of
an antimetabolite such as 5-fluorouracil (5-FU) is more cura-
tive, and it can be applied concomitantly (7). For home use
Acne and Rosacea
by patients, 0.5% 5-FU solution is prepared by dissolving the
All acne lesions involve retention of follicular stratum cor- drug in 70% glycolic acid. The solution is applied twice daily
neum. Hydroxyacids are therefore therapeutically effec- with a cotton applicator to the center of the wart, which is then
tive for topical management of acne (33). Topical action of covered with tape. Applications are discontinued if discomfort
a hydroxyacid at lower concentrations can diminish cor- occurs and resumed if the wart lesion is not yet resolved. We
neocyte cohesion and dislodge early comedones from fol- have found that this treatment usually results in complete reso-
licular orifices (6). A gel or solution formulation in water, lution of lesions within 3 to 4 weeks.
Eczema and Pruritus coarse and deep wrinkles. Aging of the face and the hands in
elderly people is due to a combination of intrinsic aging and
Eczema may be defined as persistent inflammatory skin photoaging. Physiological aging cannot be stopped, but signs
lesions with constant or repeated itch. Eczematous disorders of extrinsic cutaneous aging can be modified by topical appli-
can occur at any age and in various forms, such as nummu- cation of AHAs, PHAs, ABAs or combinations to improve
lar eczema and lichen simplex chronicus, and is a common appearance and slow the process (40–43) (Figure 8.3).
skin disease in Asian countries. Eczema may be caused by
endogeneous and exogeneous factors. Pruritus is the main
disturbance. Corticosteroids have been used for topical treat- Sunburn Cells
ment of eczema, and the pruritus diminishes secondarily as
Sunburn cells are dead or dying keratinocytes caused by
the inflammatory process is subdued. In cases of eczema
UV radiation and are physiologically programmed for cell
wherein inflammation is not a primary event, topical corti-
death (apoptosis). The cells are eosinophilic and appear
costeroids are not very effective in eradicating the pruritus.
in the epidermis within 30 minutes and are maximal at 24
Hydroxyacids such PHAs and ABAs incorporated into topi-
hours after UVB radiation (290–320 nm) (44). The action
cal antipruritic formulations can greatly enhance efficacy. For
spectrum appears to be just below 300 nm, and UVA (320–
example, addition of gluconolactone, lactobionic acid, and/
400 nm) radiation does not seem to produce any detectable
or maltobionic acid to diphenhydramine topical formulations
or significant numbers of sunburn cells in epidermis. The
greatly enhances antipruritic efficacy. The best results are
mechanism of action is unknown. It appears that DNA dam-
obtained when gluconolactone, lactobionic acid, and/or malto-
ages have occurred in certain keratinocytes at the lower epi-
bionic acid are combined with hydrocortisone-17-valerate and
dermis after the UVB radiation, and these sunburn cells
diphenhydramine in cream or lotion vehicles.
move rapidly upward through the epidermis into the stra-
tum corneum.
Onychomycosis Preliminary study showed that glycolic acid 10%, pH 3.5, on
topical application for 12 weeks decreased minimal erythema
Onychomycosis is a paramount cosmetic affliction, heretofore dose by 18% and increased the number of sunburn cells by
difficult to treat. When an AHA is incorporated into a compo- twofold, as compared to control group (45). Under the same
sition containing an antifungal drug, the formulation becomes test conditions, a cosmetic surfactant, sodium lauryl sulfate at
topically very effective for nail infections. Improvement of 0.5% concentration, increased the number of sunburn cells six-
fingernail and toenail infections progresses at the rate of nail fold. Topical formulations containing an AHA and a sunscreen
growth; approximately 1 mm per week for a fingernail and 0.5 agent with a sun protection factor (SPF) approximately 3–4
mm per week for a great toenail. The improvement rates also appeared to prevent any increase of sunburn cells (46). Topical
suggest that fungal infection of the nail is arrested by topi- formulations containing a PHA, 5% to 10% gluconolactone,
cal treatment with synergistic compositions containing both without any sunscreen agent have been shown to provide thera-
AHA and antifungal drug. Fungal infections of fingernails peutic effects and protect the skin from any increase in sunburn
have been regularly eradicated with up to 6 months of topical cells (47).
treatment with solutions containing 2% clotrimazole and 20% Nevertheless, regular use of a sunscreen is advisable.
glycolic acid.
Hydroxyacids: Intrinsic and

Extrinsic Skin Aging
Cutaneous aging is caused by internal and external factors
(36–39). Intrinsic aging is a physiological degeneration caused
by declining ability and functions inherent with increasing
age. Upper arms and buttocks are typical skin areas showing
intrinsic aging, where the skin thins and develops fine wrin-
kles. Daily topical application of glycolic acid, gluconolac-
tone, or lactobionic acid 5% to 10% cream or lotion has been
found to be beneficial for prophylactic as well as topical treat-
ment of sun-protected areas of aging skin.
Extrinsic aging is a combination of intrinsic aging and
accelerated degeneration caused by ultraviolet (UV) radiation,
ionizing radiation, air pollution, wind, cold, heat, dampness,
chemicals, smoke, and cigarette smoking. Face and hands are
typical skin areas showing extrinsic skin aging. Photoaged FIGURE 8.3 Fifty-five-year-old woman with photoaged skin, including
coarse wrinkles and textural signs of elastosis on her face, before (a) and
skin is rough, dry, mottled, yellowish, leathery, and thickened. after (b) 70% glycolic acid peels monthly and home use of twice-daily
It lacks elasticity, has keratoses and pigmented age spots and 10% glycolic acid cream for 9 months.
Actinic Keratoses
Actinic keratosis is a precancerous lesion of keratinocytes,
also called solar keratosis, which is caused by photodam-
age. The lesions are on the sun-exposed areas of skin. Actinic
keratosis may progress to squamous cell carcinoma. One con-
ventional treatment is continued topical application of 5-FU
for several weeks. A combination of a hydroxyacid and 5-FU
can shorten the treatment time and the period of discomfort
from several weeks to just 1 week. First, the lesions or sites
of actinic keratoses are identified by topical application of 5%
5-FU cream twice daily to affected areas for 5 to 7 days before
the office procedure. Once the lesions are identified, 70% gly-
colic acid in ethanol:propylene glycol 80:20 is applied to the
lesions. After 2 to 5 minutes when the lesions begin to blanch,
5% 5-FU solution is applied.
Alternatively, the lesions may be treated with 0.5% to 1%
5-FU dissolved in 30% glycolic acid aqueous solution (7). In FIGURE 8.4 Eighty-year-old woman with photodamaged skin, including
coarse wrinkles and multiple lesions of actinic keratoses on her face, before
most cases, this procedure results in complete eradication of (a) and after (b) 70% glycolic acid peels and home use of 10% glycolic acid
the lesions. cream for 4 years.
Age Spot Keratoses

Aging-related macules and papules on the face and the back
of the hands are pigmented lentigines, non-pigmented kerato-
sis, and/or seborrheic keratoses. For rapid removal of kerato-
ses, 100% pyruvic acid, 90% lactic acid, or 70% glycolic acid
peel solutions may be used as an office procedure (Figure 8.4).
After the area is degreased with 70% ethanol, the peel solution
is applied with a fine camel-hair brush, and the skin is neutral-
ized with 5% sodium bicarbonate solution when epidermolysis
occurs. Among the aforementioned peel solutions, 70% gly-
colic acid is preferred. The skin peel may be repeated after
an interval of several weeks to eradicate remaining lesions.
Home treatment with a cream or gel containing 10% hydroxy-
acid with or without 2% hydroquinone may be continued to
subdue re-emergence or new lesions. Age spots on the dorsa of
the hands and forearms, more resistant to simple topical treat-
ment, may need sustained treatment with 20% or higher con- FIGURE 8.5 Sixty-three-year-old man with age spots, including
multiple lesions of seborrheic keratoses and lentigines on his left face,
centration of hydroxyacid (7). The addition of hydroquinone before (a) and after (b) twice-daily topical application of 10% glycolic acid
seems more effective in the eradication of pigmented skin and 2% hydroquinone cream for 21 months.
spots such as lentigines and freckles (Figure 8.5). The time
required for their clinical resolution is variable, from a few Five parameters may be used to monitor the progress of
months to a year or more. therapeutic effects: improvement in dyspigmentation, skin tex-
ture, overt fine lines, overt wrinkles, and increased skin thick-
ness. It is essential that “before” and “after” photos be taken
Wrinkles and Aging Skin
for each patient to assess progress.
AHAs are therapeutically effective for topical treatment of skin
changes associated with aging because they increase skin thick-
ness by stimulating biosynthesis of GAGs and collagen fibers.
Antioxidants and Photoaging
An AHA such as glycolic acid at concentration of 10% can be The human body needs oxygen for energy and life itself.
used by a patient at home to treat fine wrinkles on the face Therefore, oxidation is inherent to living. Reactive oxygen
(6, 7). Substantial improvement may be perceived after several species (ROS) are produced by oxidation or peroxidation
months of treatment. However, the time required for clinical and include superoxide, hydrogen peroxide, hydroxyl radi-
improvement of coarse wrinkles may take years, depending on cals, and peroxyl radicals (51, 52). Among these ROS, the
the degree of severity. Office procedures using 90% lactic acid hydroxyl radicals are most reactive and cause cellular and
or 70% glycolic acid peels seem to provide faster resolution tissue stress by reacting with proteins, nucleic acids, lipids,
of coarse wrinkles, combined with sustained home use of an and other biochemical entities. Under quiescent conditions,
AHA at or near 10% concentration (8, 41, 48–50). endogenous or available antioxidants and reductive enzymes
in the body are capable of neutralizing these harmful ROS. and mandelic acid. We have found that BHAs as a group are
Known antioxidants and enzymes include vitamin C, vitamin similar to AHAs in many ways, and the same is true between
E, reduced α-lipoic acid, reduced ubiquinones (coenzyme Q), ABAs and PHAs. However, PHAs and ABAs are function-
reduced glutathione (GSH), reduced nicotinamide adenine ally different from AHAs and BHAs in certain aspects, as
dinucleotide phosphate (NADPH), and superoxide dismutase, shown in Table 6.8. Because of multiple hydroxyl groups in
which converts superoxide to hydrogen peroxide and oxygen. the molecule, PHAs and ABAs are antioxidants, are gentle
Catalase and glutathione peroxidase in turn convert hydrogen to the skin, and they do not increase sunburn cells following
peroxide to water and oxygen. Many other antioxidants prob- UV radiation. Certain members of PHAs, such as glucuronic
ably have ancillary or primary roles. acid and iduronic acid, are known constituents of GAGs. In
Sunlight is essential for life on earth, but UV radiation is the past, AHAs, especially glycolic acid, have been used quite
harmful to human skin. Human skin is equipped with antioxi- extensively for cosmetic and dermatologic indications. More
dant systems that counteract or dispose of some ROS induced recently, PHAs and ABAs, such as gluconolactone and lactobi-
by UVB (53). However, the amount of these endogenous or onic acid, are used as unique ingredients in cosmetic products.
available antioxidants may not be sufficient to overcome the
increased ROS produced by continued exposure to UVB. The
Antagonistic Acetoxyacids
skin reactions or damages caused by UVB include erythema,
edema, exfoliation, tanning, abnormal thickening (elastosis) Like some substances with antagonists in nature, hydroxy-
or thinning of the epidermis and dermis, and numerous other acids appear to have their own antagonistic counterparts.
changes known as photoaging, including carcinogenesis. When the hydroxyl group at the α position of an AHA is
Hydroxyacids have been shown to improve the appearance acetylated to an acetoxyl compound, the modulation on kera-
of photoaged skin by improving epidermal renewal and des- tinization changes to reverse direction, causing hyperkerati-
quamation and by increasing dermal biosynthesis of GAGs and nization. The antagonistic action is noticeably pronounced
collagen fibers (5, 10). Because PHAs and ABAs are antioxi- when an aralkyl AHA such as mandelic acid, benzilic acid,
dants, they can be used to prevent or counteract ROS induced or phenyllactic acid is acetylated to O-acetyl-mandelic acid,
in the skin by UVB, in conjunction with sunscreens and sun- O-acetyl-benzilic acid, or 0-acetyl-phenyllactic acid, respec-
blocks in cream, lotion, or gel form to prevent sun damage (35). tively. Aralkyl O-acetyl-AHA 5 to 10% creams have been
shown to increase thickness and compactness of stratum cor-
neum in hairless mouse and human forearms (3). The hyper-
keratotic action of aralkyl O-acetyl-AHAs has been found to
Similarities and Differences of Hydroxyacids be useful and effective for topical treatment of brittle nails,
The chemical structure of a hydroxyacid determines whether psoriatic nails, and cheilitis caused by oral administration of
the substance belongs to AHA, BHA, PHA, or ABA, and such 13-cis-retinoic acid.
classification is also based on its characteristics and usage.
Different members of the same group may possess different
N-Acetylamino Acids and N-Acetyl Compounds
physicochemical properties, e.g., hydrophilic or lipophilic,
but they have similarities in their topical actions with differ- An amino acid is an organic acid having one or more than one
ent degrees of potency; these include glycolic acid, lactic acid, alkaline radical such as amino, guanidino, imino, or hydrazine
TABLE 8.8
Similarities and Differences in Characteristics and Use of Hydroxyacids
Characteristics/Use AHAs BHAs PHAs ABAs
Physiological nutrients or natural substances + + + +
Antioxidants against superoxides, free radicals * + +
Gentle to sensitive skin + +
Gel matrix formation/wound-healing +
Constituents of GAGs +
Modulate keratinization, dry skin, acne, keratosis + + + +
Increase dermal components GAGs, collagen, elastin + + + +
Reduce wrinkles, photoaging + + + +
Synergistic effects of corticosteroids, antifungal agents + + + +
Abreviations: AHAs,α-hydroxyacids; BHAs, β-hydroxyacids; PHAs, polyhydroxy acids; ABAs, aldobionic acids; GAGs, glycosaminoglycans.
Note: Some NAAs and N-acetylaminocarbohydrates occur in nature as metabolites, biopeptides, glycoproteins, or glycosaminoglycans, e.g. N-acetyl-L-
glutamic acid in liver (54), N-acetyl-L-aspartic acid in brain (55), N-acetyl-L-serine in melanocyte-stimulating hormone (α-MSH) (56), N-acetyl-L-
tyrosine in N-acetyl-β-endorphin (56), N-acetyl-D-glucosamine in hyaluronic acid and keratan sulfate (57), and N-acetyl-D-galactosamine in chondroitin
sulfate and dermatan sulfate (57).
* Polycarboxy AHAs, malic acid, citric acid, tartaric acid are antioxidants.
radical attached at any carbon atom other than carbon one, and as shown in Table 8.9. We have found that N-acetyl-L-proline
NAA is obtained by N-acetylation of the amino group. In fact, and N-acetyl-D-glucosamine at 5% to 10% concentration are
the NAA can be considered as the organic acid in which one topically effective for ichthyosis and also for eradication of itch
H is replaced by an acetamino group. There are 20 common associated with eczema and xerosis.
amino acids present as L form in natural proteins, and there are NAC is a potent antioxidant against free radicals such as
also a number of related amino acids with different chemical hydroxyl radical (58) and is a good precursor for glutathione
structures and configurations. These common amino acids and synthesis in the body. NAC is used as a mucolytic, detoxifying,
related amino acids can form NAAs and are related N-acetyl and antiviral agent. We have found that NAC 8% in hydrophilic
compounds. N-Acetylglucosamine, N-acetylgalactosamine, ointment is topically effective for ichthyosis (Figure 8.6).
and N-acetylmannosamine are N-acetylated derivatives An amino acid can be in amide or hydrazide form, e.g.
of aminocarbohydrates glucosamine, galactosamine, and N-acetylaminoamide and N,N’-diacetylaminohydrazide. We
mannosamine, which are organic aldehydes instead of have found that N-acetyl-L-tyrosinamide and N,N’-diacetyl-
organic acids. Topical actions of N-acetylglucosamine and L-tyrosinhydrazide in oil-in-water emulsion on topical
N-acetylgalactosamine have some similarities to that of NAA,
TABLE 8.9
N-Acetylamino Acids and N-Acetyl Compounds
Topical effects
Chemical name Chemical structure Ichthyosis Itch
N-Acetyl-L-alanine CH3 CH(NHCOCH3) COOH
Nα-Acetyl-L-arginine H2NC(=NH)NH(CH2)3 CH(NHCOCH3)
COOH
N-Acetyl-L-aspartic acid HOOC CH2 CH(NHCOCH3) COOH
N-Acetyl-DL-asparagine H2NOC CH2 CH(NHCOCH3) COOH 4+
N-Acetyl-L-cysteine HSCH2 CH(NHCOCH3) COOH 3+
N-Acetyl-glycine CH2(NHCOCH3) COOH 3+
N-Acetyl-L-glutamic acid HOOC CH2 CH2 CH(NHCOCH3) COOH 4+
N-Acetyl-L-glutamine H2NOC CH2 CH2 CH(NHCOCH3) COOH 4+
N-Acetyl-L-histidine C3H3N2 CH2 CH(NHCOCH3) COOH
N-Acetyl-L-isoleucine CH3 CH2 CH(CH3) CH(NHCOCH3) COOH
N-Acetyl-L-leucine (H3C)2CH CH2 CH(NHCOCH3) COOH
Nα-Acetyl-L-lysine H2NCH2 (CH2)3 CH(NHCOCH3) COOH 4+
N-Acetyl-L-methionine (H3C)SCH2 CH2 CH(NHCOCH3) COOH
N-Acetyl-L-phenylalanine C6H5 CH2 CH(NHCOCH3) COOH
N-Acetyl-L-proline N(COCH3)C4H7 COOH 4+ 4+
N-Acetyl-L-serine HOCH2 CH2(NHCOCH3) COOH
N-Acetyl-L-threonine H3C CHOH CH(NHCOCH3) COOH
N-Acetyl-L-tryptophan C8H6N CH2 CH(NHCOCH3) COOH
N-Acetyl-L-tyrosine HOC6H4 CH2 CH(NHCOCH3) COOH 4+
N-Acetyl-L-tyrosinamide HOC6H4 CH2 CH(NHCOCH3) CONH2 4+
N-Acetyl-L-valine (H3C)2CH CH(NHCOCH3) COOH
N-Acetyl-β-alanine CH2(NHCOCH3) CH2 COOH 4+
N-Acetyl-γ-aminobutanoic acid CH2(NHCOCH3) CH2 CH2 COOH 3+
Nα-Acetyl-L-ornithine H2NCH2 (CH2)2 CH(NHCOCH3) COOH
N-Acetyl-L-citrulline H2NCONH(CH2)3 CH(NHCOCH3) COOH
N-Acetyl-creatine H2NC(=NCOCH3)N(CH3) CH2 COOH
N-Acetyl-creatinine -HNC(=NCOCH3)N(CH3) CH2 CO-
N-Acetyl-phenylglycine C6H5 CH(NHCOCH3) COOH
N-Acetyl-4-hydroxyphenylglycine HOC6H4 CH(NHCOCH3) COOH 3+
N-Acetyl-D-glucosamine HOH2C (CHOH)3 CH(NHCOCH3) CHO 4+ 4+
N-Acetyl-D-galactosamine HOH2C (CHOH)3 CH(NHCOCH3) CHO 4+
Ichthyosis: 3+, 75%; 4+, 100% improvement.
Itch: 4+, eradicate itch completely for 8 hours.

FIGURE 8.6 Six-year-old boy with lamellar ichthyosis before (a) and after (b) topical application of 8% N-acetyl-L-cysteine in hydrophilic ointment
twice daily for 4 weeks.
application to normal human skin can stimulate biosynthesis treatment. As shown earlier (5) increased skin thickness was
of hyaluronic acid and increase skin thickness. due to increased biosynthesis of GAGs and collagen fibers,
improved quality of elastic fibers, less clumping of melanin,
and lighter appearance of age spots. Therefore, increased skin
N-Acylpeptides
thickness is expected to improve aging-related skin changes,
NAP is an acylated peptide derivative. A peptide is formed including fine lines, wrinkles, photoaging, age spots, blotches,
from two or more amino acids by a covalent amide bond, hyperpigmented skin, mottled skin, and can be used for
C(=O)NH, when the carboxyl group on one amino acid reacts younger-looking skin and skin lightening (Table 8.10).
with the amino group of the other amino acid in a dehydra- NAP derivatives at concentrations of 0.5% to 5% on topi-
tion reaction. A dipeptide is formed from two amino acids, a cal application have been found to eradicate itch within a few
tripeptide is formed from three amino acids, and a polypeptide minutes and improve eczema lesions within a few weeks with
is formed from multiple amino acids. The 20 common amino continuing topical application (Figure 8.7).
acids are represented by chemical names, such as “glycine,” or
abbreviated symbols such as three letters, “Gly,” or one letter,
“G.” Except for glycine, all other common amino acids have TABLE 8.10
stereoisomers, i.e. enantiomer, D, or L form. The amino acids Representative Creatine Derivatives
in most natural peptides and proteins are all in L-form.
Compound Compound name/
The three-letter symbols used for the 20 common amino No. Analgesic effect Structure
acids are as follows: alanine (Ala), arginine (Arg), aspartic
acid (Asp), asparagine (Asn), cysteine (Cys), glycine (Gly), C11 Creatinamide 1+ H2NC(=NH)N(CH3)
CH2CONH2
glutamic acid (Glu), glutamine (Gln), histidine (His), isoleu-
C12 Ethyl creatinate 2+ H2NC(=NH)N(CH3)
cine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phe- CH2COOC2H5
nylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), C13 N-acetyl creatine 3+ H2 NC(=NAc)N(CH3)
tryptophan (Trp), tyrosine (Tyr), and valine (Val). CH2COOH
Common acyl groups are acetyl (Ac) and propanoyl (Pa) radi- C15 N-acetyl ethyl creatinate H2NC(=NAc)N(CH3)
cals, such as N-acetyldipeptide and N-propanoyldipeptide. The 4+ CH2COOC2H5
NAP derivatives can have different forms at carboxyl terminal C20 N-benzoyl ethyl creatinate H2NC(=NBz)N(CH3)
group such as free acid (OH), amide (NH2), ethyl ester (OEt), 3+, 4+ CH2COOC2H5
hydrazide (NHNH2), and N-acetyl hydrazide (NHNHAc). C26 N-2-acetoxybenzoyl ethyl H2NC(=NAb)N(CH3)
NAP derivatives at concentrations of 0.5% to 10% on topi- creatinate 3+, 4+ CH2COOC2H5
cal application have been found to increase skin thickness. For C27 N-2-acetoxybenzoyl creatine H2NC(=NAb)N(CH3)
example, N-acetyldipeptide amide, N-Ac-L-Tyr-L-Tyr-NH2, 3+ CH2COOH
at 3% increased skin thickness 15% to 20% after 4 weeks; C29 N-acetyl propyl creatinate H2NC(=NAc)N(CH3)
2+ CH2COOC3H7
N-acetyltripeptide amide, N-Ac-L-Tyr-L-Tyr-L-Tyr-NH2,
C30 N-2-acetoxybenzoyl propyl H2NC(=NAb)N(CH3)
at 0.5% increased skin thickness 5% to 10% after 7 days;
creatinate 2+ CH2COOC3H7
N-acetyltripeptide ethyl ester, N-Ac-L-Tyr-L-Tyr-L-Tyr-OEt, at
C31 N-phenylacetyl creatine H2NC(=NPc)N(CH3)
0.5% increased skin thickness 20% to 30% after 10 days. The 2+ CH2COOH
increased skin thickness or plump was not due to increased C32 N-phenylacetyl ethyl creatinate H2NC(=NPc)N(CH3)
water retention or edema of the skin because the thickness 3+ CH2COOC2H5
was maintained for many months after discontinuation of the
Abbreviations: Ac, acetyl; Ab, ac.
Creatine Derivatives represents substantial but incomplete relief of pain for less
than 6 hours; 3+ (75%), which represents complete relief of
Creatine is believed to improve strength, increase lean muscle pain for less than 6 hours; and 4+ (90–100%), which repre-
mass, and help the muscles recover more quickly during as sents complete relief or eradication of pain for more than 6
well as after exercise. This muscular boost may help athletes hours.
achieve bursts of speed and energy, especially during short
bouts of high-intensity activities such as weight lifting or
sprinting (59–61).
Creatine is a physiological organic acid, also known as N-methyl- Conclusion, Discussion, and Perspectives
N-guanylglycine and has the following chemical formula
Organic acids cover various organic compounds, which include
retinoic acid, salicylic acid, α-hydroxyacids (AHAs), polyhy-
H2NC(=NH)N(CH3)CH2COOH
droxy acids (PHAs), aldobionic acids (ABAs), N-acetylamino
acids (NAAs), and N-Acylpeptides (NAPs). On topical admin-
Creatine is an amphoteric compound, both positively and neg-
istration, these organic acids exert distinctive pharmacologi-
atively charged in aqueous solution. Therefore, creatine cannot
cal actions on keratinization and/or biosynthesis of dermal
readily penetrate into the human skin and is not bioavailable
components, i.e. glycosaminoglycans, collagen, and elastic
for any therapeutic effects. Therefore, it is necessary to synthe-
fibers. However, these organic acids also have certain simi-
size various creatine derivatives that are not amphoteric and
larities and differences in topical actions. Both salicylic acid
are in bioavailable form as shown in Table 8.11 (62).
and glycolic acid have similar beneficial effects on disturbed
keratinization, e.g. acne, ichthyosis, calluses, etc. Glycolic acid
increases while salicylic acid diminishes the biosynthesis of
Evaluation of Analgesic Effectiveness
dermal components, i.e. glycolic acid but not salicylic acid is
Five scales were useful to evaluate the efficacy of analge- beneficial for wrinkles and aging skin. NAAs and NAPs have
sic effect: 0 (zero) for no effect; 1+ (25%), which represents similar beneficial effects on disturbed keratinization, e.g. ich-
partial relief of pain for less than 6 hours; 2+ (50%), which thyosis, and hyperkeratoses.
TABLE 8.11
N-Acylpeptide Derivatives
N-acylpeptide derivatives Aging-related skin changes Itch, eczema
N-Ac-L-Ile-L-Ala-NH2 2+ 4+
N-Ac-L-Ieu-L-Ala-NH2 3+ 4+
N-Ac-L-Ieu-L-Ala-OH 2+ 3+
N-Ac-L-Val-L-Ala-NH2 4+ 4+
N-Ac-L-Val-L-Ala-OH 2+ 4+
N-Pa-L-Val-L-Ala-OH 2+ 4+
N-Ac-L-Cys-L-Cys-NH2 3+ 2+
N-Ac-L-Cys-L-Cys-OH 3+ 2+
N-Ac-L-Ile-Gly-NH2 3+ 4+
N-Ac-L-Ile-Gly-OH 2+ 4+
N-Ac-L-Ieu-Gly-NH2 3+ 4+
N-Ac-L-Ieu-Gly-OH 2+ 3+
N-Pa-L-Ieu-Gly-OH 2+ 3+
N-Ac-L-Pro-Gly-NH2 2+ 4+
N-Ac-L-Val-Gly-NH2 2+ 4+
N-Ac-L-Val-Gly-OH 2+ 4+
N-Ac-L-Ala-L-Ile-NH2 2+ 3+
N-Ac-L-Ile-L-Ile-NH2 3+ 4+
N-Ac-L-Cys-L-Tyr-NH2 2+ 3+
N-Ac-L-Tyr-L-Tyr-NH2 4+ 4+
N-Ac-L-Tyr-L-Tyr-OH 4+ 4+
N-Ac-L-Tyr-L-Tyr-NHNH2 4+ 2+
N-Ac-L-Tyr-L-Tyr-NHNHAc 4+ 4+
N-Ac-L-Tyr-L-Tyr-L-Tyr-OH 2+ 3+
N-Ac-L-Tyr-L-Tyr-L-Tyr-OEt 3+ 4+
N-Ac-L-Tyr-L-Tyr-L-Tyr-NH2 4+ 4+
N-Ac-L-Val-L-Val-L-Ala-NH2 2+ 3+
N-Ac-L-Tyr-L-Val-L-Tyr-NH2 3+ 4+
Note: Aging skin including age spots; itch and eczema: 2+: 50% efficacy; 3+: 75% efficacy; 4+: 95%−100% efficacy.

FIGURE 8.7 Forty-three-year-old woman with chronic eczema on both arms, before (a) and after (b) N-Ac-L-Val-L-Ala-NH2 0.5% in oil-in-water
emulsion applied twice daily for 4 weeks.
N-Acetyl-L-tyrosinamide is more effective than N-acetyl- hydroxyacids and other organic acids can be utilized to nudge
L-tyrosine for increasing the skin thickness by stimulation skin form and function toward a more youthful state. They
of hyaluronic acid biosynthesis. N-Acetyl-L-glutamic acid can be topically applied to decelerate the otherwise inexorable
diethyl ester is more effective than N-acetyl-L-glutamic acid progression toward old-looking integument.
for topical treatment of ichthyosis. Based on these observa- The antioxidant PHAs and ABAs are especially beneficial
tions, the active form of the NAA or NAP may not be in free and can be utilized to repair and prevent damage caused by
acid or anion form. UV radiation. However, these latter substances are still new
Since 1974, many studies have shown that physiologic and on the scene, and expanding use is projected. Dermatologists,
nontoxic hydroxyacids can promote normal keratinization cosmetologists, pharmacologists, pharmacists, and formula-
and increase synthesis of dermal components, including hyal- tors need to be closely familiar with chemical attributes of the
uronic acid and collagen fibers. AHAs, specifically glycolic various hydroxyacids and other organic acids including PHAs
acid, have been widely used in cosmetic products and derma- and ABAs, their clinical performance, and how best to design
tologic practice for topical treatment of dry skin, acne, kera- and compound formulations to provide maximal achievement
toses, wrinkles, photoaging, and photodamaged skin. Because of intended objectives.
of multiple hydroxyl groups in the molecules, gluconolactone
(a PHA lactone) and lactobionic acid (an ABA) are gentle to
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9
Retinyl Propionate and Related Retinoids
John E. Oblong
biochemistry, and molecular biology as well as human study

Introduction findings. Additionally, the principle focus in terms of treat-
ment effects will be upon photodamaged skin.
Retinoids represent a class of lipophilic compounds that are
comprised of natural derivatives of vitamin A (retinol) as
well as synthetic analogues. Naturally occurring retinoids are
sourced via dietary intake of beta-carotene as well as retinyl Biochemistry and Molecular Biology of
esters, both of which are found in a broad range of food stuffs
Topical Retinol and Retinyl Esters
and animal by-products. Structurally, beta-carotene exists
essentially as a dimer form of retinol and the enzymatic con- Of most relevance to the cosmetic industry was the confir-
version in the intestinal tract via retinal production is the ini- mation that cosmetic forms of retinoids have the potential to
tial sourcing of retinoids for usage by the human body. Most be enzymatically converted to various retinoid metabolites
eukaryotic cells have the capability of enzymatically convert- including tRA when topically administered (3–8). The bio-
ing retinol and retinyl esters to various metabolites that are chemical conversions are shown schematically in Figure 9.2a
critical in maintaining cellular homeostasis, regulating pro- where retinol is oxidized via small chain alcohol dehydroge-
liferation and differentiation patterns, as well as embryonic nases to retinal and in turn to form tRA (5, 9). This process is
development. Of the metabolites generated, the true “business begun when free retinol associates with a specific cytoplasmic
end” of retinoids is retinoic acid, which is present in cells as retinol-binding protein (CRBP). This family of proteins with
various cis conformations as well as trans-retinoic acid (tRA). high retinoid specificity includes CRBP as well as retinoic acid
Since retinoids play such a critical role in developmental biol- binding protein (CRABP), of which there are two isoforms,
ogy and the metabolic pathways are tightly regulated. This I and II (7). These binding proteins play a direct role in regu-
includes not only enzymatic processes but transport via cel- lation of retinoid responses in cells by acting as chaperones
lular retinoid binding proteins as well. in enzymatic conversions, sequestration and stabilization. The
Topical usage of potent forms of natural and synthetic reti- retinol-CRBP complex is a substrate for retinol dehydroge-
noids such as tRA has shown a high degree of efficacy against nase, a microsomal enzyme uniquely capable of catalyzing the
acne, psoriasis, icthyosis, and actinic keratosis. Relative to conversion of retinol to retinaldehyde. Retinaldehyde is then
photodamaged skin, tRA has clearly been established as hav- rapidly and quantitatively oxidized to retinoic acid by retinal-
ing a robust effect (1, 2) and is currently marketed as a pre- dehyde oxidase (5, 10). However, the primary reaction that
scription drug. These retinoid effects in diseased skin can be occurs with CRBP-bound retinol is esterification of retinol via
ascribed on some level as being a normalization of altered lecithin:retinol acyltransferase (LRAT) or acyl-CoA:retinol
skin conditions. However, two of the key negatives associated acyltransferase (ARAT) to retinyl esters, the primary storage
with highly potent topical retinoids are irritation that, in some form in lipid bilayers and of which retinyl palmitate is the major
instances, does not mitigate itself completely even after long species in human skin (11, 12). Recent work has identified the
term chronic exposure and teratogenic side effects. neutral lipid synthesis enzyme acyl-CoA:diacylglycerol acyl-
Less potent topical retinoids such as retinol and various transferase 1 (DGAT1) as a novel ARAT enzyme present in
retinyl esters (Figure 9.1) have been building a rich history murine skin that regulates retinol oxidation to retinoic acid
of usage in the cosmetic marketplace. More importantly for (13). Additionally, retinyl stearate has been identified as the
the cosmetic marketplace is the ability of retinoids to posi- major form that is present in circulating serum in mammalian
tively impact changes in the appearance of photodamaged systems (14). This multi-step processing of retinyl esters serves
facial skin, particularly for fine lines and wrinkles, as well as a point of regulation to control the level of active retinoid in
as pigmentation related changes. Additionally, understand- the skin and may thus contribute to the lower irritation poten-
ing the basic biochemical metabolic processes that control tial of these derivatives.
endogenous retinoid levels and synthesis has shown that cos- The molecular mechanistic route that tRA follows in skin
metic-type retinoids present an attractive compromise for less is via its function as an agonist for binding to a family of
serious conditions such as photodamaged skin. This chapter nuclear receptors called the retinoic acid receptors (RAR)
will focus on cutaneously delivered retinyl esters, and the and which also includes the retinoid X receptors (RXR). In
topics covered will include an overview of the metabolism, each of these two families, three isoforms exist and interact to
DOI: 10.1201/b22897-9 87
form heterodimers as the functionally active form. Significant activity via higher expression levels leads to a decrease to
research has gone into understanding these various dimer steady state levels.
combinations, including agonist binding as related to various In summary, the biochemical confirmation that topical reti-
tissues and cells. Upon binding of tRA by RAR and dimeriza- nol and retinyl esters can be metabolized to the more active
tion with a member of RXR, this active complex becomes a form of tRA in skin cells has provided a richer understanding
transcriptional regulator that binds to select sequences in proof how cosmetic retinoids are capable of having subtle effects
moter regions of select genes, termed retinoic acid responsive upon photodamaged skin. As we begin to understand deeper
elements or RARE (15). the molecular biology changes that are caused via tRA binding
As with most biological processes that involve highly potent to RAR/RXR, novel mechanistic insights into the efficacy as
agents, the retinoid pathway has several regulatory feedback well as the negative irritation side effects could allow for an
loops that help maintain an optimal level of tRA. One of the improvement in current commercialized products.
most important ones is depicted in Figure 9.2b, which shows
the degradation of tRA to the less active metabolites via
hydroxylation to 4-hydroxy-retinoic acid and 4-oxo-retinoic Potential to Break the Retinoid Efficacy to
acid, catalyzed by members of the CYP26 family (16). As tRA
Irritation Correlation with Retinyl Esters
levels become temporarily elevated, increased hydroxylase
Over the past few decades, retinol has been used extensively in
cosmetic products with the levels of retinol ranging from barely
detectable to upwards of 1.0%. The relative dosage levels vary
in part due to intolerance amongst consumers of irritation side
effects that is connected in part by a sensitivity to formulation
differences. One approach to reduce retinoid-induced inflam-
mation is to attempt to regulate skin penetration and delivery
rates into the skin via usage of nanoparticles and sponges (17). It
is unclear yet whether this provides an advantage versus merely
reducing delivery loads and reducing efficacy as well. As high-
lighted earlier, it has been generally assumed that any efficacy
from topically delivered retinol occurs via its sequential con-
version via the intermediate retinal to tRA (8). For example,
it has been shown that 0.4% retinol can significantly improve
the appearance of wrinkles on the surface of skin but also have
measured histological changes in the extracellular matrix com-
FIGURE 9.1 Chemical structures of retinol and retinyl esters. ponents of epidermal glycosaminoglycans and dermal collagen
FIGURE 9.2 Retinoid metabolic pathways in skin.

Retinyl Propionate and Related Retinoids 89
Type I (18). The authors also speculated that retinol treated skin table was performed under semi-occlusive patch, the ability of
would be more resistant to future skin injury, including ulcer the retinoids to penetrate into the viable cell layers is lessened
formation amongst elderly consumers. These reported effects as a variable for this comparison but may not explain the com-
are hallmark responses associated with topical tRA. A human plete story for retinyl palmitate (21). A review of the clinical
study compared 0.1%, 0.3%, or 1.0% retinol and determined that data on numerous retinoids, including both drug and cosmetic
0.3% and 1.0% retinol gave comparable efficacy but with lower compounds and formulation variables concluded that further
adverse events from 0.3% retinol (19). clinical testing was needed on the cosmetic retinoids (22).
Several natural and synthetic esters of retinol have been As would be suspected, this rank ordering of retinoid-based
evaluated for retinoid-like effects, including acetate, propionate, activity (efficacy) is also indirectly proportional to the level
palmitate, ascorbate, beta-glucuronide, and retinyl N-formyl of irritation that some topical retinoids can induce on skin
aspartamate. While the chemical structure of retinol is con- (20, Oblong, unpublished data). A comparison of human reti-
ducive to being esterified via the alcohol group, the ability for noid activity data from Table 9.1 with irritation date from a
retinyl esters to deliver efficacy that approaches retinol becomes human back cumulative irritation protocol using nearly identi-
limited by variables such as skin penetration, cellular uptake, cal formulations, one can see that there is a general correla-
hydrolase active site binding, re-esterification via acyl transfer- tion amongst the esters and retinol between retinoid activity
ases, and general pharmacokinetics. As with most retinoid ana- and irritation with the one exception of retinyl propionate at
logue work, the objective of evaluating retinyl esters is to be able 0.18% levels (Figure 9.3). This supports in-house clinical find-
to provide a retinoid-like response on facial skin but without the ings that retinyl propionate does not cause as much irritation as
negatives of irritation associated with topical usage.
Since retinyl esters are dependent upon an additional bio-
chemical processing step before releasing a free form of retinol
(Figure 2A), it is anticipated that topical retinyl esters would
have a weaker retinoid responsiveness range when compared
with retinol. A human forearm biopsy study was performed
that evaluated via histology the effect of tRA, retinol and three
retinyl esters (acetate, propionate, and palmitate) for the effects
upon changes in epidermal and granular layer thickness com-
pared to a placebo control (Table 9.1). Both retinyl acetate and
retinyl propionate were able to show a significant increase in
both thickness measures as compared to the placebo control.
The results with retinyl propionate are similar to what has been
previously reported (20). These results also highlight that there
is a relative rank ordering based on the biochemical processing
steps amongst the retinoids tested. In comparing the retinyl
esters, there also appears a ranking in terms of chain length
from shortest to longest, with shorter chained esters being
more potent than longer chained esters. While less intuitive,
the potential that shorter chained retinyl esters can be acted
upon by other esterases could partially explain their enhanced
retinoid response profile compared with retinyl palmitate, the FIGURE 9.3 Correlation between human irritation measures and
endogenous storage form. Since the experimental data in the epidermal thickening for retinyl acetate, retinyl propionate, and retinol.
TABLE 9.1
Changes in Epidermal and Granular Layer Thickness in Forearm Skin Due to Retinoid Treatment
Epidermal Significance vs. control Granular layer Significance vs. control
Topical treatment Code thickness (microns) and other treatments* thickness (microns) and other treatments*
Emulsion control A 50.75 — 3.03 —
1.0% Retinyl palmitate B 52.07 ns 4.88 ns
0.172% Retinyl acetate C 65.45 ABGHI 10.73 ABH
0.30% Retinyl acetate D 79.00 ABCeF 12.34 ABH
0.18% Retinyl propionate E 68.83 ABGHI 10.61 ABH
0.30% Retinyl propionate F 64.87 ABGHI 10.73 ABH
0.075% Retinol G 80.13 ABCEF 14.06 AB
0.15% Retinol H 85.66 ABCEF 17.44 ABCDEF
0.025% t-Retinoic acid I 80.64 ABCEF 14.72 AB
* Uppercase letters denote significant differences (p < 0.05), while lowercase letters denote directional differences (p < 0.10); ns = not significant.
retinol and still is able to positively impact the appearance of retinyl palmitate showed an apparent biochemical advantage
fine lines and wrinkles in 12-week human facial studies (23). for retinyl propionate (29). More specifically, retinyl propionate
While additional data would be required around the doses responded with a stronger signal in retinoid response models and
tested to confirm, these results support the suggestion that pharmacokinetic testing of these three retinoids in human skin
retinyl propionate is capable of eliciting a retinoid response in explants showed a stronger conversion of retinyl propionate. It
human skin but with a weaker overall retinoid irritation profile. is possible that the shorter alkyl chain length of retinyl propio-
In terms of application to photodamaged skin, retinyl pro- nate in contrast to retinyl palmitate renders it having an altered
pionate has recently become of interest since it is capable of recognition and binding affinity by retinol ester hydrolases,
affecting human skin much like retinol but with a lower irrita- acyltransferases, or other esterases. Other examples include the
tion profile than other retinoids (24, 25) (Figure 9.3). While the published clinical findings that showed the photostable ester
relative activity of retinyl propionate on photodamaged skin is retinyl N-formyl aspartamate was able to deliver retinoid like
weaker than retinol (25), it is clear that some of the effects are effects on photodamaged skin without significant irritation (30).
still significant (23). More recently, a retinyl propionate formu-
lation that also contained niacinamide and collagen fragment
peptides showed an equivalent level of efficacy compared with Conclusion
0.02% tRA (26). This combination of significant efficacy with
an overall lower irritation profile has been noted in cross com- Retinoids are a broad family of molecules that can be metabo-
parison of human biopsy studies, back cumulative irritation lized via endogenous enzymatic pathways to generate agonists
and human facial skin clinicals (Figure 9.3). While less criti- for members of the RAR and RXR nuclear receptor family. In
cal than its overall efficacy and irritation profile, retinyl pro- turn, this denotes their critical role in regulating gene expres-
pionate has been reported to have a better chemical stability sion profiles via RAR/RXR binding to RAREs. In dermatology,
profile compared to other esters, thereby increasing half-life prescription forms of natural and synthetic retinoids have been
upon skin during topical delivery (26). shown to have beneficial effects upon acne, psoriasis, icthyo-
The more potent ester retinyl acetate has been shown in in sis, actinic keratosis, and photodamaged/aging skin attributes.
vivo models as being able to induce a retinoid-like response as Relative to photodamaged skin, the cosmetic industry has been
measured by epidermal thickening as well as indirect markers using retinol and various retinyl esters for several decades. This
of epidermal proliferation (28). Additionally, the kinetics of class of molecules continues to be one of the more efficacious
the accommodation response to retinyl acetate as measured by materials available to consumers to help combat photoaged
erythema has a similar time curve over a 20-day period as has skin appearance. While the overall efficacy provided by these
been observed in human studies for accommodation to retinol cosmetic forms of retinoid are generally less potent than the
(Oblong, unpublished results). Since retinyl acetate has a similar prescription forms such as tRA, the knowledge that these forms
pharmaco activity and irritation profile as retinol, there appears can be metabolized to more active forms supports the indirect
to be no advantage of this ester over retinol in cosmetic products. mechanism of action that they utilize. Of the retinyl esters cur-
Of the retinyl esters currently practiced in the cosmetic mar- rently practiced in the marketplace, there appears to be advan-
ketplace, retinyl palmitate appears to be one of the weaker ret- tages for the usage of retinyl propionate over retinyl acetate in
inoids in terms of efficacy for generating a retinoid response in terms of having a similar efficacy response range but with an
human skin, including effects on photodamaged skin. This is improved irritation profile. In contrast, retinyl palmitate has a
more than likely due to the primary storage role of endogenous very low efficacy response range, rendering its low irritation
retinyl palmitate, which is a key regulatory point. Although profile as moot in terms of being able to have any positive ben-
some level of topically applied retinyl palmitate can be con- efits for affecting the appearance photodamaged skin.
verted to retinol, the small amount of retinyl palmitate that Future research in better understanding the connections
actually penetrates the skin would be expected to become between efficacy and retinoid-induced irritation should allow
accumulated into endogenous storage pools (4). Based on pub- for the identification of novel retinoids or combinations with
lished information and historical cosmetic usage, it’s accepted technologies that mitigate irritation and thus can decouple
that retinyl palmitate has at best an overall weak activity pro- these two phenomena. The results presented with retinyl pro-
file and is non-irritating (21). Evaluation of epidermal and pionate suggest the potential exists. Additionally, there would
granular layer thickening also shows the weak retinoid effect appear to be an opportunity to identify a final solution that
in human biopsy studies (Table 9.1). combines optimized levels and formulations as well as poten-
Finally, it has been observed that there may be a plateau of tially additional materials to maintain or elevate retinoid-like
responsiveness amongst retinyl esters as observed in various efficacy but with a reduced overall irritation profile.
retinoid-sensitive models (J. Oblong, unpublished data). This
suggests a threshold level in which excess retinol derived from REFERENCES
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GJ. (1994) Biological activity of all-trans retinol requires 21. Duell EA, Kang S, Voorhees JJ (1997) Unoccluded retinol
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ated through activation of nuclear retinoid receptors in cluded retinyl palmitate or retinoic acid. J Invest Dermatol
human keratinocytes. J Biol Chem 269:32821–32827. 109:301–305.
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retinal and retinoic acid. Exp Dermatol 7:27–34. dence for conventional and nanoformulations. Adv Ther
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Physiol 17:124–128. tation profile. Cosmeceuticals and Active Cosmetics: Drugs
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10
Antioxidants
Frank Dreher
either reverts to the ground state by energy dissipation or acts

Introduction as highly reactive intermediate leading to skin photodamage
via two pathways. In type I photoreactions, the excited chro-
Exposure of skin to solar ultraviolet radiation (UVR), air pol- mophore directly reacts with a substrate molecule via electron
lutants and other external as well as internal stressors results in or hydrogen atom transfer and gives rise to free radical for-
the formation of reactive oxygen and nitrogen species (ROS, mation. In the presence of molecular oxygen (minor type II
RNS). Those chemicals can react with skin biomolecules and reaction), this reaction may lead to the formation of superoxide
lead to oxidative skin damages (1, 2). To counteract the oxida- anion radical •O2−. Subsequently, •O2− gives hydrogen perox-
tive stress, skin is equipped with a variety of antioxidants form- ide (H2O2) by a dismutation reaction either spontaneously or
ing an antioxidant network. They intervene at different levels of catalyzed by cutaneous superoxide dismutase (SOD). Further,
oxidative processes by scavenging and removing free radicals or in the presence of metal ions such as Fe(II) or Cu(II), H2O2
oxidatively damaged biomolecules. However, skin’s antioxidant can be converted to the highly reactive hydroxyl radical •OH.
defence system can get overwhelmed by extended exposure to Otherwise (major type II reaction), electronically excited and
such sources of oxidative stress. In addition, the system may reactive singlet oxygen 1O2 is formed by photoenergy trans-
be compromised due to malnutrition or certain health condi- fer from UVA-excited chromophores in the presence of triplet
tions. Solar UVR-induced skin damage includes acute reactions oxygen 3O2 (molecular oxygen in its ground state).
manifesting as sunburn. Premature skin aging (photoaging) and Following their formation, ROS species including 1O2, •O2−,
photo-carcinogenesis are the consequences of chronic UVR • OH and H O react with an array of skin biomolecules includ-
2 2
exposure. Besides UVR and air pollutants such as particulate ing lipids, proteins, DNA and carbohydrates. For instance,
matter and hydrocarbons, the use of ROS-forming medica- (poly)unsaturated lipids (LH) may react with ROS forming
tions and the exposure of skin to photoreactive chemicals can lipid peroxyl (LOO•) and alkoxyl radicals (LO•), which may
be additional sources of cutaneous oxidative stress. Although initiate a chain-propagating autocatalytic reaction. ROS can
chronic UVR exposure is widely considered as the major cause also cause modifications of amino acids of proteins result-
of photoaging, all spectral regions of solar light including vis- ing in functional changes of structural or enzymatic proteins.
ible and near infrared radiation can cause free radical formation Besides a multitude of ROS-mediated DNA damages, reac-
and therefore contribute to oxidative stress in skin. tion of singlet oxygen with DNA results in the formation of
8-hydroxy-deoxyguanosine. Since DNA absorbs strongly
in the UVB region (280–320 nm) and is only a weak chro-
mophore in the UVA region, UVB is largely considered as
Reactive Oxygen Species
a direct, ROS-independent inducer of DNA damage. UVB
Several steps lead to the formation of ROS during UVR expo- absorption of DNA leads to major base modifications such
sure, a well understood source of oxidative stress in skin (1, as pyrimidine dimer or (6–4) photo-adduct formation. These
2). Solar UVA radiation (320–400 nm) at doses corresponding modifications together with indirect DNA damage induced by
to realistic sun exposure is known to induce major oxidative ROS are involved in solar genotoxicity.
stress in skin cells. UVA effects are mediated by numer- Additionally, oxidative damage to mitochondrial DNA
ous skin chromophores that absorb UVA. Several classes of (mtDNA) has been described to play a major role in photoaging
such skin chromophores, including bilirubin, flavins, mela- (4, 5). Studies have shown that a common deletion of mtDNA
nin and its precursors, porphyrins, pterins and B6 vitamins, is increased about 10-fold in photoaged skin as compared to
have established or likely roles as sensitizers of photooxida- sun-protected skin in the same individual (6). Although nor-
tive stress (3). While urocanic acid is also a skin chromophore mal ATP production in the mitochondria results in some level
and acts as a mediator of skin photo-immunosuppression, of oxidative stress, it is thought that UVA exposure increases
its role as an endogenous sensitizer of photooxidative stress oxidative stress in the mitochondria what leads to mutations of
remains ambiguous. Similarly, tryptophan and tryptophan mtDNA and consequently to a defective respiratory chain. The
photooxidation products have been described to act as both defective respiratory chain results in reduced energy produc-
UV-photosensitizers as well as quenchers of free radicals. tion by the mitochondria and increased production of ROS.
Photon absorption by a chromophore causes the formation This increase in ROS leads to more mtDNA mutations which
of the chromophore in a photoexcited state which subsequently further perpetuate the production of ROS. As a consequence,
92 DOI: 10.1201/b22897-10
Antioxidants 93
mtDNA mutations will increase even in the absence of UV can exhibit pro-oxidant properties since easily oxidized, vita-
exposure. This hypothesis has been termed the defective pow- min E prevents its oxidation. Uric acid, which is also present in
erhouse model of premature skin aging. skin, has both antioxidant and pro-oxidant properties in vitro
by scavenging and production of ROS (8). Its role within the
cutaneous antioxidant network is less well understood.
Catalase, GPX, GST, SOD and few other cellular stress
Constitutive Skin Antioxidant Network
response enzymes are under the transcriptional control of the
To protect against oxidative stress, skin is equipped with nuclear factor erythroid 2-related factor 2 (NRF2) which sig-
a complex network of enzymatic and nonenzymatic anti- nalling pathways are activated in response to oxidative stress
oxidants (1, 2). Antioxidant enzymes such as SOD, catalase, (9, 10). In recent years, the role of NRF2 in skin cytoprotection
glutathione reductase (GR) and peroxidase (GPX), glutathion- has become apparent.
S-transferase (GST), thioredoxin reductase and peroxidase α-Tocopherol, the predominant vitamin E homologue in
interact with low molecular weight lipophilic antioxidants skin, is known to efficiently scavenge lipid peroxyl and alkoxyl
including vitamin E homologues (tocopherols and tocotri- radicals by intercepting lipid chain propagation, which results
enols) and ubiquinols (coenzyme Q) as well as hydrophilic in the formation of the metastable tocopheroxyl radical. This
antioxidants such as vitamin C (ascorbic acid or ascorbate) and radical then either reacts with another lipid radical, leading to
glutathione (GSH) (Figure 10.1). Carotenoids are additional α-tocopherol consumption, or abstracts a hydrogen atom from
important antioxidants supporting the entire antioxidant status polyunsaturated lipids to give α-tocopherol and lipid radical.
of the human stratum corneum (SC), the horny outermost layer In the latter case, occurring preferentially at low lipid radical
of the epidermis (7). Lycopene, carotenes and lutein/zeaxan- concentration, the lipid radical may later react with oxygen to
thin account for approximately 60% of all SC carotenoids; the form a lipid peroxyl radical. This reaction consequently starts
remaining approximately 40% are phytoene and phytofluene. the α-tocopherol mediated lipid peroxidation chain reaction.
Using non-invasive Raman spectroscopy methods, carotenoids Formation of one molecule of α-tocopherol radical results in
can be rather easily studied as marker substances of the overall the formation of many lipid hydroperoxides. However, as dem-
antioxidant status of the human SC in vivo. The carotenoid onstrated in vitro in lipid and cellular systems, when ascor-
concentration is highest in the SC compared to the viable epi- bic acid or ubiquinol are present, the tocopheroxyl radical is
dermis and the dermis. rapidly reduced, regenerating α-tocopherol. The α-tocopherol
Retinol (vitamin A1) and dehydroretinol (vitamin A2), which mediated lipid peroxidation chain reaction is thereby termi-
can be metabolized in the skin to retinal and further to retinoic nated. In addition, because of its high reduction potential,
acid, also exhibit some antioxidant properties. While retinol ascorbic acid is an efficient scavenger of a series of ROS
FIGURE 10.1 Postulated activation of interactive network of antioxidants and antioxidant enzymes by oxidative stress in skin; note that some of the
depicted antioxidant recycling mechanisms have been found in vitro and in other than cutaneous systems.
including superoxide anion and hydroxyl radicals, singlet to the decreased water content of the human SC as compared
oxygen as well as water-soluble peroxyl radicals. The result- with less keratinized epidermal layers.
ing ascorbic acid radical is either recycled to ascorbic acid by In contrast to GSH and also ubiquinol, ascorbic acid, the
co-antioxidants such as glutathione or, respectively, is further vitamin E homologues, carotenoids and vitamin A cannot
oxidized to dehydroascorbic acid and then irreversibly decom- be synthesized by humans and must be taken up by the diet.
posed. Glutathione also reacts with singlet oxygen, superoxide Consequently, the skin’s antioxidant defense is dependent
anion radicals and hydroxyl radicals resulting in the formation on nutritive factors. Knowledge of the physiological regula-
of the thiyl radical GS• and subsequently glutathione disul- tion of ascorbic acid and vitamin E in skin is emerging. For
fide GSSG. The latter can be recycled to GSH by the NAD(P) instance, once ascorbic acid reaches skin via dermal blood
H-dependent enzyme glutathione reductase. vessels, it eventually enters the dermis where it is taken up
GSH is also a cofactor for a few reducing enzymes, among by fibroblasts using a specific, sodium-dependent vitamin C
them GPXs. GPX utilizes lipid peroxides as substrate and con- transporter 2 (SVCT2), or further diffuses through the dermis,
verts them into hydroxy fatty acids. GPX also catalyzes the finally reaching the epidermis and supplying keratinocytes
conversion of H2O2 into water and oxygen. As mentioned, less mainly via SVCT1 (15). In addition to its antioxidant activ-
reactive H2O2 is produced by SOD catalyzing the dismuta- ity, L-ascorbic acid acts as cofactor in a multitude of meta-
tion reaction of superoxide anion radicals. SOD is present in bolic processes involved in skin formation. For example, it is
skin as Cu/Zn- and Mn-SOD. GSH is likewise used by GSTs, required in hydroxylation reactions during collagen synthesis
which catalyze the conjugation of GSH to a variety of elec- to form connective tissue (16) and participates in biosynthesis
trophils, including oxidized lipids, DNA and other molecules. of epidermal barrier lipids (17).
GSTs therefore play an important role in removing products of α-Tocopherol is known to be a significant constituent of
oxidative stress. human sebum and is continuously secreted to the skin surface
Skin further comprises catalase, which is similar to GPX (18, 19). Therefore, sweat and/or sebum secretion is believed to
and eliminates H2O2. However, catalase contributes to scav- be tocopherol’s relevant physiological delivery pathway to the
enging H2O2 differently than GPX with respect to its cellular epidermis; same as for carotenoids and vitamin A (7). To a con-
distribution, enzyme stability, and reaction rate. The enzy- siderable degree, this helps explain their concentrations in the
matic activity of catalase is much higher than that of GPX in superficial SC. In fact, in vivo Raman spectroscopy revealed
human epidermis. Besides GPX, skin contains another sele- that the carotenoid concentration in the SC has two maxima;
nium-dependent enzyme, thioredoxin reductase. Thioredoxin one near the surface and one near the bottom of the SC. This
reductase, together with its electron acceptor thioredoxin and can be explained by the two independent delivery pathways:
thioredoxin peroxidase, participates in the cutaneous H2O2 from the inside due to keratinization and blood circulation
turnover similarly to the enzymic thiol redox couple GR/GPX. and from the outside with sweat and/or sebum secretion. The
In general, nonenzymic antioxidant concentrations as well physiological role of vitamin E in human sebum may be to par-
as enzymic antioxidant activities are significantly higher ticularly limit the formation of toxic skin surface lipid photoox-
in the epidermis as compared to the dermis. This probably idation products, such as squalene mono-hydroperoxides (20).
reflects the fact that the epidermis is directly exposed to vari-
ous exogenous sources of oxidative stress and might have
therefore evolved to possess a more pronounced antioxidant Effects of Environmental Stressors
defence capacity than the dermis. On a molar basis, hydro-
on Skin Antioxidants
philic nonenzymatic antioxidants including L-ascorbic acid
and GSH appear to be the predominant antioxidants in human Numerous in vivo studies documented the effects of UVR on
skin. Their dermal and epidermal overall concentrations are cutaneous antioxidants after acute and chronic exposure (1, 2).
more than approximately 10- to 100-fold greater than found The studies revealed that the antioxidants of the SC are vul-
for vitamin E or ubiquinol/ubiquinone. Ascorbic acid and nerable to UVR. For example, already a single suberythemal
GSH (11), and vitamin E (12) as well as catalase and SOD dose of solar-simulated UVR depleted human SC α-tocopherol
(13, 14) were also detected in the outermost epidermal layer, by almost half, while dermal and epidermal α-tocopherol were
the human SC. On the other hand, GPX activity seems not to depleted only at much higher doses (12). The high susceptibil-
be detectable in human SC (14). It was found that the distri- ity of SC vitamin E to UVR can be at least partially explained
bution of antioxidants in SC is not homogeneous, but follows by a lack of co-antioxidants in the outermost skin layer. The
a gradient with lower concentrations toward the skin surface lipophilic antioxidant ubiquinone-10 (oxidized form of ubi-
(12). Such a gradient may be explained by the fact that the quinol-10), the most abundant ubiquinol/ubiquinone found
outer skin layers are more directly exposed to environmental in human skin, was undetectable in human SC. Similarly,
sources of ROS/RNS. A second reason may be related to the the most significant decrease in the carotenoid concentration
longer exposure of the superficial SC layers to oxidative stress in human SC was observed two to three hours after UVB-
as compared to the lower layers, as a consequence of the physi- irradiation, while the recovery of carotenoids in the SC to the
ological turnover of keratinocytes during their differentiation initial level lasted up to three days (7). Under real life con-
process. Interestingly, while human SC concentrations of vita- ditions, regular sunlight exposure (for about 2 hours over 4
min E are as high as in lower epidermal layers, concentrations weeks in summer) of untreated and unprotected skin caused
of hydrophilic antioxidants ascorbic acid are in the range of an approximately 14% decrease in carotenoid concentration as
one to two orders of magnitude lower. This is most likely due average for all the study participants.
Antioxidants 95
Besides the lipophilic antioxidants, the hydrophilic anti- particular in the SC which is the most susceptible skin layer for
oxidants were also shown to be sensitive to UVR. However, oxidative stress. Accordingly, today’s sunscreen products fre-
it seems that ascorbic is less susceptible to solar-simulated quently combine sunscreen actives with several antioxidants.
UVR than α-tocopherol or ubiquinol-10 (21, 22). Relating to Oral supplementation of antioxidants, which is another strat-
antioxidant enzymes, murine epidermal GSH levels were sig- egy to prevent photodamage of skin, is not the subject of this
nificantly depleted within minutes after UVB exposure but chapter and has been reviewed elsewhere (34–36)
returned to normal levels after half an hour (23). And, expo-
sures of hairless mice to solar simulated UVR demonstrated
that dermal and epidermal catalase is more susceptible to Vitamin E
photo-inactivation than SOD, and far more than GSH peroxi- Vitamin E is present in eight isoforms: α-, β-, γ-, and
dase and GSSG reductase (24, 25). δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol. The photopro-
Along with solar radiation, air pollutants are another major tective effects of α-tocopherol have been studied extensively
factor in impacting the cutaneous antioxidant network. The (1, 2, 37). Significantly reduced acute skin responses including
common pollutants are particulate matter, volatile organic erythema and edema, sunburn cell formation, lipid peroxida-
compounds, ozone, nitrogen, and sulfur dioxide whereas both tion, DNA adduct formation, immunosuppression and UVA-
their concentrations and compositions vary across the world. induced binding of photosensitizers were demonstrated when
In addition to the lung, skin is the direct target organ and vitamin E was applied before UVR exposure. As shown in ani-
mostly affected by all these pollutants. mals, skin wrinkling and skin tumor incidence due to chronic
For instance, effects of ground-level (tropospheric) ozone UVR exposure was also diminished by topical vitamin E.
on skin antioxidants have been reported (26, 27). Similarly, A human study proved that an alcoholic preparation contain-
as found for sun exposure, the SC is the most susceptible skin ing 2% α-tocopherol significantly diminished the erythemal
layer for ozone-induced depletion of antioxidants and lipid per- responses when applied 30 minutes before UVR exposure (38).
oxidation. Based on transepidermal water loss changes mea- While this preparation had no sunscreening properties, some
sured in hairless mice after exposure to either solar-simulated α-tocopherol preparations may also act as sunscreens (39).
UVR or repetitive high doses of ozone, UVR appears a more In addition, diverse vitamin E esters such as vitamin E in
damaging oxidative stressor than ozone for skin (28). Whereas particular were also shown to reduce UVR-induced skin dam-
ozone at ground-level concentrations seems unable to pene- age. However, their photoprotective effects are less pronounced
trate deeply into the skin and therefore reacts predominantly as compared to vitamin E. Vitamin E esters need to be hydro-
with the skin lipids and proteins of the outermost epidermis, lyzed during skin absorption to show antioxidant activity. For
ozone’s impact on the skin barrier may be more significant in instance, bioconversion of vitamin E acetate into α-tocopherol,
conjunction with sun exposure. its active antioxidant form, seems slow and occurs only to some
A complex regulation in the antioxidant system of human extent. There is evidence that vitamin E acetate is not hydro-
skin was revealed during the intrinsic aging processes (13, 29). lyzed in the SC and that its bioconversion into α-tocopherol
α-Tocopherol concentrations were significantly lower in the only may occur after penetration into the nucleated epidermis
epidermis of aged skin but not for the dermis. Ascorbic acid and is slow (40, 41). Consequently, the inconsistent observa-
levels were lower in both epidermis and dermis of aged skin; tions of photoprotective effects of topically applied vitamin
total glutathione levels were also lower. Further, protein oxida- E acetate may be explained by a limited bioavailability of the
tion is increased in intrinsically aged, and, most significantly, active, ester-cleaved form during oxidative stress at the site of
in photoaged human skin. Here, the oxidative damage is most action. Intriguingly, the bioconversion of vitamin E acetate
pronounced in the papillary dermis and correlates well with into its active form may be enhanced when skin is exposed to
solar elastosis. Protein oxidation and a sharp decline in cata- sun, possibly by an UVB dependent increase in esterase activ-
lase protein levels were both found in the SC but not in the ity as demonstrated in murine epidermis (42).
lower epidermal layers of photoaged human skin. An age- and
UVR-dependent decline of SC catalase enzyme activity was
later demonstrated (14). Interestingly, single nucleotide poly- Vitamin C
morphisms for genes responding to catalase, but also GPX, The topical use of vitamin C (ascorbic acid) has been explored
SOD and NRF-2 have been correlated to skin aging (30). for several decades due to its antioxidant potential and whiten-
ing action and the essential role it plays in the synthesis and
maintenance of collagen. Because ascorbic acid is unstable
Photoprotection of Human Skin derivative molecules and stabilization strategies have been
explored to facilitate its incorporation into skin care products.
by Topical Antioxidants
Pioneering the research of topical vitamin C using a porcine
Together with sunscreens to help protect from solar light skin model, the investigators Darr and Pinnell demonstrated
reaching the skin, supplementation of skin with topically that it protects from UVB-induced erythema and sunburn cell
applied antioxidants and thereby strengthening its antioxida- formation when formulated at high concentrations (e.g., 15%)
tive capacity is in the meanwhile a well-established approach in an appropriate vehicle at low pH (e.g., pH 3.2) (43, 44). In
in limiting oxidative stress-induced skin damage (2, 31–33). In later human studies, it was shown that the application of gener-
fact, topical application of antioxidants provides an efficient ally only concentrated vitamin C preparations and over a pro-
means of increasing antioxidant tissue levels in human skin; in longed period of time is beneficial for skin (38, 45).
As indicated, the main challenge in the development of indirectly as antioxidants through inhibition of “pro-oxidant”
ascorbic acid products is its high instability and reactivity (46). enzymes such as inducible nitric oxide synthase, lipoxygen-
Ascorbic acid is reversibly oxidized into dehydroascorbic acid ases and cycloxygenases, and further induce the antioxidant
upon exposure to light, heat, transition metal ions and pH (alka- enzymes GSH-S-transferases, SOD and possibly also NRF2
line condition), then dehydroascorbic acid further irreversibly (57, 58). Protective effects of green tea extract and its major
hydrolyzes to form 2,3-diketogulonic acid. Vitamin C can be polyphenolic constituent EGCG on UVR-induced skin damage
stabilized in an aqueous formulation at rather acidic pH when after topical application were first observed in animals. These
kept under oxygen exclusion (47). More practical, water-free effects were later confirmed in humans, where topical applica-
silicon-based preparations allow stabilizing vitamin C over a tion of green tea extracts or EGCG significantly decreased ery-
prolonged period of time (48). Additionally, esterified vitamin thema responses, lipid peroxidation and DNA damage (59–61).
C derivatives such as magnesium or sodium ascorbyl phosphate, Further, while a placebo-controlled clinical study showed that
aminopropyl ascorbyl phosphate and tetrahexyldecyl ascorbate three-time daily topical use of a lotion containing 0.4% of a
(tetra-isopalmitate ascorbate) are stable alternatives to vitamin green tea extract with 40% to 50% total polyphenol content
C (49, 50). However, as described for vitamin E esters, these reduced the UVB-mediated increase in sunburn cell formation
esters must be hydrolyzed to vitamin C to reveal antioxidant and p53 expression in keratinocytes, it did not reduce signs of
properties. This can take time and occur only to a limited extent. erythema or formation of thymidine dimers (62).
Furthermore, few of those derivatives (e.g., tetrahexyldecyl A large number other polyphenols have also been stud-
ascorbate) are of significantly higher molecular weight as com- ied. For instance, resveratrol, a polyphenol belonging to the
pared to vitamin C, what may lower their skin permeability and stilbene family, is found in various plants, including grapes,
consequently their antioxidant efficacy after topical application. soybeans, blueberries and plums. Several studies investigated
the function of resveratrol in oxidative stress-induced skin
cellular senescence indicating that resveratrol prevents skin
Polyphenols
cellular senescence by activating the SIRT1/FOXO pathway
Polyphenol-rich ingredients obtained from plants and veg- (53). In addition, resveratrol can limit oxidative stress-induced
etables have gained extensive attention as promising topical skin inflammation caused by particulate matter air pollutants.
agents in protecting skin from sun induced photodamage Quercetin, a flavonoid class widely present in many fruits and
(51–53). Polyphenols are chemicals containing two or more vegetables such as apples, capers and onions, is another impor-
hydroxyl groups bound to an aromatic ring what provides tant polyphenol known for its health benefits (63). It helps
them their antioxidant properties. They are synthesized con- maintaining the oxidative balance in the body and stimulates
jointly with ascorbic acid, vitamin E and other antioxidants by synthesis of catalase, GSH and SOD.
plants as a response to mitigate cellular damage under oxida- Moreover, a milk thistle extract containing silibinin as
tive conditions. Their antioxidant properties arise from their predominant polyphenol was shown to inhibit UVB-induced
high reactivity as hydrogen or electron donors, from the abil- immunosuppression, reduce UVB-induced sunburn cell for-
ity of the polyphenol-derived radical to stabilize the unpaired mation, prevent DNA adduct formation and prevent photo-
electron, as well as from their ability to chelate transition carcinogenesis after topical application in mice (64, 65). In
metal ions such as Fe(II), thereby interfering with hydroxyl another study, topical administration of genistein (typically
radical production. Besides hydroxyl radicals, polyphenols are found in soybean and few other plants) substantially inhibited
believed to quench singlet oxygen, superoxide anion radicals UVR-induced hydrogen peroxide formation, lipid peroxidation
and peroxyl radicals. Along with being photostable and non- and DNA damage in mice and protected human skin against
phototoxic, some polyphenols possess additionally effective UVB-induced erythema (66). Furthermore, topical applica-
UVA/B sunscreening properties (54). Not surprisingly, there- tion of a tropical fern extract reduced erythema when applied
fore, being entirely “natural” makes polyphenol interesting before UVR exposure as shown in humans (67). In a clinical
additions to classical sunsceens in helping preventing photo- study, 1% coffee berry extract (containing diverse phenolic
aging and UV-related skin pathologies. Polyphenols further compounds including chlorogenic and ferulic acids) resulted
possess anti-inflammatory and other properties beneficial for in a significant improvement in signs of skin aging when com-
skin. Depending on their chemical structure, they can be clas- pared to vehicle (68). Pomegranate fruit extract, comprising
sified as flavonoids, lignans, phenolic acids or stilbenes. They the polyphenol ellagic acid, possesses strong antioxidant and
can exist as free molecules or more commonly in a form bound anti-inflammatory properties and limited UVB-mediated
to sugars as glycosides. Flavonoids are the best-known group damage in a human reconstituted skin model (69). Another
of polyphenols. Flavonoids include flavones, flavonols, flava- natural extract, a parthenolide-depleted extract of feverfew,
nones, isoflavones, anthocyanins and chalcones. significantly reduced UV-induced erythema in humans (70).
Extracts from the açaí palm fruit, coffee berry, chamomile,
feverfew, green tea leaves, milk thistle, pomegranate, tropical
Other Antioxidants
ferns, turmeric and wine grapes—all containing a wide variety
of polyphenols—were particularly well studied under topical use. Thiol antioxidants, such as GSH, N-acetylcysteine, lipoic acid
Green tea (Camellia sinensis) extracts are one of the best stud- and their derivatives are a further interesting group of radical
ied plant-derived antioxidants for skin (55, 56). Green tea leaves scavengers. They play a role in cysteine homeostasis, thiol/
contain a high level of catechin polyphenols such as epigallocat- disulfide redox state and redox-sensitive signaling pathways
echin gallate (EGCG). Catechins were additionally found to act (71). Topical administration of GSH, GSH-ethyl ester and
Antioxidants 97
N-acetylcysteine, respectively, efficiently protected against UVB which are a cluster of heterogeneous molecules that are gener-
radiation-induced epidermal lipid peroxidation, cytotoxicity and ated in a non-enzymatic reaction by the binding of sugars with
apoptosis using pig skin ex vivo as a skin model (72). However, amino groups of DNA, lipids and proteins.
their photoprotective effects have been reported in only a few
clinical studies. Topical treatment with N-acetylcysteine under
Antioxidant Combinations
occlusion resulted in an increased GSH level and eliminated its
oxidized form (GSSG) in humans (73). This suggests that the Antioxidants interact when combined and emanating radical
stimulation of GSH biosynthesis may be a key mechanism in the or oxidized forms of antioxidants after ROS/RNS scavenging
photoprotective effects of N-acetylcysteine. are regenerated in the presence of appropriate co-antioxidants.
Ergothioneine, a naturally occurring thiourea derivative of Accordingly, an enhanced photoprotective effect can be
histidine, represents another potent antioxidant (74, 75). It is obtained by applying distinct combinations of antioxidants.
capable of scavenging various ROS/RNS; notably, it reacts Ample evidence exists about the interactive dependence of
with singlet oxygen at a much higher rate than ascorbic acid. vitamins C and E in diminishing photodamage. For example, a
It has been shown to improve the stability of other antioxi- single topical application of a combination of 2% α-tocopherol
dants, even though the specific effect of ergothioneine on the and 5% ascorbic acid resulted in a significantly more pro-
antioxidant network remains unclear. Ergothioneine is linked nounced photoprotective effect as compared to the application
to the GSH/GSSG redox couple, promoting the cycling reac- of either antioxidant alone in the identical vehicle (38). This
tion, while GSH reverses its oxidation. Despite the promising clinical study further revealed that the most significant effect
features, however, clinical trials are currently lacking to show is obtained by a combination of α-tocopherol and ascorbic acid
ergothioneine’s benefits after topical use in humans. with melatonin. Another well studied combination is ferulic
Melatonin (N-acetyl-5-methoxytryptamine), a phylogeneti- acid (a phenolic antioxidant found in wheat, oat, rye, barley,
cally ancient molecule, is widely distributed in nature (76). and few other plants) together with 1% α-tocopherol and 15%
Being a multifunctional hormone, it acts also as an antioxidant; ascorbic acid (80). A significantly enhanced antioxidative effi-
likely by the stimulation of antioxidant enzymes as well as direct cacy was also found for the combination of α-tocopherol, ascor-
scavenging of variety of reactive ROS and RNS. Melatonin has bic acid and green tea polyphenols (81). Studies revealed that
been shown to significantly reduce UVR-induced erythema in the antioxidant synergism of this combination may be due to
humans, although its potential sunscreening properties as well the regeneration of α-tocopherol by the green tea polyphenols,
as its immunomodulatory function may have contributed to the while the latter are regenerated by ascorbic acid. Furthermore,
observed photoprotective effects (38, 77). using an electron spin resonance spectroscopy-based antioxi-
Carnosine (β-alanyl-l-histidine) is an interesting molecule dant assay (see next paragraph), a silicon-oil based preparation
with direct and indirect antioxidant properties, able to influ- comprising 15% L-ascorbic acid, 1% α-tocopherol, EGCG, the
ence cellular lifespan and the onset of age-related change with synthetic vitamin E analogue dimethylmethoxy chromanol and
an apparent rejuvenation of senescent fibroblasts at physiologi- creatine was significantly more effective in neutralizing free
cal concentrations (78, 79). Its mechanisms of action are still radicals in vitro as compared to a solution of 15% L-ascorbic
not well characterized even though several studies have dem- acid, 1% α-tocopherol and 0.5% ferulic acid (Figure 10.2) (82).
onstrated the involvement of metal ion chelation, the scaveng- Additional antioxidant combinations are currently being eval-
ing of ROS and reaction with peroxynitrite. Carnosine further uated for additive or potentially synergistic ROS/RNS scav-
prevents the formation of advanced glycation end products, enging properties using various testing methods.
FIGURE 10.2 The antioxidant product A (mixture with 15% ascorbic acid and 1% tocopherol combined with EGCG, dimethylmethoxy chromanol
and creatine in a silicon-oil based preparation) provided the highest antioxidant power with the fastest reaction time. Whereas antioxidant products A, B
(mixture with 15% ascorbic acid and 1% tocopherol combined with ferulic acid) and C (mixture of 10% ascorbic acid and 1% tocopherol) provided high
antioxidative capacities, the antioxidant products D (mixture with coffee arabica fruit extract) and E (mixture with tetrahexyldecyl ascorbate, tocopheryl
acetate, tocotrienols and ergothioneine) demonstrated relatively low antioxidative capacities (82). (a) Antioxidant power (mean ± standard deviation) of
the test products A to E as measured via ESR. (b) Antioxidant reaction time (mean ± standard deviation) of the test products A to E as measured via ESR.
Finally, it is important to keep in mind that antioxidants are

Evaluating Antioxidants of protective nature (i.e., from oxidative stress) and generally
have no effect in reversing existing skin damage, including
How to determine the potency of antioxidants or antioxidant fine lines and wrinkles. Only actives promoting extracellular
combinations to eliminate ROS/RNS is an important ques- matrix component formation such as retinoids, human growth
tion when studying antioxidants. Accurate quantification of factors and a few peptides, have been shown to help reverse the
antioxidant potency, what should include reaction time, is signs of skin aging to some extent.
challenging, however (83). Currently, there is no single assay
available that can sufficiently meet this task. Oxygen radical
absorbance capacity (ORAC) is a frequently used antioxidant
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11
Topical Retinol
An Efficacious Solution for Improvement
of Main Photodamage Signs
Christiane Bertin, Thierry Oddos, and Georgios N. Stamatas
Metabolism of Retinol
Introduction
Diet is the normal source of retinol in the body. It originates from
Clinically, skin aging is associated with a variety of signs such carotenoids in plants and of the long-chain fatty acid esters of
as wrinkles, uneven pigmentation, skin roughness, skin color, retinol (as retinyl palmitate) in animal tissue. In the intestinal epi-
and laxity. These clinical features are consecutive to the struc- thelium carotenoid molecules are split in the middle to form reti-
tural and metabolic changes that occur during the passage of nal, which is in turn reduced to retinol and esterified into retinyl
time (chronological aging). However, external factors such as ester. Retinyl esters are transported and stored in the liver, which
repeated skin exposure to solar ultraviolet (UV) radiation can is the main storage site in the body. Retinol is then delivered in
induce premature or photoaging of the skin. These changes the bloodstream being associated with a specific transporter, the
are attributed to a decrease in fibroblast numbers and collagen retinol-binding protein (RBP). Under healthy conditions, most of
synthesis, concomitant to an increase in UVinduced collagen the circulating retinol is associated with RBP and the level of
degradation by matrix metalloproteinases (MMPs). An accu- retinol in healthy volunteers fluctuates above 30 μg/mL (4).
mulation of non-functional elastin is also observed in the der- In the epidermis retinol uptake by keratinocytes is mediated
mis, leading to loss of skin elasticity and firmness. In addition, through the binding of the RBP-retinol complex to specific
a consistent hallmark of skin aging and photoaging is epidermal receptor(s), such as the 61kD retinal pigment epithelium (RPE)
thinning, which is triggered by a decrease in keratinocyte turn- protein, leading to its internalization (5–7).
over rate (1). Photoaging is also associated with dysregulation in Retinol is stored in keratinocytes in the form of retinyl esters
melanin synthesis and distribution, as well as a general increase (mainly palmitate, oleate, and acetate esters) (8, 9) primarily
in the inflammatory status of the skin leading to the appearance through the action of lecithin-retinolacyl transferase (10). It is then
of brown spots, increase in skin redness, and telangiectasia. oxidized into retinal and retinoic acid by different alcohol dehy-
Retinoids have shown beneficial effects in reducing skin drogenases (11). Other proteins responsible for retinol transport
photoaging. For instance, it has been demonstrated that all- play an important role in retinol metabolism. The cellular retinol-
trans retinoic acid (ATRA) improves the appearance of the binding protein (CRBP) shows a high affinity for all-trans retinol,
signs of skin photoaging (2). This clinical efficacy was mainly whereas the cellular retinoic acid binding proteins (CRABP I and
attributed to the effect of ATRA on collagen metabolism by CRABP II) bind specifically to retinoic acid. CRABPII is the pre-
stimulation of synthesis of collagen that ultimately accumu- dominant retinoic acid binding protein in the epidermis and its
lates in the upper part of the papillary dermis. Moreover, expression is enhanced by keratinocyte differentiation and treat-
ATRA downregulates UV-induced MMP1 and MMP9 ment with retinoids. The role of these proteins has not been com-
expression (3), thereby replenishing collagen levels. Although pletely elucidated. CRBP could play a role in presenting the retinol
ATRA is recognized as an effective therapy for the treatment molecule in the appropriate conformation to the dehydrogenase
of photoaged skin through its regulatory effect on collagen enzymes. They are also believed to control the level of free retinol
metabolism, it has been suggested that retinol (ROL), known and free retinoic acid and the translocation of these two molecules
as vitamin A, may also alleviate some major signs of photoag- to specific cellular compartments, which is the case for the translo-
ing with a milder irritation profile. cation of retinoic acid into the nucleus by CRABPII (12).
Retinoids are all derived from the naturally occurring all-
trans retinol. This molecule is composed of 15 carbons. Three
Biological Effects of Retinol on
parts of the molecule can be distinguished: a cyclic group, a
Different Types of Skin Cells
polyene group, and a polar group (primary alcohol for retinol –
CH2OH, and aldehyde –CHO for retinaldehyde and a carbox- Retinol plays a major role in the skin, as it is essential for regu-
ylic function –COOH for retinoic acid (Figure 11.1). Natural lating keratinocyte differentiation as suggested by the early
isomers carrying specific biological activities have also been observation of abnormal keratinization in vitamin A–deficient
described as 11-cis retinaldehyde and 9-cis retinoic acid. rats (13) and humans (14). Topically, retinol stimulates the
DOI: 10.1201/b22897-11 101

mechanisms that could explain in part its potential to protect

the skin against photodamage (3).
Clinical Aspects
Retinoids have been widely studied over the past decades for their
activity on human skin. In 1969, Kligman et al. proved the thera-
peutic efficacy of topical tretinoin (all-trans retinoic acid) in acne
vulgaris (20) and later in 1986 pioneered the use of retinoids in
cosmetic dermatology by demonstrating its effects on photoaged
skin (21). He conducted an open study on eight elderly patients
receiving 0.05% tretinoin cream on the face for 6 to 12 months,
while six other patients received the vehicle alone. Although
only slight clinical differences were observed, histology showed
a thickening of the previously atrophic epidermis, decrease of
keratinocyte dysplasia and atypia, more even dispersion of mela-
nin, and formation of new dermal collagen and blood vessels.
Since then, several clinical studies have been performed to
assess the activity of tretinoin on humans, especially in the treat-
ment of photoaging. Voorhees et al. in 1988 performed the first
double-blind randomized placebo-controlled study by apply-
FIGURE 11.1 Chemical structure of most common retinoids (all-trans
conformation): (a) retinol; (b) retinaldehyde; (c) retinoic acid. ing 0.1% tretinoin on the forearm and face of 30 patients for
16 weeks (22). They demonstrated a significant improvement of
photoaging in the tretinoin-treated areas. The greatest improve-
proliferation of the basal keratinocytes through the release ment was in the reduction of fine wrinkles, with a statistically
of heparin-binding–epidermal growth factor (HB-EGF) by significant difference occurring 8 weeks after beginning the
suprabasal keratinocytes (15, 16). The influence of retinol on study. Other features such as coarse wrinkles, roughness, and
keratinocyte differentiation is evidenced by the increase of sallowness also showed an improvement, but to a lesser degree.
some differentiation markers such as keratins (keratin 4, kera- In 1990 Lever et al., using a preparation containing 0.05% treti-
tin 10, keratin 13, and cytokeratin 19), while other markers like noin applied topically over 12 weeks, observed an improvement
filaggrin, transglutaminase, or loricrin are decreased. in clinical signs of photoaging (fine lines and wrinkles) (23).
The overall effect of topical retinol in the epidermis is stimula- One year later Grove et al., assessing different concentrations
tion of cell proliferation in the basal layer and inhibition of the ter- of tretinoin (from 0.05 to 0.001%) over 24 weeks, demonstrated
minal differentiation of suprabasal keratinocytes. Taken together, a better efficacy of the dose activity with the highest concentra-
these effects lead to a general thickening of the epidermis (8). tion (0.05%) of the ingredient, assessed on the Rz parameter
In aged dermal fibroblasts retinol has been able to potently (local mean amplitude) on skin replicas (24). In 1992 Olsen et
stimulate growth, as well as stimulate procollagen I and procol- al. showed a decrease of skin roughness, hyperpigmentation,
lagen III synthesis (17). A suggested mechanism for the induc- and fine wrinkling over a 24-week period in 296 subjects, using
tion of collagen synthesis by retinol involves the cysteine-rich the same range of concentrations as Grove et al. (25).
protein 61 (CCN1), a negative regulator of collagen homeostasis. Unfortunately, tretinoin tends to be irritating, with many
Topical treatment with retinol for 7 days significantly reduced patients experiencing redness, flaking, and increased skin sen-
CCN1 mRNA and protein expression in both chronologically sitivity. Some patients also reported increased sun sensitivity
and photoaged human skin in vivo (18). It has been shown that during tretinoin therapy (26).
retinol could also affect elastin synthesis and elastin fiber forma- Retinol, an alternative to tretinoin, is associated with fewer
tion (19). Indeed, retinol treatment of dermal fibroblasts cultures side effects and is better tolerated in cosmetic preparations aim-
as well as topical treatment on human skin explants resulted in ing for the improvement of photodamage signs. In 1995, Kang
tropoelastin and fibrillin-1 gene expression and elastin fiber for- et al. demonstrated that the application of retinol up to 1.6%,
mation as measured by qPCR and immunohistochemistry. on human skin under an occlusive patch, was unable to induce
Retinol represses the overexpression of UV-induced MMP1 significant erythemal reaction versus vehicle (8). Retinol evokes
and MMP9, two enzymes involved in the degradation of col- the same physiological response as the 0.025% erythemogenic
lagen molecules. The underlying mechanism is the repression concentration of retinoic acid, demonstrated by epidermal thick-
of AP1 transcriptional activity that drives the expression of ening and enhancement in CRAPBII mRNA concentration and
MMP1, MMP3, and MMP9 by the activated retinoic recep- protein expression. This activity of retinol was obtained without
tor. Skin exposure to UV light leads to stimulation of MAP a detectable increase of retinoic acid in the epidermis. Duell et
kinases such as ERK, JNK, or P38 followed by the overex- al. showed that topical retinol penetrated the epidermis more and
pression of the Jun protein which controls the level of AP1 produced less irritation than the acid form (27). Finally, Goffin
in the cell. Thus, retinol is able to decrease the UV-induced in 1997 tested 0.075% of retinol for 8 weeks with corneosurfam-
overexpression of MMPs and increase collagen synthesis, two etry and demonstrated its better tolerance versus tretinoin (28).
Topical Retinol 103
Non-invasive detection of retinol penetration in the epi- a significant improved tactile roughness values and over-
dermis is feasible through the use of in vivo confocal Raman all appearance of chronologically aged skin. Skin biopsies
microspectroscopy (RCM) due to the characteristic band of demonstrated thickening of the epidermis and a significant
all-trans-retinol at 1594 cm–1. Pudney et al. used this method to increase in GAG expression and procollagen I accumulation in
compare two different formulations in their efficacy to deliver the dermis compared to the vehicle-treated arm. In this study,
0.3% retinol into the epidermis (29). The same group later adverse reactions were reported by most subjects, although
studied the effectiveness of penetration enhancers to deliver rated as mild, including erythema, peeling, pruritus, dryness,
retinol through the stratum corneum (30). More recently, and burning or stinging, with the withdrawal of three subjects
Krombholz et al. compared the in vivo CRM method with ex following severe enough symptoms (33).
vivo tape stripping as methods to study retinol penetration in Our group explored the action of retinol on the signs of pho-
the skin and established a correlation between those methods toaging at a lower and better tolerated concentration (0.1%)
(31). Finally, Caspers et al. use retinol penetration as a model (34). In a first blind randomized vehicle-controlled study, 48
to demonstrate that RCM is able to give quantitative measures volunteers (41–60 years old) topically applied to the face either
of molecular flux in the skin (in µg cm–2 h–1) (32). the retinol 0.1% containing product or the vehicle, every day
for 56 weeks. The clinical evaluation, performed by an expert
grader after 12, 24, and 56 weeks of application, showed that
Clinical Efficacy of Retinol
wrinkles under the eyes, fine lines at the crow’s feet area, and
Although it has been demonstrated that retinol can induce a skin tone evenness significantly improved versus both base-
physiological response typical of retinoids in human skin, only line and vehicle. The improvement of the fine lines in the
a few clinical studies were published demonstrating its effi- crow’s feet area was also demonstrated with digital imaging
cacy in improving the signs of skin aging. In 2007, Kafi et al. and with surface profilometry. A progressive improvement
demonstrated in a clinical study the beneficial effects of retinol was seen between baseline and after 24 and 36 weeks of treat-
on the signs associated with chronological aging on the skin ment (Figure 11.2). The improvement in fine lines was also
appearance (33). This randomized study versus vehicle was documented by surface profilometry, and a progressive disap-
performed on 23 elderly subjects over 80 years old (average pearance of the fine lines in the crow’s feet area was observed.
87 years old). Retinol 0.4% and vehicle were topically applied Moreover, we demonstrated that retinol stimulates epidermal
on the upper inner arm for 6 months. The results showed a cell proliferation during the treatment. The epidermal cell
significant improvement in fine wrinkles versus vehicle after turnover rate was evaluated using in vivo fluorescence spec-
2 months of application. This improvement increased with troscopy by measuring the fluorescence maximum attributed
the continued application of retinol and was associated with to tryptophan moieties. The placebo-treated group did not
FIGURE 11.2 Examples of improvement of crow’s feet area following treatment with a formulation containing 0.1% retinol (a–d).
TABLE 11.1
Clinical Assessment of Retinol’s Antiaging Efficacy
Vehicle Retinol 0.1%
Parameter 4 Weeks 8 Weeks 4 Weeks 8 Weeks
Under-eye wrinkles 0% 2.2% 4.3%* † 6.5%*†
Crow’s feet fine lines 8.1%* 10.8%* 29.7%*† 35.1%*†
Crow’s feet wrinkles 0% 0% 2.8%* 8.3%*†
Forehead wrinkles 0% 0% 6.4%*† 6.4%*†
Skin radiance 16.7%* 20.8%* 34.8%*† 43.5%*†
Cheek wrinkles 0% 0% 7.3%*† 9.8%*†
Overall photodamage 3.8%* 3.8%* 17.3%*† 19.2%*†
* Statistical significance vs. baseline (p < 0.05); †Statistical significance vs. vehicle (p < 0.05).
Note: Values represent the percentage of improvement versus baseline.
show any significant change from baseline for any time point.
In contrast, for the actively treated group the intensity of tryp- Conclusion
tophan fluorescence increased versus baseline at 12 weeks and
then reached a plateau. Most importantly, the change in the Skin aging is a complex process involving numerous different
fluorescence intensity from baseline was significantly higher mechanisms such as loss of cell proliferation, decreased poten-
for the active-treated group than for the vehicle-treated group tial of extracellular matrix synthesis, and overexpression of
at the 36-week time point. These antiaging effects of retinol matrix-degrading proteinases. Retinoids are naturally present
were confirmed in two other shorter term double-blind ran- in the skin and regulate epidermal cell differentiation, activate
domized studies performed with moisturizing product con- collagen synthesis, and attenuate the UV-induced overexpres-
taining 0.1% retinol. In the first study the retinol-containing sion of MMPs. The potential of regulating several pathways
product was topically applied on 44 subjects (35–60 years involved in skin chronological and photoaging makes them
old) once a day for 8 weeks (35). The effect of the product good candidates as active ingredients to alleviate facial signs
was compared to the effect of its vehicle which was applied of aging. Although retinoic acid has been the first retinoid to
on 41 subjects. The results showed that the application of demonstrate efficacious improvement in the appearance of
0.1% retinol significantly improved the facial features of wrinkle, the skin irritation side effects induced by its topi-
photodamaged areas as early as 4 weeks of use (Table 11.1). cal application warrant the identification of other retinoids
Results from the second study have been published (36). for this benefit. Retinol was identified as a good alternative
In this 8-week, split-face, double-blind randomized clini- to retinoic acid, as its topical application induces a low level
cal study, a 0.1% retinol-containing moisturizer was tested of skin adverse reaction while delivering physiological skin
(36 subjects) versus placebo (28 subjects) in women with responses similar to those induced by retinoic acid. Moreover,
moderate facial photodamage. Clinical evaluation of photo- the retinoic acid level in the epidermis observed after topical
damage signs by a dermatologist demonstrated significant application of retinol is extremely low or undetectable and thus
improvement versus placebo in the appearance of fine lines, provides a substantial margin of safety with respect to possible
wrinkles, elasticity, firmness, and overall photodamage after systemic effect. Results presented here focus preferentially on
4 weeks. Thus, using a low level of retinol could still deliver a the clinical efficacy of well-tolerated doses of retinol. Indeed,
significant and rapid anti-aging efficacy, while maintaining a in two double-blind randomized placebo-controlled studies,
good tolerance profile, since only a few subjects experienced retinol at 0.1% demonstrated a significant visible improvement
a slight adverse skin reaction without any withdrawal in the of facial aging features such as fines lines and wrinkles within
group using the retinol product. In the two studies, the num- 1 month of daily application.
ber of adverse reactions observed with the retinol product was
not significantly higher than with the vehicle. These clinical
results were later confirmed by two other clinical studies per- REFERENCES
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12
Urokinase and Plasmin in Dry Skin, Skin
Aging, and Skin Pigmentation
Yuji Katsuta
Approach to Finding Intra-Epidermal

Introduction Secondary Factors That Cause Dry Skin
Urokinase (urokinase-type plasminogen activator, uPA) To elucidate the mechanism of dry skin occurrence and develop
belongs to trypsin-like serine protease family and activates effective compounds for preventing dry skin, attempts have been
inactive plasminogen into its active form plasmin. Because made to identify intra-epidermal secondary factors that cause
plasmin degrades fibrin clots, urokinase and plasmin are dry skin (1, 3, 4). These putative secondary factors are thought
called fibrinolytic enzymes. These fibrinolytic enzymes func- to respond to primary factors, such as a dry environment, and
tion not only in the blood systems but also in other organs, cause further changes in dry skin. Plasmin is identified as one
including the epidermis. They function in wound repair and of the secondary factors by means of the following approach.
in many disorders such as psoriasis and pemphigus. From the Detergent is a well-known cause of dry skin and is often
cosmetic point of view, urokinase and plasimin are involved used for an experimental dry skin model. Topical application
in dry skin, skin aging, and skin pigmentation. This chap- of sodium lauryl sulfate (SLS) induces the features of dry skin,
ter reviews the roles of urokinase and plasmin in these skin such as dryness, scaling, and rough texture. Physiologic values
conditions. are also changed in the SLS-treated area. The water content of
the stratum corneum is reduced, and the transepidermal water
loss (TEWL) values are increased. These physiologic features
of the SLS-induced dry skin model resemble those of naturally
Urokinase and Plasmin in Dry Skin occurring dry skin. This model was used in the screening for
the secondary factors.
Dry Skin
The barrier recovery test was also used because the decrease
Dry skin is visually characterized by dryness, scaling, and of barrier function is one of the most important phenomena
rough texture (1, 2). This condition can be experienced by associated with dry skin (4). The barrier function of the stra-
any healthy person, especially in a dry, cold season. There tum corneum was destroyed by tape-stripping or the applica-
are many external and internal factors that change the skin tion of a detergent or a solvent. Then the time course of TEWL
surface morphology and cause dry skin. The external factors was measured.
include exposure to extremes of climate (cold, wind, dryness), Many kinds of compounds were assayed in the experi-
chemicals (detergents, solvents), and ultraviolet radiation. The mentally dry skin model and the barrier recovery test.
internal factors include various abnormalities in physiologic Nonsteroidal anti-inflammatory agents such as acetylsalicylic
functions, illness, and mental stress. The effects of dry skin acid, indomethacin, mefenamic acid, ibuprofen, and sodium
are not limited to the appearance. The barrier function of the diclofenac were tested, but these compounds did not exhibit
stratum corneum is reduced. Proliferation of keratinocytes is suppressive effects. Then protease inhibitors were tested and
accelerated and turnover of the epidermis is increased. The tranexamic acid [trans-4-(aminomethyl) cyclohexane carbox-
epidermis becomes hypertrophic. The differentiation of kera- ylic acid (t-AMCHA)] prevented epidermal hypertrophy and
tinocytes is also abnormal in dry skin, leading to the incom- suppressed the appearance of dry skin. This compound is an
plete formation of the stratum corneum. inhibitor of plasmin. In contrast, ethylenediaminetetraacetic
For these reasons, supplying moisture to the skin surface acid (EDTA; a metalloprotease inhibitor), pepstatin (an aspar-
is not sufficient to prevent and improve dry skin. Applying tate protease inhibitor), and chymostatin (a chymotrypsin-type
creams topically for the purpose of occluding the skin sur- serine protease inhibitor) had no beneficial effect.
face is effective in improving the damaged barrier function, Because t-AMCHA, a plasmin inhibitor, was effective in ame-
but this is not a fundamental treatment. To maintain the skin liorating dry skin, plasmin was the candidate for the secondary
in a healthy state, it is essential to protect the epidermis from factor that causes dry skin. To confirm this, immunohistochem-
inside. Maintaining the normal proliferation of keratinocytes istry was performed. As shown in Figure 12.1, the localization
and keeping epidermal differentiation normal are important of plasmin was localized is restricted to the basal layer in the
requirements for preventing dry skin. intact skin of the inner forearm. On the other hand, plasmin was
106 DOI: 10.1201/b22897-12

Urokinase and Plasmin in Dry Skin, Skin Aging, and Skin Pigmentation 107
localized throughout the epidermis of experimentally induced Involvement of Plasmin in Skin Diseases
dry skin on the inner forearm. This result shows that the amount
of plasmin was increased with the induction of dry skin, sug- Plasmin is a trypsin-like serine protease that is distributed
gesting that plasmin is one of the secondary factors of dry skin. mainly in plasma. Although its main function is fibrinolysis in
Treatment with t-AMCHA was effective in preventing changes coagulated fibrin clots, plasmin also exists in adrenal, kidney,
in the intra-epidermal distribution of plasmin associated with testis, heart, lung, uterus, spleen, thymus, and gut (5).
dry skin as well as in suppressing epidermal hypertrophy. Plasmin exists in the epidermis as well. It is known to be
Efficacy of t-AMCHA was also shown in naturally occur- expressed in diseases such psoriasis (6). The epidermis of pso-
ring dry skin. A double-masked clinical test was carried out riatic skin is extremely hypertrophic, and the proliferation of
in the dry, cold winter season. The texture of the facial skin keratinocyte is rapid. The expression of plasmin is scattered
treated with t-AMCHA was significantly improved. throughout the epidermis in lesional psoriatic skin. The increased
plasmin activity may contribute to the disease manifestation.
Wounding epidermis also increases plasmin (7). At the
wound edge, keratinocytes proliferate and migrate rapidly to
cover the wounded area. Plasmin degrades the extracellular
matrix at the wound edge to aid proliferation and migration of
keratinocytes.
Epidermal hypertrophy is common in psoriasis, wounding,
and dry skin. Plasmin may be involved in promoting the pro-
liferation and migration of keratinocytes, resulting in epider-
mal hypertrophy.
Urokinase in Dry Skin

Plasmin is biosynthesized as an inactive precursor called plas-
minogen. The cleavage of Arg560-Val561 of plasminogen
activates this precursor molecule. Two major proteases are
involved in plasminogen activation. One of them is urokinase-
type plasminogen activator (uPA) and the other is tissue-type
plasminogen activator (tPA). These plasminogen activators
also belong to the trypsin-like serine protease family, as well
as plasmin.
Aberrant plasmin activity in the epidermis may require
increased levels of plasminogen activators. The lesional epi-
dermis from patients with psoriasis contains elevated levels of
plasminogen activators compared with nonlesional epidermis
or epidermis from normal individuals (8, 9). In psoriasis, tPA
is thought to be the major plasminogen activator (10), whereas
urokinase may be predominant in wounding.
The activity of plasminogen activator was detected in dry
skin. Stratum corneum obtained from dry skin by tape strip-
ping had the activity of lysing fibrin in vitro. Because this lysis
was inhibited when antibody against urokinase was added, the
major plasminogen activator in dry skin might be urokinase.
In situ zymography was carried out to confirm the presence
of plasminogen activator activity. The activity of plasminogen
activator was detected in the epidermis of the SLS-treated
skin, whereas little activity was seen in the control skin (4).
Urokinase Activity in Stratum Corneum of Dry Skin

Urokinase is produced and secreted as an inactive single-chain
precursor called pro-uPA. Cleavage of Lys158-Ile159 is essential
for its activation. It was found that urokinase is activated in stra-
tum corneum after barrier disruption (11). As a result of in situ
zymography, plasminogen activator activity was detected in the
FIGURE 12.1 Localization of plasmin in intact skin (a), in experi stratum corneum 1 hour after barrier disruption (Figure 12.2).
mentally induced dry skin (b), and in experimentally induced dry skin
treated with t-AMCHA (c). (From Kitamura K et al., J Soc Cosmet Chem This indicated that urokinase is activated in the stratum corneum
Jpn; 29:133–45, 1995, with permission.) at an early stage of dry skin formation. The stratum corneum
forms the surface layer of our bodies and is always exposed to The effectiveness of t-AMCHA and t-AMCHA methylam-
the environment. This activation of urokinase in the stratum cor- ide in preventing dry skin was compared in experimentally
neum might be the trigger process in dry skin formation. induced dry skin (Figure 12.4c). t-AMCHA methylamide sup-
The activation of urokinase in the stratum corneum was also pressed dry skin more potently than t-AMCHA at the same
tested in vitro. Human stratum corneum was homogenized in a concentration. This result suggests that inhibiting the physi-
glass homogenizer. The homogenate was washed with glycine cal interaction between urokinase and the stratum corneum is
buffer to remove endogenous urokinase. Pro-uPA was acti- more effective in preventing dry skin than inhibiting plasmin
vated after the incubation with the insoluble components of activity. Inhibition of urokinase activation in stratum corneum
the stratum corneum homogenate. by t-AMCHA methylamide in vivo was confirmed by using in
Pro-uPA activation must have taken place on the surface situ zymography (12).
of solid stratum corneum, because only the insoluble compo- Efficacy of t-AMCHA methylamide in ameliorating natu-
nents were used in the in vitro urokinase activation assay. To rally occurring dry skin was demonstrated in a double-masked
estimate the physical interaction of pro-uPA and the insoluble clinical test. After 1 month’s efficacy test in dry, cold win-
components of the stratum corneum homogenate, the mixture ter lotion containing t-AMCHA methyamide significantly
was filtrated to divide the soluble and insoluble components. improved dry skin. The skin surface texture of two cases
Then the amounts of urokinase in both soluble and insoluble before and after the treatment is shown in Figure 12.5. The
components were evaluated. Pro-uPA was found to bind to the efficacy of t-AMCHA methyamide indicates that inhibiting
insoluble components of stratum corneum homogenate in this the physical interaction between urokinase and stratum cor-
assay. The physical interaction is likely to be important for the neum is a useful approach for preventing dry skin.
activation of urokinase.
t-AMCHA Methylamide Is Effective Urokinase and Plasmin in Skin Aging

for Preventing Dry Skin
Basement Membrane in Photoaged Skin
The methylamide derivative of t-AMCHA (Figure 12.3) has
The epidermal basement membrane (BM), located at the
less inhibitory activity against fibrinolysis than t-AMCHA
dermal-epidermal junction, plays several important roles in
(Figure 12.4a). However, t-AMCHA methylamide strongly
controlling skin functions. It links the epidermis and dermis
inhibited the physical interaction between urokinase and the
tightly, and determines the polarity of keratinocytes (13). The
insoluble components of the stratum corneum homogenate in
proliferating keratinocytes remain attached to the BM and the
vitro (Figure 12.4b).
daughter cells migrate into the upper layers and differentiate
(14–16). The BM is mainly composed of type IV and VII col-
lagens, laminins (laminin 332, 331, and 511), nidogen, and
perlcan (17–19). Laminin 322, α2β4 integrin, type XVII col-
lagen, and type VII collagen are essential to epidermal attach-
ment, and mutations in the genes encoding these proteins lead
to blistering at the dermal-epidermal junction (20–22).
Skin aging can be classified as intrinsic aging or photo-
aging (23). Photoaging is caused by chronic exposure of skin
to ultraviolet radiation. Photoaged skin is characterized by
several clinical features such as wrinkling, laxity, roughness,
sallowness, pigments, telangiectasis, and neoplasia (24, 25).
The histological changes of photoaged skin include decrease
in collagen, dermal elastosis, loss of polarity, and flattening
of the dermal-epidermal junction (26, 27). Another feature
FIGURE 12.2 Detection of plasminogen activator activity in intact

skin (a) and skin after barrier disruption (b). Loss of fluorescence
indicates plasminogen activator activity. Plasminogen activator activity FIGURE 12.3 Molecular structures of t-AMCHA (a) and t-AMCHA
was detected in stratum corneum after barrier disruption (arrow). methylamide (b).
FIGURE 12.4 (a) Inhibition of fibrinolysis by t-AMCHA and t-AMCHA methylamide. t-AMCHA methylamide (1 mol/L) had less inhibitory effect
on fibrinolysis than t-AMCHA in vitro ±S.D. (b) Inhibition of physical interaction between urokinase and stratum corneum. t-AMCHA methylamide
inhibited (1% solution) the attachment of urokinase to the insoluble components of stratum corneum homogenate more potently than t-AMCHA ±S.D.
(c) Inhibition of experimentally dry skin by application of SLS. t-AMCHA methylamide (1% solution) suppressed the increasement of TEWL than
t-AMCHA ±S.E.
of photoaged skin is disrupted BM structure. As shown in

Figure 12.6, the BM is a single-layer sheet in the sun-protected Urokinase and Plasmin in Skin Pigmentation
skin, but it changes to multilayer in the sun-exposed skin
(27–29). Skin Pigmentation
Skin pigmentation is a condition characterized by the darken-
Involvement of Urokinase and Plasmin ing of a person’s skin colour and one of the most concerned
in the Disruption of BM skin conditions especially among Asian women. There are dif-
ferent types of skin pigmentation which include solar lentigo,
Ultraviolet exposure increases proteases such as matrix freckles, melasma, seborrheic keratosis, and post-inflamma-
metalloproteinases (MMPs) and urokinase (30–33). These tory hyperpigmentation. In any types of pigmentation, skin
enzymes were reported to damage the BM. These enzymes pigmentation is caused by increased melanogenesis or the
were also confirmed in in vitro skin-equivalent models (34). overproduction of melanin in epidermis. Because ultraviolet in
Skin-equivalent models show only a faint BM because BM solar light is the most stimulating factors for melanin synthe-
components were degraded by MMPs. In addition to MMPs, sis, protecting skin from solar exposure is the most effective
urokinase was detected in the condition medium by ELISA method in preventing skin pigmentation.
assay. The condition medium of the skin-equivalent model
showed fibrinolytic activity in the presence of additional plas-
minogen. It indicated that the added plasminogen was acti- Urokinase and Plasmin in Skin Pigmentation
vated by the urokinase in the skin-equivalent model. The mechanism of t-AMCHA in the reduction of the skin
BM in the skin-equivalent model is degraded in the pres- pigmentation is regarded as follows. The excess melanogen-
ence of plasmin. The addition of plasminogen disrupted the esis in the skin pigmentation is caused by arachidonic acid
deposition of the BM components such as laminin 332, type and its metabolites prostaglandin, and leukotriene. Plasmin is
IV collagen, and type VII collagen. The depositions of these involved in the activation of phospholipase A2, which produce
BM components are reduced and discontinuous at the dermal- arachidonic acid (41). Plasmin induces a receptor-mediated
epidermal junctions (Figure 12.7). Furthermore, the epidermis arachidonate release in endothelial cells (42). Furthermore,
showed abnormal differentiation without filaggrin expression. plasmin induces the production of leukotriene (43). Because
The urokinase inhibitor t-AMCHA improved the deposition t-AMCHA is a urokinase inhibitor, t-AMCHA inhibits the
of these BM components, and the epidermis recovered to a activity of urokinase and plasmin system in epidermis and
normal differentiation state. then inhibits the production of arachidonic acid, prostaglan-
din, and leukotriene.
Laminin 332 Can Be Degraded by Plasmin
Because the deposition of laminin 332 was reduced by the Urokinase in the Skin with Pigmentation
addition of plasminogen, the degradation of laminin 332 by Because t-AMCHA is effective in the treatment of skin pig-
plasmin was analysed by means of Western blotting. The pro- mentation, urokinase is thought to be activated in the pigmen-
cessed form of laminin 332 is composed of two 160- and 150- tated skin area. To confirm this hypothesis, the activity of
kDa α3 chains, a 140-kDa β3 chain and a 105-kDa γ2 chain. urokinase in the pigmented skin area was evaluated and com-
On the other hand, the plasmin-treated laminin 332 was compared with the control skin area without pigmentation using
posed of two 140- and 145-kDa α3 chains, a 110-kDa β3 chain the synthetic substrate Glu-Gly-Arg-pN. The result showed
and a 105-kDa γ2 chain. These chains were presumably gen- that urokinase activity was increased in the pigmentated skin
erated by the cleavage of a 5- or 10-kDa fragment from the area significantly (Figure 12.8). The activated urokinase is the
carboxyterminal end. one of the deteriorating factors for the skin pigmentation.
FIGURE 12.5 The improvement of skin surface texture after 1 month’s treatment with t-AMCHA methyamide. Skin surface texture before treatment
(a, c) and after treatment (b, d).
FIGURE 12.6 Transmission electron microscopic images of the basement membrane (BM) of human skin. (a) Neither disruption nor duplication is
observed in the sun-protected abdomen skin of a 34-year-old woman, but (b) disruption and reduplication of the BM are observed in the sun-exposed
cheek skin of a 30-year-old woman.
FIGURE 12.7 Disassembly of BM at the dermal-epidermal junction in the presence of plasmin, and the recovery of BM assembly by the addition of
t-AMCHA. Skin equivalents (SEs) were cultured in the absence (a–d) or presence of plasminogen (e–l). The control SE showed linear and sharply defined
deposition of laminin 332, type IV collagen, and type VII collagen (b–d). In the presence of human plasminogen, impaired deposition of BM components
is observed (f–h). The impairment of BM assembly is blocked in the presence of t-AMCHA (j–l). HE, hematoxylin and eosin staining (a, e, i).
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13
4 -Hexyl-1,3-Phenylenediol, a NF-κB Inhibitor,
Improves Clinical Signs of Aging
Cécilia Brun, Simarna Kaur, Michael D. Southall, Christiane Bertin, Thierry Oddos, and Georgios N. Stamatas
homology domain, containing a DNA-binding site, a dimer-

Introduction ization domain, and a nuclear localization domain.
Both homodimers and heterodimers are sequestered in the
Aging can be defined as a physiological process that is charac- cytoplasm in an inactive form due to their association with a
terized by an alteration of the physical and intellectual abilities member of the IκB family of inhibitory proteins, that can mask
of the human body. The fight against aging is easily recognized their nuclear localization domain and thus prevent their trans-
as one of the major challenges of the twenty-first century. location to the nucleus (5). Activation of the dimers requires
Skin aging could be considered as a reflection of the overall the activity of IκB kinases (IKK), which phosphorylate two
aging of the human body. Indeed, the appearance of wrinkles serine residues (Ser32 and Ser36) on IκB proteins leading to
is one of the first visible signs of aging. Among several fea- their ubiquitination and degradation in the proteasome. The
tures, skin aging can be characterized by the appearance of degradation of IκB proteins unmasks the nuclear localization
wrinkles but also an emergence of brown spots, loss of skin sequence of NF-κB allowing it to translocate to the nucleus
tissue, or reduced wound healing capacity. Cosmetic indus- and finally bind to specific sequences on the promoter region
tries attempt to mitigate the appearance of these signs of aging of various target genes (6).
through “antiaging” product lines. Therefore, the develop-
ment of these products requires prior knowledge of skin aging
mechanisms and many research teams try to identify mark-
ers of aging and evaluate the cellular and molecular altera- NF-κB and Skin Homeostasis
tions responsible for these skin changes. Briefly, skin aging
The NF-κB pathway was first studied for its role in the devel-
is associated with epidermal atrophy, decreased proliferative
opment and function of immune cells (7). More recently, its
capacity of skin cells, and loss and/or alterations of dermal
implication in non-immune cell growth and function regula-
extracellular matrix (ECM) protein expression.
tion has been extensively investigated, especially for skin
At the cellular level, the aging process, also called cellular
homeostasis. More specifically, several studies have shown
senescence, involves cell cycle arrest accompanied by a certain
that NF-κB signaling plays a particularly important role for the
loss of function and an alteration of the gene expression pat-
maintenance of immune homeostasis in epithelial tissues (8).
tern. Over the past 20 years, NF-κB (nuclear factor kappa B)
The skin is comprised of two major compartments, the
activation has been recognized as a hallmark of the aging
epidermis and the dermis. The latter is mainly composed of
process as it regulates the expression of numerous genes,
fibroblasts surrounded by ECM proteins such as collagen and
some of which are involved cell maintenance and entry into
elastin. The epidermis is a stratified epithelium containing
senescence.
various layers of keratinocytes. The basal layer is mitotically
active and contributes to cell renewal, whereas in the layers
above it, proliferation stops as cells migrate to the skin surface
and undergo terminal differentiation.
NF-κB Signaling
Khavari et al. have demonstrated a critical role of NF-κB
First described in 1986 by Sen and Baltimore (1), NF-κB is a in epidermal homeostasis. They observed cytoplasmic local-
well-known transcription factor involved in the regulation of ization of NF-κB proteins within cells of the basal layer and
numerous target genes related to innate and adaptative immu- nucleic localization in non-proliferating cells of the layers
nity, inflammation, apoptosis, or cellular growth (2, 3). NF-κB above, suggesting that NF-κB activation plays a role in the
has also been shown to be involved in several diseases includ- switch from the proliferative basal cell phenotype to the non-
ing arthritis, asthma, and cancer (4). proliferative one of suprabasal layers (9). Furthermore, inhibi-
The NF-κB family members such as p50, p52, p65, c-Rel, tion of the NF-κB function resulted in epithelial hyperplasia,
and RelB are found as homodimers or heterodimers in the demonstrating a potential role for NF-κB activation in nega-
cytoplasm of unstimulated cells, with the most common form tive growth regulation, in contrast to other tissues. In vitro
being a heterodimer of p65 and p50. These proteins share overexpression of active NF-κB subunits in normal epithe-
highly conserved sequences of amino acids known as the Rel lial cells inhibits cell cycle progression and favors cell cycle
DOI: 10.1201/b22897-13 113

inhibitor expression such as p21 (10). Likewise, IKK deficient p65 and p50 NF-κB subunits in young cells resulted in signifi-
mice display abnormal skin development with thicker epider- cantly lower expression of COL1A1. Furthermore, overexpres-
mis associated with hyper-proliferation and defects in kerati- sion of p65 induced senescence in fibroblasts from young and
nocyte terminal differentiation (11). old donors. Altogether, this set of data strongly suggests that
The epidermis is exposed to harmful solar ultraviolet (UV) NF-κB signaling might be involved in the skin aging process
radiation. In this context, NF-κB binding activity was shown by favoring skin cell senescence and preventing collagen syn-
to be rapidly induced in nuclear extracts from skin submitted thesis, both features leading to the appearance of the clinical
to UV radiation, suggesting a role for the transcription factor signs of aging. Supporting this hypothesis, the work of Adler
in keratinocyte protection and survival (12). et al. revealed that tissue-specific NF-κB inhibition in mice
At the dermis level, NF-κB was shown to inhibit the expres- reversed key features of epidermal aging such as loss of pro-
sion of collagen 1 alpha 1 (COL1A1) gene (13). This inhibi- liferative potential of keratinocyte from the basal layer, p16
tion is mediated through the recruitment of p65 subunit to the expression, and SA-βGal-positive staining (19).
COL1A1 gene promoter by physical interaction with COL1A1 NF-κB pathway can also be activated in response to oxida-
transcription activators c-Krox, Sp1, and Sp3 (14). NF-κB is tive stress triggered by ionizing radiation or exposure to UV
thus a potent negative regulator of dermal ECM homeostasis. with a subsequent enhanced DNA binding activity and NF-κB
Furthermore, overexpressing an NF-κB super-repressor in protein expression (24, 25). Skin sites that are chronically
adult mice resulted in defective morphogenesis of hair follicle exposed to solar radiation over life, with enhanced NF-κB
and other appendices (15). activity might favor cellular senescence related to skin aging
Altogether, these data clearly indicate that NF-κB proteins and in particular photoaging.
are strongly involved in skin homeostasis. UV radiation and photoaging are often associated with accu-
mulation of DNA damage as a result of increased concentra-
tions of reactive oxygen species (ROS) (26). Our preliminary
experiments suggest that NF-κB might favor DNA damage
NF-κB Activation during (Skin) Aging
accumulation following UV exposure (27). Indeed, topical
There is growing evidence supporting an increased NF-κB pretreatment of skin equivalents with an NF-κB inhibitor
activity as a function of age. This alteration was first observed (4-hexyl-1,3-phenylenediol) significantly reduced UV-induced
on rodents by Salimen et al., who demonstrated an age-related DNA damage as determined by T-T dimer formation in skin
increase in NF-κB binding activity in mouse cardiac muscle cells. However, NF-κB was also shown to be involved in dou-
and rat brain (16, 17). However, neither IκB inhibitor protein ble strand break removal and repair by stimulating homologous
levels nor IKK protein levels and phosphorylation activity recombination, potentially through BRCA2, the expression of
were affected by aging (18), suggesting a potential retention which can be induced by NF-κB (28, 29). Conversely, experi-
of the transcription factor into the nucleus. The role of NF-κB ments in which human primary keratinocytes were treated
signaling during aging was further investigated by motif mod- with NF-κB inhibitors (Bay-11–7082 and 4-hexyl-1,3-phenyl-
ule mapping technique. These experiments on various tissues enediol) following UV exposure, indicate that NF-κB activity
from mice and humans revealed that the NF-κB motif was could delay DNA repair in keratinocytes (27). Cells imme-
the motif most strongly associated with aging (19). Another diately treated with NF-κB inhibitors (0.1 μg/mL and 1 μg/
study suggested that NF-κB might be activated upon senes- mL) displayed significantly lower DNA damage after 1 or
cence (20). More recently, a genome-wide expression profil- 2 hours of treatment as measured by the Comet assay com-
ing identified various upregulated and downregulated genes pared to untreated cells, strongly suggesting improved DNA
during cellular senescence as downstream targets of NF-κB. repair capacity as a result of NF-κB inhibition. Sauvaigo et al.
Reversion of senescence by abrogation of p53/p21 and p16/pRb demonstrated in human skin fibroblasts that both base exci-
pathways inhibited the up-regulation of these NF-κB target sion repair and nucleotide excision repair were significantly
genes. Silencing of NF-κB subunits did manage to overcome reduced with age (30, 31). As previously mentioned, the NF-κB
growth arrest. This suggests that NF-κB signaling has a causal binding activity was found to be significantly increased in der-
role in promoting senescence (21). mal fibroblasts from older donors compared with younger ones
Of interest, various studies demonstrated an association (23). Taken together, these data clearly suggest that elevation of
between NF-κB signaling and skin aging. Indeed, senescent NF-κB transcriptional activity might contribute to the decrease
keratinocytes were shown to display higher NF-κB DNA in DNA repair capacity of skin cells with aging.
binding activity than young ones and inhibition of its activity
resulted in decreased senescence-associated β-galactosidase
(SA-βGal) staining in old cells. Moreover, overexpression of
A New Target for Skin Aging
NF-κB subunits in normal young keratinocytes induced pre-
mature senescence of these cells (22). Likewise, Bigot et al. Since NF-κB is clearly associated with skin aging, it appears
observed elevated amounts and binding activities of p65 and as a promising target. As previously mentioned, the work of
p50 NF-κB subunits in dermal fibroblasts isolated from aged Adler et al. clearly supports the idea that NF-κB inhibition
skin (23). This alteration is associated with a significant loss of could reverse the skin aging phenotype (19). In a chrono-
COL1A1 expression in older cells compared to younger ones. logically aged mouse model, tissue specific inducible genetic
NF-κB was previously shown to inhibit the transcription of the blockade of NF-κB in the epidermis (through introduction of a
COLIA1 gene (13, 14); thus, as expected, forced expression of p50 mutation under control of the keratin 14 promoter) reduced
4-Hexyl-1,3-Phenylenediol Improves Clinical Signs of Aging 115
gene expression of 225 genes compared to gene expression (Figure 13.1). At the clinical level, an 8-week, double-blinded,
levels observed in younger ones. This inducible NF-κB path- randomized placebo-controlled study demonstrated significant
way inhibition reversed key features of epidermal aging such improvements regarding crow’s feet fine lines, cheek wrin-
as loss of the proliferative potential of basal keratinocytes, p16 kles, and forehead wrinkles in females treated with 4-hexyl-
expression, and SA-βGal-positive staining (19). 1,3-phenylenediol compared with those treated with placebo.
Molecular NF-κB inhibitors are also frequently investigated Skin radiance, mottled pigmentation, and age spots were also
for their protective effects against skin aging. For example, significantly improved (44). These results are in accordance
Tanaka et al. have extensively explored this topic and dem- with the anti-tyrosinase activity of 4-hexyl-1,3-phenylenediol,
onstrated that some plant extracts such as parthenolide (from as previously described (41).
Tanacetum parthenium), magnolol (from Magnolia ovovata), More recently, 4-hexyl-1,3-phenylenediol has been reported
or cynaropicrin (from Cynara scolymus L.) efficiently pro- to inhibit the formation of advanced glycation end products
tected skin cells from photoaging (32–34). Likewise, our own (AGEs) which may contribute to the improvement in skin
results strongly indicate that the NF-κB inhibitor 4-hexyl- aging. AGEs are formed by the cross-linking sugars with
1,3-phenylenediol, also known as HEXINOL™, can protect proteins, causing damage to the structure and function of
skin cells from UV-induced DNA damages and increase DNA proteins and which can ultimately contribute to skin aging.
repair capacity, thus preventing the photoaging process (27). For example, glycation of elastin fibers has been shown to
decrease fiber elasticity on tensile tests (45) and glycation may
contribute to the sallowness appearance that occurs in aging
skin (46). 4hexyl-1,3-phenylenediol has been shown to inhibit
4-Hexyl-1,3-Phenylenediol: A New α-glucosidase activity in a non-competitive way and can block
Technology against Skin Aging the formation of AGEs (47). It remains unclear if the inhibition
4-hexyl-1,3-phenylenediol is an amphiphilic compound, com- of AGE formation is mediated through a NF-κB-dependent
monly used in food processing as anti-browning agent (35). or a NF-κBindependent mechanism. Taken together, 4-hexyl-
It is an analog of resorcinol with a long history of use as dis- 1,3-phenylenediol may improve skin aging by reducing the
infectant in topical or oral formulations (e.g. throat lozenges) formation of AGEs, thereby preserving the integrity and func-
for its antioxidative and antimicrobial properties (36–38). tion of proteins in the skin which could lead to improved skin
Compounds with a 4-substituted phenylenediol motif mimic elasticity, firmness, and a reduction in the appearance of fine
tyrosine, the natural substrate of tyrosinase, which renders lines and wrinkles.
them potent inhibitors of tyrosinase activity (39, 40), an In summary these observations strongly indicate that
enzyme involved in melanin synthesis. In a previous report we 4-hexyl-1,3-phenylenediol, through its action of reducing skin
described that 4-hexyl-1,3-phenylenediol significantly reduced hyperpigmentation, blocking formation of advanced glycation
melanogenesis in primary human melanocytes, murine mel- end products, acting as antioxidant, and inhibiting NF-κB-
anoma cells, and pigmented human epidermal equivalents mediated skin damage such as reduced ECM expression or
through inhibition of tyrosinase enzyme activity and protein decreased DNA repair capacity, is an important agent to be
expression (41). A double-blinded, randomized controlled considered when designing anti-aging strategies.
clinical study confirmed that topical application of a formula
containing 4-hexyl-1,3-phenylenediol significantly reduced Clinical Study
skin hyperpigmentation (41). These findings clearly establish
4-hexyl-1,3-phenylenediol as an effective agent for the treat- To further investigate the effects of the HEXINOL™ technol-
ment of undesirable human skin hyperpigmentation such as ogy on skin aging, we performed a clinical study on 42 female
the appearance of brown spots, one of the key features of skin volunteers from 45 to 70 years old. A topical formulation con-
aging process. taining the 4-hexyl-1,3-phenylenediol (1%) or a placebo for-
The phenolic ring of 4-hexyl-1,3-phenylenediol can act mulation was applied by the subjects on half face and neck
as a proton donor, which allows it to scavenge free radicals for 12 weeks, twice a day. Active and placebo formulations
generated during high levels of oxidative stress, for example were randomly assigned to left and right sides. At baseline,
following exposure to UV radiation (42). This explains the volunteers participating in the study presented wrinkles on the
antioxidant activity of this molecule. forehead, the crow’s feet area, underneath the eyes, the cheek
As previously mentioned, 4-hexyl-1,3-phenylenediol is also area, nasolabial folds, and the corner of the lips. They also
known as a potent inhibitor of NF-κB (43). Given the promi- displayed pigmented spots to the face (at least one of 3 mm in
nent role of the transcription factor in aging and in particular diameter on each half-face), problems with skin tonicity, and
skin aging, we investigated whether NF-κB inhibition through dull complexion.
4-hexyl-1,3-phenylenediol could improve photodamaged skin Skin aging features were clinically assessed by a dermatolo-
and clinical signs of aging. In another study, our team first gist using a visual analog scale. Brown spots were also char-
confirmed an increased NF-κB transcription activity in cells acterized using a colorimeter, and viscoelasticity of the skin
isolated from older skin samples compared with younger cells, was measured. Assessments were performed before the first
activity that was dose-dependently inhibited with 4-hexyl- application (T0), then after 4 weeks (T4), 8 weeks (T8), and 12
1,3-phenylenediol (44). Furthermore, treatment with 4-hexyl- weeks (T12) of product daily use.
1,3-phenylenediol restored collagen and elastin synthesis, Results of the clinical grading are presented in Table 13.1.
which had been inhibited by NF-κB signaling enhancement At T4 no improvements were observed with either treatment.
TABLE 13.1
Percentage of Improvement on Skin Aging Features Conferred by Application of the Product Containing 4-Hexyl-1,3-Phenylenediol
(1%) at 8 and 12 Weeks of Treatment
T8 T12
Feature % Improvement vs baseline Significance vs placebo % Improvement vs baseline Significance vs placebo
Forehead wrinkles 5,00 * 8,00 *
Crow’s feet wrinkles 17,00 * 25,00 *
Under the eye wrinkles 19,00 * 29,00 *
Cheek wrinkles 10,00 * 18,00 *
Marionette wrinkles 5,00 NS 7,00 NS
Nasolabial fold 4,00 * 7,00 *
Crow’s feet fine lines 9,00 * 13,00 *
Under the eye fine lines 13,00 * 21,00 *
Color intensity of pigmented 11,00 * 24,00 *
spots 3,60 NS 6,00 NS
Size of the pigmented spots 8,00 * 16,00 *
Number of pigmented spots 9,00 * 16,00 *
Overall photodamage 18,00 NS 26,00 NS
Skin brightness 26,00 * 33,00 *
Complexion homogeneity 26,00 * 35,00 *
Skin firmness 21,00 * 28,00 *
Skin elasticity 21,00 * 30,00 *
Softness 32,00 * 46,00 *
Smoothness
Note: Results are presented as percentage of improvement as compared to T0.
* p < 0.05 versus placebo.
Abbreviation: NS: Non-significant.
FIGURE 13.1 Mechanism of action of 4-hexyl-1,3-phenylenediol (HEXINOL™) as an agent fighting the effects of aging. In young cells there is a
balanced level of NF-κB activation, which becomes excessive in aged cells, leading to reduced collagen and elastin synthesis. 4-hexyl-1,3-phenylenediol
inhibits NF-κB nuclear translocation, blocking the downstream effects.
4-Hexyl-1,3-Phenylenediol Improves Clinical Signs of Aging 117
placebo. At T8 the tested product had a significantly higher activ-

ity as compared with placebo. Moreover, b* values were signifi-
cantly reduced by both treatments, indicating a decrease in spot
coloration. The product containing the active also had a signifi-
cantly higher activity on b* values as compared with placebo.
These data strongly demonstrate that HEXINOL™ technology
is effective in reducing age-induced brown spots.
Taken together, the clinical study performed with a product
that contains the active ingredient 4-hexyl-1,3-phenylenediol
clearly confirms the anti-aging properties of 4-hexyl-1,3-phen-
ylenediol and validates the NF-κB pathway as a promising tar-
get to fight skin aging.
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14
Perfumes
perfume and is usually of a simple composition, consisting of

Definitions few ingredients. Certain fragrance ingredients such as farnesol
and geraniol have antibacterial properties and may be used as
A fragrance ingredient is any basic substance used for its odor- biocides.
ous, odor-enhancing, or blending properties in the composition Plant extracts are regarded by some as functional ingredi-
of perfumes. A perfume is a blend of fragrance ingredients ents, claimed to act as, for example, anti-irritants. The same
diluted in ethanol and experienced over a certain time frame. ingredients may in other cases be used just to provide a pleas-
It is also named the fragrance formula and may consist of 10 ant odor.
to several hundred ingredients. A fragrance ingredient may be Perfumes are part of daily life in modern society as it was
either a chemical or a natural product (1). in ancient times. The most intense skin exposure comes from
Natural fragrance ingredients are produced from natural cosmetic products, especially stay-on cosmetics, which is also
products such as plant parts—for example, petals, leaves, the cause of most contact allergic reactions.
bark, roots, or fruits from certain plant families (1). Animal
secretions such as musk from the male musk deer have been
used for their odoriferous properties but have for decades been
replaced by blends of chemicals. The fragrance ingredients Adverse Skin Reactions to
are extracted from the plants by processes such as distillation, Fragrance Ingredients
extraction, or expression.
The resulting natural products are often complex mixtures Skin reactions as contact urticaria, photoallergy, and photo-
consisting of numerous ingredients. In some cases, the charac- toxicity are well recognized but infrequent skin side effects
teristic odor is due to a particular ingredient, and the isolation of fragrance ingredients. Psoralens in naturally occurring
of these odor determinants is the original basis of production fragrance ingredients were previously the cause of phototoxic
of chemical ingredients. Fragrance chemicals may be isolated reactions giving rise to acute erythema and followed by long-
from the natural products or synthesized from basic organic standing hyperpigmentation. The content of the light sensi-
chemicals. The synthesized chemicals may be nature-iden- tivity–inducing substances is now regulated and the problem
tical, that is, imitations of naturally occurring substances or has diminished. In the 1970s, the fragrance ingredient musk
entirely new chemicals never identified in nature. Most fra- ambrette was the cause of an epidemic of photoallergy, par-
grance ingredients are natural or nature-identical (1). About ticularly in men following the use of after-shave. The usage
3.600 fragrance ingredients are declared in current use (https:// of musk ambrette (4-tert.-butyl-3-methoxy-2,6-dinitrotoluene)
ifrafragrance.org/priorities/ingredients/ifra-transparency-list). was reduced, and in 1995 the substance was prohibited from
use in cosmetics in Europe.
Immediate contact reaction to fragrance ingredients is often
of the nonimmunological type (2). This means that most indi-
viduals will react with local erythema and edema if exposed
Applications of Perfumes to the substance in a sufficient concentration. The fragrance
Perfumes are added to many types of consumer products such ingredient cinnamal is capable of producing nonimmuno-
as cosmetics, detergents, air fresheners, sanitary napkins, and logical contact urticarial reactions, as are Balsam of Peru and
toys. Perfumes are also used in aromatherapy and herbal rem- cinnamic acid (2, 3). Allergic contact dermatitis is the most
edies as well as industrial settings. Perfumes are products in frequently reported adverse reaction in relation to fragrance
themselves sold as parfum, eau de toilette, and eau de cologne. ingredients (4).
A perfume is usually developed for one particular type of prod-
uct, and the composition may have to be changed to retain the
same odor if it is incorporated into a different type of product.
Allergic Contact Dermatitis
Perfumes may be used to mask unpleasant odors from the
basic ingredients, for example, in skin care products. If a per- Fragrance ingredients are low molecular weight substances,
fume is added for this purpose only, it is termed a masking which easily penetrate intact skin. About 240 of the 3,600
DOI: 10.1201/b22897-14 119

ingredients used for compounding perfumes have been It is recommended to patch test with the 26 fragrance ingre-
described as contact allergens (5). Fragrance ingredients are dients to be labelled on cosmetic products in EU (Table 14.1) in
the most common cause of allergic contact dermatitis because addition to the baseline series (25), as it seems that only 40% of
of cosmetics, being responsible for 25% to 45% of the aller- patients with fragrance contact allergy will be picked-up by test-
gic reactions depending on the population under study, closely ing with the baselines series allergens only (25). Even in doing
followed by the preservatives (6, 7). Allergic contact dermati- this attention should be paid to that contact allergy may exist
tis due to fragrance ingredients may involve the face, hands, to other fragrance ingredients including essential oils in some
the axilla, or be generalized, depending on the causative patients.
products (4). A natural resin Myroxylon pereirae is also part of the
Contact allergy to fragrance ingredients is diagnosed in European baseline series and is used in some countries in topi-
10% to 15% of eczema patients in Europe and North America cal medicaments and also in the form of extracts and distillates
(4). In terms of population frequencies, a study in the general in fragrances (26). Nearly 80 essential oils have been reported
adult population in five countries in Europe showed an overall to cause contact allergy (27). Fifty-five of these have been
prevalence of 4.7% (95% CI 3.9–5.5) had contact allergy to fra- tested in consecutive patients suspected of contact dermatitis,
grance ingredients, when patch tested with the baseline series and nine (laurel, turpentine, orange, tea tree, citronella, ylang-
at the time (8). In EU28, this corresponds to 20 Million people. ylang, sandalwood, clove, and costus root) showed greater than
While contact allergy in children to cosmetic ingredients 2% positive patch test reactions (27). Work has been done to
previously was rare, allergy to fragrance ingredients is seen in optimize the identification of contact allergy caused by natural
at least 2.1% of adolescents 16 years of age with a statistically extracts (5, 11, 12, 27, 28) (Table 14.2).
equal frequency in boys and girls (9). Furthermore, fragrance Some natural extracts have a simple composition, consisting
ingredients are among the most common causes of allergic of only a few chemicals; an example is clove oil, that contains
contact dermatitis in the paediatric population, when patch up to 80% eugenol, a well-known allergen. Other extracts have
tested (10). a very complex composition, and even though they are well
recognized as causes of allergic reactions, the allergens in
the extracts are not known. An example is Evernia prunastri
(oakmoss absolute). As E. prunastri is a major cause of aller-
Causative Ingredients and Diagnosis gic reactions, investigations have been undertaken to pinpoint
Since the beginning of the 1980s, a mixture of eight fragrance the major allergens, chloroatranol and atranol; still other less
ingredients, named fragrance mix I, has been used for screen- important allergens exist in the mixture (29). This opens the
ing purposes in the routine investigation of allergic contact possibility of producing extracts of E. prunastri with no or low
dermatitis (Table 14.1). The mixture has been valuable in diag- levels of these two strong allergens (30).
nosing fragrance contact allergy, and only few modifications Some natural products from the terpene family, such as
have been made to its original composition over the years. In limonene and linalool, will form allergens when oxidized,
1984 the initial patch test concentration of 16% was reduced but while they in their unoxidized state have only weak or no
to 8% because of many irritant reactions, which seemed to allergenic properties. The allergens formed are mainly hydro-
be caused mainly by the presence of cinnamal. As many fra- peroxides with strong allergenic potential (31). These oxi-
grance ingredients are used in composing perfumes, investi- dized terpenes are major causes of fragrance contact allergy
gations have been conducted to identify significant fragrance and should be included in the test series for fragrance contact
ingredients not present in the fragrance mix I (11–15). From allergy (32, 33). Antioxidants can prevent oxidation for some
this knowledge base a new test was designed, fragrance mix II, time, but when the antioxidant is consumed, oxidation starts
which contains six fragrance chemicals (16–18) (Table 14.1), immediately.
compiled to a test concentration of 14% in pet. This has also
been included in the European baseline series together with
its main ingredient hydroxyisohexyl 3-cyclohexenecarboxal- Cosmetic Products and Allergic Contact
dehyde (Lyral) (19).
Dermatitis to Fragrance Ingredients
In a European investigation covering 2019–2020, fragrance
mix I gave positive reactions in 6.8%; fragrance mix II in 3.8% Investigations of fragrance-allergic individuals have shown
and hydroxyisohexyl 3-cyclohexenecarboxaldehyde in 1.3% of that initiation of disease typically is caused by a fragranced
patch tested eczema patients (21). In North America top aller- deodorant, a cologne/perfume, or both (34–36). High levels
gens in the period 2007–2016 included fragrance mix I (10.6%) of well-known allergens have been shown particularity in
and fragrance mix II (4.9%). There were increasing trends for fine fragrances. A parfum may contain up to 30% of fra-
both the mixes and cinnamic aldehyde (22). In 2019–2020 a grance ingredients, while 1% is typical for deodorants. This
continuous increase was seen with 12.8% positive to fragrance means that the individual ingredients are present in much
mix I and 5.2% to fragrance mix II (23) A significant decline higher concentrations in parfums than in other products. The
in contact allergy to hydroxyisohexyl 3-cyclohexenecarboxal- same allergens have been found also in significant concen-
dehyde has been seen in Europe after the announcement of a trations in naturally based perfumes, deodorants, and toy
full ban from use in cosmetic products in 2012 due to contact perfumes (4).
allergy, with a decision in 2017 and full implementation in EU The risk of sensitization will depend primarily on exposure
in 2021 (24). concentration. The exposures as well as the sensitivity of the
Perfumes 121
TABLE 14.1
Fragrance Ingredients Included in the List of Substances to Be Labelled as Ingredients If Present in Cosmetics in Europe and Their
Inclusion in Diagnostic Test Preparations
Name (INCI) CAS no. In FM I In FM II
Amyl cinnamal 122-40-7
Benzyl alcohol 100-51-6
Cinnamyl alcohol 104-54-1 X
Citral 5392-40-5 X
Eugenol 97-53-0 X
Hydroxycitronellal 107-75-5 X
Isoeugenol 97-54-1 X
Amylcinnamyl alcohol 101-85-9 X
Benzyl salicylate 118-58-1
Cinnamal 104-55-2 X
Coumarin 91-64-5 X
Geraniol 106-24-1 X
Hydroxyisohexyl 3-cyclohexene 31906-04-4 X
carboxaldehyde (Lyral)
Anisyl alcohol 105-13-5
Benzyl cinnamate 103-41-3
Farnesol 4602-84-0 X
Butylphenyl methylpropional 80-54-6
Linalool 78-70-6
Benzyl benzoate 120-51-4
Citronellol 106-22-9 X
Hexyl cinnamal 101-86-0 X
D-Limonene 5989-27-5
Methyl 2-octynoate 111-12-6
Alpha isomethyl ionone 127-51-5
Evernia prunastri 90028-68-5 X
(oakmoss extract)
Evernia furfuracea (treemoss extract) 90028-67-4
Abbreviations: INCI, International Nomenclature of Cosmetic Ingredients; FM, mixture of fragrance ingredients used for diagnosing fragrance allergy.
Note: The presence of the substance must be indicated in the list of ingredients when its concentration exceeds 0.001% in leave-on products and 0.01%
in rinse-off products according to the Cosmetic Directive in EU (https://single-market-economy.ec.europa.eu/sectors/cosmetics/cosmetic-ingredi-
ent-database_en). Information regarding the presence of other fragrance ingredients in cosmetics may be made available by fragrance industry on
a case-by-case basis (20).
individual are decisive factors in whether eczema develops in

a sensitized individual. A key determinant in exposure is the The Fragrance-Allergic Patient
concentration of allergen per unit of skin surface. However,
There is considerable inter-individual variation in the sensitiv-
the formulation of a product also influences the risk of elici-
ity of fragrance-allergic individuals. Some cannot tolerate any
tation of allergy; for example, from experiments it seems that
fragrance products at all; others may be able to use some type
deodorant sprays are more likely to provoke reactions, given
of products such as shampoos without problems because of the
the same conditions and contents of allergens, as deodor- short contact time and the dilution factor and may even tolerate
ant sticks. Other factors that affect the risk of elicitation in some stay-on products. The products most difficult to tolerate
humans are the number of allergens in a product, frequency on the skin are perfumed deodorants, perfumes/colognes, and
of exposure, region of application, the skin condition (4). skin care products. In a questionnaire study of the strategies of
The intensity of skin contact is important, which means that fragrance-allergic eczema patients in their choice of cosmetic
stay-on products generally give a higher risk of sensitization products, 45.3% answered that they had found some scented
and elicitation than wash-off products given the same con- products that they could tolerate, 31.6% had not tried to find
centrations of allergens. However, frequent use of a product any scented products, and 22% had tried but could not find
such as a liquid soap may compensate and cause the same any (38). The methods most often used were trying different
risk as a stay-on cosmetic product. Another frequent cause products and reading the ingredient label. The quality of life
of fragrance contact allergy is topical medicaments in some in patients, especially younger women with fragrance allergy,
countries (37). has been shown to be severely affected (20).
TABLE 14.2 perfume-allergic patient. It is often possible to tell if a prod-

Natural Extracts Frequently Reported as Causing Positive Patch uct contains fragrance ingredients by the (pleasant) scent.
Tests in Eczema Patients
Cedarwood oil
Citronella oil Interventions and Regulations Update
Clove oil
Costus root oil The International Fragrance Association (IFRA) was founded
Dwarf pine needle oil in 1973 by fragrance manufacturers and has since issued
Eucalyptus oil recommendations for the safe use of fragrance ingredients.
Evernia furfuracea (treemoss abs) Guidelines for more than 250 ingredients are published (https://
Evernia prunastri (oakmoss abs) ifrafragrance.org/safe-use/library). Many recommendations
Geranium oil bourbon are due to skin effects, especially allergic contact dermatitis.
Jasmine abs In spite of these guidelines, fragrance ingredients still are one
Lavender oil of the most frequent causes of allergic contact dermatitis. The
Laurel leaf oil fragrance industry has developed new models for estimation of
Lemongrass oil exposure levels which are not expected to sensitize (40). The
Lemon oil efficacy of these models is unknown, and already-sensitized
Myroxylon pereirae (Balsam of Peru) consumers will not be protected.
Narcissus abs In Europe, ingredient labelling of cosmetics was introduced
Neroli oil in 1997, while it has been in force in the United States for
Orange oil decades. In both cases, fragrance compositions were referred
Patchouli oil to as “parfum,” and disclosure of the individual fragrance
Peppermint oil ingredients was not given. By the amendment of the Cosmetic
Sandalwood oil Directive in Europe (2003), labelling of certain fragrance
Spearmint oil ingredients recognized for their sensitizing potential has been
Tea Tree oil introduced (Table 14.1) to improve diagnostics and help the
Turpentine oil sensitized consumer to avoid relevant allergens. The list has
Ylang-ylang oil I been proposed to be expanded to more than 100 substances in
Ylang-ylang oil II a 2012 (4) revision of the original opinion from 1997. Whether
Sources: Larsen W et al., Am J Contact Dermatitis; 9:202–6, 1998; Frosch this will be implemented in practice is still being discussed.
PJ et al., Contact Dermatitis; 47:279–87, 2002; Uter W et al., Contact A number of fragrance ingredients have been restricted or have
Dermatitis; 63:277–83, 2010; De Groot AC., Schmidt E. Dermatitis 2016; been banned from use in cosmetic products mainly because
27(4):170–5 Geier J et al. Contact Dermatitis; 87:71–80, 2022. of their sensitizing properties (https://single-market-economy.
Note: A more extensive list can be found in Refs. 5 and 26. ec.europa.eu/sectors/cosmetics/cosmetic-ingredient-database_
en). The fragrance ingredient hydroxyisohexyl 3-cyclohexene
Indicative of the clinical problems, the fragrance-allergic carboxaldehyde as well as the main allergens in E. prunastri
individual may have, is their level of sensitivity at patch testing (oak moss absolute) must not be used in cosmetic products in
with standard test concentrations. It has been shown that patients the European Union due to their sensitizing properties.
giving a +++ or ++ grading at patch testing with the fragrance A decline in contact allergy to hydroxyisohexyl 3-cyclohexene
mix or one of its ingredients are very sensitive and likely to react carboxaldehyde (23) as well as fragrance mix I and II have
to normal use of cosmetics containing the allergen in question. been noted (41) while in North America, where no official
A total 82.1% of a group of eczema patients who had been specific regulations of sensitizing fragrance ingredients have
diagnosed with fragrance contact allergy within the past 2 been introduced, contact allergy to fragrance ingredients are
years reported some degree of eczema presently. Most had continuously high and increasing (21, 22). Still a considerable
hand eczema (55.5%), followed by facial eczema (33.3%), and number of patients are sensitized to fragrance ingredients also
42.7% had eczema at multiple locations (38). to ingredients not part of the baseline series and new fragrance
Fragrance-allergic patients are advised to avoid the spe- ingredients are being developed, where some may be impor-
cific fragrance ingredient(s) they cannot tolerate accord- tant skin sensitizers.
ing to the patch test results. However, if they are allergic
to multiple fragrance ingredients, fragrance ingredients not
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15
Alternative and Natural Treatments in Dermatology
Conor Palleschi and Cheryl Levin
Supplementation to traditional drugs has gained popularity Ascorbic Acid and Niacinamide
in recent years, particularly within the field of dermatology
where diseases are often chronic and treatments may at times Ascorbic acid is a known tyrosinase inhibitor. It also is known
be frustrating (1, 2). The intent of this review is to survey to prevent the absorption of UV light. Finally, it acts as an
some of the more recently reported alternative and comple- antioxidant, preventing free radical generation and thereby
mentary dermatologic treatments, with an emphasis on those preventing increased melanin production (9). Espinal-Perez
that follow evidence-based dermatology guidelines (3, 4). et al. conducted a double-blind randomized trial that assessed
Specifically, this review focuses on those difficult to treat skin the efficacy of 5% ascorbic acid versus 4% hydroquinone in
conditions in which significant developments have been made, treating 16 women with melasma. Participants included in the
including skin pigmentation disorders, onychomycosis, atopic study had bilateral and symmetric facial melasma, and were
dermatitis, psoriasis, acne, and alopecia areata. instructed to apply hydroquinone to one side of the face and
ascorbic acid to the other side daily for 16 weeks. Endpoints of
the study were subjective assessment by the patient (measured
as “very good,” “good,” “moderate,” and “mild” in terms of
Hyperpigmentation improvement) and objective colorimetric assessment. Of the
participants, 62.5% rated their response to ascorbic acid as
Melanin is produced by melanocytes in the basal layer of
“very good” or “good,” whereas, 93.75% rated their responses
the skin and is primarily responsible for skin pigmentation.
to hydroquinone as “very good” or “good.” Objective colorim-
Humans all have approximately the same number of melano-
etry found no difference in success rates between the two com-
cytes, implying that variation in skin color is attributable to a
pounds. However, this may be due to several factors including
variety of other factors, such as the number and size of mela-
the small sample size or the short 16-week endpoint. Notably,
nosomes within each melanocyte, the ratio of different types
positive results from hydroquinone were visible within the first
of melanin produced (eumelanin and pheomelanin), degree of
month of treatment, while positive results from ascorbic acid
melanocyte activity, and environmental factors. From a bio-
were not noticeable until month three. Greater than two-thirds
chemical standpoint, tyrosinase catalyzes three reactions in
of patients experienced skin irritation from the hydroquinone,
melanin formation: hydroxylation of tyrosine to DOPA, oxi-
and only one patient experienced irritation from the ascorbic
dation of DOPA to DOPAquinone, and oxidation of DHI to
acid. The authors propose that a higher percentage ascorbic acid
indolequinone. Consequently, this enzyme is a popular target
solution will likely produce more dramatic results. Ascorbic
for inhibition in treating subjects with hyperpigmentation (5).
acid is known to be an unstable molecule given it is reversibly
Melasma is quite common, yet the precise pathogenesis is
oxidized into dehydroascorbic acid (DHA), which is further
not fully understood. It is thought that sun exposure is the
irreversibly hydrolyzed into 2,3-diketogulonic acid, following
most common trigger. Mechanistically, the thought is that
exposure to light, heat, transition metal ions, and pH (10). This
sunlight stimulates nitric oxide production, which increases
high instability and reactivity makes it extremely difficult to
melanocyte tyrosinase activity, thereby increasing mela-
advance the development of ascorbic acid into commercially-
nin production, resulting in patches of hyperpigmentation
used products. It is possible that as ascorbic acid is better sta-
in sun-exposed skin. The second most common trigger is
bilized in cream or solution formulation, it will have a greater
believed to be estrogen, with a predilection often observed
efficacy. One promising method of such stabilization involves
in pregnancy, oral contraceptive use, or hormone replace-
shielding ascorbic acid from the aforementioned environmen-
ment therapy. Pregnancy-associated melasma often clears
tal factors via encapsulation within a layer of wall material.
within several months postpartum, whereas the other forms
There are also several studies examining innovative delivery
may take years (6). Topical hydroquinone is the gold stan-
technologies for this unstable molecule, including microflu-
dard treatment. A novel formulation, described by Kligman
idic, melt extrusion, spray drying, and chilling (11–14). It is
and Willis in 1975, utilizes hydroquinone in combination with
possible that as ascorbic acid is better stabilized in cream or
a topical corticosteroid and topical retinoid to provide addi-
solution formulation, it will have a greater efficacy. Hakozaki
tional depigmentation (7). Many alternative therapies have
et al. conducted several in vitro and in vivo studies assessing
been investigated, including kojic acid, azelaic acid, and gly-
the impact of niacinamide on melanin and hyperpigmentation.
colic acid (8).
DOI: 10.1201/b22897-15 125

Regarding the in vivo studies, investigators determined that are niacinamide and AG effective at reducing hyperpigmen-
niacinamide does not impact the activity of mushroom tyrosi- tation, but that ultrasound is likely responsible for approxi-
nase, nor does it impact melanocyte production of melanin. mately half of the efficacy. No adverse effects were reported
Interestingly, the final in vivo study demonstrated that niacin- by any subjects during the study (16). Interestingly, there is a
amide inhibits transfer of melanosome from melanocytes to cream, Fair & Lovely (Unilever), that contains niacinamide
keratinocytes, when melanocytes, keratinocytes, and niacina- and ascorbyl phosphate, among other ingredients. This cream
mide are cultured together. Two keratinocyte cell lines were was launched in Kenya and is now a popular choice worldwide
used, and melanin transfer was inhibited by 35% in one cell for treatment of hyperpigmentation (8).
line and 68% in the other. Two in vivo clinical studies were
conducted assessing the efficacy of niacinamide at reducing
Plant Extracts
hyperpigmentation. Study 1 involved 18 Japanese women with
areas of facial hyperpigmentation—slight–moderate solar len- Assorted plant extracts are potent inhibitors of melanin forma-
tigines, melasma, or freckles—who applied 5% niacinamide tion and many have been investigated as potential depigmenting
moisturizer to one side of the face and the vehicle to the other agents. The bioflavonoids as a class, and specifically the flava-
side, for 8 weeks. Study 2 included 120 Japanese women with nones, have been identified as potent tyrosinase inhibitors (17).
“moderate to deep facial tan,” randomized to one of three Flavanones, including hesperidin, eriodictyol, and narin-
groups. Group 1 members applied the vehicle to one side of genin, have a chemical structure similar to hydroquinone.
the face and sunscreen to the other. Group 2 members applied In a study by Zhang et al., hesperidin, found in the peel and
sunscreen to one side of the face and 2% niacinamide + sun- membranes of citrus fruits, was applied to melanoma B16
screen to the other side. Group 3 members applied the vehicle cells and human primary melanocytes. A dose-dependent
to one side of the face and 2% niacinamide + sunscreen to inhibition of tyrosinase activity versus control was observed
the other. Outcome measures included objective imaging with (18, 19). Flavonoids from licorice roots, such as glabrene, gla-
computer analysis of percent change in pigmentation, visual bridin, and isoliquiritigenin, have also been found to inhibit
assessment by blinded judges, and self-assessment. In study 1, tyrosinase (20). In one study, glabridin applied to cultured
all three outcome measures demonstrated a greater reduction B16 murine melanoma cells at concentrations from 0.1 to
in pigmentation with niacinamide as compared to the vehicle, 1.0 μg/mL-1 inhibited tyrosinase activity without affecting
with the greatest difference observed with objective image DNA synthesis (19, 21).
analysis. In study 2, the lightening ability of niacinamide + The licorice extract liquiritin, another flavonoid, was also
sunscreen compared to sunscreen alone on “tan” skin was less found to be effective in decreasing skin pigmentation. In a clin-
conclusive. Self-assessments did not demonstrate a significant ical trial, 2% liquirtin cream at a dose of 1 g day-1 was applied
difference between the two arms of the study. However, imag- to 20 women with melasma for 4 weeks. Eighty percent of the
ing with objective computer analysis did demonstrate a statis- treated cases had a reported excellent response (22). Of note,
tically significant difference between sunscreen + niacinamide liquiritin does not inhibit tyrosinase activity. Depigmentation
and sunscreen alone in lightening capacity at 4 weeks; how- is thought to be secondary to melanin dispersibility and epider-
ever, at 8 weeks, the difference between these two categories mal stain-removing property. Pycnogenol, a flavonoid-contain-
were no longer significant. Both the niacinamide + sunscreen ing bark extract, has also decreased pigmentation in melasma
and sunscreen alone showed significant lightening capacity patients. In a study of 30 women with melasma, a 25-mg pyc-
compared to the vehicle alone at 4 and 8 weeks (15). nogenol tablet taken three times daily led to a statistically sig-
Hakozaki et al. performed a subsequent in vivo clinical trial nificant decrease in melasma pigmentation, as measured by the
that explored the efficacy of vitamin C derivative ascorbyl average pigment intensity and average melasma area (23).
gluocoside (AG) plus niacinamide, in conjunction with sono- A recent study by Yamakoshi et al. studied the effects of
phoresis, in treating hyperpigmentation. The subjects were 60 grape seed extract in treating melasma-associated hyperpig-
Japanese women with bilateral facial hyperpigmentation— mentation. Twelve Japanese women with melasma took pro-
solar lentigines, melasma, or freckles. A 5 MHz ultrasound anthocyanidin-rich grape seed extract three times daily for
device set at an intensity of 0.7 W/cm2 and the gel contain- between 6 and 12 months while not using any other treatments
ing 2 AG and 3.5% niacinamide were used. The subjects were for their melasma. There was a significant decrease in their
divided into two groups of 30. Group 1 applied 2.6 mL of the gel melasma as measured by reflectance spectrophotometry and
to one side of their face and used the ultrasound for 10 minutes clinical parameters as compared to baseline (24).
nightly and applied nothing to the other side of their face. Arbutin, a hydroquinone derivative found in the bear-
Group 2 used the gel and ultrasound on one side as described berry plant, has been found to inhibit tyrosinase and DHICA
earlier and gel only on the other side. The duration of the study (5,6-dihydroxyindole-2-carboxylic acid) polymerase activities
was 4 weeks. Results of the study were measured in a variety (25), possibly through competitive inhibition (19). A clinical
of manners, though most telling was the high resolution digital trial of topical deoxyarbutin (dA,4-[tetrahydrofuran-2-yl-oxy]-
imaging with computer quantification of pigmentation reduc- phenol) applied to solar lentigines for 12 weeks led to sig-
tion. In group 1, the side of the face treated with ultrasound nificant lightening in light-skinned individuals and minimal
and gel showed a 9.4% greater reduction in pigmentation lightening in dark-skinned individuals (26). Alpha-arbutin
compared to the no-treatment side. In group 2, the ultrasound (4-hydroxyphenyl alpha-glucopyranoside) exhibits greater
plus gel demonstrated a 4.8% greater reduction in pigmenta- chemical stability and stronger inhibition of tyrosinase when
tion when compared to gel alone. This implies that not only compared to arbutin (27).
Alternative and Natural Treatments in Dermatology 127
Multiple in vitro studies were conducted to investigate the Serine Protease Inhibitors
inhibitory capacity of aloesin, an aloe extract, on tyrosinase.
First, experimenters looked at aloesin’s inhibitory capacity on Keratinocyte phagocytosis of melanosomes, regulated by
fungal, murine, and human tyrosinase and compared to it to protease-activated receptor 2 (PAR-2), has been confirmed to
two well-known tyrosinase inhibitors, arbutin and kojic acid. be an important biochemical pathway in pigmentation regula-
Aloesin was consistently shown to be a less potent inhibition. Serine protease inhibitors found in soybeans—soybean
tor than kojic acid and a more potent inhibitor than arbutin. trypsin inhibitor (STI) and Bowman-Birk protease inhibitor
Additionally, aloesin was shown to inhibit melanin produc- (BBI)—modulate this pathway, potentially resulting in depig-
tion in a dose-dependent fashion in murine melanoma cells, mentation. Wallo et al. conducted a 12-week, parallel, random-
stimulated with alpha-MSH. Specifically, aloesin was shown ized, double-blind, and vehicle-controlled study involving 63
to inhibit both the tyrosine hydroxylase and DOPA oxi- subjects with evidence of photoaging and compared the effects
dase reactions. However, aloesin dissolved in ethanol when of a facial moisturizer with sunscreen, STI, and BBI to one
applied to cadaveric skin was found to have poor penetra- with only sunscreen when applied twice daily. The study end-
tion. Subsequently, the authors conducted a preliminary trial point was improvement in skin tone and texture, as evaluated
that demonstrated a localized decrease in melanin production by the patient, dermatologist, and digital photography with
when a hydrophilic patch impregnated with 1% aloesin was colorimetry. Improvement in skin tone was defined as reduc-
applied to human volunteers’ skin (5). tion in mottled hyperpigmentation, lentigines, and blotchiness
Khan et al. conducted in vivo and in vitro studies exploring with an increase in brightness. Improvement in skin texture
the efficacy of extracts from two plants known to have medici- was defined as reduction in surface roughness or improvement
nal properties. Cassia fistula, also known as the golden shower in fine lines and wrinkles. While both groups showed clinical
tree, is a yellow-flowering tree, previously described in litera- improvement, the experimental group showed a statistically
ture as effectively treating a variety of skin conditions, includ- significant greater improvement than the control group in skin
ing boils, leprosy, ringworm, and burning skin sensation. tone and texture as per dermatologist evaluation. However,
Hippophae rhamnoides, common sea-buckthorn, is a berry- objective colorimetry found no significant difference (30). See
producing shrub found throughout Europe whose medicinal Table 15.1 for alternative treatments.
properties were discovered over 1000 years ago. Extracts from
both of these plants—found to be rich in the antioxidant cat-
echin, part of the flavenoid family—were tested. This was a Onychomycosis
single-blinded, 12 week study that involved 50 Asian subjects
with melasma, divided into two groups of 25 subjects each. Onychomycosis is a condition that results in disfigurement
One group applied H. rhamnoides to one cheek (referred to as of the nails and can often be embarrassing (31). In addi-
F1) and C. fistula (F2) to the opposite cheek, while the other tion to social and emotional ramifications, there are medical
group applied F2 to one cheek and placebo (F3) to the other; concerns, including secondary bacterial infection, pain, and
both groups applied the formulation twice daily. Skin pigmen- spread of infection to others (32). Onychomycosis is respon-
tation was measured objectively by the Mexameter®, a spec- sible for one-third of all fungal skin infections and approxi-
trophotometer sensitive to the presence of melanin. Results mately one-half of all nail disease. Trichophyton rubrum is
at 12 weeks were significant for a mean melanin reduction of the most common causative organism, primarily infecting
16.35% in those using F1, the H. rhamnoides formulation, and the nail bed and underside of the nail plate (31). While oral
a reduction of 13.0% in those using F2, the C. fistula formula- systemic treatments have been the traditional choice and are
tion. The side of the face receiving F3, the placebo, actually among the most effective in treating this condition, they are
showed mild increases in melanin. Side effects of F1 and F2 associated with a higher rate of adverse effects and drug–drug
were limited to mild to moderate itching and skin irritation interactions than other treatment modalities (33). This section
experienced by approximately 10% of patients (28). addresses the alternative therapies that can be used in manag-
Just as the golden shower tree and common sea-buckthorn ing onychomycosis.
are known to be rich in tyrosinase-inhibitory catechins, Acacia
nilotica, a tree long reputed for its medicinal properties, is Ciclopirox
known to possess similar phenolic catechin compounds. Ali
et al. conducted a 12-week, blinded, controlled study assessing Ciclopirox is a “substituted pyridone” topical agent with broad
the efficacy of Acacia bark extract in reducing skin pigmenta- antifungal activity. Its exact mechanism of action is unknown;
tion and erythema content in 11 subjects. Subjects applied the however, it is thought to exert its antifungal effects by interfer-
vehicle to one side of the face and the experimental cream to ing with fungal transmembrane transport as well as DNA and
the other twice daily. Skin melanin and erythema content were RNA synthesis (34).
measured using the Mexameter spectrophotometer every other Two U.S., multicenter, randomized, double-blind, vehicle
week. Throughout the study, the Acacia extract cream pro- controlled studies, conducted with similar protocols, were
duced continuous reduction in erythema and melanin content, performed to assess the efficacy of Ciclopirox 8% lacquer in
while the control cream did not. At the conclusion of the study, the treatment of toenail onychomycosis. Four hundred sixty
there was a statistically significant reduction in skin melanin subjects with 20%–65% involvement of the target nail were
and erythema content when the active cream was used and included in the study and randomized to apply the Ciclopirox
insignificant reductions when the control cream was used (29). or vehicle to all nails daily for 48 weeks. The mycological
cure, defined as negative culture and KOH stain, was 34% for Tea Tree Oil
the Ciclopirox group and 10% for the vehicle group. Treatment
Several studies have been performed to assess the efficacy of
cure rate, defined as 100% clearance of clinical signs of fungal
tea tree oil in the treatment of onychomycosis. Tea tree oil is
infection as well as negative culture and KOH, was 7% for
derived from the Australian tree Melaleuca alternifolia, and
the Ciclopirox group compared to less than 1% in the vehicle
the active ingredient is Terpinen-4-ol (37).
group (35).
A double-blind, multicenter, randomized controlled trial
Friedlander et al. conducted a prospective, randomized,
involving 117 subjects with distal subungual onychomycosis
double-blinded, vehicle-controlled study assessing the
compared the efficacy of 1% clotrimazole solution to 100%
efficacy of Ciclopirox 8% nail lacquer in treating toenail
tea tree oil in treating this condition. Patients were instructed
onychomycosis without matrix involvement, in a pediatric
to apply the assigned solution to the affected nails twice daily
population. Of the 40 subjects enrolled in the study, 30 were
for 6 months, with follow up at 1-, 3-, and 6-month intervals
assigned to the experimental arm, and 10 were assigned to for clipping and debridement. Outcome measures were fun-
the vehicle arm of the study. Subjects applied their assigned gal culture, clinical appearance, and subjects’ perception of
lacquer to all toenails daily for 32 weeks, and 7/9 of the appearance and symptoms at 9 months after initiation. Of the
subjects in the vehicle arm were crossed over to the experi- 108 participants to complete the trial, one-half to two-thirds
mental arm at week 12, for lack of noticeable improvement. demonstrated clinical improvement or reported subjective
Results at 32 weeks were as follows: 34% of the Ciclopirox improvement of their fungal nail infection, without statisti-
group achieved complete cure (defined as IGA score of 0 and cally significant differences between the two groups. Analysis
negative culture), 71.4% of the Ciclopirox group achieved of fungal culture results was limited due to 35% dropout at 6
effective treatment (defined as ≥50% clearance/IGA score months, when the culture was to be performed (37).
of 1–2 and negative culture), none of the crossover subjects Another randomized, double-blinded, placebo-controlled study
achieved complete cure, and the two subjects remaining in involving 60 patients compared the efficacy of 5% tea tree oil
the vehicle group achieved complete cure. Of those who with 2% butenafine, a phenol-substituted benzylamine derivative,
achieved complete cure at 32 weeks, 92% remained disease which has been shown in prior studies to have fungicidal effects
free at 1-year follow-up. Authors of the study suggest that versus 5% tea tree oil alone in the treatment of toenail fungal infec-
the thinner and potentially faster growth rate of nails in the tions. Mycological cure was defined as negative fungal culture
pediatric population may be part of the explanation for the and potassium hydroxide stain, clinical cure was defined as 100%
higher efficacy in this treatment population than in adults. remission or > 90% improvement, and overall cure was defined as
Additionally, given the two children achieving complete both mycological and clinical cure. Patients applied their assigned
cure in the vehicle arm, watchful waiting may be a feasible cream three times daily to the affected toenail for 8 weeks, with
option in the pediatric population. Interestingly, T. rubrum debridement of the nails occurring as deemed necessary by the
was found to be more resistant to treatment than other infec- examiners. They were evaluated on a weekly basis for the first
tious fungi (36). 16 weeks, then monthly until week 36. Eighty percent (32/40) of
TABLE 15.1
Alternative Treatments for Hyperpigmentation
Alternative medication Study type Experimental result Source
Acacia bark extract In vivo—blinded, controlled Decrease melanin and erythema (Ali, Akhtar et al. 2012)
Aloesin In vitro Decrease tyrosinase activity (Jones et al. 2002)
Arbutin In vitro Decrease tyrosinase and DHICA (Chakraborty, Funasaka et al. 1998)
Ascorbic acid In vivo—double-blind, randomized Decrease melasma pigmentation (Espinal-Perez et al. 2004)
Ascorbyl glucoside with In vivo Decreases hyperpigmentation (Hakozaki et al. 2006)
sonophoresis
Deoxyarbutin In vivo Decreases solar lentigines (Boissy, Visscher et al. 2005)
Glabridin In vitro Inhibit tyrosinase (Fu, Li et al. 2005)
C. fistula and H. rhamnoides In vitro and in vivo (single blinded) Tyrosinase inhibition (in vitro) (Khan et al. 2013)
Reduction in melanin (in vivo)
Grape seed extract In vivo—open design study Decrease melasma pigmentation (Yamakoshi, Sano et al. 2004)
Hesperidin In vitro Inhibit tyrosinase (Zhang, Zhu et al. 2008)
Liquirtin In vivo—clinical trial Decrease melasma pigmentation (Amer and Metwalli 2000)
Niacinamide In vitro and in vivo Inhibition of melanosome transfer (Hakozaki et al. 2002)
from melanocytes to keratinocytes
(in vitro)
Pigmentation reduction (in vivo)
Pycogenol In vivo Decrease melasma pigmentation (Ni, Mu et al. 2002)
Soybean—soybean trypsin inhibitor In vivo—parallel, randomized, Improvement in skin tone and texture (Wallo et al. 2007)
and Bowman–Birk protease inhibitor double-blind, vehicle controlled
the experimental group achieved overall cure, while none of the evaluated at 52 weeks, with endpoints defined as complete cure
control group (0/20) achieved overall cure. Mild inflammation (i.e., 0% clinical involvement of the nail and negative culture/
was the only reported side effect. The investigators suggested that KOH stain) or treatment success (i.e., <10% clinical involve-
8 weeks may not have been a long enough duration for tea tree ment of the nail). In studies 1 and 2, 18% and 15% of subjects
oil to achieve its full effect, explaining its lack of efficacy in this in the treatment arm achieved complete cure, respectively.
study (38). Complete cure rate was only 3% and 6% in the vehicle arm
in studies 1 and 2, respectively. For those treated with efina-
conazole, treatment success was achieved in 45% and 40% in
Vicks ® VapoRub
studies 1 and 2, respectively, whereas only 17% (study 1) and
Vicks VapoRub has been reported as a folk remedy for onycho- 15% (study 2) reached treatment success in the vehicle arm.
mycosis. Ramsewak et al. conducted an in vitro study inves- Given the high treatment success rate achieved with efinacon-
tigating the inhibitory activity of both the active and inactive azole at 48 weeks and that toenails may take up to 78 weeks for
ingredients found in VapoRub on fungal pathogens which completely new growth, the authors suggest that longer treat-
cause onychomycosis. The study demonstrated that camphor, ment duration may increase complete cure rates. Additionally,
menthol, thymol, and Eucalyptus citriodora oil (composed of the authors commented that given the minimal side effect pro-
monoterpenes) are all effective inhibitors when used singly as file of efinaconazole, it could be used as a maintenance medi-
well as when used in combination (39). Disruption of the fun- cation or adjunct to prevent recurrence of onychomycosis in
gal cell membranes and inhibition of ergosterol synthesis by those previously treated with systemic therapy (45).
thymol and monoterpenes has been suggested as the mecha-
nism of action in laboratory studies (40, 41).
A clinical case series examined the effect of daily topical Photodynamic Therapy
application of VapoRub in 18 human subjects with clinically Photodynamic therapy (PDT) refers to the use of light-
confirmed and culture-positive fungal nail infections. Outcome activated compounds that react with a certain wavelength of
measures at the study endpoint of 48 weeks were defined as light to produce oxygen free radicals which interact with cells,
“mycological cure,” based on KOH and nail sample cultures, resulting in cell damage and/or death (46). While the U.S.
and “clinical cure,” which could be either “complete,” “par- Food and Drug Administration (FDA) has not approved PDT
tial,” or “no change,” dependent on the appearance of the nail. for the treatment of onychomycosis (47), there is evidence to
Five subjects experienced mycological cure, ten demonstrated suggest that PDT likely has a role and can be used in treating
partial clinical cure, and three showed no significant change. this condition.
Interestingly, the six subjects who were culture-positive for An in vitro study by Smijs et al. demonstrated the fungicidal
T. rubrum, the most common causative pathogen of onycho- activity of certain photosensitizing porphyrin molecules when
mycosis, had only “partial cure” or “no change,” whereas the exposed to wavelengths of light in the red spectrum. Notably,
five individuals who demonstrated “complete cure” were cul- PDT was demonstrated to not only eradicate the fungal hyphae,
ture-positive for either Candida parasilosis or Trichophyton but to also inactivate the T. rubrum spores, which have been
mentagrophytes (42). implicated in the recurrence of tinea unguium infections after
treatment with traditional oral agents. Use of red light has the
Tavaborole additional benefit of increased tissue penetration when com-
pared to white light, making it an attractive agent for treating
Tavaborole is a boron-containing compound developed by fungal nail, which requires adequate tissue penetration (46).
Anacor Pharmaceuticals (Palo Alto, CA) that has been shown A subsequent in vitro study demonstrated that T. rubrum,
to inhibit a fungal enzyme needed for fungal protein synthesis. when exposed to 5-aminolevulinic acid (5-ALA), generates
Two phase III trials—approximately 600 subjects per trial— the photosensitizing molecule protoporphyrin IX, which can
assessing the efficacy of topical application of tavaborole in be irradiated with red wavelengths of light—636 nm and
treating onychomycosis were recently completed and demon- 708 nm—resulting in a nearly 50% inhibition of fungal growth
strated promising results (43). Primary publication data could compared to control (48).
not be found with a PubMed search for “Tavaborole,” however, Utilizing the technology discussed above, there have been
a recent review article quoted complete cure rate of 6.5% in the several in vivo case reports of successfully treated onychomy-
treatment arm versus 0.5% in the vehicle arm (44). cosis using PDT. One case was that of a 78-year-old woman
with onychomycosis of the bilateral great toenails. Treatment
included removal of the affected nails after softening with
Efinaconazole
40% urea ointment, application of 5-ALA (Metvix 160 mg/g)
Efinaconazole is the first triazole antifungal developed for the cream, and irradiation with 37 J/cm2 light-emitting diodes in
treatment of onychomycosis. Two identical multicenter, ran- the red spectrum—630 nm wavelength. This regimen was
domized, double-blind, vehicle-controlled studies involving a repeated every 15 days for 45 days, totaling three treatment
total of 1655 subjects were conducted to assess the efficacy sessions. While KOH stain and cultures were positive imme-
of topical efinaconazole 10% solution in treating onychomy- diately after the last session, follow-up at months three through
cosis. Subjects were randomized to efinaconazole or vehicle month 24 demonstrated complete mycologic and clinical reso-
and applied the assigned solution daily for 48 weeks and were lution of the infection (49).
Additionally, two case reports of successfully treated ony- treating four different types of onychomycosis—total dys-
chomycosis involving urea, 5-ALA, and irradiation with red trophic form, distal, proximal, and endonyx—in 72 patients
light have been described by Watanabe et al. However, in these with 194 affected nails caused by T. rubrum, T. mentagro-
cases, 20% urea was used to soften the nail without subsequent phytes, Candida, or Aspergilus niger. After microscopic and
removal and an excimer-dye laser with a fluence of 100 J/cm2 culture confirmation of positive fungal infection, subjects
at 630 nm wavelength was used. While the laser caused “some underwent four sessions—three irradiations during each ses-
pain” for the patients during treatments, it was temporary in sion—at 1-week intervals, in which affected nails were irra-
nature, and the laser was chosen as the light source due to its diated at fluences of 35–40 J/cm2, pulse duration 35ms, and
greater tissue-penetrating capabilities than other light sources. rate 1Hz. Variation in fluence was due to variations in nail
One patient required seven treatments and the other required thickness, with thicker nails requiring higher fluence. Three
six treatments with no recurrence of infection recorded at participants had particularly thick nails, which were pre-
6-month and 3-month follow-ups, respectively (50). treated with a urea preparation to improve laser penetration.
Sotiriou et al. conducted a single-center open trial involving Nail plate temperatures were raised to 45±5°C, with cold air
30 Caucasian subjects with diagnosed toenail onychomycosis. cooling used during treatments, with the majority of patients
Therapeutic regimen included treatment with 20% topical urea rating their pain as “mild,” none rating their pain as “severe”
cream with subsequent removal of the affected nail, 3-hour or “intolerable.” At 3-month follow-up, 69/72 subjects were
treatment with 20% 5-ALA, and irradiation with a noncoher- cleared of fungal infection and the three affected subjects
ent, 40 J/cm2 dose of red light ranging in wavelength from repeated the therapeutic protocol. All 72 subjects were free
570–670 nm. Three treatments were performed at 2-week of infection at 6- and 12-month follow-ups. The mechanism
intervals for 6 weeks. During irradiation, approximately one- of action underlying this therapy is in line with the previously
third of patients endorsed pain or burning requiring a brief discussed theory that 1064 nm wavelengths are absorbed by
interruption, and almost all patients experienced other minor fungal cell wall melanin, leading to “local hyperthermia,”
side effects such as erythema, edema, and blistering around and consequent fungal destruction. This study extrapolates
the site. Cure at 12- and 18-month follow-ups was defined as on the “local hyperthermia” and destruction, suggesting that
“100% absence of clinical signs” or “subungual hyperkerato- thermal injury likely results in a combination of fungal DNA
sis” affecting less than 10% of the nail plate with “negative damage, production of reactive oxygen species, and protein
mycological laboratory results.” This study demonstrated a denaturation, all triggering fungal cell apoptosis, leading to
cure rate of 43.3% (13/30) at 12 months and 36.6% (11/30) at 18 mycological cure (53).
months, suggesting that PDT is somewhat efficacious, though Kalokasidas et al. conducted a clinical study involving
room for improvement exists (51). 131 subjects, investigating the inhibitory effects when both
1032 nm and 532 nm wavelengths are used together. Prior to
irradiation, the severity of onychomycosis was graded and sub-
Laser Therapy
jects’ affected nails were mechanically debrided with a nail
In addition to PDT, many studies have begun exploring the file. Using the Q-switched Nd:YAG 1064 nm/532 nm laser,
therapeutic effect of lasers on onychomycosis. The following affected nails were first irradiated with a 1064 nm wavelength
in vitro study by Vural et al. investigated the effects of a vari- laser, received a 2-minute break, and then irradiated with a
ety of laser systems, wavelengths, and fluences on T. rubrum 532 nm wavelength laser. Participants attended two treatment
growth inhibition. T. rubrum colonies were grown on culture sessions—on days 0 and 30—and the aforementioned regimen
plates and irradiated by a variety of lasers, with fungal colony was conducted during each session. The results of this study
size and growth rate measured on days 1, 3, and 6 post-irradia- reflect that of the prior study, with 125/131 subjects demon-
tion. While a majority of the lasers were ineffective at inhibit- strating mycological cure (negative microscopy and culture)
ing growth, the Q-switched Nd:YAG laser used at independent at 3-month follow-up. Notably, of the types of onychomycosis,
wavelengths of 532 nm and 1064 nm, with varying fluences, “distal subungual” demonstrated the best response to treat-
both retarded fungal growth. The authors suggest that the ment and of the infecting organisms, T. rubrum showed the
growth retardation observed with 532 nm irradiation is likely most prompt response. Given the promising results, if laser
due to xanthomegnin, a T. rubrum pigment that absorbs in therapy does not supplant systemic therapy, it could potentially
that spectrum, leading to “photothermolysis,” as opposed to be used in conjunction with it, reducing treatment duration.
“nonspecific thermal damage.” Similarly, irradiation with the This study’s clinical outcomes have yet to be fully assessed
1064 nm wavelength is postulated to cause its “photothermo- at 12-month follow-up, and as the authors point out, negative
lytic” damage due to absorption by melanin, a pigment found cultures do not always equate with mycological cure, as there
in the cell walls of T. rubrum. The Q-switched Nd:YAG laser’s is high false negative rate (32).
“short pulse width” adds to its inhibitory effects on T. rubrum While many studies have shown laser therapy to be effica-
growth by inducing thermal and mechanical damage via rapid cious in the treatment of onychomycosis, a recent in vitro and
heating and cooling, as well as “acoustic shock wave” produc- in vivo study by Carney et al. brings the efficacy of Nd:YAG
tion, respectively. Fluences chosen in this study were similar in 1064 nm laser therapy into question. A few common nail der-
energy to fluences used in other dermatologic procedures, such matophytes, including T. rubrum, were chosen for the in vitro
as port-wine stain and unwanted hair or tattoo removal (52). portions of the study. In phase one of the in vitro portion, sus-
A subsequent clinical study demonstrated strong efficacy pensions of the fungi were heated to varying temperatures—
of the VSP long-pulse Nd:YAG 1064 nm laser therapy in 45°C, 50°C, and 55°C—for varying durations, then plated
on agar and monitored for growth. T. rubrum growth was pruritic symptoms through reduction of nitric oxide levels.
retarded when exposed to 50°C for 5 minutes, and a fungicidal A double-blinded, randomized, placebo-controlled, intra-
effect was observed when exposed for 15 minutes. In phase individual study conducted in 2009 examined the effects of
two, T. rubrum suspensions were plated on agar, then irradi- topical vitamin B12 on atopic dermatitis in the pediatric popu-
ated with the laser at varying combinations of fluence, pulse lation. Participants’ ages ranged from 6 months to 14 years
width, and Hz, and temperature was recorded. In phase 3, T. old. Parents were instructed to apply the vitamin B12 cream
rubrum was grown on an agar plate until red pigmentation to one side of their child’s body and the vehicle to the other
was visible; 3-mm punch biopsies of mycelium were taken and twice daily for 4 weeks, the study duration. Efficacy of the
transplanted to another plate, which was subsequently irra- creams was evaluated using the modified SCORAD scale. At
diated with the same variations as used in phase 2. In both the study’s completion, there was a statistically significant dif-
phases 2 and 3, no growth inhibition of T. rubrum was noted ference between SCORADs. When B12 was used, the average
after irradiation and temperatures only reached 40°C in phase baseline SCORAD value of 13.19 decreased by 4.52 points,
2, suggesting that prior clinical trials proposing fungicidal whereas the control’s baseline SCORAD value of 12.57 only
effects due to thermal destruction is unlikely. Phase 4 was the decreased by 1.61 points. Side effects were minimal; 22 sub-
24-week in vivo portion of the study in which five laser treat- jects started the 4-week study and 21 subjects completed the
ments were performed on eight individuals with 14 affected study, with one subject experiencing side effects to both the
nails over the course of the initial 7 weeks. Nail assessments, experimental and control creams. A similar study had previ-
microscopic and culture evaluation were performed intermit- ously been conducted in adults. This was the first to be con-
tently throughout the study. Notably, eight of the 14 affected ducted in the pediatric population (56).
nails showed only mild clinical improvement, though this did
not correlate with microscopic or culture findings, and notably,
Oatmeal
two subjects changed Onychomycosis Severity Index (OSI)
categories, both of which increased in disease severity. OSI Oats, a secondary crop derived from a weed of the primary
rates two measures, “area of involvement” and “proximity of cereal domesticates wheat and barley (57), are commonly
the disease to the nail matrix,” from 1–5. These two values used to treat skin conditions such as atopic dermatitis. In fact,
are multiplied, and 10 points are added if either a longitudinal oatmeal has been deemed an effective skin protectant by the
patch/streak or subungual hyperkeratosis greater than 2 mm FDA (58). In an assessor-blind study of 35 burn wound heal-
are present. OSI categories include “mild” (1–5), “moderate” ing patients, 5% colloidal oatmeal in a liquid paraffin suspen-
(6–15), and “severe” (16–35). While recognizing differences sion applied twice daily was compared to liquid paraffin alone.
in study protocols, particularly the wide variation in laser set- Patients applying colloidal oatmeal reported significantly less
tings, the results of this study have compelled the authors to itch and required significantly less antihistamine than those
conclude that laser therapy is thus far not a reliable treatment applying vehicle alone (59).
modality for onychomycosis and thermal damage is unlikely
the mechanism underlying clinical improvement when laser
therapy is performed (54). See also Table 15.2.
Plant Oils
Topical application of different natural oils has continually
remained a choice alternative therapy for treatment of atopic
dermatitis, especially considering the hallmarks of dry skin
Atopic Dermatitis and impaired barrier function common to almost all AD diag-
noses. Consistent moisturization is an essential aspect of any
Atopic dermatitis is a common disease affecting up to 20% eczema treatment plan, and there are many promising plant
of the pediatric population and about 1%–3% of adults in the oils with demonstrated therapeutic value in addition to their
industrialized world. The disease is characterized by pru- emollient properties.
ritus, rash on the extensor surfaces and face of young chil- Sunflower seed oil (Helianthus annuus) contains high levels
dren, lichenification of the flexural surfaces of older children, of linoleic acid, a free fatty acid (FFA) compound that dem-
recurrent skin infections, and personal or family history of onstrates anti-inflammatory properties and can improve the
atopic disease. The pathogenesis of the disease is complex skin barrier (60). One study of 80 pediatric patients with mild
and multifactorial, involving interplay of genetic susceptibility to moderate AD found 2% sunflower oleodistillate cream to
resulting in decreased skin barrier and immune system dys- exhibit significant improvement in disease severity and quality
regulation and hyper-reactivity (55). Many traditional thera- of life, comparable to that achieved by hydrocortisone butyro-
pies exist; however, side effects may limit their use (56). This propionate at days 7 and 21 of treatment (61). Not all natural
has prompted a search for additional, alternative treatment oils, however, are associated with improved skin barrier func-
modalities for this condition. tion and integrity. When compared with topically applied olive
oil, sunflower seed oil was found to preserve stratum corneum
integrity and therefore improve hydration while olive oil had
Vitamin B12
the opposite effect: reduced stratum corneum integrity and
Pruritus is a common symptom of atopic dermatitis and is resulting xerosis and erythema (62). Thus, it becomes clear
thought to be due to increased nitric oxide and cytokines. that, contrary to popular belief, not all natural oils are benefi-
Vitamin B12 is a nitric oxide scavenger, thereby reducing cial to the skin.
TABLE 15.2
Alternative Treatments for Onychomycosis
Ciclopirox Multicenter, randomized, double- 34% Mycological cure rate; 7% (Gupta and Joseph 2000)
blind, vehicle-controlled in vivo clinical cure rate
Ciclopirox Randomized, double-blinded, 34% achieved complete cure; 72% (Friedlander et al., 2013)
vehicle-controlled, crossover, in with greater than 50% clearance
pediatric population in vivo
Efinaconazole Multicenter, randomized, double- 15%–18% Complete cure rate and (Elewski et al., 2013c)
blind, vehicle-controlled in vivo 40%–45% with <10% clinical
involvement
Laser therapy: Q-switched Nd:YAG In vitro Retardation of fungal growth (Vural et al., 2008)
Laser therapy: VSP long-pulse In vivo 100% cure rate (Kozarev and Vizintin, 2010)
Nd:YAG
Laser therapy: Q-switched Nd:YAG In vivo 9% With excellent clinical (Kalokasidis et al., 2013)
improvement and 95% mycological
cure rate
Laser therapy: long-pulsed Nd:YAG In vivo and in vitro In vitro demonstrated no fungal (Carney et al., 2013)
growth inhibition
In vivo showed 57% with clinical
improvement and 43% without
clinical improvement or worsening
Photodynamic therapy In vitro Eradication of fungus (Smijs et al., 2004)
Photodynamic therapy In vitro 50% Inhibition of fungal growth (Kamp et al., 2005)
Photodynamic therapy Single case report in vivo Clinical and mycological cure (Piraccini et al., 2008)
Photodynamic therapy 2 case reports in vivo Clinical improvement and (Watanabe et al., 2008)
mycological cure
Photodynamic therapy Single-center open trial in vivo 36.6% Cure rate (Sotiriou et al., 2010)
Tavaborole Phase 3 clinical trials in vivo 6.5% Complete cure rate (Anacor Pharmaceuticals)
Tea tree oil (100%) Multicenter, double-blind, Improvement in onychomycosis (Addino et al., 1994)
randomized in vivo
Tea tree oil (5%) Randomized, double-blinded, No improvement (Syed et al., 1999)
placebo-controlled in vivo
Vick’s VapoRub In vitro Effective inhibition of fungal growth (Ramesewak et al., 2003)
Vick’s VapoRub Clinical case series in vivo 28% Mycological cure rate and (Derby et al., 2011)
55.5% partial clinical cure rate
Essential fatty acids (EFAs) are fatty acids that need 2 years of age. Infants were evaluated for atopic dermatitis
to be obtained through the diet, because the body cannot at 3, 12, and 24 months of age, and the SCORAD scale—
synthesize them. As previously noted, immune system dys- mentioned earlier—was used to assess severity. Interestingly,
regulation is thought to play a role in atopy, and it is known 81.7% of the infants in this study had either one or two par-
that EFAs—notably n-3 and n-6 fatty acids—have a role ents with a personal history of atopy, thereby increasing the
both in inducing inflammation and modulating it. Previous infants’ predisposition to atopy. At both 3 months and 24
studies have suggested that having an optimal ratio of n-3 months of age, there was no statistically significant differ-
fatty acids to n-6 fatty acids (1:3–1:4) plays an important ence between the two treatment groups with regard to the
role in properly programming the fetal and infant immune atopic dermatitis rates. However, at 12 months of age there
system. was a statistically significant difference between the two study
Blackcurrant is a commonly cultivated berry in Europe, and groups, 33% and 47.3% with atopic dermatitis in the BCSO
blackcurrant seed oil (BCSO) possesses the optimal ratio of and olive oil groups, respectively. Additionally, according to
these EFAs. Therefore, Linnamaa et al. conducted a double- the SCORAD, those with atopic dermatitis in the BCOS group
blind, placebo-controlled trial assessing the efficacy of BCSO had statistically significantly less severe disease than those in
dietary supplementation in preventing the development of the placebo group. The lack of statistically significant differ-
atopic dermatitis in infants. Pregnant women were randomly ences at ages 3 and 24 months may be explained by the gen-
assigned to receive 3 g of either BCSO or olive oil, the control. eral low prevalence and adoption of a less healthy diet at those
The pregnant women received their first dose at 8 weeks and ages, respectively. Previous studies have shown no side effects
16 weeks gestation, then daily through the end of the exclu- to blackcurrant supplements, making this a viable option for
sive breastfeeding phase. After breastfeeding was complete, preventing and reducing the severity of atopic dermatitis early
infants received the oils orally, in the form of drops, until in life (63).
Gentian Violet superior on all accounts compared to mineral oil (67).

The dual functionality of coconut oil in these instances (i.e., as
Chronic inflammation associated with atopic dermatitis is in both an emollient and antibacterial agent) is of particular inter-
part thought to be associated Staphylococcus aureus coloni- est to clinicians looking for natural and effective alternatives
zation, and the S. aureus burden has been shown to correlate to conventional AD treatments.
with eczema severity. Gentian violet (GV) is a known antimi- In addition to contributing to chronic inflammation asso-
crobial agent, and Brockow et al. performed a study assessing ciated with atopic dermatitis, microbial infections, includ-
the efficacy of topical GV, the potent topical steroid diflucor- ing Staphylococcus aureus among others (e.g., Escherichia
tolone-21-valerate (DC), and the tar solution liquor carbonis coli, Streptococcus pyogenes, Corynebacterium spp, and
detergens (LCD) in treating S. aureus–colonized atopic der- Pseudomonas aeruginosa), can prolong the inflammatory
matitis. Twenty-one adults with S. aureus–colonized atopic phase of wound healing, impeding the formation of new skin
dermatitis were assigned to one of three groups—GV, DC, structure and increasing risk of patient mortality (68). Burns
or LCD—and were instructed to apply their assigned topical are some of the most severe wounds that must be treated
agents—active and vehicle—to both eczematous and normal with careful attention to antimicrobial measures. In addition
skin twice daily for 4 days. The severity of the eczematous to antimicrobial effects, other properties that can enhance
lesions was evaluated prior to and 2 days after completing wound healing and recovery are the anti-inflammatory, anti-
the treatment regimen using the modified SCORAD scale, oxidant, and fibroblast enhancement potential of certain topi-
and S. aureus burden was quantified daily. In patients treated cally applied compounds. Thus, the medicinal compounds
with GV, both unaffected and eczematous skin showed sta- natural essential oils, and their counterpart carrier oils, are of
tistically significant decreases in S. aureus density, and there high interest to dermatologists seeking alternative treatments
was a statistically significant difference between those areas for burns and other wounds, given they exhibit many of the
treated with GV and those treated with control. Two days after aforementioned properties (69). Although 1% silver sulfadia-
treatment, S. aureus density returned to pretreatment baseline. zine is an effective antimicrobial agent used in most practices
Eczematous patches showed statistically significant reduc- to treat burn wounds, its application is somewhat limited by
tions in SCORAD values during treatment with GV, as well as the occurrence of sulfur allergies, as well as patients who have
control. Subjects treated with DC and LCD did not show sig- heightened skin sensitivity from eczema and other conditions.
nificant reductions in S. aureus colonization in either affected When applied to this subset of patients, silver sulfadiazine
or unaffected skin during the treatment phase, though inter- can actually have detrimental effects on skin restoration and
estingly, S. aureus density decreased 2 days following treat- wound healing (70).
ment. SCORAD values improved for the eczematous lesions Essential oils and carrier oils both have an important role to
treated with DC and LCD, as well as their associated controls; play in alternative treatments for wounds, with essential oils
however, the improvement was more dramatic when the active providing an antimicrobial effect, and carrier oils contribut-
agents were used. The in vitro portion of the study demon- ing anti-inflammatory, anti-oxidant, and collagen stimulation
strated the bactericidal effect of GV on S. aureus and DC’s and properties. Structurally, the two oils are distinct, but can be
LCD’s lack of antibacterial effects (64). Notably, a more recent used in conjunction, with carrier oils acting as a medium into
case report of group A Streptococcus impetiginized atopic which essential oils can be mixed. Essential oils on their own
dermatitis treated with topical 1% GV and oral doxycycline can be toxic to the skin, and often evaporate more readily than
was presented in the Journal of the American Academy of absorbing into the skin. Carrier oils are believed to be capa-
Dermatology. Not only did the GV successfully treat the infec- ble of enhancing skin absorption of the diluted essential oils,
tion and dermatitis, it offered almost instantaneous relief of mainly due to their composition of small molecules that are
the associated discomfort. The authors suggest that it is often closely related to sebum, the skins naturally producing oil (71).
difficult to distinguish whether or not the underlying process One of the most popular carrier oils used in dilution of
is inflammatory, infectious, or both, and GV is a viable option essential oils is Aloe vera. The plant is used worldwide as one
for treating both (65). of the most popular natural compounds used in wound heal-
ing (72). In gel form, Aloe vera has been shown in vivo and in
clinical trials to be effective in wound healing and pain relief.
Plant Oils (Cont’d) (Essential and Carrier)
The variety of wounds treated in these trials include burns, leg
Another compound that has been found to be effective in treat- ulcers, diabetic ulcers, pressure ulcers, caesarean, episiotomy,
ing infection by S. aureus is virgin coconut oil. An RCT com- and split-thickness skin graft donor sites (73–75). Aloe gel
paring coconut oil to virgin olive oil found that while both oils has also demonstrated an ability to treat wounds colonized by
reduced S. aureus colonization and improved disease severity, antibiotic-resistant strains of S. aureus (penicillin, clindamy-
coconut oil accomplished this at a much higher rate (95% of cin, co-trimoxazole and cefoxitin resistant) and P. aerugi-
subjects treated with coconut oil were cleared of S. aureus, nosa (amoxiclav, ceftizoxime, co-trimoxazole and ofloxacin
compared to only 50% of subjects treated with olive oil) (66). resistant) after conventional antibiotics have proven ineffec-
In another study of 118 patients, virgin coconut oil was com- tive (76). Aloe vera has also exhibited several other proper-
pared with mineral oil as an antibacterial agent. Both groups ties conducive to wound healing, including anti-inflammatory,
demonstrated significant improvement in SCORAD, trans epi- antioxidant, and antipruritic activities (77, 78). Finally, Aloe
dermal water loss, and skin capacitance assessments compared has demonstrated the important wound-healing aspect of pro-
with baseline; however, coconut oil was also significantly moting the proliferative phase, given studies have shown the
plant extract’s ability to increase human fibroblast intracellular Based on the four parameters, subjects were given a numeric
communication and proliferation, thus propagating maturation score, and improvement was defined as receiving a score up to
of collagen and enhancing formation of granulation tissue, epi- 75% of baseline. At the study’s end, 96% of participants in the
thelialization, and angiogenesis (79, 80). experimental arm and 32% in the placebo arm demonstrated
Another popular carrier oil used in wound healing is improvement, which was statistically significant (89).
Calendula officinalis (calendula). This compound contains Despite the promising findings of EPO in the Senapati et al.
several important fatty acids, including calendic, linoleic, study, a recent Cochrane Review suggests the contrary. This
oleic, and palmitic acid, and has been shown to enhance the review of 19 studies, including two meta-analyses—one with
healing of foot ulcers by accelerating the tissue repairing pro- seven studies and other with eight studies—concluded that
cess (81). In another study, calendula in lamellar gel emulsion there was no statistically significant difference in improve-
form was shown to exhibit anti-inflammatory activity and ment between those treated with oral EPO and those treated
stimulate increased collagen production, thereby expediting with placebo. Additionally, side effects of EPO noted in the
the healing process (82). Additionally, Cocos nucifera (coco- report were predominantly GI upset and EPO’s anticoagulant
nut oil), Helianthus annuus (sunflower oil), Linum usitatissi- effects. Therefore, Cochrane’s recommendation is that EPO
mum (linseed oil), and Persea americana (avocado oil) have not be used in treating atopic dermatitis, and further studies
all shown promise as carrier oils demonstrating antimicrobial, evaluating the effects of EPO on atopic dermatitis “would be
anti-inflammatory, and collagen production stimulating prop- hard to justify” (90).
erties (83–86). In addition, the Cochrane Report reviewed the efficacy of
Given that microbial proliferation is one of the biggest borage oil (BO) versus placebo in treating atopic dermatitis.
impediments to wound healing and tissue formation, accu- While no meta-analysis was performed for the BO studies,
rately quantifying bacteria and other microorganisms is Cochrane reviewed eight studies and concluded that BO is not
imperative to the trials of effective topical compounds used efficacious in treating eczema (90).
in wound healing. Although traditional bacteria quantifica- Although the Cochrane Review suggests that oral supple-
tion involves determining the number of colonies (also called mentation with BO does not improve atopic dermatitis, the fol-
colony forming units) grown from a known volume on solid lowing study suggests that topical BO likely has a role. While
growth medium after an incubation period, this methods fails EPO contains 8%–10% GLA, BO (also known as starflower
to account for the number of dead bacteria or the viable but oil) (91), contains 24% GLA, making it a suitable consider-
non-culturable (VBNC) cells (87). Alternatively, fluorescent ation for the treatment of atopic dermatitis. Kanehara et al.
dyes SYTO 9 and propidium iodide (PI) used together with conducted a double-blind, placebo-controlled trial assessing
a fiber-based spectroscopic device called the optrode can pro- the efficacy of BO-coated undershirts in treating atopic der-
vide ultra-precise differential counts of live and dead bacteria matitis. Investigators had BO chemically bonded to cotton
in a mixture of both. The optrode is used to measure fluores- undershirts, which would be gradually released; BO remained
cence from mixtures of live and dead Escherichia coli cells on the shirts after 60 washings. Thirty-two pediatric subjects
that are stained with the fluorescent dyes. By dipping the fiber participated in the study, with 16 assigned to the BO-coated
probe of the optrode directly into fluorescently tagged bacte- undershirt group and 16 to the uncoated group. Subjects were
rial suspensions, the optrode can accurately measure the emis- evaluated by a single clinician at baseline for a variety of signs
sion signals at the cell population level. This method proves and symptoms associated with atopic dermatitis (erythema,
cost-effective, easy to use, and also has a compact design (88). itch, papules, erosion, scaling, and lichenification—rated on
Such efficiency and accuracy in testing is critical for the iden- a scale of 0–3), instructed to wear the undershirts daily, and
tification of effective antimicrobial agents to be used in the were reassessed 2 weeks later for the same signs and symp-
treatment of wounds. toms. As evaluated by the clinician, participants in the BO
Evening primrose is a tall herbal plant with yellow flowers group showed a statistically significant improvement in symp-
that bloom in the evening. It was first described by the Native toms of “itch” and “erythema” after 2 weeks, while those in
Americans in 17th century as being used to treat “swelling the placebo did not show statistically significant improvement
in the body.” Evening primrose oil (EPO) contains 8%–10% in any signs or symptoms. Notably, 75% of parents of children
gamma-linolenic acid (GLA)—n-6 EFA—and can be used as in the BO group reported symptomatic improvement, while
an alternative or adjunctive treatment for atopic dermatitis. 56.2% in the placebo also reported symptomatic improve-
Senapati et al. carried out a randomized, placebo-controlled ment. Authors speculate that the symptomatic improvement
study assessing the efficacy of oral EPO in treating atopic observed by parents in the placebo group may be due to high
dermatitis in an Indian population. Twenty-five subjects quality, pure, organic undershirts that their children were
were enrolled in both the experimental and placebo arms wearing. Of note, those in the BO group showed a statistically
and instructed to take age-dependent oral doses—in capsule significant decrease in transepidermal water loss (TEWL)
form—of either EPO or sunflower oil, respectively. Patients after 2 weeks of treatment, while the placebo group did not.
were followed for 5 months and investigators evaluated par- Individuals with atopic dermatitis have defective epidermal
ticipants’ disease monthly, based on four parameters: extent, function, leading to increased TEWL and subsequent dry skin
intensity, dryness, and itching. On average, subjects treated and associated symptoms. Therefore, the implications of topi-
with EPO gradually and progressively improved in all param- cal BO in treating atopic dermatitis are twofold: decreasing
eters during the course of the study, while those in the placebo inflammation and restoring epidermal structure and function,
group on average demonstrated inconsistent improvement. thereby decreasing water loss (92).
Balneotherapy weighed during visits. Analysis of the data after 16 weeks

demonstrated statistically significant improvement in the
Given that a commonly reported feature of atopic dermatitis SCORAD scores in both the TCHM and placebo groups.
is increased transepidermal water loss (TEWL), it follows that However, there was not a statistically significant difference
balneotherapy, or interventions focused on water and bath- between the two groups. While SCORAD values did not dif-
ing, can prove very helpful and effective in an attempt to limit fer, the TCHM group showed a greater than 30% improve-
TEWL and consequently improve eczema symptoms. Such ment in CDLQI scores, while the placebo group showed no
bathing therapies are ancient practices, with roots originat- improvement at the study’s end; TCHM’s improvement com-
ing in 1800s Europe (93). Togawa studied the efficacy of ion- pared to baseline and compared to the placebo group were
exchange water softeners in a group of 12 Japanese children both statistically significant. In addition to an improvement in
with mild to moderate eczema (EASI <= 20). Results of this CDLQI scores, those in the TCHM group demonstrated sta-
study suggested that while ultra-pure soft water (i.e., water tistically significant decrease in the number of days topical
that does not contain “hardness” ions such as magnesium, cal- corticosteroids were used per month, when compared to base-
cium, and bromide) does not significantly improve patients’ line. Additionally, the quantity of steroid used by the TCHM
EASI scores, it does provide a significant reduction in patients’ group was statistically significantly less than both the amounts
self-reported pruritus, thus leading to improved overall patient used at their baseline and the amount used by the placebo
satisfaction (94). Another RCT of 104 children showed signifi- group during the study. Interestingly, prior studies evaluating
cantly improved eczema severity following both balneotherapy the chemical makeup of the TCHM have shown it to have no
and traditional topical corticosteroid treatment. When calcu- chemical similarity to corticosteroids. Side effects of TCHM
lating SCORing Atopic Dermatitis (SCORAD) ranges, topical in this study were “generally mild and self-limiting” (97).
corticosteroids proved to be more effective than balneother- Mast cells are known to play a role in allergic processes.
apy in reducing scores; however, IGA, Patient’s Self Global In response to triggers, mast cells release pro-inflammatory
Assessment (PSGA), Children’s Dermatology Life Quality mediators such as histamine, cytokines, and prostaglandin D2
Index (CDLQI), and Family Dermatitis Impact Questionnaire (PGD2). Subsequent to the 2007 Hon et al. study, several inves-
(FDIQ) score improvements were similar. Additionally, tigators from the same research group conducted an in vivo
patients treated with balneotherapy had lower incidence and study exploring the effects of the five substances in the PTH
duration of disease relapse at 4-month follow-up (95). formula on mast cells in an attempt to explain PTH’s modula-
tory effect on atopic dermatitis. In part one of the study, rat
Mahonia aquifolium peritoneal mast cells (RPMCs) were incubated with each of
the five herbal components and then triggered to release pro-
Another topical agent studied for the treatment of atopic der- inflammatory mediators. In part two of the study, human mast
matitis is extract from Mahonia aquifolium, an evergreen cells (HMC-1) were incubated with either dexamethasone,
shrub related to the barberry. In one study, 30 patients with PTH formula, or one of the five components, and then trig-
atopic dermatitis were treated with three times daily appli- gered, and cytokine production (GM-CSF, IL-6, IL-8, IL-10,
cation of Relieva cream, a homeopathic product containing TNF-alpha) was measured. PHF as well as one component of
a proprietary 10% M. aquifolium extract. Eczema area and PHF, namely Cortex moutan (CM) alone, demonstrated statis-
severity index (EASI) scoring revealed significant improve- tically significant decreases in histamine concentrations from
ment in both short-term (4-week) and long-term (12-week) RPMCs as compared to controls. Likewise, statistically signif-
improvement as compared to baseline (96). However, no pla- icant reductions in PGD2 concentrations were observed upon
cebo control was utilized in this study. exposure to PHF, CM, and Flos lonicerae (FL). One compo-
nent of PHF, namely C. phellodendri (CP) seemed to increase
histamine response and PGD2 release. While the aforemen-
Traditional Chinese Herbal Medicine
tioned 2007 Hon et al. study demonstrated no improvement
Traditional Chinese Herbal Medicine (TCHM), also known as in the severity of atopic dermatitis when treated with TCHM,
the PentaHerbs (PTH) formulation, is a “widely used ancestral authors suggest in this report that proportions of the individual
Chinese concoction” of five herbal extracts, which includes Flos components may have been subtherapeutic or an optimal ratio
lonicerae, Herba menthae (HM), Cortex moutan, Rhizoma of the components was not present. Researchers recommend
atractylodis, and C. phellodendri in the quantities of 2 g, 1 g, that increasing the ratio of CM or HM and decreasing CP
2 g, 2 g, and 2 g, respectively. It is quite commonly used in could potentially increase the efficacy of PTH in lessening the
Asia and China to treat children with atopic dermatitis. Hon et severity of atopic dermatitis (98).
al. conducted a randomized, double-blind, placebo-controlled Interestingly, there are also conflicting studies examining
trial assessing the efficacy of oral TCHM in treating atopic effects of the identical five-ingredient oral mixture. Hon et
dermatitis. Eighty-five subjects were enrolled—42 TCHM, 43 al. later showed this formulation (FL, HM, CM, RA, and CP)
placebo—and instructed to take three capsules twice daily for to fail in significantly reducing disease symptoms or severity
12 weeks. Participants were assessed every 4 weeks (at weeks when compared with placebo (99). Shapira et al. also demon-
4, 8, 12, and 16) using the SCORAD scale and the CDLQI, strated the unreliability of certain herbal combinations when a
as well as the Allergic Rhinitis Score (ARS). Subjects were mixture of Eleutherococcus senticosus, Achillea millefolium,
instructed to continue using prior medications and amount and Lamium album demonstrated a similar lack of efficacy
of topical corticosteroids—0.1% mometasone furoate—were in improving atopic dermatitis symptoms (100). These mixed
reports on the efficacy of TCHM could be in part due to its in these patients, despite the lack of skin manifestations that
many variations, both in chemical composition and propor- would be salient for most dermatologists (107).
tional distribution.
Topical mixtures of herbal ingredients have also been
explored as atopic dermatitis therapies. One such topical appli- Psoriasis
cation is Hypericum perforatum (St. John’s wort extract). This
herb contains hyperforin, a compound traditionally used to Among dermatologic conditions, psoriasis carries significant
treat burns and wounds that has suspected anti-inflammatory psychological burden and is associated with widespread treat-
properties. 1.5% hyperforin cream was shown to be signifi- ment dissatisfaction (108, 109). Patients with psoriasis there-
cantly more effective than vehicle control in treating 21 patients fore often turn to alternative therapies to complement their
with mild-to-moderate AD (p < 0.05). Efficacy of this study medical treatments.
was determined by measuring SCORAD ranges at weeks 1,
2, and 3 (101). Another head-to-head and placebo study com-
Aloe Vera
pared the efficacy of Kamillosan cream (containing chamo-
mile extract) against 0.5% hydrocortisone cream and a vehicle Aloe vera, a succulent plant that probably originated in
placebo. Following a 2-week treatment period, Kamillosan Northern Africa, the Canary Islands, and Cape Verde, is a
cream demonstrated modest superiority over 0.5% hydrocor- commonly used herbal medicine. Conflicting results have been
tisone cream, although only marginal difference against pla- observed in the treatment of psoriasis. In one study by Syed
cebo (102). Another RCT of 108 patients demonstrated licorice et al., aloe vera cream applied three times daily to 60 patients
extract at concentrations of 1 and 2% significantly reducing with slight to moderate psoriasis showed improvement as com-
erythema, edema, and pruritus compared with placebo. In this pared to placebo. Improvement was determined by a “positive
study 2% extract was more effective than 1% extract in ame- response,” measured as a composite of decreased erythema,
liorating symptoms (103). Similar to oral herbal treatments, infiltration, reductions of lesions, desquamation, and lower
certain TCHM topicals have failed to demonstrate efficacy in psoriasis-associated severity index (PASI) score (110). A more
treating AD. A topical ointment containing Mahonia aquifo- recent investigation of aloe vera gel applied twice daily for
lium, Viola tricolor, and Centella asiatica extract did not sig- 4 weeks to 41 patients with slight to moderate psoriasis vulgaris
nificantly reduce symptoms compared with placebo in a study showed a greater improvement in placebo-treated patients as
of 88 patients with mild-to-moderate disease (104). Despite compared to those with aloe vera. Efficacy was measured uti-
the variable results of these TCHM studies, the collective vol- lizing a modified PASI score (111).
ume of research makes it difficult to dispute the fact that some
herbal preparations can have legitimate therapeutic effects in
Dead Sea Salts
the treatment of AD. However, the complexity and inconsis-
tency of these mixtures can make it difficult for practitioners The Dead Sea, a salt lake bordering Jordan, the West Bank,
to apply such therapies in daily patient care. Overall, there are and Israel, is the deepest hypersaline lake in the world, and
far too many conflicting studies and unanswered questions to with 33.7% salinity it is one of the world’s saltiest bodies. It is
justify regular use of the herbal remedies, and further research purported to have many health benefits and has been investi-
is warranted to elevate herbal therapies to alternative treat- gated in the treatment of psoriasis. In a double-blind, random-
ments of choice for atopic dermatitis. ized control clinical trial by Cheesbrough et al., 24 patients
were treated with either a 30% Dead Sea salt lotion or placebo
for a total of 12 weeks. There was no statistically significant
Stress
improvement in either the Dead Sea salt lotion or vehicle dur-
Stress has been shown to play a role in atopic dermatitis and ing the treatment period (112). A more recent study by Dawe
the frequency of flares (105). Therefore, therapies that aim to et al. investigated Dead Sea salt (DSS) soaks plus NB-UVB
reduce daily stress consequently may have implications for versus NB-UVB alone in the treatment of plaque psoriasis in
reducing atopic dermatitis severity and flare-up frequency. a randomized, single-blind, controlled, right/left comparison
Such stress-reduction therapies include but are not limited to: study. Sixty-six patients pretreated one limb with DSS soaks
hypnotherapy, biofeedback (a relaxation/awareness technique and then underwent NB-UVB for 12 weeks. There was no
based on a physiological feedback device that measures gal- significant difference between the DSS soaks plus NB-UVB
vanic skin resistance), massage therapy, and cognitive behav- when compared to NB-UVB alone (113).
ioral stress (CBS) management therapy. Sokel et al. conducted
a study of 44 pediatric patients, in which hypnotherapy and bio-
Indigo naturalis
feedback processes both produced significant reduction in sur-
face damage and epidermal lichenification demonstrated in the Indigo naturalis, derived from the leaves of plants such as
experimental group when compared to the control group (106). Baphicacavthus cusia, has been investigated in the treatment
Another randomized control trial (RCT) including 28 patients of psoriasis. A recent randomized, observer-blind, vehicle-
and spanning 14 weeks found that CBS management therapy controlled, intrapatient comparison study by Lin et al. evalu-
showed no significant improvement in atopic dermatitis sever- ated the efficacy of a topical indigo naturalis ointment versus
ity when compared with the non-treatment group. However, vehicle in the treatment of recalcitrant plaque-type psoriasis
CBS did reduce endocrine and psychological stress responses in 42 patients. Statistically significant reductions in the sum
of scaling, erythema, and induration scores were observed Niacinamide

in indigo naturalis–treated patients as compared to controls
(114). A follow-up study in the Journal of Investigative Science Another alternative topical treatment for acne is niacinamide,
found that the antipsoriatic effects of indigo naturalis involve, which is also commonly used as CAM therapy in hyperpig-
at least partially, modulating the proliferation and differentia- mentation. Niacinamide is a form of vitamin B3 and carries
tion of keratinocytes (115). strong potential for treatment of acne due to its anti-inflamma-
tory and antioxidant effects (124). There are many observed
mechanisms by which niacinamide works to reduce comedo-
Mahonia aquifolium genesis. The effect of 2% niacinamide on sebum production
and levels was observed in two separate clinical trials (Japan
Finally, just as M. aquifolium has been studied for the treat-
and USA) by Draelos et al. In the Japanese group, sebum
ment of atopic dermatitis, so too, it has been investigated for
excretion rate was significantly reduced after 2 and 4 weeks
its use in treating psoriasis. The study consisted of 200 patients
of niacinamide use, whereas in the Caucasian group reduced
treating one plaque of psoriasis with Relieva twice daily for
sebum levels were observed, although the sebum excretion rate
12 weeks. PASI scores were significantly improved in the
was not significantly reduced after 6 weeks of niacinamide use
Relieva-treated patients as compared to placebo (116, 117). See
(125). Another mechanism by which niacinamide improves
further Table 15.3.
acne lesions is inhibiting P. acnes production of interleukin-8
(IL-8) through the NF-kappaB and MAPK pathways in kera-
tinocytes (126). Interleukins are a type of cytokine that play
essential roles in the activation and differentiation of immune
Acne cells, and they can have both pro- and anti-inflammatory
Another dermatologic condition for which alternative and effects (127). In a multi-center randomized trial, 4% niacina-
complementary therapies have become increasingly popu- mide emulsion was shown to be more effective than both 1%
lar is acne vulgaris. Patients often seek out such treatments clindamycin emulsion and the vehicle control in treating acne
due to frustration regarding the chronicity of acne and the vulgaris (128). Interestingly, when used in combination, topi-
recurrent breakouts that often occur despite initial clearance cal niacinamide-clindamycin products showed no significant
(118). A recent study showed that many patients felt as though difference when compared to clindamycin-only products in
complementary and alternative medicine (CAM) therapies two studies (129, 130). Also worth noting, the side effect pro-
provided equal or better efficacy and less risk of adverse reac- file of both niacinamide and clindamycin is similar, with the
tions when compared to conventional topical acne treatments majority of reported side effects being limited to application
(119). Given the growing interest in these alternative/natural site reactions (131). Given the similar efficacy and decreased
therapies, this section aims to provide a summary of some of antibiotic resistance when compared to a topical prescription
the most common CAM therapies for acne, in order to famil- like clindamycin, niacinamide may be an appealing alterna-
iarize clinicians with important studies that evaluate efficacy tive for those experiencing inadequate response to a conven-
compared to placebos, as well as traditional treatments. tional treatment or simply looking for an alternative/natural
therapy.
Ascorbic Acid
Zinc
Vitamin C (ascorbic acid) has many therapeutic and cosmeti-
cally advantageous effects when used topically. Due to the Zinc is an essential trace element known to decrease oxi-
molecule’s instability, vitamin C is now available in numer- dative stress and demonstrate bacteriostatic effect against
ous modified formulations, with sodium ascorbyl phosphate P. acnes (132). Zinc is often utilized to improve efficacy of
(SAP) being the most commonly studied, as well as com- topical antibiotics in combination preparations. Several stud-
mercially available (120). SAP demonstrates efficacy in ies have shown that the addition of 1.2% zinc acetate to 4%
treating acne, in large part due to its antimicrobial effect on topical erythromycin forms a complex that enhances epider-
P. acnes, as well as its reduction of lipid oxidation, leading mal penetration of the compound (133, 134). Another study
to a decrease in inflammation and follicular keratinization. of 30 patients showed that 30 mg zinc gluconate supplementa-
A human in vivo, 12-week study including 60 patients found tion, taken once daily for 2 months, reduced the number of
that 5% SAP cream demonstrated greater efficacy in treat- inflammatory acne lesions (135). An oral methionine-based
ing acne vulgaris when compared to the popular 5% benzoyl zinc antioxidant complex, containing vitamin C, mixed carot-
peroxide cream (121). Multiple randomized control trials enoids, d-alpha-tocopherol acetate and chromium, produced a
(RCTs) have shown the therapeutic effects of SAP, both as significant improvement in acne when taken three times daily
mono- and combination therapy. Ruamrak et al. demonstrated for 3 months (136). Another study of 235 patients with inflam-
the synergistic effects of 5% SAP and 0.2% retinol in treating matory acne exhibited the therapeutic effects of a prescription
inflammatory acne lesions, and Woolery-Lloyd et al. demon- dietary supplement containing zinc oxide, niacinamide, azelaic
strated the ability of 5% SAP lotion to produce improvements acid, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc,
in Investigator’s Global Assessment Scores, Subject’s Global Vernon Hills, IL). Patients taking this supplement experienced
Assessment Scores, and lesion counts when compared to pla- a statistically significant improvement in acne severity, follow-
cebo (122, 123). ing treatment periods of both 4 and 8 weeks (137). Oral zinc
TABLE 15.3
Alternative Treatments for Atopic Dermatitis, Psoriasis, Pruritus
Aloe vera Double-blind, placebo-controlled Slight to moderate improvement in (Syed, Ahmad et al. 1996)
(in vivo) psoriasis
Aloe vera Double-blind, placebo-controlled No improvement in psoriasis (Paulsen, Korsholm et al. 2005)
(in vivo)
Blackcurrant seed oil, oral Double-blind, placebo-controlled Improvement in atopic dermatitis in (Linnamaa, Savolainen et al. 2010)
(in vivo) infants
Borage oil, oral Cochrane Review (in vivo) Improvement of atopic dermatitis is (Bamford, Ray et al. 2013)
no greater than placebo
Borage oil, topical Double-blind, placebo-controlled Symptomatic improvement in atopic (Kanehara, Ohtani et al. 2007)
(in vivo) dermatitis
Traditional Chinese Herbal Randomized, double-blind, Overall improvement of atopic (Hon, Leung et al. 2007)
Medicine, oral placebo-controlled (in vivo) dermatitis no greater than placebo
Improvement in quality of life and
decreased amount of topical steroid
needed to treat
Traditional Chinese Herbal Medicine In vitro Reduction in rat peritoneal mast cell (Chan, Hon et al. 2008)
(PentaHerbs formula) release of pro-inflammatory
mediators of atopic dermatitis
Traditional Chinese Herbal Medicine Placebo-controlled (in vivo) No reduction in atopic dermatitis (Klovekorn, Tepe et al. 2007)
mixture (Mahonia aquifolium, symptoms as compared to placebo
Viola tricolor, Centella asiatica)
Colloidal oatmeal suspension Alternating assignment, assessor- Improvement in pruritus in burn (Matheson, Clayton et al. 2001)
blinded (in vivo) wound healing patients
Dead Sea salt lotion Placebo-controlled (in vivo) No improvement in psoriasis (Cheesbrough 1992)
Dead Sea salt soaks (with NB-UVB) Randomized, observer-blinded, No additional improvement in (Dawe, Yule et al. 2005)
paired comparison (in vivo) psoriasis as compared to NB-UVB
alone
Evening primrose oil, oral Cochrane Review and meta-analyses Improvement of atopic dermatitis is (Bamford, Ray et al. 2013)
(in vivo) no greater than placebo
Evening primrose oil, oral Randomized, placebo-controlled Improvement in atopic dermatitis (Senapati, Sabyasachi et al. 2008)
(in vivo)
Gentian violet Case report Improvement of Streptococcus (Stoff, MacKelfresh et al. 2010)
impetiginized atopic dermatitis
Gentian violet Placebo-controlled trial (in vivo; Reduces S. aureus skin burden and (Brockow, Grabenhorst et al. 1999)
in vitro) improves atopic dermatitis that is
colonized with S. aureus
Helianthus annuus In vivo Improvement in disease severity and (De Belilovsky et al. 2011)
quality of life as compared to
hydrocortisone butyro-propionate
Hypnotherapy and biofeedback In vivo Reduction in surface damage and (Sokel, Lansdown et al. 1993)
processes decreased epidermal lichenification
as compared to control group
Indigo naturalis ointment Randomized, observer-blinded, Improvement in psoriasis (YK, CJ et al. 2008)
vehicle-controlled (in vivo)
Mahonia aquifolium In vivo Improvement in psoriasis (Bernstein et al 2006; Smith et al
2009)
Virgin coconut oil Randomized, placebo-controlled (in Reduced S. aureus colonization and (Verallo-Rowell et al. 2008)
vivo) improved disease severity
Vitamin B12, topical Double-blind, randomized, Improvement in atopic dermatitis (Januchowski, 2011)
placebo-controlled (in vivo)
gluconate also appears to be a safe option in pregnant patients. Botanicals

A retrospective review on zinc gluconate supplementation
Another category of popular and well-studied alternative
found doses less than 75 mg to have no harmful fetal effects therapies includes botanicals such as tea tree oil, green tea,
(138). This is particularly salient for clinicians seeking to offer and resveratrol. Tea tree oil (TTO) is an essential oil included
a wide range of treatments to fit a variety of patient needs. in many over-the-counter products targeting acne, and TTO
represents the second most commonly used topical acne prod- have significant ramifications for emotional and mental health
uct behind 2.5% benzoyl peroxide (139). TTO has demon- of affected patients (148). Part of the difficulty encountered
strated both broad-spectrum antimicrobial activity, as well as in treating alopecia areata is the lack of guideline or FDA-
anti-inflammatory properties that are beneficial in the treat- approved conventional medications. In 2022, the approval of
ment of acne (140). A study of 124 patients found that both oral baricitinib (Olumiant) for the treatment of adults with
5% TTO and 5% benzoyl peroxide significantly reduced the severe AA was a step in the right direction, but this newer
number of both inflamed and non-inflamed acne lesions. therapy comes with a number of potentially concerning side
The TTO treated group experienced fewer side effects; how- effects, including serious infections and increased risk of
ever, the onset of action in this group was slower than those cancer, blood clots, major adverse cardiovascular events, and
treated with 5% benzoyl peroxide (141). One consideration death. (149). Other conventional therapies such as topical cor-
to keep in mind is that TTO is a relatively common contact ticosteroids, diphenylcyclopropenone, or topical minoxidil
allergen, with a number of studies reporting positive patch also may be associated with undesired side effects like atro-
test reactions ranging from 0.1% to 3.5% (142). Green tea is phy, pruritus, and dermatitis. In addition to the risk of side
produced from fresh leaves of the plant Camellia sinensis, effects, conventional therapies for AA have reportedly unreli-
resulting from methods that prevent oxidation of catechins able efficacy (150), making the topic of complementary and
such as (-)-epigallocatechin-3-gallate (EGCG). In vitro studies alternative (CAM) medicine for this condition particularly
show that EGCG exhibits antimicrobial effects, in addition to useful, both in theory and in practice. Although the quality
suppressing sebum production through inhibition of 5-alpha and quantity of evidence supporting most CAM therapies for
reductase, reducing inflammation, and propagating apop- AA is still limited, this section aims to summarize some of the
tosis of human sebocytes (143). In a recent study of healthy most efficacious and safe therapies that can be used in place of
human volunteers, a 3% green tea emulsion was shown to sig- conventional treatments.
nificantly reduce sebum production in a group of males (144).
Additionally, an open-label study of 20 patients with mild-to-
Acupuncture
moderate acne found that twice-daily application of 2% green
tea lotion reduced the mean total lesion count by approxi- Acupuncture is the practice of inserting one or more needles
mately 58% after 6 weeks (145). Another botanical treatment into specific areas of the body for therapeutic purposes; this
option is resveratrol, a phytoalexin found in spermatophytes technique is one of the most commonly studied and practiced
such as grapes, peanuts, mulberries, spruce, and eucalyptus CAM methods (151). Pertaining to AA, acupuncture may help
(118). This compound has demonstrated the ability to impede mitigate hair loss by reducing inflammatory activity against
sebocyte growth via inactivation of the Akt pathway (146). the hair bulb. Acupuncture may also stimulate hair follicles,
A single-blind study of 20 patients with acne vulgaris found warm local collaterals, and activate blood circulation (152).
that treatment with a resveratrol-containing hydrogel resulted One case report of a 22-year-old female with a ten year history
in reduced Global Acne Grading System scores and average of alopecia totalis demonstrated clinical benefit from treat-
areas of microcomedones, along with decreased acne lesions ment with electroacupuncture. The treatment involved trans-
when compared to those treated with a vehicle control (147). verse needle insertion at points GB20 (located at the nape of
See further Table 15.4. the neck) and GV16 (located at the nape of the neck midline)
Treatment of acne vulgaris is often a multifaceted and for a duration of 30 minutes once weekly. After three sessions,
seemingly perpetual process, given the chronicity of acne, the patient experienced a 25% regrowth, and after eight ses-
mixed etiology, and ability of pertinent bacteria to develop sions she had 55% regrowth, along with increased pigmented
resistance. Given the suboptimal results often observed with terminal hair. After 4 months of this treatment, the patient had
conventional treatment, and the preference some patients have an impressive 70% hair regrowth (153).
for natural and milder treatments, there is a growing need for
alternative treatments that have proven efficacy. Several stud-
ies have demonstrated such efficacy in a variety of products
Cryotherapy
that are becoming more readily available, including vita- Another alternative therapy technique with modest evi-
min C, niacinamide, zinc, tea tree oil, green tea extract, and dence supporting its efficacy is cryotherapy. Various studies
resveratrol. on cryotherapy use in AA postulate that the cold-induced
inflammation may serve to alter the immunological process
and structural components largely responsible for the disease
state. A cross-sectional, non-randomized, non-blinded study
Alopecia Areata
of 44 patients with AA examined treatment of hair loss areas
Another condition that proves particularly challenging to treat with a closed contact CO2 system with metallic probes for
for patients and providers alike is alopecia areata. Alopecia 10–15 seconds on average. Varying degrees of hair growth
areata (AA) is a chronic, inflammatory autoimmune disease were detected at week 4 (23 patients/52.5%) and week 8
of hair follicles, resulting in patches of nonscarring hair loss. (29 patients/65.9%) follow-ups. Treatment-related adverse
Certain severe forms of this condition include complete hair events were fairly common but relatively mild, with 18 cases
loss of the scalp (alopecia totalis) or entire body (alopecia uni- of partial leukotrichia, 14 cases of post-inflammatory hypopig-
versalis). Given the important role hair plays in people’s image mentation, and 2 cases of post-inflammatory hyperpig
and confidence, hair loss conditions like AA can oftentimes mentation (154).
TABLE 15.4
Alternative Treatments for Acne
Sodium ascorbyl phosphate (SAP) In vivo Improvement in acne (Klock, Ikeno et al. 2005)
5% SAP lotion In vivo Improvement in Investigator’s Global (Woolery-Lloyd, Baumann et al.
Assessment Scores, Subject’s 2010)
Global Assessment Scores, and
lesion count compared to placebo
2% Niacinamide 2 Clinical trials Reduced sebum excretion rate and (Draelos, Matsubera et al. 2006)
sebum levels
4% Niacinamide emulsion Multi-center randomized trial Improvement in acne compared to (Morganti, Berardesca et al. 2011)
(in vivo) 1% clindamycin and vehicle
30 mg Zinc gluconate, oral In vitro and in vivo Reduction in inflammatory acne (Dreno, Fouic et al. 2005)
lesions
-(-)Epigallocatechin-3-gallate In vitro Antimicrobial effects (Li, Summanan et al. 2015)
(EGCG) Decrease in sebum production,
reduced inflammation, and increased
apoptosis of human sebocytes
2% Green tea lotion Open-label study (in vivo) Reduction in mean total lesion count (Elsaie, Abdelhamid et al. 2009)
Resveratrol-containing hydrogel Single-blind study (in vivo) Reduced Global Acne Grading (Fabbrocini, Staibano et al. 2011)
System scores, reduced average
areas of microcomedones, and
decreased acne lesions compared to
treatment with vehicle control
Essential Oils induction of vasodilation, or modulation of the immune system

(157). A randomized, double-blind controlled study (RDBCT)
Topical agents that have shown promise in treating refractory including 40 patients observed two treatment groups: one
cases of alopecia areata include essential oils derived from group underwent twice-daily treatment with 0.1% betametha-
plants, flowers, and wood resins. A randomized, double-blind, sone valerate cream and 5% topical garlic gel for three months,
placebo-controlled trial (RDBPCT) by Hay et al. showed that while the other group received twice-daily application of
once-daily topical application of a combination of cedarwood, betamethasone cream alone for 3 months. After this period
lavender, thyme, and rosemary oil within a mixture of carrier of treatment, the group treated with combination topical cor-
oils (jojoba and grapeseed) significantly decreased hair loss at ticosteroids and garlic gel demonstrated significantly greater
3- and 7-month assessments compared to vehicle control, as total and terminal hairs when compared to those treated with
measured by scored photographic assessments and computer- betamethasone cream alone (P = 0.001). Furthermore, the size
ized calculation of areas of hair loss (155). As with this trial, of hairless patches in this combination treatment group were
many studies on essential oil therapy in treatment of AA use significantly decreased (P = 0.04), and no adverse effects were
combination treatments, making it difficult to identify the spe- reported throughout the duration of the trial (158).
cific components responsible for alleviating disease severity.
Phytotherapy
Primula obconica
In an effort to identify long-lasting treatments for AA with
The leaves and flowers of Primula obconica, a plant native minimal side effects, many practitioners have turned to phy-
to China, have demonstrated potential as an irritant that can totherapy, or the use of plants or herbs, as an alternative to
increase blood circulation at the site of application. A case conventional treatments. While the exact mechanism of phy-
series of five patients observed hair regrowth after sensiti- totherapy in treating AA depends on the specific herb being
zation to P. obconica and application to the scalp twice per used, therapeutic effects from these compounds can gener-
week. Although observation of hair regrowth began as early ally be attributed to management of hair cycles, keratinocyte
as 1 month into treatment, more evident results were seen at proliferation, apoptosis, angiogenesis, hormones, and inflam-
2-month follow-up (156). mation (159). Certain products, such as Brevilin A, are being
marketed as innovative and effective botanical compounds
that can be used to regrow hair. Brevilin A is derived from the
Garlic Extract
medicinal plant Centipeda minima, and it has shown strong
Garlic extract may also be used as a topical therapy for cases inhibition of JAK-STAT signaling in vitro and in vivo. This
of AA. While the mechanism employed in this therapy is pathway is commonly targeted in AA and other inflamma-
still relatively unclear, certain studies have postulated the tory conditions, given that inhibition of this pathway is likely
hair-stimulating effects may be due to the antibacterial and beneficial through reduction of T lymphocyte proliferation.
sterilizing properties of allicin (main component of garlic), Pertaining the hair loss, inhibition of the JAK-STAT pathway
TABLE 15.5
Alternative Treatments for Alopecia Areata
Acupuncture Case report Hair regrowth and increased (Deng, Zhuo et al. 2022)
pigmented terminal hairs
Cryotherapy Cross-sectional, non-randomized, Varying degrees of hair growth at (Mohammad, Mohsen et al. 2013)
non-blinded study (in vivo) weeks 4 and 8
Topical combination of cedarwood, Randomized, double-blind, Significantly decreased hair loss at (Hay, Jamieson et al. 1998)
lavender, thyme, and rosemary oil placebo-controlled trial (in vivo) 3 and 7 months compared to vehicle
control
Primula obconica Case series (in vivo) Hair regrowth (Rhodes, Dolman et al. 1981)
0.1% Betamethasone valerate Randomized, double-blind Greater total and terminal hairs when (Hajheydari, Jamshidi et al. 2007)
cream and 5% topical garlic gel controlled study (in vivo) compared to betamethasone-only
group
Brevilin A 300mg/day and Brevilin Case series (in vivo) Clinical improvement in SALT scores (Muscianese, Magri et al. 2021)
2% cream twice-daily combination (did not reach statistical
therapy significance)
is also believed to increase stimulation of the anagen hair 7 Kligman A., Willis I. A new formula for depigmentating
phase. A case series including participants with alopecia uni- human skin. Arch Dermatol. 1975; 111:40–48.
versalis, alopecia totalis, ophiasis pattern, and male andro- 8 Sarkar R., Arora P., Garg K.V. Cosmeceuticals for hyper-
genetic alopecia examined the simultaneous use of systemic pigmentation: What is available? J Cutan Aesthet Surg.
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A therapy for 18 months. This treatment was well tolerated, 9 Espinal-Perez L.E., Moncada B., Castanedo-Cazares J.P.
with no adverse effects reported for the duration of the study. A double-blinded randomized trial of 5% ascorbic acid vs.
A clinical improvement in Severe Alopecia Tool (SALT) hydroquinone in melasma. Intl J Dermatol. 2004; 43:604–607.
scores was observed, but this measure did not reach statistical 10 Yin X., Chen K., Cheng H., et al. Chemical stability of ascor-
significance (160). See further Table 15.5. bic acid integrated into commercial products: A review on
Despite the difficulties experienced by many clinicians bioactivity and delivery technology. Antioxidants (Basel).
treating alopecia areata and the relatively limited collection 2022; 11(1):153.
11 Comunian T.A., Abbaspourrad A., Favaro-Trindade C.S.,
of approved therapies, there is significant promise in the emer-
Weitz D.A. Fabrication of solid lipid microcapsules con-
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Chem. 2014; 152:271–275.
consistently significant results, the limited reports and case
12 Chang D.W., Abbas S., Hayat K., et al. Encapsulation of
studies that do exist demonstrate a variety of efficacious treat-
ascorbic acid in amorphous maltodextrin employing extru-
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14 Alvim I.D., Stein M.A., Koury I. P., et al. Comparison
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16
Sunless Tanning Products
Stanley B. Levy
present in solution. Glyceraldehyde may degrade into formal-

Introduction dehyde and formic acid. In acidic solution (pH 4), this isom-
erization and therefore these latter undesirable ingredients are
With improvements in formulation and aesthetics, sunless or minimized. Commercially available formulations generally
self-tanning products have become a viable alternative to UV contain 2.5% to 10% DHA (Figure 16.2).
tanning. Public awareness as to the hazards of both natural and The Maillard or browning reaction has been defined as the
artificial UV tanning has facilitated self-tanners becoming a reaction of an amino group of amino acids, peptides, or pro-
significant component of the overall suncare market. Ten to teins with the glycosidic hydroxyl group of sugars. DHA in
over 20% of adolescent and young adults in both the United the context of this reaction may be considered a 3-carbon
States and Australia reported using these products (1–3). sugar, reacting with free amino groups available as amino
Individual users were also more likely to have sunburned con- acids, peptides, and proteins supplied by the keratin to form
sistent with higher use of these products in fairer Caucasians. products or chromophores referred to as melanoidins (14).
In other studies, exclusive users of sunless tanners were more Melanoidins have some physicochemical properties similar
likely to practice overall sun protection (4, 5) and decrease to naturally occurring melanin (15). Electron spin resonance
their use of UVL tanning beds (6, 7). A randomized trial at has shown that free radicals are produced in vivo by the
the beach for skin cancer prevention promoting sunless tan-
ning reduced sunbathing and sunburns (8). A larger, nationally
representative, cross-sectional study suggested that improved
TABLE 16.1
behaviors may not be associated with sunless tanning (9).
Dihydroxyacetone (DHA), a keto-sugar, is the active ingre- Tanning Product Types
dient in sunless or self-tanners, and is responsible for darken- Product type Active ingredient
ing the skin by staining. DHA is classified in the International
Sunless or self-tanner Dihydroxyacetone
Cosmetic Ingredient Dictionary and Handbook as a colorant
Bronzer Dyes
or a colorless dye. Other similar sugars such as erythrulose
Tanning simulator Melanins
and glyceraldehyede are occasionally used. Products contain-
Tanning preparation UVB sunscreens
ing DHA should not be confused with bronzers intended to
Tan accelerator Tyrosine
produce a darker color on the skin by the use of water-soluble
Tanning promoter 5-Methoxypsoralen
colorants or dyes. Other agents that have been used to enhance
Tanning pill Canthaxanthin
skin pigmentation with and without stimulation by UV with
Hormone Synthetic analogues α-MSH
varying degrees of success and toxicity (Table 16.1) will not be
discussed in detail here (10, 11).
Chemistry
Dihydroxyacetone (C3H6O3) is a white, crystalline hygro-
scopic powder. This 3-carbon sugar forms a dimer in freshly
prepared aqueous solution (Figure 16.1). With heating to effect
a solution in alcohol, ether, or acetone it reverts to the mono-
mer. The monomeric form is less stable but more important in
the browning reaction leading to the skin color change (12).
DHA is stable between pH 4 to 6, but above pH 7 efficacy is
lost with the formation of brown-colored compounds. A buff-
ered mixture at pH 5 is most stable. Heating above 38°C for
long periods of time will also affect stability. DHA needs to
be stored in a cool, dry place, ideally 4°C and low atmospheric
humidity (13). Glyceraldehyde, the isomer of DHA, is also FIGURE 16.1 Chemical structure of DHA.
146 DOI: 10.1201/b22897-16

Sunless Tanning Products 147
Maillard reaction (16). A recent study documented a DHA- As in the formulation, the pH of the skin before applica-
induced specific cutaneous stress response distinct from tion may have effects on the tonality of the skin color (12).
solar UV-induced tanning (17). Alkaline residues from soaps or detergents will interfere with
the reaction between DHA and the amino acids on the skin
surface, resulting in a less natural (more yellow) appearing
color. Wiping the skin surface with a hydroalcoholic, acidic
Mechanisms of Action toner just prior to DHA application may improve results. Ex
The site of action of DHA is the stratum corneum (18). Tape vitro epidermal studies suggest that skin hydration (24) and
stripping of the skin quickly removes the color (19), as does relative humidity (25) influence the development of coloration.
mechanical rubbing. Deeper staining in areas with thicker stra- Careful application is key with using these sunless tanning
tum corneum and no staining of mucous membranes without products (Table 16.2). The skin may be prepared with a mild
a stratum corneum is also consistent with this being the site of form of exfoliation. Even application is required, with lighter
action. DHA may be used as a substitute for dansyl chloride as application around elbows, knees, and ankles to avoid exces-
a measure of stratum corneum turnover time (20). Microscopic sive darkening in these areas. Care also needs to be taken
studies of stripped stratum corneum and hair reveal irregular around the hairline where lighter hair may darken. Hands
pigment masses in the keratin layers (21, 22) consistent with need to be washed immediately after use to avoid darken-
melanoidins. These melanoidins are formed via the Maillard ing of the palms, fingers, and nails. Skill and experience are
reaction with DHA as a sugar reacting with the amino groups necessary with using these products resulting in greater user
supplied by the keratin. satisfaction.
Spray-on tanning formulations may aid in providing an
even application. Larger air-operator assisted delivery units
are available for airbrushing on by a technician (26). Tanning
Application booths using sprays are now commonplace in spas and salons.
This form of application introduces the potential hazard of
Following application of a typical DHA containing self-tan- inhalation of sprayed material.
ning lotion, color change may be observed within an hour (23). Some formulations include colorants as used in bronzers,
This color change may be seen under Wood’s light (black light) including dyes and caramel, to achieve an immediate effect.
within 20 minutes. Maximal darkening may take 8 to 24 hours Similarly tinting with iron oxides or titanium can provide
to develop. Individuals can make several successive applica- immediate color and allow the user to more easily visual-
tions every few hours to achieve their desired color. Color may ize the evenness of application. Metal oxides may, how-
last as long as 5 to 7 days with a single application. Depending ever, induce degradation of DHA (27). Vitamins, botanical
on anatomical location, the same color can be maintained extracts, antioxidants (28), anti-irritants, and even alpha
with repeat applications every 1 to 4 days. The face requires hydroxy acids may be added to broaden the manufacturer’s
fewer applications but more frequent reapplication to maintain claims made with a given product. The addition of sunscreen
the color than the extremities. Depth of color varies with the ingredients to self-tanners warrants a more detailed discus-
thickness and compactness of the stratum corneum. Palms sion in the next section.
and soles stain deepest necessitating washing of hands after
application to avoid staining. Hair and nails will color but
not mucous membranes lacking a stratum corneum or keratin
layer. Rough hyperkeratotic skin over the knees, elbows, and
Sunscreen Activity
ankles will color more unevenly as will older skin with kera-
toses and mottled pigmentation. Color will also persist longer DHA itself has at most a modest effect on SPF (29), provid-
in these areas. ing perhaps SPF 3 or 4 protection. SPF increases with DHA
FIGURE 16.2 Degree of skin darkening with concentrations of DHA.

concentration and number of applications (30). Low level SPF

persists for several days, decreasing with loss of color (31). The Safety
brown color obtained on the skin does absorb in the low end
of the visible spectrum with overlap into long UVA and may The visible color change associated with the use of artificial
provide some UVA I protection (32). Melanoidins can act as tanning products might suggest to some users that these prod-
free-radical scavengers as they demonstrate an electron spin ucts are hazardous. Based on the chemistry of DHA and its
resonance signal (33). Superficial skin coloration induced by toxicological profile, it can be considered nontoxic. It reacts
frequent topical application of DHA in high concentrations quickly in the stratum corneum, minimizing systemic absorp-
delays skin cancer development in hairless mice irradiated tion. The acute toxicity of DHA was investigated for diabetics
with moderate UV doses (34). in the 1920s, with oral intake well tolerated (41). The phos-
Individuals using DHA-containing tanning products need phate of DHA is found naturally as one of the intermediates in
to be cautioned that despite visible darkening of their skin, the Krebs cycle. Toxicity based on inhalation in closed spray-
these products provide minimal sun protection. Confusion on tanning booths is unknown.
may be compounded by the addition of UV filters to the for- Contact dermatitis to DHA has only rarely been reported (42).
mulation providing significant sun protection. The stated SPF As with other topical products with active ingredients, such
for the product is applicable for a few hours after application, as sunscreens, much the reported sensitivity is secondary to
but not for the days during which the skin color change may other ingredients in the vehicle (43). Adverse reactions are
remain perceptible. Care should be taken with using lasers more likely to occur based on irritation and not true allergy.
utilizing wavelengths in the 400–700 nm range for a week Ultimately all claims related to product safety are based on
after application, as increased absorption has been noted testing the final formulation.
with DHA (35). Although not approved by regulatory agencies, some of the
alternative agents for increasing skin pigmentation (Table 16.1)
are available to individuals. Tanning pills containing carot-
enoids such as canthaxanthin have been reported to cause reti-
Indications nopathy, urticaria, hepatitis, and aplastic anemia (44). More
recently, injections of analogues of melanocyte-stimulating
Even with recent improvement in DHA formulations, the
hormone may be gaining in popularity (45). Of potential ben-
color achieved remains dependent on skin type. Individuals
efit to individuals with photosensitive disorders (46), synthetic
of medium complexion with skin phototypes II or III (36), as
analogues of α-MSH may drive proliferation of neoplastic
opposed to those who are lighter or darker, will obtain a more
melanocytic cells in the nevi of predisposed individuals (47).
pleasing color. Individuals with underlying golden skin tones
New analogues may be on the horizon (48).
will achieve better results than individuals with a rosy, sallow,
or olive complexion. Older consumers with roughened, hyper-
keratotic skin or mottled pigmentation with freckling may be
less pleased with their use. Conclusion
Dermatologists regularly recommend these products for
tanning as a safe alternative to UV exposure. They may be Increasing awareness as to the hazards of UV light should fuel
used to camouflage some skin irregularities such as leg spi- ongoing interest in self-tanning products. It is incumbent on
der veins. Light to medium complected patients with vitiligo dermatologists to be familiar with this category. The benign
who show increased contrast with the vitiliginous areas with toxicologic profile of DHA reinforces the notion that these
natural or unavoidable tanning in their normal skin may also products represent a safe alternative to a UV-induced tan. The
benefit (37, 38). DHA provides some protection for individu- results obtained are dependent on the final formulation, indi-
als with certain photosensitivity disorders (39). Protection vidual application technique, and the consumer’s skin type.
of uninvolved skin by DHA during psoralen-UVA (PUVA) Greater experience in formulation combined with increasing
treatment allows higher UVA exposures to be tolerated, sophistication on the part of the consumers has led to increas-
with fewer treatments resulting in faster clearing, known as ing satisfaction with the use of these products.
Turbo-PUVA (40). Users need to be clearly informed that these products do not
offer significant protection against UVB. If formulated with
standard sunscreens, individuals should be cautioned that the
TABLE 16.2 duration of UV protection is more short-lived than the color
change.
Application Instructions for Self-Tanners
Prepare skin with mechanical exfoliation
Spot test
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17
Percutaneous Penetration
Sunscreens
Uli Osterwalder
United States, currently only two UV filters (TiO2 and ZnO)

Introduction are considered “generally recognized as safe and effective”
(GRASE) [10] and that only two UVA filters are available
Sunscreens serve an important purpose in society. Besides
(Figure 17.1).
preventing sunburn short-term, and mitigating the signs of
Contrary to the United States, there has been a steady
skin aging long-term, they are an important tool in the pre-
stream of new UV filters in Europe over the last few decades,
vention of skin cancer. Often the question comes up, do sun-
which will be called “modern” UV filters in this chapter
screens at all work to protect against malignant melanoma?
[15, 16]. The major driver for the innovation in Europe has
Epidemiological studies are not likely to affirm this any time
been the need for better UVA protection. To cover the UVA
soon, although according to a recent meta-study the odds ratio
range, i.e. the longer wavelengths, 320–400 nm, UV filters
of melanoma in the presence of sunscreen has been dropping
with larger molecular weight had been developed, which is
to 1 over the last 3 decades [1]. But we know from a much nar-
welcome for the safety aspect since the molecular weight is
rower study by Green et al, that sunscreens have a protective
correlated with less skin permeation. We will discuss more in
effect against squama’s cell carcinoma and melanoma [2–4].
this chapter. The specific performance of sunscreens and its
UVA-radiation plays an important role in the incidences of
malignant melanoma [5, 6]. testing is not part of this chapter, but it is described in great
Dudley et al. refer to better UVA protection as “Spectral detail elsewhere [18–21].
Homeostasis—The Fundamental Requirement for an Ideal The reasons to study and write about skin permeation of UV
Sunscreen” [7]. For wearing sunscreen-protection, compliance filters are safety concerns when such UV filters become bio-
is of course key. Long-term, people only put on sufficiently available. The growing awareness for the need of sun-protective
from a sunscreen they like, therefore formulating pleasant measures led to a situation that more people are using sun-
sunscreens with a good skin feel is also key [8]. Sohn et al screen more frequently or even daily. Therefore, the safety of
describe the challenges in sun care from a UV filter supplier sunscreens has become under more scrutiny by most regulatory
point of view [9]. bodies in the world, irrespective of the mode of regulation, i.e.
The global regulatory environment can be roughly split as a drug like in the United States, Canada, or Australia, or as
in two parts, the US jurisdiction with the FDA regulating cosmetics like in most parts of the world. Under special scrutiny
as drugs, and the rest of the world regulating UV filters as are the UV filters that are absorbing UV radiation and convert
cosmetics, with the EU commission being the most active and release it as innocuous infrared radiation.
jurisdiction. Hence, the need to regulate sunscreens is well The topic has already been reviewed from time to time,
recognized, but there are nuances how to do it [10–13]. e.g. by Walters et al., Percutaneous Absorption of Sunscreens
The United States was one of the first regions in the world [22, 23], and most recently by Surber et al [24]. The topic has
to develop a comprehensive cosmetics legislation. Published attracted more attention because sunscreens and mainly face
in 1938, for many years, it set the trend on how to differ- creams with UV protection are more often used or applied
entiate between cosmetics and drugs. Drugs, on the other daily, thus leading to a higher exposure to sunscreens and UV
hand, are defined as “articles intended for use in the diagno- filters. In most jurisdictions UV filters require pre-marketing
sis, cure, mitigation, treatment, or prevention of disease . . . approval. In the European Union there is a well-established
and articles (other than food) intended to affect the structure review process based on scientific opinions that lead to adapta-
or any function of the body.” This leads to a rather limited tions of the cosmetic regulation [14].
understanding of cosmetics and confines them to providing Figure 17.2 shows observations conducted by the FDA. In
beauty-related and superficial effects. For sunscreens, the the blood benzophenone-3 is detected within hours after sun-
consequences of these definitions are such that every new screen application, and it takes days to flush it out in the urine.
UV filter needs to be registered as a new active drug ingre- This led the FDA to ask for more safety data of the existing
dient [14]. The regulative framework has been changing UV filters and also setting conditions for the approval of new
several times over the last few decades. We note that in the UV filters.
DOI: 10.1201/b22897-17 151

FIGURE 17.1 UV filters used in sunscreens launched, United States vs European Union [15]. We note that there are fewer UV filters available in the
United States; in fact there are only two UVA filters, i.e. avobenzone and zinc oxide, and these two may not even be combined in a sunscreen due to
FDA restrictions [10, 16]. In the rest of the world the sunscreen world looks much brighter (compare Tables 17.1a and 17.1b).
FIGURE 17.2 (a) Plasma concentration of Oxybenzone with daily topical application. (b) Urine concentration of Oxybenzone with daily topical
application. (From Ref. 10 under government licence.)
The objective of this chapter is to answer two questions: in this area, the United States and the European Union, as well
as their rational how to approach the efficacy and mainly the
1) Is a certain UV filter bioavailable? safety question.
A UV filter is bioavailable, once it has entered the blood
And if yes, stream or has entered the living epidermis. This happens in
principle by dermal or oral route or airborne via the lungs. For
2) Would the potential harm of a certain concentration a drug to have an effect, a prerequisite is to be bioavailable;
of a UV filter in the body outweigh the benefit of that therefore the mechanism of making substances bioavailable
particular UV filter in the sunscreen. has intensely been studied in the research of delivering drug-
substances, much less so in studies with the objective to avoid
This chapter will be presenting an overview of the possible bioavailability of a certain substance, which is the objective of
bioavailability of the current UV filters in use worldwide, by sunscreen actives. Therefore, the latter studies can learn from
characterizing and quantifying, if possible, the skin perme- the former, although the ultimate answer whether a substance
ation and dermal absorption. The basis of this overview are permeates the skin can only be answered with studies on the
data collected and available from the two major jurisdictions skin.
Percutaneous Penetration 153
hand, is to protect against the environment and thus, in prin-

Skin Permeation Theory ciple, to avoid letting “anything” in or out. By learning how
to optimize bioavailability, one may also learn how to avoid
The bioavailability question posed in cosmetics can piggy bioavailability, at least to some extent. We will therefore cover
back on the extensive drug research for both dermally and drug delivery studies and rules but also discuss methods and
orally applied drugs, where bioavailability is the target. The results of studies with the explicit objective of avoiding dermal
knowledge and experience from drug research are of great absorption.
help in understanding percutaneous permeation. However, It is certainly worthwhile knowing what criteria make a sub-
how little of some unwanted substance is eventually permeat- stance suitable to become a drug (orally applied in most cases).
ing through the skin is not the subject of drug research; rather Then, violating such criteria makes a substance less bioavail-
a toxicological approach is necessary, which normally means able, which is exactly where we want to be with UV filters.
that it requires specific knowledge as well as skin penetration/ An important tool in drug design is the Lipinski “rule of five”
permeation studies to determine how little is bioavailable. (Ro5) [25–27]. The Ro5 is based on a distribution of calcu-
lated properties among several thousand drugs. The Ro5 has
Drug Delivery
revolutionized substance screening in drug design. It is based
Drugs are normally delivered orally and occasionally rectal, on four parameters that are globally associated with solubility
by inhalation or trans-cutaneous. The latter application comes and permeability, namely molecular weight, Log P, the num-
of course closest to the topical application of sunscreen and is ber of H-bond donors, and the number of H-bond acceptors.
thus of particular interest. Nonetheless most research is dedi- Similarly, to setting the confidence level of an assay at 90 or
cated to oral drugs; that is why we find most knowledge in that 95%, these four parameters were then adjusted so that about
area. 90% of orally active drugs (USAN) had parameters in a calcu-
Figure 17.3 shows schematically how the skin and the small lated range associated with better solubility and permeability.
intestine are connected via the systemic circulation. They both Because the cutoffs for each of the four parameters were all
serve as a principal interface of our body with the environ- close to 5 or a multiple of 5, this led to the simple mnemonic
ment. The gut’s major task is to absorb about 60 tonnes of “rule of 5.” The original Ro5 deals with orally active com-
nutrients during our lifetime [17]. The skin’s task, on the other pounds and defines four simple physicochemical parameter
FIGURE 17.3 Systemic bioavailability via permeation through skin or gut, not to scale. (Courtesy of Alice Osterwalder.)
ranges (associated with 90% of orally active drugs that have scope of sunscreens. In Table 17.1b, the UV filters are ordered
achieved phase II clinical status [26]): along increasing molecular weight (MW). It is interesting to
note that this order along the MW automatically leads to yet
1) MW < 500 another classification that has to do with innovation and regu-
2) log Po/w < 5 lation. We can call the UV filters 1–8 the classic UV filters;
3) H-bond donors < 5 they have been around for a long time and have a rather low
4) H-bond acceptors < 10 molecular weight and are all soluble, or miscible if they are a
liquid themselves for that matter.
The Ro5 was deliberately created to be a conservative predic- In this line-up along the MW, we can call the higher
tor in an era where medicinal and combinatorial chemistry molecular weight substances, modern UV filters (9–16),
produced too many compounds with very poor physicochemi- compared to classic UV filters (1–8). We note, that whereas
cal properties. The goal was to change chemistry behavior in it is only the lipophility that makes the classic UV filters vio-
the desired direction. If a compound fails the Ro5 there is a late the Ro5 (2–8) (exception oxybenzone), it is in addition
high probability that oral activity problems will be encoun- the criterion MW > 500 that makes these modern UV filters
tered. However, passing the Ro5 is no guarantee that a com- less drug-like. Only two UV-filter, Ethylhexyl Triazone (15)
pound is drug-like. and Polysilicone-15 (16), also fails on a third parameter, the
In the following, the idea is applying the Ro5 to UV filters H-bond acceptor count, which makes them even less drug-like
and thus getting an idea about how “drug-like” they are, i.e. than the rest of the UV filters.
what is the propensity of a particular UV filter to become bio- The inorganic, insoluble UV filters (17,18) are in this
available (Table 17.1a). The exercise with the UV filters reveals table for comparison. They may be called classic inorgan-
that except for one, oxybenzone, most commonly used UV fil- ics. They are currently the FDA’s benchmark when it comes
ters fail the Lipinski Ro5 of being “drug-like.” This is already to the GRASE criteria. What all modern UV filters, soluble
good news since we can expect a rather low bioavailability. and insoluble, have in common, besides the higher molecular
There are basically two groups of UV filters: 1) soluble weight, is the fact that they are all approved in the European
and 2) insoluble. The property “insoluble” depends of course Union but not yet available in the United States. This tells us
on the definition and the solvent, but we look at it now in the where the innovation comes from.
TABLE 17.1a
Drug-Like Assessment of UV Filters According to the Lipinski Rule of Five [17]; Good News: Only (1) Oxybenzone UV “Qualifies”
as Drug-Like According to Ro5; The Trend Is Moving Away from Drug-Like
Drug-like?
Lipinski Ro5 (1) (2) (3) (4) Drug-like? Water solubility
(rule of five) MW log Po/w H-Bond Donor H-Bond Acceptor (Ro5) (mostly insoluble . . .
Drug-like if: < 500 <5 <5 < 10 Score i.e. < 1 mg/L)
1 Oxybenzone soluble 228 3.7 1 3 yes (4/4) 13 mg/L
2 Octisalate. Miscible 250 5.9 1 3 no (3/4) 0.074 mg/L
3 Homosalate miscible 262 6.3 1 3 no (3/4) 0.091 mg/L
4 Ensulizole soluble 274 −1.5 2 4 no (3/4) soluble
5 Meradimate soluble 275 5.8 1 3 no (3/4) 0.14 mg/L
6 Octinoxate miscible 290 6 0 3 no (3/4) 0.05 mg/L
7 Avobenzone soluble 310 6.1 0 3 no (3/4) 2.2 mg/L
8 Octocrylene miscible 361 6.1 0 3 no (3/4) 9–153 µg/l
9 DHHB soluble 398 6.2 1 5 no (3/4) 16 µg/l
10 TBPT (nano) *538* 10.4 0 3 no (2/4) < 0.03 μg/l
11 PBDT *541* 10.5 0 6 no (2/4) < 0.02 μg/l
12 Bemotrizinol soluble 628 > 5.7 2 8 no (2/4) 0.004 µg/l
13 Bisoctrizole (nano) *659* 12.7 2 6 no (2/4) *) < 5 ng/l
14 HAA299 (nano) *677* 4.8 2 10 no (2/4) 1.7 μg/l
15 Ethylhexyl triazone sol. 823 15.5 3 12 no (1/4) 5–7 μg/l
16 Polysilicon-15 soluble 6000 >6 0 84 no (1/4) ≤ 0.1 mg/L
17 TiO2 (nano) *80* — 0 0 —

18 ZnO (nano) *81* 0.16 0 0 —
*xyz* particles (> 1,000,000 Da) *) In lotion 1.0–3.2 mg/L
Source: Data from SCCS Opinions, PubChem, and ECHA Registration Dossiers.
TABLE 17.1b
Molecular Structures of UV Filters: Classic (1–8) and Modern (9–16)
1) BP-3, Oxybenzone, v -3 2) EHS, Octisalate, 3) HMS, Homosalate, 4) PBSA, Ensulizole,
MW 228 Ethylhexyl Salicylate Homomenthyl Salicylate Phenylbenzimidazole
MW 250 MW 262 Sulfonic Acid MW 274
5) Meradimate, 6) EHMC, Octinoxate, 7) BMBM, Avobenzone, 8) OCR, Octocrylene

MW 275 Ethylhexyl Methoxy-cinnamate ButylMethoxydibenzoyl-methane MW 361
MW 290 MW 310
9) DHHB, Diethylamino 10) TBPT (nano), 11) PBDT, Phenylene 12) BEMT, Bemotrizinol,
Hydroxybenzoyl Tris Biphenyl Triazine Bis-Diphenyltriazine Bis-Ethylhexyloxyphenol
Hexyl Benzoat MW 538 MW 541 Methoxyphenyl Triazine
MW 398 MW 628
13) MBBT (nano), 14) HAA299 (nano), 15) EHT, Ethylhexyl triazone 16) Polysilicon-15,
Bisoctrizole, Bis-(Diethylaminohydroxybenzoyl MW 823 Dimethicodiethylbenzal-malonate
MW 559 Benzoyl) Piperazine MW 6000
MW 677
Source: Data from PubChem (National Center for Biotechnology Information, PubChem compound summaries, at https://pubchem.ncbi.nlm.nih.gov)
and SCCS (Scientific Committee on Consumer Safety, Opinions, at https://health.ec.europa.eu/scientific-committees/scientific-committee-consumer-
safety-sccs/sccs-opinions_en).
Bos and Meinardi have narrowed down the Lipinski Ro5 by had been applied to the modern UV filters (13, MBBT) and
focusing on dermal drug delivery [28]. The human integument (14, HAA299). The largest soluble UV filter is Polysilicon-15
is able to resist the penetration of many molecules. However, with a MW of 6000 and thus practically no chance to enter the
especially smaller molecules can surpass transcutaneous. They skin (16).
are able to go by the corneal layer, which is thought to form the Figure 17.4 visualizes the currently used UV filters in the con-
main deterrent. The authors argue that the molecular weight text of the 500 Da rule. Based only on the MW criterion (500 Da
(MW) of a compound must be under 500 Dalton to allow skin cut off) all classic UV filters (1–8) would have a propensity to
absorption. Larger molecules cannot pass the corneal layer: permeate the skin. That this is not the case is due to their highly
lipophilic nature (Log Po/w). The only exception is BP-3.
1) Virtually all common contact allergens are under The higher molecular-weight modern UV filters we do
500 Dalton, larger molecules are not known as con- not expect significant permeation of normal skin. Molecules
tact sensitizers. They cannot penetrate and thus can- > 500 Da also show exponentially less penetration according
not act as allergens in man. to Kasting et al [31, 32] who described diffusion through the
2) The most commonly used pharmacological agents skin as being similar to diffusion through a polymer and indi-
applied in topical dermatotherapy are all under cated that the diffusion coefficient should be an exponential
500 Dalton. function of the molecular weight. The authors concluded that
3) All known topical drugs used in transdermal drug- every increase of 110 Dalton in molecular weight results in an
delivery systems are under 500 Dalton. order of magnitude decrease in the predicted cutaneous flux.
Also, Potts and Guy [33, 34] concluded that permeation should
In addition, clinical experience with topical agents such as be related to an exponential function of molecular weight or
cyclosporine (MW 1203), tacrolimus (MW 804), and ascomy- molecular volume.
cins (MW 792) gives further arguments for the reality of the Nonetheless, for most UV filters the drug delivery analogy
500 Dalton rule [see 29]. is only of limited value. It shows, that it is unlikely that UV
From this, the lesson for the design of new UV filters seems to filters can enter the body to a great extent (except BP-3), but
be clear. In reverse-analogy to Bos’ and Meinardi’s 500-Da rule for an analysis of the small quantities that could still perme-
for transdermal drugs, we postulated at Ciba Specialty Chemical ate and could thus be toxicologically relevant, specific skin
(now BASF) in the early 2000 an Inverse 500-Da Rule [30]: penetration-absorption-permeation models and methods are
necessary.
For topical cosmetic development purposes, it seems

logical to restrict the development of new innovative Mechanistic Model of Percutaneous Absorption
UV filters to a MW of OVER 500 Dalton, when topi-
Guy wrote an excellent review and overview entitled “Skin—
cal Sun Protection is the objective.
‘That Unfakeable Young Surface’” where he described the
“golden era” in the understanding of skin barrier function,
In Table 17.1a we see that the modern UV filters (9–16) do percutaneous penetration and (trans)dermal drug delivery,
mostly have a MW > 500 Da. Ethylhexyl triazone (Table 17.1b, during the 20- to 25-year period from the mid-1960s to the
15) was the first UV filter of this group that had actually inten- early 1990s [35]:
tionally been synthesized with the idea of enlarging the MW
in mind. The UV absorbing entities consists of a compound A series of papers by Blank, Scheuplein and col-
called 2-Ethylhexyl 4-aminobenzoate (MW 249), which had leagues [36–38] were the first to apply solid physi-
also been used as UV filter in the past. Three such units are cochemical thinking, and Fick’s laws of diffusion,
combined via the triazine core molecule. The same strategy to the interpretation of skin permeability data. It is
FIGURE 17.4 (a) Estimated penetration barrier characteristics for normal human skin (NS), atopic dermatitis skin (AD), mucosa (M), and
phonopheretically disrupted skin (US). (From Ref. 28 with permission.) (b) Current UV filters and the 500-Da rule (MW numbers from Table 17.1a).
Poliysilicon-15 lays outside the scale (MW = 6000). (Based on Ref. 28 with additional material.)
instructive to list here some of the prescient deduc- Michaels et al. [43] explored a number of other mechanis-
tions, which could be confidently drawn from these tic, which subsequently occupied the minds of several distin-
studies: guished researchers over the next decade or more. Specifically,
they drew attention to the “brick-and-mortar” structure of the
(a) the stratum corneum (SC) invariably represents the
SC and hypothesized that an important factor contributing to
skin’s rate-limiting barrier;
this membrane’s impermeability was that penetrant diffusion
(b) the flux of a penetrating compound across the skin was constrained to the minor phase component (i.e. the lipid-
increases in direct proportion to its applied concen- filled intercellular “cement”) of its heterogeneous structure.
tration until the vehicle is saturated (i.e. maximum In so doing, they constructed a mathematical model, based
thermodynamic activity is attained); on an idealized model of the SC (Figure 17.5), with which
(c) transport across the skin increases with increasing to test their ideas against experimental data, as illustrated in
solubility and increasing diffusivity of the penetrant Figure 17.6. Here, one observes skin permeability coefficients
in the SC; increasing linearly with drug oil-water partition coefficient up
(d) penetrant flux through viable skin tissue is much to what appears to be a limiting value of approximately 0.01
faster than that through the SC; cm/h.
(e) there are different molecular pathways available When we add the data of the UV filter Benzophenone-3, in
for diffusion across the SC, including transcellular, Figure 17.6 from [23], we realize that BP-3 is not only drug-
intercellular and appendageal. like, as it has been revealed in Table 17.1a, but it also ranks
top among proven trans-dermal drugs like Nitroglycerin or
While these insights were based on the results of in vitro exper- Fentanyl. If we take Figure 17.7 as a benchmark, the other
iments, their applicability to in vivo situations has been consis- UV-filters which are more lipophilic than BP-3 fall outside the
tently demonstrated over the years for all classes of chemicals, scale at the right (assuming that the mineral oil/water partition
whether drugs, cosmetics, or potentially harmful substances, coefficient is correlated with the octanol/water partition coef-
such as pesticides. Speaking of in vivo studies, it was circa ficient which is given in Table 17.1a).
1970 that Feldmann and Maibach also published a series of Data from Oxybenzone (in red: BP-3 = Benzophenone 3)
important percutaneous absorption experiments conducted on from [23], as octanol/water partition coefficient (alternative to
human volunteers [39–41]. Data from this work quite quickly mineral-oil/water partition coefficient; there may be a slight
became considered as the “gold standard” against which all difference, i.e. shift in X-axis).
other models were compared, for example, the in vitro study This work of Michaels et al and several other important con-
of Franz [42] that forever linked his name with diffusion cells tributors to the progress in transdermal drugs and the under-
used in skin penetration experiments. standing of skin permeation is acknowledged by Hadgraft
In a remarkable article published in the American Institute and Lane in their interesting “Historical Perspective, Skin
of Chemical Engineers Journal, Michaels et al provided a Permeation: The Years of Enlightenment” [44].
blueprint with which the feasibility of drug candidates for
transdermal administration could be evaluated [43]. Amongst Estimation of Undesired Bioavailability
the ten compounds considered experimentally in that paper, Our core interest is avoiding skin permeability in order to
four were commercialized: the first of these, scopolamine, was avoid bioavailability. With the introduction of toxic syn-
approved in the United States in 1979, just 4 years after the thetic chemicals such as plasticizers in industry, and the use
AIChE Journal paper had appeared; the others, nitroglycerin, of highly potent insecticides in agriculture, hazards from the
estradiol, and fentanyl, all achieved significant market success, toxic effects after percutaneous absorption have become very
with the latter being the first transdermal drug to have sales real ones. Now also UV filters and other chemicals used in
over USD 1 billion per year. cosmetics are under scrutiny.
FIGURE 17.5 Idealized representation of the SC, representing a heterogeneous structure with lipid (“mortar”) and proteinaceous (“brick”)
phases. Corneocytes (length = L; thickness = τ) depicted in grey; intercellular, lipid-filled spaces (width = δ) shown in white. (From Ref. 43 with
permission.)
FIGURE 17.6 Measured maximum fluxes (diamonds) and permeability coefficients (filled circles) of 10 drugs, across human skin in vitro following
application in aqueous solution, as a function of the corresponding mineral-oil/water partition coefficient. OUA = Ouabain; A = atropine; DIG =
digitoxin; SCP = scopolamine; DEC = diethylcarbamazepine; CPH = chlorpheniramine; EPH = ephedrine; NTG = nitroglycerin; EST = estradiol;
FEN = fentanyl. (From Ref. 43 with permission.)
FIGURE 17.7 Percutaneous absorption of UV filters. (based on data in Ref. 60.) The FDA threshold of 0.5 ng/ml is the level that indicates a chemical
could harm. When exposure occurs above this threshold (limit), the FDA had been requesting long-term toxicity testing [10].
The industry organization Cosmetics Europe (CE) (https:// partition and diffusion coefficients, metabolism [48, 49] and
cosmeticseurope.eu) [45] has established an ADME task skin penetration [50]. CE argues that the development of pre-
force (TF studying toxicokinetics: Absorption, Distribution, dictive in silico skin penetration models for the safety assess-
Metabolism and Elimination) [46]. Several projects are aimed ment of dermally applied cosmetics is needed to enable moving
at measuring relevant parameters to help predict local and sys- away from the 50% dermal bioavailability assumption in the
temic bioavailability of topically exposed compounds. Endpoint SCCS’s Notes of Guidance [51] to a more realistic one assessing
measurements include solubility in different solvents [47, 48]; the actual fraction of a systemically absorbed compound.
In Vitro versus In Vivo Dermal Testing In spite of all the theory, there is a need to conduct studies
to find out to what extent a particular UV filter will actually
The gold standard to assess skin permeation is the OECD be bioavailable. The key jurisdictions to turn to for guidance
428 test guideline, e.g. it is used to create SCCS opinions [51]. on this matter are the European Commission (EC) with its
Hewitt et al used a OECD test guideline 428 compliant proto- Scientific Committee for Consumer Safety (SCCS) and the US
col using human skin to test the penetration of 56 cosmetic- Food and Drug Administration (FDA).
relevant chemicals [50]. The penetration of finite doses (10 μL/
cm2) of chemicals was measured over 24 hours. The dermal
delivery (DD) (amount in the epidermis, dermis, and recep- Overview I Rational (Europe)
tor fluid [RF]) ranged between 0.03 ± 0.02 and 72.61 ± 8.89
The SCCS is an advisory body that provides the Commission
μg/cm2. The DD of seven chemicals was comparable with in
with scientific advice and safety evaluations for Annex sub-
vivo values. The DD was mainly accounted for by the amount
stances and compounds for which some concern for human
in the RF. Overall, the ranking of DD was the same in vitro
health exists. Its consultation for this task is compulsory. The
as in vivo, such that hydrocortisone, testosterone, and nitro-
mandate, the work, and the expectations of the quality of the
benzene were poorly absorbed, and caffeine was relatively
submissions are all laid down in the SCCS Notes of Guidance
well absorbed. Hewitt et al hope that this general analysis of
for the Testing of Cosmetic Ingredients and their Safety
these data can be used to 1) help have a better understanding
Evaluation [51].
of factors influencing skin bioavailability of chemicals; 2) help
The SCCS works with three working groups, dealing with
interpret skin toxicity results (sensitization, genotoxicity); and
cosmetic ingredients, methodology, and nanomaterials. Safety
3) use as input data to test and develop in silico dermal pen-
evaluations and advice are taken up in opinions. A comment-
etration models.
ing period of minimum 8 weeks is foreseen for draft opinions
The CE ADME TF is developing in silico, in vitro, and other
before they are finalized and published.
alternative approaches to predict the local distribution and sys-
The UV filters mentioned in Table 17.1a have been stud-
temic fate of topically applied cosmetic ingredients. Grégoire
ied and have received an opinion by the SCCS or one of its
et al evaluated six in silico skin penetration models [47]. While
predecessor committees (SCCP, SCCNFP). The Scientific
in vitro skin penetration assays can provide information on the
Opinions are published on the SCCS website. In the Notes
penetration of single applications of chemicals to the skin,
of Guidance, we find under the subtitle 3–3.5.1.1 DERMAL/
other dosing scenarios, such as long-term repeated exposure
PERCUTANEOUS ABSORPTION the indications for ingre-
experiments representing the use of daily cosmetics products,
dients with very low dermal absorption [56].
are not possible. For some chemicals, in vitro skin penetration
assays may not be possible due to the instability or lack of a
radiolabel and/or insufficiently sensitive analytical methods. Substances with Very Low Dermal Absorption
In conclusion, their evaluation highlighted important dif-
A retrospective study with the data collected by the SCCS over
ferences in the in silico skin penetration models tested. The
the years (Opinions [2000–2014]) of the SCCS and its prede-
five more complex in silico models could predict the dermal
cessors has shown that the cosmetic ingredients characterized
delivery of chemicals relatively well, especially if the fraction
by the following physicochemical properties may be indicative
evaporated was considered. Secondly, there was also a good
of very low dermal absorption, MW>500 Da, High degree of
prediction of RF kinetics by the three models in which these
ionization, Log Pow ≤–1 or ≥ 4, Topological polar surface area
simulations were run. The amounts of chemical in the epider-
>120 Å2, and Melting point > 200°C [57], which is in line with
mis and dermis were less well predicted, which suggests better
the Ro5 and the 500-Da rule described before.
modelling is required to recapitulate diffusion/retention prop-
In such a case, the following minimum set of data should
erties in the viable epidermis and dermis.
be made available in order to assess the safety: experimentally
The in silico skin penetration models can already be used
determined physicochemical data, local toxicity, mutagenic-
for screening purposes to rank substances according to their
ity/genotoxicity, and high-quality in vitro dermal absorption
ability to pass through the skin. In future, they could also be
study. In the absence of experimentally determined dermal
used for safety assessment as an alternative to more costly in
absorption, the SCCS advises a 50% default value is used. This
vitro skin penetration assays.
conservative value may also be used in cases where only inad-
equate dermal absorption data are available. This is a strong
incentive to conduct the studies and also to develop simpler
procedures such as in silico, and it was the main reason why
Studies with UV Filters
CE got involved, as discussed before [47].
To formulate elegant sunscreens that also perform, UV fil-
ters must be kept in solution or well dispersed until they are
applied on the skin [53, 54]. Since skin permeation is influ-
Overview I Rational (United States)
enced by the different ingredients, it is in principle possible In the United States, the FDA issued a proposed rule that gives
to control the skin permeation by choosing ingredients that guidance to the industry what studies have to be conducted
retard rather than enhance skin permeation [55]. However, [10]. Because nonprescription sunscreens are topically applied,
there are so many other challenges in formulating sunscreens a critical safety consideration is whether dermal application
that such undertakings have had low priority so far [8]. results in skin penetration and systemic exposure to their
active ingredients and, if so, to what extent. This information Hojerová et al conducted a study comparing Oxybenzone
helps identify potential safety concerns and helps determine (1) and Ethylhexyl Triazone (15) [61]. In Table 17.1a these
whether an adequate safety margin exists within which an two happen to be the UV filters with the lowest and the
active ingredient is GRASE for use in sunscreens. highest MW.
Since the mid-1990s, topical (prescriptive) product new- The potential for systemic absorption of Benzophenone-3
drug-applications (NDAs) have included a Maximal Usage (BP3, 10%) and Ethylhexyl Triazone (EHT, 5%) in a silicone-
Trial (MUsT) as part of the clinical pharmacology/bioavail- based water-in-oil emulsion was assessed in vitro using a full-
ability assessment. This is now also required for over-the- thickness porcine-ear skin mimicking in-use conditions. The
counter (OTC) drugs such as sunscreens. A MUsT is designed estimated Systemic Exposure Dose (SED) after the sunscreen
to capture the effect of maximal use on absorption into the application at 1.0 mg/cm2 for 6 h (i) on the face; (ii) on the
blood with standard pharmacokinetic assessments (e.g. C, T, whole-body skin, was (i) 136 and 30; (ii) 4200 and 933 mg/
area under the curve, half-life, clearance, and volume of distri- kg_bw/d for BP3 and EHT, respectively.
bution). Bashaw et al provide further information about how to Hojerová et al calculated for three realistic exposure sce-
conduct a MUsT [58]. narios the Margin of Safety (MoS) of 48, 34, and 34 for BP3
and MoS of 536, 390, and 300 in the sunscreen applied on
the whole-body, indicating some concerns regarding the safety
Soluble UV Filters for consumers (MoS < 100) in the case of BP-3. Hojerová et
Soluble “Classic” UV Filters al suggest (2017) that, BP3 concentration allowed in EU cos-
(Organic, MW < 500 Da) metics (max. 10%) should be reviewed, especially in products
intended for whole-body applications and that the development
The FDA conducted two in vivo dermal absorption stud- of new UV filters should be focused on their specific physico-
ies with four and six sunscreen actives [59, 60]. The sun- chemical properties. In the meantime, the European Union
screen actives used, all fall into the category “classic” UV has indeed reacted. The maximum concentration of BP-3 for
filters (compare Table 17.1a): Oxybenzone (1), Octisalate full body application has been lowered in two steps, based on
(2), Homosalate (3), Octinoxate (6), Avobenzone (7), and updated SCCS opinions: First to 6% (as allowed in the United
Octocrylene (8). The first study demonstrated that all four States) and then to 2.2% [62] (EU Regulation, Annex VI).
tested sunscreen active ingredients were absorbed systemi- Hence the Hojerová calculation with the same data from 2017
cally and remained in plasma for at least 3 days after the last yields now MoS > 100.
application [59]. The second study collected additional infor-
mation on one formulation from the prior study and three
additional formulations along with three active ingredients
not evaluated in the previous study (Homosalate, Octisalate,
Preliminary Clinical Pharmacokinetic
and Octinoxate), the systemic absorption levels after apply- Evaluation of Bemotrizinol
ing sunscreen only once on day 1 and extending follow-up to A new sunscreen active ingredient being considered for
21 days, and residual skin levels during the washout phase. inclusion under FDA’s over-the-counter (OTC) sunscreen
The key results of this study are displayed in Figure 17.7. The monograph [63]. Some of the “modern” UV filters listed in
exceptionally high skin permeation of Oxibenzone is con- Table 17.1a have been on the market all over the world for
firmed, more than an order of magnitude higher than all other over 20 years, but not so in the United States. If everything
classic UV filters. goes well, Bemotrizinol (BEMT) will be the first modern
The FDA threshold of 0.5 ng/ml is the level that indi- UV filter that will be approved in the United States in early
cates a chemical could harm. When exposure occurs above 2024.
this threshold, the FDA is requesting long-term toxicity BEMT, aka Tinosorb® S or Parsol® Shield, is the first new
testing [59]. sunscreen active ingredient to be evaluated for inclusion in the
over-the-counter (OTC) sunscreen monograph using FDA’s
Conclusions and Relevance (by the FDA) new Generally Recognized as Safe and Effective (GRASE)
testing guidelines. An in vitro skin permeation test (IVPT)
All six of the tested active ingredients administered in four and clinical pilot pharmacokinetic Maximum Usage Trial
different sunscreen formulations were systemically absorbed (MUsT) were completed to support the GRASE determina-
and had plasma concentrations that surpassed the FDA thresh- tion for 6% BEMT. IVPT results indicated an oil +10% etha-
old for potentially waiving some of the additional safety stud- nol as the model sunscreen intervention for the pilot MUsT.
ies for sunscreens. However, the FDA is pointing out that these The open-label trial revealed BEMT concentrations rarely
findings do not indicate that individuals should refrain from exceeded FDA’s defined threshold (0.5 ng/mL) in plasma, no
the use of sunscreen. evidence for BEMT accumulation or steady-state concentra-
tions above threshold, and only one moderate and few mild
treatment emergent adverse events (TEAEs). Therefore, maxi-
Soluble “Modern” UV Filters (Organic, Larger MW)
mal topical applications of 6% BEMT in a model sunscreen
Based on their higher molecular weight, we expect the “mod- formulation did not contribute to meaningful systemic expo-
ern UV filters” (Table 17.1a, Nos 9–16) to permeate less into sure. These results support the safety of BEMT 6% for human
the skin than the classic UV filters (Table 17.1a, Nos 1–8). sunscreen use.
Insoluble UV Filters weight than UVB filters. Since making bigger and bigger mol-
ecules oil-soluble proved to become more and more difficult,
Insoluble “Classic” UV Filters the researchers made a virtue out of necessity by making the
(Inorganic, TiO2, ZnO, Nano) low solubility even lower, so that some UV filters ended up
In the course of the reevaluation of all UV filters in the United in the form of particles that were insoluble in cosmetic oils.
States, published as Proposed Rule, [10], the FDA has classi- MBBT was the first of these organic micronized UV filters.
fied TiO2 and ZnO as Category I UV filters because the existing Later a few more particulate UV filters followed: TBPT [71],
data are sufficient to support a positive GRASE determination. and HAA299, which was designed as a doubling of an existing
In Europe, ZnO had been approved specifically as a UV filter UV filter, DHHB.
in 2016, based on the SCCS opinion 2012 and its amendment The dermal absorption of MBBT and its 2nd generation
2014. Both the United States and Europe conclude that there is TBPT is indeed very low, around the limits of quantifica-
nothing to worry about dermal permeation for ZnO. tion in the order of 0.1%. Just looking at the TBPT molecule
Zinc oxide is insoluble in water and largely insoluble in in Table 17.1b tells us how insoluble it must be in cosmetic
biological fluids. This insolubility precludes the possibility of formulations. Furthermore, it is not only the molecules we
its systemic absorption from topical application of sunscreen are dealing with. These UV filters come as particles which
products beyond a de minimis amount, even if zinc oxide is are of course even less likely to penetrate and permeate the
included at its maximum eligible concentration of 25% and skin than single molecules. So these insoluble, particulate
regardless of the formulation of the product. The available UV filters bring us to a next higher level of avoiding bio-
studies on the dermal penetration of zinc oxide confirm that its availability. Details can be found in the SCCS opinion of
penetration—regardless of particle size—is primarily limited each UV filter.
to the upper layers of the non-living stratum corneum, with
most penetration occurring only into skin folds and furrows or NANO Means BIG
hair follicles. And should any de minimis penetration occur no
adverse health effects would be expected, given the high levels “Nano means Big” may sound surprising, but it is of course
of endogenous zinc in the human system. true with respect to UV filters. Compared to the soluble mole-
For similar reasons, the FDA proposes that titanium diox- cules of the “classic” and the “modern” UV filters, any particle
ide is also a Category I active ingredient. Titanium dioxide is is huge in size (Figure 17.8). Watkinson et al conclude in their
essentially insoluble in water and in biologic fluids [64]. As theoretical perspective that “Nanoparticles Do Not Penetrate
with zinc oxide, this lack of solubility prevents the transder- Human Skin” [72].
mal absorption of more than a de minimis amount of titanium In Europe, nano particles have to be declared in cosmetic
dioxide, regardless of either the concentration of titanium diox- products, with the addition of “nano” in brackets after the
ide or the formulation of the product [65, 66]. Further, unlike INCI name. There is a somewhat arbitrary threshold set
zinc oxide, which, if dissolved, would dissociate into zinc and at 100 nm. Several agencies are dealing with nano [73–75].
oxygen [67], the chemical stability of titanium dioxide is such Recently Surber at al discussed the issues and challenges with
that it does not dissociate under the conditions that exist in nanoparticulate UV filters [76]. Despite advanced regulation,
(or on) the human body [68]. Even if titanium dioxide were to rigorous approval procedures for nanoparticulate UV filters
dissociate into titanium and oxygen, titanium is unreactive in and early notification for products containing nanoparticles,
physiologic conditions and (for this, among other, reasons) is widespread reservations remain towards sunscreens and other
frequently used in medical devices and structures implanted in products containing nanoparticles. Possible reasons could be a
the human body [68, 69]. lack of knowledge about the current legislation, or mistrust in
We should all be aware that there are sometimes papers, the latter, unclear conceptions about the behavior of nanopar-
e.g. Peclova et al, suggesting that “Minor Amount of Nano ticles in sunscreen products and, as a result, an unclear percep-
TiO2 is Absorbed in Humans” [70]. In this latter case, tion of hazards and risks.
the authors disqualify themselves by writing contradic- In conclusion, insoluble (particulate) filters are a viable
tory statements in their discussion and conclusion sections alternative to soluble filters. The illustration of the anatomical
respectively. After discussing that “TiO2 nanoparticles in proportions in the skin barrier and the size ratios of insoluble/
sunscreen are absorbed through healthy human skin,” they nanoparticulate and soluble UV filters are a clear indication
conclude that “TiO2 detected in the blood and urine from that no significant absorption of nanoparticulate UV filters can
sunscreen may not necessarily be present in the form of TiO2 take place. Scientists should inform the public, engage with the
nanoparticles.” media outside of their environment in communicating at their
level of understanding and, above all, avoid using metaphors
that serve known fears. Last, but not least, the press should
Insoluble “Modern” UV Filters
inform correctly and avoid sensationalization.
(Organic, Particulate, Nano)
UV filters are ideally dissolved in the oil-phase of an emul-
sion. The difficulty to make new UV filters soluble led to an
Safety Assessment and Management of Risk
interesting development at Ciba Specialty Chemicals in Basel,
CH in the 90s (now part of BASF, DE). UVA or broad-spec- Understanding the regulation and safety assessment (aka
trum UV filters have usually an inherently larger molecular risk analysis) in the major regulatory regions (EU and US) is
FIGURE 17.8 Nano means BIG. Molecular weight, size, and particle diameter of soluble and insoluble (particulate) UV filters. Compare Table 17.1a:
BEMT (12), EHMC (6), EHT (15), HAA299 (14), MBBT (13), PBDT (11), PBSA (4), Polysilicon-15 (16), TBPT (10). See further Ref. 76.
necessary to operate in the sunscreen market. In the previous The SCCS calculates the margin of safety according to their
sub-chapters, the question was “if” and “how much” of a UV notes of guidance, whenever it is necessary, e.g. new data
filter can or may be bioavailable due to skin permeation. Once become available. This happened recently with BP-3 and
this is established and the answer is > 0, the next question that Homosalate and is ongoing with other UV filters. The pro-
arises is: “so what?”, i.e. what does this bioavailability of a cedure is straight forward if bioavailability and toxicological
low quantity of a UV filter mean from a toxicological point of data are available. Regarding UV filters consideration as dis-
view, as well as from a societal and individual risk manage- cussed in this chapter can be used in the “weight of evidence”
ment point of view? approach that is very much encouraged by the EC [51, 78].
Europe—There Is No Risk/Benefit
Assessment Carried Out for Cosmetics USA—Increased Consumer Exposure
to Sunscreen Active Ingredients
The regulation requires that all cosmetic products placed on
the EU market “shall be safe for human health when used under Consumer exposure to sunscreen active ingredients has
normal or reasonably foreseeable conditions of use” [14]. This increased dramatically since FDA began its initial safety
requirement is unconditional and applies in the same manner evaluations of the sunscreen active ingredients at issue in this
to all types of cosmetic products, including sunscreens. Unlike proposed rule [10]. Many factors have influenced this increase,
for drugs, there is no risk/benefit assessment carried out for including the following:
cosmetics, even those cosmetics that have proven to provide a
positive benefit to public health. The Regulation does not fur- • Significant increases in the number and types of con-
ther define “safety,” which is a societal consensus rather than sumers using sunscreen products
an absolute measure. This is well described in the EU General • Sunscreen products containing a greater number of
Product Safety Directive 2001/95/EC [77], which states that a active ingredients at greater concentrations
“safe product” means: • Increased awareness of the risks of sun exposure and
encouragement of routine sunscreen use by medical
any product which, under normal or reasonably fore- and public health authorities
seeable conditions of use . . . does not present any
• Evolving directions for use on sunscreen products
risk or only the minimum risks compatible with the
product’s use, considered to be acceptable and con- instructing consumers to use greater amounts of sun-
sistent with a high level of protection for the safety screen per application and to reapply sunscreen prod-
and health of persons, . . . The feasibility of obtain- ucts more frequently
ing higher levels of safety or the availability of other • Expanding availability and use of many differ-
products presenting a lesser degree of risk shall not ent types of sunscreen products, including daily-
constitute grounds for considering a product to be use products such as facial makeup, moisturizing
“dangerous.” creams, and lipstick
• Increased consumer exposure to sunscreen active Union and the United States center their assessment on dermal
ingredients has been the introduction and wide- absorption studies. Whereas the EU gold standard is the in
spread adoption of sunscreen products with higher vitro study after OECD guideline 428, the United States insists
labeled SPF values on a MUsT PK study, for Category III and for new ingredients.
For educators and informed consumers, it makes sense to
The FDA discusses the existing data and data gaps for each of look at basically two different categories of UV filters—1) sol-
the sunscreen monograph active ingredients and explains why uble and 2) insoluble—and to keep in mind that “Nano means
they propose that these active ingredients are GRASE or not Big” in the context of UV filters. Against this background fur-
GRASE for use in sunscreens. Those ingredients for which the ther sub-categories and detailed physicochemical properties of
existing data are sufficient to support a positive GRASE deter- particular UV filters may be considered as well.
mination are proposed as Category I. Those ingredients for The theoretical assessment of drug-likeness of the UV fil-
which additional data are necessary before a GRASE deter- ters according to the Ro5 proved to be very useful. It is good to
mination can be made are proposed as Category III. In cases know that Benzophenone-3 (BP-3, Oxybenzone) is an excep-
where the FDA’s evaluation of the existing safety data deter- tion, as the only “drug-like” UV filter. It did indeed also stick
mined that the risks associated with the ingredients outweigh out in the FDA-PK study of Matta et al; its dermal absorption
their benefits, the ingredients are proposed as Category II (not is more than 10-fold that of all the other classic UV filters [59].
safe and not effective). Based on the review of the publicly In this context it is interesting to note that BP-3 has not been
available data for these ingredients, zinc oxide and titanium used in the European for the last 20 years. Sunscreen manu-
dioxide are the only proposed as Category I, so far. facturers did not like BP-3 because of its somewhat elevated
allergy potential. In the European Union sunscreens with BP-3
must be labelled “Contains Oxybenzone.” So the European
Developmental and Reproductive Toxicity Studies
market forces have taken care of this UV filter, long before its
FDA expects that a systemic carcinogenicity study would maximum use concentration has been lowered from 10% to
not be needed to support a GRASE determination for a sun- 6% and the 2.2% for full-body applications.
screen active ingredient if an adequately conducted human Risk management is the process leading to a choice among
pharmacokinetic MUsT resulted in a steady state blood level alternative courses of action and establishing the priorities and
less than 0.5 ng/mL, and an adequately conducted toxicology strategies for implementation. People perceive risk differently
program did not reveal any other safety signals for the ingre- depending on their awareness and understanding of the risk in
dient or any known structurally similar compound indicating question and also based on their perception of how they might
the potential for adverse effects at lower levels. The threshold suffer personally as a consequence of the risk. In his recent
value of 0.5 ng/mL is based on the assessment that the level book Sun Protection—A risk management approach, Diffey
would approximate the highest plasma level below which the discusses solely the risk of UV-exposure [81, 82], but with the
carcinogenic risk of any unknown compound would be less questioning of efficacy and safety of sunscreens, a new dimen-
than 1 in 100,000 after a single dose. This threshold value is sion is added to the risk management. Sunscreen, the very
consistent with the Threshold of Toxicological Concern (TTC) means intended to reduce the risk of UV radiation, has now
concept, which was applied to impurities in the ICH guidance become itself the subject of risk management (Figure 17.9).
for industry “M7 Assessment and Control of DNA Reactive Figure 17.9 has been adapted to include sunscreen as well
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential since for many people there are now two perceived threats,
Carcinogenic Risk” [79, 80]. The FDA expects that the 0.5 ng/ UV radiation and sunscreen use. Sunscreen, the very means
mL concentration will be sufficiently above the assay’s limit of intended to reduce the risk of UV radiation, has now become
quantitation—limit of detection to allow a signal-to-noise ratio itself the subject of risk management in the public. In the
that ensures confidence in either the derived concentrations (in United States, the European Union, and most other countries,
the case of “exaggerated” values) or lack of concentrations. UV filters have been subject to risk/safety assessment by the
We soon expect to see if this process works for the approval authorities for a long time.
of Bemotrizinol (Table 17.1a), it would be the first “modern” There may indeed be nuances in the safety among approved
UV filter in the United States, over 20 years after launch in the UV filters, be they on the positive list in Europe or Category
rest of the world. In contrast to the European Union, the US I and Category III in the United States. Although, the EC
procedure looks like an all-or-nothing approach, whereas the explicitly stresses that approved UV filters must not be called
EU process is allowing for continuous incremental improve- “dangerous,” individuals may make their own assessment and
ments and adaptations. management of risk. Certain groups of people with special
potential vulnerability, e.g. parents on behalf of their chil-
dren, pregnant woman or breast-feeding mothers, may take
the decision to minimize the possibility for having any UV
Conclusion filter bioavailable in their body. So these individuals could
As the major jurisdictions globally, regarding safety of sun- for example refrain from using sunscreens altogether or only
screens, the European Union and the United States pursue choose sunscreens with UV filters that do not permeate the
different strategies to assure that the current and future sun- skin, i.e. insoluble UV filters and possibly soluble UV filters
screen products are and will be safe in use. Both the European with larger MW.
FIGURE 17.9 Management of risk; contributors to the risk management process with particular reference to solar UV exposure and sunscreen use.
(Based on Ref. 81 with permission, with additional material.)
7. Dudley DK, Laughlin SA, Osterwalder U. Spectral homeo-

Acknowledgments stasis—The fundamental requirement for an ideal sun-
screen. Curr Probl Dermatol. 2021;55:72–92.
The author would like to acknowledge the assistance of Bernd 8. Hanay C, Osterwalder U. Challenges in formulating sun-
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DSM-Firmenich, CH; Carl D’Ruiz, DSM-Firmenich, US; new challenges in sun care. SOFW J. 2020;146:7+8/20.
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11. FDA. Amending over-the-counter monograph M020:
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18
Photodamage
Protection and Reversal with Topical Antioxidants
Karen E. Burke
Our skin is the organ that suffers most from environmental

Introduction free-radical stress from exposure to sunlight, pollution, and
smoking. This contact, furthermore, depletes the level of vitamin
More than ever, our generation enjoys the luxury of travel and C in the skin. Even minimal UV exposure of 1.6 minimal ery-
leisure time for outdoor sports, markedly increasing our expo- thema dose (MED) decreases the level of vitamin C to 70% of the
sure to solar ultraviolet (UV) radiation. Exposure is increased normal level, and exposure to 10 MED decreases the vitamin C
at high altitudes and with reflection from surfaces covered to only 54% (2). Exposure to 10 parts per million of ozone in city
with snow, sand, water, or concrete. Our skin suffers the great- pollution decreases the level of epidermal vitamin C by 55% (3).
est damage—both acutely, with erythema and sunburn, and That was the bad news. The good news is that the most effec-
chronically, resulting in photoaging with mottled pigmenta- tive way to increase the skin level of vitamin C significantly is
tion, wrinkling, dryness, and precancerous keratoses as well by topical application. To optimize percutaneous absorption and
as the severe consequence of skin cancer. full activity of vitamin C, the precise formulation is of the utmost
Certainly sunscreens are essential for protection, but they importance (4). Since L-ascorbic acid is an excellent antioxidant,
are not enough. The most significant inherent limitations are making it an inherently unstable molecule, creation of an effec-
inadequate application (too little, too infrequently) and incom- tive topical delivery system is crucial. Many products contain
plete spectral protection from both UVA and UVB radiation. stable esterified derivatives (such as ascorbyl-6-palmitate or
The skin naturally uses nutritional antioxidants to protect magnesium ascorbyl phosphate), which are not metabolized
itself from photodamage, and when effective formulations are by the skin to the active ascorbic acid, so they have no activ-
applied topically, sun protection is enhanced. Topical applica- ity (5). Furthermore, the ester molecules are not absorbed per-
tion of these antioxidants can give far higher concentrations cutaneously (5). Some of these esterified derivatives have been
in the skin than even maximal oral intake. The challenge is to reported to give contact allergy (6, 7). Other formulations do not
make formulations that are stable and give effective transcuta- result in measurable absorption of vitamin C because they are
neous absorption to deliver effectively high concentrations of not at the correct pH. Delivery of L-ascorbic acid (pKaΔ = 4.2)
the active forms to the dermis as well as the epidermis. depends upon removing the ionic charge—achieved optimally
This chapter describes the necessary concentrations, molec- at a pH of 3.5 (5). New formulations stabilizing the vitamin C
ular forms, and requirements for stability and topical deliv- in microcapsules (8), liposomes (9, 10), and microemulsions (10)
ery of several antioxidants that have been proven effective: are being investigated for stability, absorption, and activity.
vitamin C, vitamin E, and selenium. New research on topical Topical absorption was proven to be effective by radioactive
application of genistein (a soy isoflavone) is also presented. labeling studies in pigs. After treatment with 10% vitamin C
cream, 8.2% was found in the dermis and 0.7% was in the blood
(4). Formulations containing 5%, 10%, 15%, 20%, or 25% vita-
min C were tested. After 24 hours, 20% resulted in the highest
Vitamin C
skin levels, with maximized concentration in the skin after 3 days
Vitamin C (L-ascorbic acid) is the body’s major aqueous-phase (5). In these experiments, levels of vitamin C after topical appli-
antioxidant and is vital for life. All animals make their own cation of 15% serum were shown to be a factor of about 27 times
vitamin C except for humans and other primates, one species that which could ever be attained by even very high oral intake.
of Indian fruit-eating bat, and the guinea pig—all of which If topical application is discontinued after skin saturation is
lack the enzyme L-glucono-γ lactone oxidase. In fact, a 59kg achieved, high levels remain in the skin for more than 3 days (5).
(130lb) goat synthesizes 13g of vitamin C per day, almost 200 Not only was absorption of vitamin C proven but also effi-
times the US Food and Drug Administration (FDA) require- cacy in enhancing antioxidant capacity was demonstrated by a
ment (1). Not only do other animals make hundreds of times clever new method by using infrared densitometry to evaluate
the vitamin C we ingest, but also, when under stress, they can the intrinsic antioxidant capacity (iAOC) of the stratum cor-
make more than ten times their normal amount of vitamin C. neum (11). Exposure to UV for 1 hour or 2 hours reduced the
Unfortunately, we humans do not have that capability (1). iAOC by about 17% and 30%, respectively, but treatment with
DOI: 10.1201/b22897-18 167

topical ascorbic acid increased the iAOC in a dose-dependent KEB). Melasma treated by QS-Nd:Yag laser (22) or fluorescent
manner, reaching an almost 2-fold iAOC with application of pulsed light (23) resolved more rapidly and effectively with
20% ascorbic acid solution. application of topical vitamin C.
Oral ascorbic acid with d-α-tocopherol (vitamin E) has been Because L-ascorbic acid may inhibit elastin biosynthe-
proven to protect against UVB-induced epidermal damage. When sis (24), it may reduce the solar elastosis of photoaged skin.
taken by human volunteers for 3 months, sunburn was significantly Also, in a histologic study of solar elastosis adjacent to skin
reduced as was the number of thymine dimers induced by UVB cancers, patients with high oral vitamin C intake showed less
exposure (12). Similar protection was attained by application of solar elastosis (25). Topical vitamin C has also been shown to
topical vitamin C. Topical vitamin C protects against solar dam- enhance collagen production in human skin. Postmenopausal
age primarily as an antioxidant that deactivates the UV-induced women who applied 5% vitamin C to one arm and half of
free radicals (13). Recent experiments with human epidermoid car- the neck for 6 months with placebo to the other side showed
cinoma cells demonstrate that vitamin C further protects against an increase in mRNA of collagens I and III (26). Tissue lev-
UV-induced apoptosis through reactivating silenced tumor sup- els of the inhibitor of metalloproteinase-I (MMP-I) were also
pressor genes p21 and p16 (14). Vitamin C is itself not a sunscreen, increased, thus decreasing UV-induced collagen breakdown.
although applying vitamin C decreases the degree of redness and However, mRNA levels of elastin, fibrillin, and tissue inhibi-
sunburn suffered even when applied after sun exposure. Protection tor of MMP-2 remained unchanged. Clinically, a significant
can be confirmed by histologic examination. Treatment with topical decrease was observed in deep facial furrows and substanti-
10% vitamin C decreases the number of abnormal “sunburn cells” ated by silicone replicas. Histology showed decreased inflam-
by 40%–60% (5) and reduces the UV damage to DNA by 62% (4). mation as well as denser collagen and elastic tissue repair (26).
Topical vitamin C is also directly anti-inflammatory. More Further research demonstrated significant decreases in the der-
aggressive techniques of laser resurfacing used in the past mal papillary index with advanced age: daily application for
caused redness for at least 3–4 months. With vitamin C applied 4 months of topical 3% vitamin C cream to the volar forearm
before and after laser surgery, redness was decreased after only of 33 women resulted in a significant increase in the density
2 months (15). Topical vitamin C can also be used effectively of dermal papillae from four weeks onward (compared to the
to treat the inflammation of rosacea (16). This anti-inflamma- vehicle), as measured by confocal laser scanning microscopy
tory action has been researched with human cells in vitamin (27). Other studies demonstrated a decrease in the crepey laxity
C-enriched media demonstrating decreased activation of the of forearm skin with restoration of a younger skinfold pattern
transcription factor nuclear factor κβ (NF-κβ), the factor respon- after 6 months of once-daily treatment with 15% vitamin C.
sible for many pre-inflammatory cytokines such as tumor necro- High-frequency ultrasound demonstrated a significant increase
sis factor-α (TNF-α) and interleukins IL-1, IL-6, and IL 8 (17). in collagen synthesis after application of topical vitamin C (28).
The main action of vitamin C on the skin is direct stimulation Because ascorbic acid is unstable because it is rapidly oxi-
of collagen synthesis. Vitamin C is an essential cofactor for the dized when exposed to air and many derivatives do not pene-
two enzymes required for collagen synthesis: prolyl hydroxylase trate transdermally, recent research has focused on developing
(which makes the collagen molecule stable) and lysyl hydroxy- new formulations that overcome these obstacles. Four new sta-
lase (which cross-links the collagen to give structural strength) bilizing conceptions are of interest:
(18). Recent research has further demonstrated that vitamin C
acts directly on DNA to increase the transcription rate and to
stabilize the procollagen messenger RNA, thus regulating and 1. The compound 3-o-ethyl-l-asocrbic acid (EA) was
maintaining the intercellular amount of collagen (19). prepared with 11 possible skin penetration enhanc-
Exciting experiments have demonstrated that vitamin C also ers, seven of which successfully permeated full
has antiaging effects. Studies compared newborn with elderly thickness porcine skin in vitro (29). However, no
(80–95-ear-old) fibroblasts (20). Elderly cells proliferate at only measurement of efficacy was studied.
one-fifth of the rate of newborn cells. However, when vitamin 2. Another new derivative, trisodium ascorbyl 6-pal-
C is added to the culture medium, the elderly cells prolifer- mitate 2-phosphate (APPS) does enhance cellular
ate better than normal newborn fibroblasts. Even the newborn ascorbic acid in ex vivo human epidermal cells, even
fibroblasts proliferate almost four times better when exposed to in the presence of ascorbic acid transporter inhibitors
vitamin C (20). Not only do fibroblasts increase proliferation (30). APPS repressed the intracellular superoxide
in the presence of vitamin C, but they also synthesize more generation and promoted viability in SOD 1 deficient
collagen. Newborn fibroblasts synthesize a larger percentage skin cells.
of collagen than elderly cells, but again, when elderly cells are 3. Tetrahexyldecyl ascorbate (THDC) is an L-ascorbic
exposed to vitamin C, they produce more collagen than the acid precursor that does penetrate the epidermis, but
normal, newborn fibroblasts (20). Surprisingly, even the new- this is unstable and activates intraferon-1, causing
born cells double the amount of collagen synthesized (20). inflammation (31). However THDC can be stabilized
Vitamin C further reverses the adverse appearance of pho- by the antioxidant acetyl zingerone: this combination
toaging by inhibiting tyrosinase (21), thereby fading unat- increased gene expression for phospholipid hemosta-
tractive solar lentigines. By directly decreasing inflammation, sis and keratinocyte differentiation, repressed MMP1
post-inflammatory hyperpigmentation can also be reduced. and MMP7 expression, inhibited MMP enzymic
Melasma and solar lentigines fade after only 2 months of daily destruction of collagen and elastin, and increased
application of topical vitamin C (15%) (personal observation, dermal fibroblast collagen synthesis.
Photodamage 169
4. Ascorbic acid loaded in “spanlastics” (composed of were clearly reduced and mottled pigmentation resolved in
span 60 and tween 60 [5:1]) showed optimal in vivo both of the subjects shown. The skin acquired a healthy, more
skin permeation with stability for 6 months and youthful glow.
improved penetration into stratum corneum (32). PCR Another important action of vitamin C on the skin is that
showed suppression of MMP2 and MMP9 in treated topical vitamin C increases the synthesis of several specific
rats by 30.4% and 65.3%, respectively. Histology lipids of the skin surface (33). Not only does this mean that
confirmed protection from UVB damage with nor- vitamin C helps the natural moisturization of the skin, but it
mal thick epidermal morphology and dense, orderly also enhances the protective barrier function of the skin (34).
dermal collagen fibers. Interestingly, topical vitamin C significantly enhances the
deposition of the sunscreen nanoparticles of zinc oxide and
This remarkable reversal of photoaging by topical vitamin C titanium dioxide on the skin without increasing their perme-
can be appreciated clinically in Figure 18.1. After 1 year of ation (35). Thus the sunscreen efficacy is optimized without
once-daily treatment with 15% topical vitamin C, wrinkles danger of absorption.
FIGURE 18.1 Correction of photoaging after 1 year of once-daily treatment with 15% vitamin C serum (SkinCeuticals). Notice the improvement of
periorbital wrinkles and lightening of solar lentigines. (Photographs courtesy of SkinCeuticals, Dallas, TX, USA.)
applied before exposure to the irritant and treats irritant con-

Vitamin E tact dermatitis if applied after exposure [48].)
After application of topical d-α-tocopherol, the concentration
Natural vitamin E is the most important lipid-soluble, mem- of vitamin E increases by a factor of 10.6 (49), far higher than can
brane-bound antioxidant in the body. Vitamin E is especially be achieved by oral supplementation. To enhance stability and
abundant in the stratum corneum, delivered there by sebum absorption, several formulations are being investigated, includ-
(36, 37). Its concentration is highest at the lower levels of the ing liposomal encapsulation (10, 50), microemulsions (10), and
stratum corneum at the dermal depth of the sebaceous glands, nanostructured lipid carriers and emulsions (51). A recent pub-
with a decreasing gradient outward. As the outermost defense lication from Pakistan describes stability and efficacy in pen-
of the body, the stratum corneum is first to absorb the oxida- etration and enhancement of skin moisturization with a new
tive stress of sunlight and pollution. Vitamin E is depleted in tocopheryl succinate loaded ethosomal gel (52). Other new
the process, so topical application can be particularly advanta- vehicles to enhance chemical stability and effective penetration
geous, especially since the lipophilic structure makes it cos- of several antioxidants have been recently reviewed (53).
metically attractive for application and absorption. Previous studies have demonstrated protection from the acute
Several forms of vitamin E exist in natural dietary sources. (49, 54–61) UV-induced damage of inflammation (erythema,
The form that is found in mammalian tissues and which has by “sunburn”) and hyperpigmentation (tanning) as well as protec-
far the greatest biologic activity is pure, nonesterified RRR-α- tion from the chronic UV-induced damage of skin cancer (49,
tocopherol (or d-α-tocopherol) (38, 39), which has three methyl 59–65) even by the various forms of vitamin E which are less
groups on the 6-chromal ring (Figure 18.2). Humans use pre- metabolically potent when applied topically than the non-ester-
dominantly α-tocopherol because a specific α-tocopherol ified Eol. Early studies using electron paramagnetic resonance
transfer protein selectively transfers α-tocopherol into lipo- (EPR) spectroscopy to detect free radical formation in Skh:1
proteins (40). The other natural forms are β, γ, and δ, which mice showed topical tocopherol sorbate to be more protec-
contain only one or two methyl groups on the 6-chromal ring. tive against skin photoaging than α-tocopherol and tocopherol
The γ-tocopherol is the most frequently obtained from the diet, acetate (66). Topical d-α-tocopherol was shown to be far more
but α-tocopherol is the most abundant form in the body (41, effective in protecting against all acute and chronic UV-induced
42). Relative to the α form, the β, γ, and δ RRR-tocopherols damage than topical d-α-tocopheryl succinate in mice (49).
give only 42%, 72%, and 40%, respectively, of the protection In a model of chemically induced skin cancer in mice, topi-
against post-UV edema (43). The synthetic form is “dl” or “all- cal α-tocopherol was further shown to protect against skin can-
rac,” a mixture of eight stereoisomers. The synthetic isomers cer and against lipid peroxidation with enhancement of several
are esterified (to acetates and succinates) for use in commer- protective enzymes such as glutathionine peroxidase and SOD
cial vitamins and some topical formulations because the esters (67). Studies showed decreased chemically induced cell prolif-
are far more stable. This ester must be hydrolyzed before there eration and inhibited MAPKs and NF-κβ signalling when vita-
is any biologic activity, a reaction which readily occurs in the min E was added to in vitro HaCaT cells (68). In another more
stomach after oral ingestion or in cell and organ culture, but recent study of incubation of keratinocytes in vitro with d-α-
is very slow and far from complete after topical application. tocopherol (0.1mM) before UVA exposure, UVA-photoinduced
The skin has only a limited capacity to cleave the esteri- oxidation of purines and formation of cyclobutene pyrimidine
fied forms of vitamin E to the active free tocopherol form, dimers (CPDs) was inhibited, and incubation after UVA expo-
so the antioxidant potential of the esters is minimal (44, 45). sure protected against post-UV chemically induced CPDs (69).
Furthermore, the all-rac form of vitamin E has been reported Human patients with actinic keratoses and basal cell carci-
to cause allergic contact dermatitis (46) and erythema mul- nomas were found to have decreased levels of α-tocopherol in
tiforme (47) when applied topically. No such adverse reac- blood cells and plasma compared with controls (70). However,
tion has been reported with d-α-tocopherol. (In fact, topical another study demonstrated increased basal cell carcinomas in
d-α-tocopherol actually prevents irritant contact dermatitis if women with vitamin E intake (71). A later French study (72)
FIGURE 18.2 Molecular structures of tocopherols.

Photodamage 171
concluded that supplementation with mixed antioxidants (includ-

ing 120mg of sodium ascorbate, 30mg of d-α-tocopherol, and
100 μg selenium-enriched yeast) did not affect the incidence of
nonmelanoma skin cancer in men or women, but that the inci-
dence of melanoma was higher in the antioxidant supplemented
women. The limitations of this study are (a) that there were only
25 melanomas in the 13,017 patients, and (b) the oral antioxidant
formulation did not provide the most important antioxidants in
the optimal molecular forms and concentrations: Higher concen-
trations (>10´) of vitamin C and d-(not dl-)α-tocopherol (1000–
3000 mg/day and 400 IU/day, respectively) are usually studied.
Α-tocopheryl ferrulate does inhibit melanin synthesis in
vitro in normal human melanocytes (73), suggesting protec-
tion against the unattractive solar lentiges of photoaged skin
and possibly protection against melanoma (74). However, a
study of correlation of vitamin intake (by retrospective vitamin
and food intake questionnaires) showed no correlation with
incidence of melanoma (75). In other mouse studies, topical
α-tocopheryl succinate and α-tocopheryl acetate not only failed
to inhibit UVB-induced immunosuppression and carcinogen-
esis, but also at higher concentrations were ineffective (68) or
even appeared to enhance carcinogenesis (76). In one study,
female mice chronically exposed to UVB and topically treated
with d-α-tocopherol experienced increased tumor growth rate
and increased DNA damage, cutaneous proliferation, and
angiogenesis compared to vehicle-treated mice (77). Topical
α-tocopheryl acetate was less effective than α-tocopherol in
protecting against UV-induced erythema in rabbits (78) and
against UV-induced photoaging in mice (79). Thus the molecu-
lar form and concentration are quite important, particularly
with topical formulations. Further clinical trials in humans are
necessary to clarify optimal concentrations and formulations.
FIGURE 18.3 Correction of periorbital wrinkles after 4 months of once-
Vitamin E has been demonstrated to reverse photoaging daily treatment with 5% d-α-tocopherol cream.
dramatically. A recent study showed that tocopherol enhanced
collagen synthesis and inhibited collagen degradation by dermal inflammation after treatment with retinoic acid or with
downregulating MMP gene expression in human fibroblasts vitamin E. Each of these parameters were graded on a scale of
stressed by exposure to hydrogen peroxide (80, 81). This model 0 (no damage) to 4 (maximal damage). As shown in Figure 18.5,
further demonstrated that γ-tocopherol decreased stress- in overall gradation, d-α-tocopherol and L-selenomethionine
induced premature senescence and apoptosis by downregulat- creams were even more effective at reversing UV-induced dam-
ing caspace-9 and caspace-3 (82). Also, vitamin E significantly age than retinoic acid, the “gold-standard” of topical antiaging
stimulated collagen and fibrinectin synthesis in cultured formulations. (KE Burke, L Ricotti, EG Gross, unpublished
human foreskin fibroblasts (83, 84). observation). Further electron microscopic analysis confirmed
Figure 18.3 shows the dramatic decrease in periorbital rhyt- correction of collagen and elastin fiber damage and demon-
ides in a 48-year-old woman after 4 months of daily application strated repair of UV-induced disruption of the basement mem-
of d-α- tocopherol (5%) cream. This correction of UV-induced brane anchoring fibrils.
damage was confirmed by histologic examination. Mice were
exposed to UVB for 6 weeks, after which epidermal hypertro-
phy with thickened stratum corneum, an increased incidence of
damaged “sunburn cells” in the basal layer, disruption of dermal
Vitamin C with Vitamin E
collagen and degradation of dermal elastin, and dermal inflam-
mation were noted, as shown in Figure 18.4. Each group was then As presented earlier, the skin uses predominantly vitamin C
treated for 8 weeks with either vehicle cream, 0.05% retinoic to protect the aqueous environment and vitamin E to protect
acid, 5% d-α-tocopherol cream, or 0.05% L-selenomethionine membranes from lipid peroxidation. Since vitamin C is natu-
cream (see following section) (85), after which multiple biopsies rally present intracellularly in relatively high concentrations,
from each mouse were evaluated (blind) by two experienced L-ascorbic acid not only acts directly as an antioxidant and
dermatopathologists. The histologic improvement in all param- as an essential cofactor in the synthesis of collagen, but also
eters of photoaging can be appreciated in Figure 18.4, with a regenerates oxidized membrane vitamin E so that the vita-
marked decrease in hyperkeratosis and epidermal hypertrophy, min E need not be replaced (86). Oral vitamin C with E in
repair of damaged dermal collagen and elastin, and clearing of high doses protects against UV-induced erythema in humans
FIGURE 18.4 Histologic correction of photodamage by topical antioxidants. Four groups of 10 Skh:2 mice were exposed to UVB 3 days per week
for 6 weeks to photodamage the skin. Then each group was treated 5 days/week for 8 weeks as follows: (i) vehicle, (ii) 0.05% retinoic acid, (iii) 5.0%
d-α-tocopherol, (iv) 0.05% L-selenomethionine (discussed in following section). (a) Biopsies taken before UVB exposure show a thin, outer keratin
layer, normal epidermis, normally aligned, fine fibrillar dermal collagen and elastin, and no dermal inflammation. (b) Biopsies after UV exposure
show a markedly thickened keratin layer, epidermal hypertrophy, degradation of dermal collagen and elastin, and prominent dermal inflammation.
After treatment for 6 weeks with (c) topical 0.05% retinoic acid or (d) topical 5.0% d-α-tocopherol, there is reversal of hyperkeratosis and epidermal
hypertrophy and repair of damaged dermal collagen and elastin with clearing of dermal inflammation (84). (The special stains that corroborate the
degradation of collagen and elastin are not shown.)
(87, 88), whereas either vitamin alone is ineffective (87). Oral and palmityl tripeptide decreased skin redness and roughness
supplementation of ascorbic acid and d-α-tocopherol in human (as documented by photography) in >40-year-old female vol-
volunteers for 3 months significantly reduced UV-induced unteers after 8 weeks of daily application (92). Another is an
epidermal damage as measured by decreased sunburn and encapsulated serum containing vitamin C (20%), vitamin E,
decreased UVB-induced thymine dimers (12). Topical and European raspberry leaf cell extract applied by 50 female
L-ascorbic acid (15%) with d-α-tocopherol (1%) gives fourfold volunteers (30–65 years old) in a split-face topical application
protection against UV-induced erythema and thiamine dimer study with confirmation of improvement in skin elasticity, pig-
formation in porcine skin (89) compared to ascorbic acid mentation, moisture, and smoothness by careful, quantitative,
(15%) alone. This protection from UV-induced erythema (90) instrumental measurement (93). A third product with vitamin
and tanning (91) by vitamins C and E combined with melato- C (20%), vitamin E (5%), silymarin, and hexylresorcinol was
nin was further clinically confirmed in humans. shown to be UVB photoprotective in skin explants (94) with
Several other formulations have recently been studied, some protection against UVB-induced changes in gene marker
with quantitative measurement of improvement in parameters expression of pro-collagen and pro-inflammatory gene mark-
of aging: One containing ascorbic acid 15%, tocopheryl acetate, ers. Yet another Brazilian formulation containing L-ascorbic
Photodamage 173
FIGURE 18.5 Gradation of histologic correction of photodamage

by topical antioxidants. Each of four histological parameters for
photodamage (hyperkeratosis, epidermal thickness, collagen disruption,
and solar elastosis) were graded on a scale of 0 (no damage) to 4 (maximal
damage) and evaluated before exposure to UVB, after exposure to UVB,
and after treatment for 8 weeks with vehicle (veh), 0.05% retinoic acid
(RA), 0.05% L-selenomethionine (SeMet), or 5.0% d-α-tocopherol (vit E).
The average gradation of all parameters of damage is shown (84).
acid (15%) with tocopherol, hyaluronic acid, and other bark

FIGURE 18.6 Photoprotection by topical antioxidant formulations.
and plant extracts was shown in ex vivo human skin to protect Skin was (a) untreated or pretreated with (b) vehicle, (c) 0.5% ferulic acid,
against pollution-induced skin pigmentation and aging after (d) 15% vitamin C + 1% vitamin E, or (e) 15% vitamin C + 1% vitamin E
+ 0.5% ferulic acid and irradiated with solar-simulated radiation (2×–10×
90 days (95). Fortunately, mixing these hydrophilic and lipo- minimal erythema dose [MED]). Visual erythema 1 day later is shown.
philic antioxidants in a topical formulation stabilizes each (88) (From Murray JC, Burch JA, Streilein RD, et al., J Am Acad Dermatol
2008; 59:418–25. With permission.)
for a cosmetically attractive application.
tumor size and incidence (104), proving that sun exposure must
be limited to benefit from antioxidant treatment. Evaluation by
Vitamin C with Vitamin E and Ferulic Acid real-time polymerase chain reaction demonstrated suppression
Ferulic acid is found ubiquitously and at high concentrations of UV-induced cytokine mRNA formation (for inflammatory
in plants (96, 97) where it cross-links polysaccharides and pro- cytokines interleukin [IL]-1α, IL-6, IL-8, and tumor necrosis
teins during lignin cell wall synthesis (98, 99). A potent antioxi- factor [TNF]-α, as well as for the immunosuppressive cyto-
dant, ferulic acid protects membranes from lipid peroxidation kine IL-10) (102).
and neutralizes alkoxyl and peroxyl radicals. It has also been This formulation was recently shown to protect against
shown to have synergistic interactions with ascorbic acid and particulate-matter atmospheric skin aging aggravated by UVA
α-tocopherol (100). Furthermore, ferulic acid itself minimally (106). Also vitamin C + E + ferulic acid is an effective adjunct
blocks UVB to give some sunscreen protection (see Figure 18.6). for decreasing melanin in melasma after Q-switched Nd:YAG
After testing the effectiveness of a series of low molecu- laser treatment (107).
lar weight antioxidants that are available in chemically pure
form, Zielinski and Pinnell (101) demonstrated that ferulic
acid provides stability of more than 90% for L-ascorbic acid
and 100% for α-tocopherol. Addition of ferulic acid (opti-
Vitamin C with Ferulic Acid and Phloretin
mally 0.5%) to the formulation of vitamin C (15%) + vitamin Phloretin is another potent plant-derived phenolic antioxi-
E (1%) doubles photoprotection to solar-simulated irradiation dant (found in both the flesh and peel of apples), which can be
of skin from fourfold to approximately eightfold as measured absorbed by the skin. When combined with vitamin C and feru-
by both erythema (as shown in Figure 18.6) and sunburn cell lic acid, phloretin enhances photoprotection to UVA-induced
formation (102, 103). Enhanced photoprotection was fur- erythema and pigmentation (108). Biopsies from human volun-
ther demonstrated immunohistochemically by inhibition of teers after UV exposure (89% UVA and 11% UVB) and treat-
UV-induced formation of thymine dimer mutations and of ment with a formulation containing vitamin C (10%), ferulic
UV-induced p53 (103), both of which are associated with skin acid (0.5%), and phloretin (2.0%) at pH = 2.5, demonstrated
cancer (102–104) This formulation of vitamin C + E + ferulic significant photoprotection as measured by decreased thy-
acid did in fact decrease the tumor number and the tumor bur- mine dimer formation, decreased matrix metalloproteinase-9
den in mice when applied topically after UVB exposure but expression, and decreased p53 expression (108). This topical
before the onset of the UVB-induced skin cancers (10) and serum also protected against UV-induced immunosuppres-
when applied to mice before, during, and after UVB-exposure sion: There was no UV-induced decrease in CD1a-expressing
(10). However, other experiments did not confirm this protec- Langerhans cells when skin was pretreated with vitamin C +
tion (105). Also, continued UV exposure did further increase ferulic acid + phloretin (108).
fungoides) were found to have decreased serum titers of sele-

Selenium nium, and stages III and IV had significantly lower levels than
the earlier stages I and II (139). Also, the patients with Sezary
Selenium, an essential trace element in humans and animals, is syndrome or mycosis fungoides who responded less well to
required by 25 selenoproteins and selenium-dependent enzymes. therapy were found to have lower levels of selenium (139).
Most important to skin care are the intracellular antioxidant A study of 240 non-melanoma skin cancer patients in good
enzymes glutathione peroxidase and thioredoxin reductase (109, general health demonstrated a significantly lower mean plasma
110). Selenium has been shown to have other protective effects selenium concentration than control subjects without skin can-
that may not directly involve selenium-dependent glutathione cer (142). In fact, those patients whose blood concentrations
peroxidase activity (111), such as protecting (112) and repair- were in the lower decile had 4.4 times the incidence of skin
ing DNA (113, 114), reducing the DNA binding of carcinogens cancer as those in the highest decile (142).
(115), inhibiting neoplastic transformation (116), and suppress- This interesting correlation led to a 10-year prospective
ing gene mutations at the lysine and histidine loci (117). study of 1312 patients with a history of at least two basal
For decades, selenium has been implicated in reducing carci- cell carcinomas and/or one squamous cell carcinoma of
nogenesis. In animal tumor models, moderate selenium supple- the skin as well as at least one skin cancer within one year
mentation at levels above the dietary requirements decreases before entering the trial (142). Selenium treatment (200 μg/
the number of tumors induced by several chemical carcinogens day L-selenomethionine or placebo) did not initially protect
(118) and viruses (119), and reduces the incidence of spontane- against further development of such skin cancers during the
ous mammary tumors (120). In addition, selenium supplements first two years of supplementation: There was no effect on the
inhibit the growth of human tumor cell lines (121) as well as the development of basal cell carcinoma but a small increase in
growth of transplanted tumors in mice (122), and decrease the risk for squameous cell carcinoma. However, selenium supple-
mutagenic activity of several known carcinogens (123–125). mentation did reduce total cancer incidence and the incidence
Recent research has elucidated precise anticarcinogenic of lung, colorectal, and prostate cancer significantly (to 42%,
mechanisms, as excellently researched by Jackson and Combs 42%, and 37% incidence, respectively) as well as total cancer
(126). Selenium metabolites have been shown to impair angio- mortality (to 50%) (143). The lack of protection against skin
genesis by tumors (127, 128) and to promote cell cycle arrest cancer during the first 2 years of supplementation may suggest
and apoptosis of tumor cells (129), as well as inhibit local that the degree of damage at the onset of the trial was suf-
invasion and migration (128, 130), even inhibiting pulmonary ficiently severe to preclude reversal of oncologic potential by
metastases of melanoma and melanoma migration (130, 131) selenium supplementation. After the first 2 years of treatment,
and metastases in mice, possibly by down-modulation of Il-18 no increase in skin cancer was observed.
expression (132). That Se can inhibit malignant spreading was A later randomized controlled trial (144) compared supple-
demonstrated by Yan and colleagues for several oral forms mentation with 400 μg/day to 200 μg/day of selenium supple-
of the element: methylseleninic acid (128), selenite (130), and mentation: Patients treated with 200 μg/day had an increase
high-Se soy protein (131). Their work showed that this effect in nonmelanoma skin cancer (NMSC), but those given 400
involves reducing adhesion of cancer cells to extracellular μg/day had no change in incidence of NMSC. Vinceti et al.
matrix (133), inhibiting the urokinase plasminogen activator (145) reviewed 83 published clinical trials investigating
(UPA) system (128) and reducing angiogenesis (128). Also, dietary selenium: Most studies concluded that there was no
two FDA-approved inhibiting histone deacetylase compounds benefit in reducing general cancer risk; some studies showed
with selenium prevent early melanocylic lesion development no effect on NMSC but an increased incidence of other types
in skin by inducing apoptosis (134). These are currently being of cancer, including melanoma. In contrast, a recent study of
investigated as potential melanoma chemopreventative agents, 375 melanoma patients showed that a low serum selenium
as is selenium incorporated into the DNA alkylating agent level was associated with an increased mortality rate in the
temogolomide for treatment of melanoma and glioma (135). 10 years following melanoma diagnosis (146). A recent in
Selenium metabolites further enhance metabolism of foreign vivo study demonstrated that melanoma cells can modify
compounds including carcinogen-detoxifying enzymes (136). selenoprotein levels as a mechanism to control tumor pro-
Some, but not all, epidemiological studies have found a gression (147). Further research demonstrated that selenium-
reduced risk for several kinds of cancer associated with a binding protein 1 is down-regulated in melanoma leading to
higher blood concentration of selenium (137–139). A decreased expression of glutathione peroxidase with reduction of mela-
selenium concentration and glutathionine peroxidase activity noma cell proliferation and suppression of blood vessel for-
in blood, and interestingly, an increase of these parameters mation within the tumor (148). In evaluating human studies,
in malignant tissue was found in lung cancer patients (138). careful analysis of possibly confounding parameters (such as
Patients with malignant melanoma were found to have sig- indoor and outdoor environmental exposure to UV, cigarette
nificantly lower levels of serum selenium, and patients with smoke, industrial pollutants, and detrimental trace minerals
more advanced disease (stage III disseminated melanoma) had [such as arsenic]) is necessary. Also conclusions must take
the lowest levels (140). In a transgenic mouse model, topical into account the diverse array of organic and inorganic sele-
treatment with L-selenomethionine resulted in a significant nium compounds, each with distinct absorption and efficacy.
delay in the time required for melanoma development (though The differing conclusions from human studies indicates that
established tumors grew more rapidly) (141). Patients with the effects of selenium on NMSC and melanoma remain
cutaneous lymphoma (Sezary syndrome as well as mycosis inconclusive.
Photodamage 175
Topical preparations containing selenium sulfide are fre- before and after UVA exposure: Selenium supplementation
quently used for the treatment of tinea versicolor (149), seb- enhanced repair of 8-oxoguanine only in young donor kera-
orrheic dermatitis (150), and dandruff (151). However, the tinocytes (161). In a senescent skin equivalent model, Jobeili
selenium from these preparations is not absorbed by the skin et al. (163) showed that selenium protects keratinocyte stem
(150). Selenium can be absorbed transdermally in guinea cells against senescence by preserving their “stemness” phe-
pigs when applied as L-selenomethionine (152). After topical notype by adhesion to basement membrane, thereby maintain-
application of 0.02% L-selenomethionine to mice, skin lev- ing homeostasis and retarding intrinsic aging. Thus, since aged
els of selenium increase by a factor of two to five over com- keratinocytes are more vulnerable to oxidative DNA damage
parable oral doses (153, 154), and after application of 0.05% and since enhanced stem cells extend the replicative life of
L-selenomethionine by a factor of 8.0 (85). This formulation keratinocytes with aging, selenium supplementation may be a
increased the MED in humans (155) and decreased UV-induced strategy to combat skin aging and photoaging.
skin damage, as demonstrated by a decrease in post-UV tan- That particular formulations of topical selenium can amelio-
ning and skin cancer in Skh:2 mice (152–154, 156). rate the appearance of aging skin has been shown clinically and
With topical application of L-selenomethionine, selenium histologically. The significant decrease in periorbital rhytides
levels were also shown to increase significantly (×5) within in a 56-year-old woman after 4 months of daily application of
tumor tissue. Thus, there was a possibility that the timing of L-selenomethionine (0.05%) can be seen in Figure 18.7. This
L-selenomethionine application could affect the degree of correction of UV-induced damage was similar to that of topical
inhibition of UVB-tumorigenesis (or maybe even enhance vitamin E as discussed previously and confirmed by histologic
tumorigenesis at some stage). Thus an investigation was examination as shown (for topical vitamin E) in Figure 18.4.
undertaken applying topical L-selenomethionine (a) before, All histologic parameters of photodamage demonstrated simi-
during, and after UVB exposure, (b) before UVB-exposure but lar reversal after treatment with topical L-selenomethionine
discontining when tumors were first clinically detected, or (c) (Figure 18.5) (85). Transmission electron microscopy further
only after tumors were first detected and continuing thereafter confirmed repair of dermal photoaging, as shown in Figure 18.8.
(157). Optimal inhibition of skin cancer was achieved by appli- Normal, non-UV-damaged dermis (Figure 18.8a) consists of
cation of topical L-selenomethionine before, during, and after
exposure. Unfortunately, statistically significant protection
was not seen with L-selenomethionine application only prior
to tumor detection. The good news is that statistically signifi-
cant protection was also attained with application only after
the onset of tumors. Thus even beginning L-selenomethionine
supplementation late in the process of tumorigenesis can help
protect from UV-induced photodamage and skin cancer (157).
Topical L-selenomethionine is highly effective not only in
preventing but also in reversing photoaging (85). Because topi-
cal L-selenomethionine penetrates transdermally, both the epi-
dermis and dermis are protected, so previous damage can be
repaired. As a cofactor for the glutathione peroxidases, selenium
quenches ROS, thus decreasing inflammation and preventing
activation of mediators which induce the metalloproteinases
(MMPs) that would otherwise degrade collagen and elastic tis-
sue. Also, selenomethionine decreases malondialdehyde (MDA,
a measure of ROS) and protects normal human skin fibroblasts
from UVA-induced metalloproteinases MMP-1 and MMP-3
which break down collagen (158), directly causing wrinkles. As
a cofactor for thioredoxin reductase, melanin synthesis is inhib-
ited and solar hyperpigmentation is corrected (159, 160).
That selenium does protect against both intrinsic and extrin-
sic aging of the skin has been demonstrated by recent research.
Comparing expression of senescent-associated genes in der-
mal biopsies from young and old human donors, the antioxi-
dant enzymes selenium-dependent glutathionine-peroxidase
and glutathionin S-transferase theta 1 were upregulated in old
dermis but not altered in skin fibroblasts exposed to UVB, sug-
gesting their involvement in intrinsic aging (161). In evaluating
the impact of selenium against skin aging and photoaging, low
doses of selenium were very potently protective against UVA-
induced cytotoxicity, whereas protection in old keratinocytes
required far higher concentrations (by a factor of 8) (162). DNA FIGURE 18.7 Correction of periorbital wrinkles after 4 months of
repair ability was drastically decreased in old keratinocytes once-daily treatment with 0.05% L-selenomethionine lotion.

FIGURE 18.8 Reversal of photodamage by topical antioxidants: transmission electron microscopy. (a) Before UV exposure, (b) after 6 weeks of UVB
exposure, (c) after treatment for 8 weeks of UVB-exposed skin with topical 0.05% L-selenomethinoine (84).
Photodamage 177
dense collagen with homogeneous bundles of uniformly dis-

persed fibers aligned parallel to the basal lamina above. The Genistein
dermal-epidermal junction shows anchoring fibrils of dense
collagen. After exposure to UV (Figure 18.8b), the dermal col- Recent epidemiologic analysis comparing Asian diets high in
lagen is sparse; bundles are not uniform and are irregularly soy (average daily intakes of 20–150 mg) (167) with American
dispersed; fibers are disoriented and fragmented. There is an diets (average daily intake of only 1–3 mg) (168) indicate that
increase in extracellular mucopolysaccharide matrix. The der- soy confers major health benefits by decreasing the incidence
mal-epidermal junction has sparse collagen with a decrease in of cancer (167–172) and reducing cardiovascular disease (167).
anchoring fibrils. Treatment with topical L-selenomethionine Since genistein is the most plentiful isoflavone in soy, this mol-
did indeed reverse this UV-induced damage (Figure 18.8c): ecule has been the most extensively studied component for its
dermal collagen was repaired, and fibers became oriented chemopreventive and anticancer effects (171).
and more regular. As collagen became denser, the increase in Extensive experimental evidence documents the direct anti-
extracellular mucopolysaccharide matrix resolved. Collagen carcinogenic action of genistein. Animal studies demonstrate
was replaced in the dermal-epidermal junction with repair of protection against bladder, breast, colon, liver, lung, prostate,
the anchoring fibrils. Clearly topical L-selenomethionine is and skin cancer (167–172) with oral genistein. Growth of many
effective in reversing photodamage of the skin (85). cancer cell lines is inhibited by genistein (172). Dietary soy
inhibits chemically induced skin cancer in mice (173). Exciting
research demonstrates that genistein arrests the growth and
induces the differentiation of malignant melanoma (174) and
inhibits pulmonary metastases of melanoma (175, 176).
Selenium with Vitamin E
The mechanism by which genistein inhibits carcinogen-
In many biologic systems, vitamin E and selenium often act esis may be through its proven inhibition of tyrosine protein
synergistically in eliminating lipid peroxides (164). Borek kinases (TPKs), the enzymes that phosphorylate proteins nec-
et al. (165) demonstrated that selenium (Na2SeO3) and RRR- essary for regulation of cell division and transformation (177).
α-tocopheryl succinate (natural vitamin E succinate) each act Of particular importance is phosphorylation of TPK-dependent
alone by different mechanisms to prevent radiogenic (x-ray epidermal growth factor receptors (EGF-R) which are related
exposure) and chemically induced (exposure to benzo(a) to tumor promotion, including initiation of transcription fac-
pyrene or to tryptophan pyrolysate, a carcinogen derived tors, release of inflammatory mediators (such as prostaglan-
from protein foods) carcinogenic cellular transformation of dins), and stimulation of cell proliferation (178). Genistein was
C23/iOT½ mouse cells in vitro. Selenium enhances cellular found to down-regulate both UVA- and UVB-induced EGF-R
destruction of peroxide by increasing intracellular glutathione phosphorylation in human epidermoid carcinoma cells (179).
peroxidase, catalase, and glutathione. Vitamin E alone inhibits By similar enzymic inhibition, genistein retards UV-induced
cellular carcinogenic transformation by different mechanisms apoptotic changes—including caspase-3 and p21-activated
including quenching the lipid free radical ROO•. In the Borek kinase 2 activation of human epidermal carcinoma cells (180)
et al study (165), inhibition was additive when cells are treated and phosphokinase Cδ in human keratinocytes (181). Recent
with both; other research suggests synergistic protection (164). experiments further show that genestein inhibits carcinogensis
Later in vivo experiments in mice comparing and combin- in pancreatic (182) and ovarian cancer cells (183) by down-reg-
ing topical L-selenomethionine with topical d-α-tocopherol ulation of oncogenic microRNAs. Hopefully this mechanism
(166) indicated that the topical combination was less effective will be investigated in UV-exposed skin.
than topical vitamin E alone—both in prolonging the onset Genistein is also a potent antioxidant. Genistein scavenges
and in decreasing the incidence of UV-induced skin cancers peroxyl free radicals, thereby protecting against lipid peroxi-
(166). However, topical L-selenomethionine with oral vitamin dation (184, 185). The decreased incidence of cardiovascular
E was more effective than either alone. Both forms of vitamin disease with high soy diets may be due to genistein’s inhibiting
E alone were equally effective and more effective than topical the oxidation of low-density lipoprotein (LDL) cholesterol in
L-selenomethionine alone (166). Topical L-selenomethionine both aqueous and lipophilic environments. Of direct impor-
(alone or in combination with each form of vitamin E) was most tance in protection of the skin from UV-induced damage,
effective in preventing the UV-induced inflammation of sunburn genistein has been shown to inhibit UV-induced DNA oxida-
(100% effective!) (166). In reducing UV-induced pigmentation, tion (186) and cellular DNA oxidation induced by benzopyrene
topical L-selenomethionine with topical or with oral vitamin E and UVA (187) and by phorbol ester stimulation (188), as well
was more effective than either one of these antioxidants alone, as by psoralen plus UVA (PUVA) therapy (189). The fact that
particularly during the first 8 weeks of UV exposure. genistein also reduces erythema and histologic inflammation
Clinical trials on a larger scale are needed to explore the induced by PUVA in mouse skin (190) may have important
potentially beneficial effects of combinations of antioxidants. implications for PUVA therapy, by reducing possible short-
Oral and topical supplementation could possibly be an adju- and long-term adverse reactions.
vant (but not a substrate) for sunscreen. Interestingly, there The use of topical genistein to prevent and reverse photo-
might be clinical benefit provided by oral antioxidant supple- aging has recently been intensively investigated, with prom-
mentation in decreasing the long-term sequelae of COVID ising results. In animal studies, Wei et al. (179) proved that
characterized by depletion in plasma antioxidants and trace topical genistein (10 μmol/cm2) indeed protects against acute
minerals (164). and chronic UV damage to the skin when applied either
60 minutes before UVB exposure or 5 minutes after UVB, with decrease in number of sunburn cells after pretreatment with
more effective protection when applied before. After exposure topical genestein (192). Histologic analysis in mice showed
of Skh:1 hairless mice to UVB, topical genistein completely that topical genistein substantially blocked the signs of chronic
blocked acute skin burns and inhibited UVB- induced cutane- photodamage: epidermal hyperplasia and reactive acanthosis
ous wrinkling (as seen clinically in Figure 18.9) (179). Another with nuclear atypia (179). At a molecular level, UV-induced
recently published study further demonstrated protection by damage to DNA as measured by the biomarker 8-hydroxy-
showing that topical genestein applied pre-UV exposure to deoxyguanosine was markedly reduced (193). Protection was
rats decreased UVB-induced wrinkling (191). This protec- also demonstrated by decreased expression of proliferating cell
tion from UV-induced erythema with topical genestein (0.5%) nuclear antigen (PCNA) (a marker of DNA repair which indi-
was also confirmed in pig skin by an increase in MED and a rectly indicates degree of UV damage) as well as by decreased
FIGURE 18.9 (A) Effect of genistein on ultraviolet B (UVB)-induced acute skin burns. Once daily for 10 days, SKH-1 hairless mice were treated
with 5 μmol of genistein 60 minutes before UVB irradiation (1.8 kJ/m2). Photographs were taken 24 hours after final UVB irradiation. (a) Negative
(sham) control; (b) vehicle + UVB; (c) 5 μmol of genistein + UVB. (B) Effect of genistein on photodamage in mouse skin chronically exposed to UVB.
Twice weekly for 20 weeks, SKH-1 hairless mice were treated topically with 5 μmol of genistein 60 minutes before or 5 minutes after UVB irradiation
(0.3 kJ/m2). (d) Negative (sham) control; (e) vehicle + UVB; (f) UVB + genistein. (Source: From Wei H, Saladi R, Lu Y et al., Isoflavone genistein:
photoprotection and clinical implications in dermatology, J Nutr. 2003;133(11 Suppl 1):3811S-3819S, with permission.)
Photodamage 179
cox-2 expression and by increased catalase concentration in Genistein has a 30-fold higher affinity for ERβ than ERα
mice treated with topical genestein (1–3mg/ml) prior to UVB (202) but a greater ERα agonist activity than ERβ (203).
exposure (194). Further recent experiments in mice corrobo- Although estradiol has 700-fold more ERα and 45-fold more
rated protection from UVB exposure by measuring inhibi- ERβ activity than genistein, the possible biologic effect of
tion of UVB-induced increased levels of nitric oxide (NO), genistein (even through dietary soy isoflavones) may be great
which lead to nitrosative skin injury (195). Compared to the (203). Keratinocytes express mainly ERβ with little or no
UV-control group, the group treated with oral genestein (10 ERα, whereas dermal fibroblasts express both. ERβ-selective
mg/kg) showed tissue protection, decreased lipid peroxide and agonists significantly reduce levels of inflammatory markers
nitrotyrosine formation, low CAT activity and DNA repair. of photoaging in both keratinocytes and fibroblasts in vitro.
Interestingly, higher doses of genestin (15 mg/kg) showed Furthermore, ERβ agonists inhibit many matrix metalopro-
more histologic damage and less efficient protection against teinase genes (including MMP-1, collagenase), thereby pre-
lipid peroxide formation (195). venting UV-induced breakdown of collagen. Application of
Inhibition of acute UV-induced erythema with topical an ERβ agonist after UV irradiation significantly reduced
genistein was also demonstrated in human volunteers: Topical wrinkle formation at all concentrations tested, providing
genistein (5 μmol/cm2) (applied 30 minutes before UVB direct evidence that genistein’s role in protecting skin from
radiation) inhibited by one MED the UVB-induced erythema photodamage may be through its phytoestrogen (especially
(179). Further immunohistologic studies on human recon- ERβ) activity. In postmenopausal facial skin, genistein was
structed skin demonstrated that pretreatment with genestein also found to increase hyaluronic acid concentration and to
(10–50 μM) inhibits UV-induced DNA damage, as measured increase collagen and elastic fibers in the dermis, thereby not
by inhibition of pyrimidine dimer formation and of expres- only decreasing wrinkles but also hydrating the skin (204).
sion of PCNA (196). The degree of protection is dose depen- The modulation of estrogen receptors by genestein is being
dent, increasing with increasing concentrations of genestein actively investigated in breast cancer in which ERβ expres-
(196). Other experiments using UVB-irradiated human sion indicates more benign tumors and ERα, more malignant
skin cells showed 34%–35% enhancement of DNA damage tumors (205). Experiments demonstrate that genestein has
repair four hours after treatment with the soy isoflavones antiproliferative effects on some breast cancer cells (206,
genestein:daidzein (in a ratio of 1:4 at a concentration of 10 207), especially those with a low ERα/ERβ ratio (206). The
μmole/L in aglycone solution) (197). Pretreatment of human potential benefits and risks of treatment with genestein are
keratinocytes with genestein in vitro suppressed the expres- dependent on the ERα/ERβ ratio for each particular breast
sion of proinflammatory cytokines and proteins released by cancer and on genestein concentration (206, 208). And estro-
UVB-treated keratinocytes (198). gen effect of genestein on B16F melanoma cells has also been
Equally impressive is the fact that topical genistein also observed (209).
inhibits the most serious consequence of chronic UVB Oral (210, 211) and topical (212, 213) estrogen increases the
damage: skin cancer. Both the incidence and the multiplic- collagen content of skin, which diminishes with aging, and
ity of UVB-induced skin tumors in Skh:2 hairless mice especially dramatically in women during and after menopause
were reduced by about 90% after 25 weeks of UVB expo- (214). Genistein may reduce the “crepey” appearance of aging
sure (179). Furthermore, after induction of skin tumors in skin by stimulating collagen synthesis both by preventing pho-
mice by 7,12- dimethyl benzanthracene (DMBA) and pro- todamage through inhibition of metalloproteinases (indepen-
motion by 12-O-tetradecanoylphorbol-13-acetate (TPA), dent of sunscreen effect) and by stimulating collagen synthesis
topical genistein (10 μM) inhibited tumor numbers by (212). Genestein has recently been shown to improve skin
60%–75% (193). repair in wound healing by interaction with selective estrogen
In order to investigate the mechanism of inhibition of receptor modulators (215). Indeed, genistein does increase col-
UV-induced skin cancer, the effect of genistein on the lagen gene expression in fibroblasts (216).
expression of the photo-oncogenes c-fos and c-jun on mRNA In other studies on normal human fibroblasts exposed to
was investigated in mouse skin (199). Expression of these chemical oxidative stress, genestein prevented disturbances
proteins induces matrix melalloproteinases that degrade in the insulin-like growth factor-1 receptor-mediated collagen
dermal connective tissue, causing the wrinkles and laxity signalling pathway (217). Also, treatment of cultured human
of photoaging (200). Overexpression of these photo-onco- dermal fibroblasts with soy extract increased synthesis of
genes is related to promotion of cell proliferation in onco- collagen and hyaluronan (218). Topical application of a soy
genesis. At low-dose UVB, genistein (20μM) substantially extract emulsion ameliorated UV-induced flattening of the
inhibited both; at high dose, genistein blocked c-fos but had dermo-epidermal junction and enhanced the number of der-
little effect on c-jun (199). Treatment of mouse skin imme- mal papillae—thus demonstrating histologically rejuvenation
diately after UVB irradiation also inhibited the expression of photoaged human skin (218). Armed with these auspicious
of both (199). In human skin, topical genestein (1%) did pre- and studies, a 6-month study of postmenopausal women com-
vent UV-induced c-jun, thereby preventing photoaging and pared topical β-estradiol (0.01%) with topical genestein (4%)
oncogenesis (200). (219). Skin biopsies showed that topical estrogens gave more
Another possible dermatologic benefit of genistein is as a correction of photodamage than did genestein, as summarized
phytoestrogen. The skin has both α and β nuclear estrogen in Table 18.1, but certainly genestein interaction with ER β
receptors (ER) (201), through which estrogen binding can might be a therapeutic target for prevention and treatment of
regulate linked genes of proliferation and differentiation. photoaging (220).
TABLE 18.1 4. Darr D., Combs S., Dunsten S., et al. Topical vitamin C pro-
Correction of Photoaging with Topical Estrogens tects porcine skin from ultraviolet radiation-induced dam-
age. Br J Dermatol 1992; 127:247–253.
β-Estradiol (0.01%) Genestein (4%) 5. Pinnell S.R., Yang H.S., Omar M., et al. Topical L-ascorbic
↑ Epidermal thickness 75% 20% acid: Percutaneous absorption studies. Dermatol Surg
↑ Number of dermal papillae 135% 0% 2001; 27:137–142.
↑ Fibroblasts 123% 0% 6. Assier H., Wolkenstein P., Grille C., Chosidow O. Contact
↑ Blood vessels 77% 36% dermatitis caused by ascorbyl tetraisopalmitate in a cream
used for the management of atopic dermatitis. Contact
Note: Biopsies of preauricular skin from postmenopausal women were Derm 2014; 71 60–61.
taken before and after topical gel treatment once/day for 24 weeks
7. Yagami A., Suzuki K., Morita Y., et al. Allergic contact
and analyzed by image digitalization (219).
dermatitis caused by 3-o-ethyl-L-ascorbic acid (vitamin C
ethyl). Contact Derm 2014; 70:376–377.
Thus, topical genistein shows great promise not only in 8. Lem P.L., Kok S.H., Bian Z.X., et al. Microencapsulation-
protection of the skin against extrinsic acute and chronic UV protected l-ascorbic acid for the application of human epi-
photodamage, but also in enhancing collagen synthesis, which thelial HaCaT cell proliferation. J Microencapsul 2014;
is diminished with normal intrinsic aging. Because genestein 31:754–758.
has low water solubility, enhancement of topical delivery to 9. Zhou W., Liu W., Zou L., et al. Storage stability and skin
deeper layers of the skin is being developed by formulating permeation of vitamin C liposomes improved by pectin
with hydrophilic cyclodextrins (221) or within solid lipid coating. Colloids Surf B 2014; 117:330–337.
nanoparticles (222). 10. Burke K.E., Zhou X., Commisso J., et al. The efficacy of
various formulations of vitamins C+E in protecting against
UV-induced skin cancer. In preparation, 2024.
11. Alnemari R.M., Brüßler J., Keck C.M. Assessing the oxida-
Conclusion tive state of the skin by combining classical tape stripping
There are two great advantages to applying an active formula- with ORAC assay. Pharma (Basel) 2022; 15:520.
tion of topical antioxidant(s) to the skin. First, the skin attains 12. Placzek M., Gaube S., Kerkmann U., et al. Ultraviolet
far higher levels of each antioxidant than can be achieved by B-induced DNA damage in human epidermis is modified
only taking these supplements orally (5). For example, the by the antioxidants ascorbic acid and D-alpha-tocopherol. J
level of vitamin C attained in the skin by topical applica- Invest Dermatol 2005; 124:304–307.
tion is 20–40 times the level achievable with oral vitamin C 13. Pinnell S.R., Madey D.L.. The benefits of topical vitamin
(5); with topical application, the concentration of vitamin E C (L-ascorbic acid) for skin care and UV protection. Aesth
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2–8 (85,153). Second, topical application arms the skin with 14. Lin J.R., Qin H.H., Wu W.Y., et al. Vitamin C protects
against UV irradiation-induced apoptosis through reac-
a reservoir of antioxidant(s) that cannot be washed or rubbed
tivating silenced tumor suppressor genes p21and p16 in a
off, a protection which stays in the skin for several days after
Tet-dependent DNA demethylation manner in human skin
application (5).
cancer cells. Cancer Biother Radiopharm 2014; 29:257–264.
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19
Actinic Keratosis
Brigitte Dréno
it is located on a risk zone such as the lip, the back of the hand,
Introduction or the ear. Dermoscopy and more recently confocal micros-
copy (CM) can help to improve the diagnosis. Dermoscopy
Actinic keratoses (AK) is a common skin condition caused has been reported to reach a 98.7% and 95.0% diagnostic sen-
by long-term exposure to the sun in susceptible individuals. sitivity and specificity, respectively. It can also help to identify
Multiple terms have been used in the literature including early signs of invasive (10). Confocal microscopy can also help
‘solar keratosis’, ‘senile keratosis’, ‘keratosis senilis’, ‘senile in the differential diagnosis of AK and invasive SCC or pig-
keratoma’, and ‘keratoma senile (1). They are characterized by mented AK and lentigo malignant (11).
atypical areas of keratinocyte proliferation and differentiation In a metanalysis, using mainly European studies in non-
on sun-damaged areas (Figure 19.1). immuno-compromised individual, factors associated with
Prevalence of AK varies across countries, depending on an increased risk of AK were: male sex, age >45 years, light
study setting, UV radiation level, and patient characteristics. Fitzpatrick skin phototype, light hair color, light eye color,
In the United Kingdom, 15%–23% of individuals have actinic freckles on face/arms, positive history of NMSC, sunburns
keratosis lesions, and 37.5% among whites 50 years of age or in childhood and adulthood, severe sunburn, chronic occupa-
older. In Australia, prevalence of AK has been reported up to tional and/or recreational sun exposure, baldness, and use of
60% of Australians over the age of 40 (2, 3). In Germany preva- potentially photosensitizing thiazide diuretics or other photo-
lence of AK, standardized for age and sex, was 2.66%; the age- sensitizing cardiac drugs. On the contrary, factors associated
standardized rate was higher for men (3.85%) than for women with a reduced risk of AK were sunscreen use and history of
(1.45%). For both, men and women, prevalence increased with atopy (12). At the genetic level, IRF4, MC1R and TYR genes
age and in the age group 61–70 years the prevalence amounted were identified as significant risk factors for AK in the north-
to 6.29% in women and 16.36% in men (4). Risk factors for the western European study population (13).
development of AK include chronic sun exposure, light skin
phototype (I/II), phototherapy, age, exposure to skin carcino-
gens, history of cutaneous squamous cell carcinoma (SCC), Progression to Cutaneous Squamous Cell
organ transplantation, and long-term immunosuppressive
treatments such as chemotherapy or biotherapy (5, 6). Carcinoma (cSCC)/Spinocellular Carcinoma
In a systematic review actinic keratoses were positive for Although no clinical, histological, or biological characteris-
beta in 58.49% and gamma HPV in 40.25% (7) and only a few tics have been able to reliably predict the progression of an
were positive for alpha subtypes.
Diagnosis
AK are diagnosed based on their clinical appearance: lesions
are keratotic, rough on palpation, of variable thickness, and
poorly delimited. They are characterized by a diameter of 1
cm or less and a variable degree of erythema. In some cases,
they can be pigmented or have a cutaneous horn shape. As AK
rarely occur alone, multiple AK are often found in surround-
ing photoexposed areas.
AK are considered to be a risk marker for SCC (8). As a
result, each lesion needs to be evaluated individually. If the
skin is thickened, the diameter is >1 cm. If infiltration, inflam-
mation, ulceration, bleeding, or pain on palpation are present,
or if there is rapid expansion, the AK should be biopsied (9).
In addition, a biopsy should be performed if the lesion recurs
within 2–3 months, if it persists after standard treatment, or if FIGURE 19.1 Isolated actinic keratosis.
188 DOI: 10.1201/b22897-19

Actinic Keratosis 189
AK lesion (Figure 19.2) to invasive SCC, a clinicopathologi- decrease in cutaneous innate immunity appear to be risk fac-
cal continuum of transformation from AK to invasive SCC tors. These two factors worsen over time lead to the final for-
is believed to exist. The relationship between any given AK mation of AK.
lesion and the development of SCC, however, is not necessar-
ily linear. If left untreated, AK can either spontaneously disap-
pear, persist without progressing to invasive SCC, or progress
to invasive SCC. In fact, the overall rate of progression from
Chronicity and Secondary Prevention
AK to SCC remains very low, with the rate of transformation The fact that lesions that have spontaneously regressed can
to SCC over the course of a year ranging from 0.01% to 0.24%, recur suggests that there is a chronic nature to the manage-
and over 10 to 25 years from 5% to 20% (14, 15). Spontaneous ment of AK (17). Whether these are the same lesions or a new
regression occurs at a rate of 15% to 25%. Fifteen percent of lesion from another cell from the same field of cancerization is
lesions that have regressed recur within a year (16). These per- hard to determine. The clinical implications, however, are the
centage remain stable for more than 40 years. same: at-risk patients should be monitored at least once a year.
Organ transplant patients also have a particularly high
rate of recurrence (19). Depending on the degree and dura-
tion of immunosuppression and the type of transplant, recur-
The Field of Cancerization
rence, as well as the development of new AK, resistance to
The complicated relationship between spontaneous regression, treatment, and progression to SCC have all been shown to be
recurrence, and progression is likely to be due to the existence increased (20). These patients are thus high risk and require
of a field of cancerization, which describes the area of skin close monitoring.
surrounding a group of AK and which has been shown to
contain genetically altered cells that can provide a reservoir
for clonal expansion (17). In any given field of cancerization
(Figures 19.3 and 19.4), the ratio of subclinical foci to AK
would be expected to be around 10:1. As a result, it is hard
to determine if an AK that spontaneously regresses but then
recurs is an actual recurrence or the manifestation of another
foci within the same field of cancerization.
In most cases, the field of cancerization contains subclinical
changes in the periphery of the visible AK lesions that can be
highlighted using non-invasive reflectance confocal micros-
copy or photo diagnosis with protoporphyrin IX-emitted
fluorescence (17). More invasive analyses that require tis-
sue samples such histology or molecular biology can also be
used (18).
The concept of field cancerization suggests that the appar-
ently normal skin circling areas of AK sustains the base for
the clonal expansion of genetically altered neoplastic cell. The
presence of a great number of mutated cells in a field is con-
sidered the determinant event to carcinogenesis. Moreover, the
association of multiple mutations of the keratinocytes and a FIGURE 19.3 Field of cancerization.
FIGURE 19.2 Hyperkeratotic actinic keratosis. FIGURE 19.4 Field of cancerization.

actinic keratosis published in 2022 (25). An analysis has been

Treatment Algorithm performed based on the best available evidence at the time it
was conducted (20, 21). The literature review was limited to
There is no evidence that shows that all AK need to be treated English language randomized trials. Strong recommendations
systematically. Rather, the decision to treat should be based on are made for using ultraviolet protection, topical imiquimod,
the clinical characteristics of the AK lesion, the patient’s cuta- topical 5-fluorouracil, and cryosurgery. Conditional recom-
neous history, the impact of the lesion on the patient’s quality mendations are made for the use of photodynamic therapy and
of life, and the patient’s preference. The most important rea- diclofenac for the treatment of AK, both individually and as
son for treatment of AKs is to prevent the transformation to part of combination therapy regimens.
invasive squamous cell carcinoma. Up to 15–63% of actinic
keratoses may regress, but the recurrence rate can be as high as
50% within the first year. The risk of progression varies from
0.025% to 20% per year and is significantly higher in immuno- Isolated Hyperkeratotic and
suppressed patients, such as solid organ transplant recipients.
Non-Hyperkeratotic Actinic Keratosis
Furthermore, if the patient has had previous cSCC in the field,
the risk for developing the second cSCC is 47% (21). Since still For isolated hyperkeratotic and non-hyperkeratotic AK, cryo-
it cannot be predicted, which lesion will progress to cSCC, and therapy and curettage followed by electrocoagulation are
even progression from mild AK can occur, treatment is rec- first-line therapies. Cryotherapy is a simple, rapid, and inex-
ommended. Treatment of AKs can be lesion-directed or field- pensive technique. Rates of complete clearance after one and
directed. Lesion-directed treatments target individual AKs, two applications are between 68% and 75% at 3 months and
whereas field-directed treatments have the advantage of treat- between 82.5% and 88% at 24 weeks after two applications.
ing multiple, widespread, and subclinical AKs that may occur Cryotherapy is very much dependent on the protocol used, with
within a field of chronic sun damage, commonly referred to as more aggressive protocols resulting in fewer recurrences. Pain
field cancerization. during and immediately after treatment is the most frequently
Thus, the initial choice of treatment should be based on reported adverse event. Hyper- or hypopigmented scars can
the number of lesions, their hyperkeratotic status, and their also occur. Surgery can be used as a second-line therapy if the
clinical appearance. The algorithm shown in Figure 19.5 was isolated AK is resistant or if it recurs. For isolated, suspicious
recently published by Dréno et al (22) and (23, 24). It has been AK with clinical signs evoking SCCs, a complete excision
confirmed more recently in guidelines for the management of with histology is suitable.
FIGURE 19.5 Treatment algorithm for the management of actinic keratosis. The initial choice of treatment is based on the number of lesions,
their hyperkeratotic status, their clinical appearance (suspicious or not). (From Dréno B et al., J Eur Acad Dermatol Venereol, 28:1141–9, 2014 with
permission.)
(28). Erythema, crusting, erosions, ulceration, and edema are

Multiple, Non-Hyperkeratotic Actinic Keratoses common local inflammation. Few reactions have been shown to
occur during the second cycle of treatment. In the special popu-
First-line treatments for multiple, non-hyperkeratotic AK lation of immunosuppressed transplanted patients, imiquimod
include topical treatments and physical treatments such as should be used with caution, as safety needs to be evaluated.
laser or photodynamic therapy (PDT). Second-line therapies
include physical treatments combined with topical treatments
or surgery. All treatments should encompass the entire field Resiquimod
of cancerization to reduce the likelihood of recurrence of a
Resiquimod is a toll-like receptor 7/8 agonist, chemi-
treated lesion and/or the development of new lesions within
cally related to imiquimod, which promotes the release of
the same field.
cytokines—IL-6, TNF-α, and IFN-α. It is available in four
The recent EADO/EDF guidelines (26) have the follow-
concentrations, 0.01, 0.03, 0.06, or 0.1%, and the greatest effi-
ing recommendations: cryosurgery shall be offered as a first-
cacy was observed with application three times weekly for
line standard treatment for solitary AK and cryosurgery in
4 weeks. The most common adverse events are erythema and
combination with curettage and topical treatments shall be
scabbing. Stockfleth et al investigated the optimal dosing regi-
offered in multiple AKs and field cancerization (grade of
mens (0.01% or 0.03% cream in five different treatment sched-
recommendation A).
ules) in terms of efficacy, safety, and tolerability in a large
study (29). Complete clinical clearance was obtained in 56 to
85% of patients, with maximal efficacy among patients receiv-
Topical Treatment Options ing the 0.03% concentration. Treatment-related adverse reac-
tions are more severe than with imiquimod. Thus, the lower
5-Fluorouracil (5-FU [5%, 4%, 0.5% with 10%] concentration and shorter duration is preferable.
Salycilic Acid, 5-FU with Calcipotriene)
5-fluorouracil is a cytotoxic antimetabolite that interferes with
Diclofenac 3%, Hyaluronic Acid 2.5%
DNA synthesis and to a lesser extent inhibits RNA transcrip-
tion. After 3 to 4 weeks of treatment, the rate of complete Diclofenac 3% is a nonsteroidal anti-inflammatory drug that
clearance varies from 43% to 96% depending on the study. In inhibits the cyclooxygenase pathway and decreases prosta-
approximately 65% of patients, lesions recur within 12 months glandin E2 synthesis. It is approved for clustered and field
of treatment. The main adverse events are pain, pruritus, burn- cancerization treatment of AKs, at a therapeutic regimen of
ing sensation, and hyperpigmentation at the site of application. twice-daily application for 60–90 days. The rate of complete
Application on healthy skin causes can cause an erythematous clearance is 31% after 2 months of treatment and 47% after
inflammatory reaction. 3 months of treatment. After 1 year, the rate of recurrence for
The three form of 5-FU alone (0.5%, 5%, and 4%) and the treated lesions that had disappeared is 21%. Local reactions occur
two combinations (0.5% fluorouracil in salicylic acid 10% frequently. These include contact eczema, cutaneous dryness,
solution and 5% fluorouracil plus calcipotriol 0.005%) can be oedema, pruritus, scaly rash, ulcerations, and vesiculobullous rash.
used for the treatment of single or multiple AK and field can- Altogether, at a dosage of two applications per day for 2–3 months,
cerization treatment (27). diclofenac gel appears to be well tolerated, but clinical data sug-
gest that the efficacy profile may be less favourable compared to
that of other topical treatments (29). It is offered for the treatment
Imiquimod 5% of single or multiple AKs and field cancerization treatment.
Imiquimod 5% and 3.75%, imidazoquinolinone-derivatives,
are toll-like receptor-7 agonists that act as a topical immune
Ingenol Mebutate 150 μg/g and 500 μg/g
response modifier that stimulates the production and release of
cytokines (tumor necrosis factor-α, interferon-γ, interferon-α, Ingenol mebutate is a biological compound that has a
and interleukin-12). cytotoxic effect that causes mitochondrial oedema and
It can be used to treat the field of cancerization as well as the dissolution of cytoplasmic membranes. It also has an immu-
AK lesions. The 5% concentration can cover a skin area of up nomodulatory effect that causes an increased production of
to 25 cm2 of the face and scalp on three times a week sched- inflammatory cytokines and the recruitment of neutrophils.
ule over a period of 4 weeks, followed by an additional cycle In pooled analyses, the rate of complete clearance observed
if partial clearance is obtained. The maximum recommended after 2 months of ingenol mebutate treatment was 42% for
duration of treatment is 8 weeks. The 3.75% concentration has AK on the face and scalp and 34% for AK on the trunk and
been approved for the treatment of larger surface area of up extremities (30). Twelve months after the end of treatment,
to 200 cm2. It is applied once daily for two cycles of 2 weeks the rate of recurrence was 54% on the face and scalp and
each, separated by 2-week rest intervals. Imiquimod has a high 56% on the trunk and extremities. Local cutaneous reactions,
clearance rate, ranging from 56.3% for 5% concentration for 4 which resolved within 2 to 4 weeks, included erythema, scal-
weeks to 63.3% for 5% concentration for 16 weeks. The 3.75% ing, crusting, oedema, vesicles/pustules, and erosions/ulcer-
concentration is associated with lower clearance rates up to ations. However recently an increased risk of skin cancer has
39.9% for 4 weeks of treatment. Recurrence rates at 12 months been demonstrated, and thus the treatment has been with-
for patients who achieve clearance at 2–3 months are 25 to 40% drawn from the market.
containing urea or salicylic acid. Cleavage of the corneodes-

Physical Treatments mosomes leads to exfoliation of the superficial layers of the
epidermis. Second-line therapies include physical treatments
Ablative and Ultra-Pulse Ablative Laser Therapy combined with topical treatments or surgery.
Therapy with an ablative ultra-pulse laser creates a thermal
effect, which causes nonselective tissue vaporization, loss of Therapeutic Perspectives
substance, and coagulation necrosis of the margins. Although
this technique is included in recommendations, clearance rates The tubulin polymerization and Src kinase signaling inhibi-
have not been evaluated in double-blind, randomized, con- tor tirbanibulin is being investigated as a topical treatment for
trolled clinical trials. The healing phase is often accompanied actinic keratosis. In two identically designed trials, tirbanibu-
by erythema, pain, irritation, pruritus, oedema, and sometimes lin 1% ointment applied once daily for 5 days was superior to
by secondary infection (31). vehicle for the treatment of actinic keratosis at 2 months asso-
Concerning ablative laser, they may be offered for single ciated with transient local reactions and recurrence of lesions
or multiple AKs but has few advantages over classical and at 1 year. Trials comparing tirbanibulin with conventional
cheaper treatments. Fractional laser has also been used to treatments and that have longer follow-up are needed (35).
improve PDT treatment for AK, but today we do not have Due to the chronicity of AK, long-term strategies need to be
strong data enough to evaluate the interest of this combination. developed in order to reduce risk.
Photodynamic Therapy Comprehensive Approaches

Photodynamic therapy selectively destroys tumour cells by tar- A multifaceted approach that combines yearly check-ups and
geting them with light after topical application of a photosen- patient education is likely to reduce risk further. Educated
sitizer. Photodynamic therapy can also be used to identify the patients are more likely to use protective clothing and sun-
limits of a field of cancerization. The rate of complete clearance screen and to adopt protective behaviour. They are also best
of treated lesions after two PDT sessions ranges from 59% to positioned to notice lesions that are changing rapidly or that
91% at 3 months (32). After a 12-month follow-up period, the have recurred after treatment.
rate of recurrence of lesions was 17%. The best clearing results
are obtained in studies that use two PDT sessions spaced 1 week Repeated Treatments
apart. The pain associated with application of the light to the
photosensitized areas is a major limitation of this technique. In Repetition of treatment can be used to increase efficacy rates.
addition, the rate of transient local reactions is high, with 60% With PDT, for example, the best clearing results are obtained
to 80% of patients reporting burning sensations, cutaneous pain, in studies that use two sessions spaced 1 week apart (36). For
crusting, and erythema. In many countries, such as France, the imiquimod, the initial cycle of three applications per week for 4
use of this technique is also limited by the fact that dermatolo- weeks can be repeated once in order to increase efficacy. Multiple
gists in private practice rarely own red/blue lamps. cryotherapies have also been shown to be more effective than
Daylight-mediated PDTs, which require shorter photosensi- single cryotherapy as the rates of complete clearance at 3 months
tizer application times and daylight-mediated PDT, have been were 68% after one application and 78% after two applications.
developed and tested in three randomized controlled trials. This
treatment appears to be associated with same efficacy and lower
Sequential Combination Treatments
levels of discomfort than conventional PDT (32). In the United
States, a 20% ALA solution is approved in combination with The sequential combination of physical and topical treatments is
illumination by blue light, while in Europe, a nano emulsion also likely to increase efficacy. Cryotherapy alone, for example,
equivalent to a 10% ALA preparation is widely available (BF- is associated with high rates of recurrence. This is likely to be
200 ALA). This formulation improves the stability and skin due to the fact that only the AK lesion is targeted and the field
penetration of ALA, resulting in high lesion clearance rates (33). of cancerization remains. After treatment with a combination of
In contrast to MAL and conventional ALA formulations, cryosurgery and topical ingenol mebutate, the rate of develop-
BF-200 ALA is also approved for the treatment of mild to mod- ment of new lesions 12 months after treatment was significantly
erate AK on the trunk, extremities, and neck. A self-adhesive reduced compared to treatment with cryosurgery alone (52% vs
ALA patch is available enabling direct and highly standardized 39%, respectively; p = 0.02) (37).
application without any prior lesion preparation. In a pivotal Combination of lesion directed treatment with field treat-
trial, the ALA patch showed higher lesion clearance compared ment, as well as the combination of field-directed treatment
to cryosurgery, lasting up to 12 months after treatment (34). should be offered to patients with simultaneous discrete and
hyperkeratotic lesions, large treatment fields, and treatment
resistance to monotherapies.
Multiple Hyperkeratotic Actinic Keratoses
For multiple hyperkeratotic AK, first-line treatments should
DNA Repair Enzymes
include resurfacing prior to the use of the topical treatments
and physical treatments described for non-hyperkeratotic AK. As UV is intrinsic in the development of AK, topical pho-
Resurfacing can be done manually or using topical keratolytics tolyase creams may become an integral part of long-term
treatment plans. These creams contain photoreactive DNA prompt management of suspicious AK, patient education, and
repair enzymes that reverse the dimerization of pyrimidines long-term follow-up is likely to be the most effective approach
that occurs from UV damage. Once the cream has been to reducing the risk of SCC. AK is one of the first clinical sign
topically applied, the enzyme needs to be photoactivated by of aging indicating that the skin’s anti-radical and immunolog-
300–500 nm light. Data have shown that use of this technique ical defences are exhausted. With the aging of the population,
after exposure to UVB radiation decreases the number of especially in Europe, AK is becoming a public health problem,
pyrimidine dimers and prevents radiation-associated immuno- and first we have to better prevent them.
suppression and erythema formation (38).
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screen products with not only a high sun protection factor B (≥ 30)
9. Salasche SJ. Epidemiology of actinic keratoses and squa-
but a protection against long UVA (+++).
mous cell carcinoma. J Am Acad Dermatol 2000;42(1):4–7.
The use of sun beds has to be avoided; discontinuation or
10. Valdés-Morales KL, Peralta-Pedrero ML, Cruz FJ et al.
change of light-sensitizing drugs (e.g., hydrochlorothiazide)
Diagnostic accuracy of dermoscopy of actinic keratosis:
has to be discussed.
A systematic review. Dermatol Pract Concept 2020;10(4):
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temic chemoprevention in high-risk situations. Agents which 11. Navarrete-Dechent, C, DeRosa AP, Longo C, et al.
were investigated for oral chemoprevention include among Reflectance confocal microscopy terminology glossary for
others oral retinoids, nonsteroidal anti-inflammatory drugs nonmelanocytic skin lesions: A systematic review. J Am
(NSAIDs), capecitabine, as well as dietary supplements and Acad Dermatol 2019;80(5):1414–1427.
vitamins (beta-carotene, nicotinamide). Most of these agents 12. Wang, J, Wang J, Aldabagh B, et al. Role of human papil-
failed to show a clear benefit for prevention and may even be lomavirus in cutaneous squamous cell carcinoma: A meta-
accompanied by harmful side effects. Oral nicotinamide (vita- analysis. J Am Acad Dermatol 2014;70(4):621–629.
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of 30% in immunocompetent individuals with two or more con- genes are risk factors for actinic keratosis independent of
firmed keratinocyte carcinomas in the past 5 years. However, skin color. Hum Mol Genet 2015;24(11):3296–3303.
there was no effect after nicotinamide was discontinued, and it 14. Frost C, Williams G, Green A. High incidence and regres-
is unclear if the preventive effects pertain to AK, too. sion rates of solar keratoses in a Queensland community.
J Invest Dermatol 2000;115(2):273–277.
15. Feldman SR, Fleischer AB. Progression of actinic keratosis
to squamous cell carcinoma revisited: Clinical and treat-
Conclusion ment implications. Cutis 2011;87(4):201–207.
16. Marks R, Foley P, Goodman G, et al. Spontaneous remis-
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Clinical, histopathological, and therapeutic aspects. Anais resiquimod dosing regimens in patients with multiple actinic
Brasileiros Dermatol 2013;88(5):775–786. keratoses: A multicentre, partly placebo-controlled, double-
18. Szeimies RM, Torezan L, Niwa A et al. Clinical, histopath- blind clinical trial. Br J Dermatol 2019;180(2):297–305.
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19. Zwald FO, Brown M. Skin cancer in solid organ transplant gel for the treatment of actinic keratosis on the face or scalp.
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Epidemiology of skin cancer in solid organ transplant recip- 31. Tai F, Shah M, Pon K et al. Laser resurfacing monotherapy
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des kératoses actiniques chez les patients transplantés 32. Lacour JP, Ulrich C, Gilaberte Y et al. Daylight photo-
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2019;146(5) Suppl 2:IIS31–IIS35. A randomised, investigator-blinded, controlled, phase III
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Consensus. Eur J Dermatol 2008;18(6):651–659. 33. Ulrich M, Reinhold U, Dominicus R et al. Red light pho-
22. Dréno B, Cerio R, Dirschka T et al. A novel actinic kerato- todynamic therapy with BF-200 ALA showed superior
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actinic keratosis: A practical report and treatment algorithm 34. Dirschka, T, Radny P, Dominicus R et al. Photodynamic therapy
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20
Gel Nail Polish and Its Side Effects
Noureddine Litaiem
Application Procedure
Introduction
To obtain a proper GNP, three layers must be applied: base coat,
The nail is an anatomic structure that protects the distal digit nail polish, and topcoat. Nail grooming is the first step. The
and enhances the esthetic appearance of the hands. Artificial cuticle is pushed back with a specially designed metallic instru-
nails have been used as early as 600 BC. In China, they were ment and then trimmed off with a cuticle cutter. The surface of
made from gold and silver, then egg whites, flowers, and wax1. the nail is buffed with an emery board to smoothen any exist-
Nail beautification is a big industry today, used worldwide by ing ridges. The base coat is the first transparent layer. It has an
millions of women who desire to have smooth, shiny finger- adhering capability. It protects the nail plate from staining and
nails and toenails, with increasing use of various nail cosmet- improves the adhesion of the color coat to the nail plate. Then the
ics, ranging from nail polish, sculpted nails, pre-formed nails, nail polish is applied. Several varieties of colors are available.
and most recently long-lasting gel nail polish (GNP)1. Nail cos- The topcoat is the last transparent layer used to increase gloss,
metics can also be used to disguise some nail diseases. provide extra protection, and smooth out any imperfection.
GNP is relatively new in the market but has become a popu- To cure, harden, and dry each layer, the nail must be exposed
lar phenomenon in a short time. Its low cost, persistence, and to ultraviolet (UV) light or a light-emitting diode (LED) light14.
easy application have been key factors in the ongoing inter- This hardening process takes 3 to 5 min with UV lamps and
est. Recently, different kits for home use have been commer- only 30 seconds with a LED source4.
cialized. Both home and professional applications of GNP Most nail salons use fluorescent UV bulbs because LED
increase the prevalence of cosmetic nails’ side effects. lamps are costly. Most of the UV light emitted by fluorescence
In a recent review, we searched the literature using the lamps is ultraviolet-A (UV-A) ranging from 320 to 400 nm
PubMed, Scopus, and Google Scholar databases, from data- with peak emission at 375 nm. LED lamps have an emission
base inception to October 7, 2021, to identify GNP-related side range from 375 nm to 425 nm9.
effects (Table 20.1)1. The latter can be divided into allergic The human nail plate completely blocks UVB penetration
contact dermatitis (ACD)2–3, mechanical and traumatic nail into the nail bed. However, UVA does penetrate10.
diseases4–5, and UV-induced lesions6,7. During the curing process, a reaction occurs as the photo-ini-
Dermatologists need to be aware of GNP-related damage to tiator in the resin reacts with the wavelengths emitted. Solvents
properly treat it and advise on safe use. This chapter aimed to evaporate and ‘tiny tunnels’ are connected by acetone-dissolvable
provide a comprehensive summary of the complications of GNP. polymers, which later facilitate the removal of the gel polish (9).
Removal
Gel Nail Polish
Gel nail polish cannot be directly wiped off by using cotton
GNP is also known as UV-curable nail lacquer, long-lasting with the nail polish remover. Acetone is the most used product
polish, ‘permanent’, and ‘semi-permanent’ polish. to remove GNP. It can cause irritant contact dermatitis. The nail
GNP has gained popularity worldwide for its cosmetic plate is soaked with 100% acetone and wrapped with aluminum
enhancement, low cost, and ease of use. for 10 to 15 minutes1. A cuticle pusher and a nail buffer are used
The gel nail polish is composed of8 to pop the gel polish layer off the nail plate. Acetone-free nail pol-
ish removers contain ethyl acetate, butyl acetate, or ethyl lactate.
• Urethane (meth)acrylate oligomers and cross-linking mono-
mers (75–95%); all GNP layers contain (meth)acrylates
• Catalysts (0.75–1.25%) such as dimethyl tolyamine Gel Nail Polish Side Effects
• Polymerization photo-initiators (1–4%)
Allergic Contact Dermatitis
• Coloring agent
Nail cosmetics are currently an important source of occupa-
More recently developed GNP hybrid formulations also con- tional and non-occupational (meth)acrylate contact derma-
tain cellulose derivatives and plasticizers as well as solvents1. titis. The incidence of sensitization has increased with the
DOI: 10.1201/b22897-20 195

TABLE 20.1
Sum ma r y of A r ticles Describing Gel Nail Polish-Associated Side Effects
Number of
c a se s
Age range
First author, and /or mean Delay after the first
Journal, year age (years) Origin application Principal symptoms Other symptoms Investigations Treatment
Allergic Gatica-Ortega 43 women (Meth)acrylate allergy The mean time was 10.55 Hand dermatitis: fingers Paraesthesia (10 = 23.3%); HPMA (95.3%)
contact et al., 20172 Mean age = 35 months (range: 2 weeks (100%) Angiodema (4 = 9.3%); HEMA (90.7%)
dermatitis Range: 21–57 to 72 months) Other sites in 18/40 (45%) Throat discomfort THFMA (79.5%)
*Face dermatitis (eyelids and (6 = 14.0%) HEA (75.9%)
cheeks)(15 = 37.5%) Generalized acute urticaria EGDMA (67.7%)
*Forearm (5 = 12.5%) (1 = 2.3%) MMA (19.44%)
*Thighs (3 = 7.5%) Some degree of onycholysis:
*Abdomen (1 = 2.5%) Most patients
Ann Sterkens 1 woman (Meth)acrylate allergy For the past 12 years Periungual dermatitis Onycholysis HEMA (++)
et al, 20208 Age= 49 HPMA (++)
EGDMA (++)
HEA (++)
Paolo et al, 10 years old girl (Meth)acrylate allergy 10 days Eczema on the dorsal aspect Gel nail polish 1% pet. Lesions disappeared
20203 after she applied her of the thumb and vesicular (++) within 2 weeks with
mother’s gel nail polish and bullous lesions on her HEMA (++) betamethasone
frequent application of fingertips HPMA (++) dipropionate (twice
the same nail cosmetic EGDMA (++) daily) and cetirizine
during the last 4 months MMA (-)
Gatica-Ortega 4 women (Meth)acrylate allergy Monthly for the first 6 3 cases: dry fingertip Paresthesia (3/4) HEA: 4/4+ 1/4: fingertip dry
et al, 20184 Range: 35–65 months, and weekly for dermatitis involving the Painful subungual pyogenic HPMA: 3/4+ dermatitis persisted
the last 6 months. hyponychium of all fingers granuloma (1/4) HEMA: 3/4+ on follow-up 3
2/4 of patients applied it 1 case: hand dermatitis Finger pain during exposureEGDMA:3/4+ months later
almost weekly without involvement of the to the LED (1/4)
fingertips Acute ‘stinging’ involving
her fingertips and toes (1/4)
Christel Scheers, 1 woman 3–4 months after the first Cheilitis and lip oedema Mild erythema of the HEMA (++)
20155 Age = 49 manicure every 3 weeks periungual area HPMA (++)
for >1 year EGDMA (++)
HEA (++)
MMA (-)
Le Q et al, 4 women Lesions on the fingers. One Paresthesia: 1/4 HEMA (100%)
20156 23;35;20; 24 patient also had lesions on HPMA (50%)
the palms; another had EGDMA (50%)
lesions on the torso, feet, and MMA (25%)
thigh; another had lesions on
the feet.
Number of
c a se s
Age range
First author, and /or mean Delay after the first
Journal, year age (years) Origin application Principal symptoms Other symptoms Investigations Treatment
Dahlin J, 20167 8 women 8 persons Eczema starting around the *Onycholysis Di HEMA (87.5%) Delay varied between
Range: 11–41 nails, with itching and pain *Paronychia UA (75%) 2 and 12 months
Mean age: 26.1 * Thin, brittle nails HEMA (75%) (average ~5.5 months
*Eczema on other parts of trimethylbenzoyl The average frequency
the body (lips, throat, eyes) phenylphosphineoxide of application
was reported (photo-initiator) (1/4 +) consumers ~10 times
Mechanical Chen et al, 5 women Application and — *Pseudoleukonychia Ultrasound and reflectance Pseudoleukonychia
and 20129 Range: 28–59 removal process *Onychoschizia lamellina confocal microscopy resolved 3 weeks
chemical Mean age = 36.4 (exfoliation of the *Brittleness (RCM) mesure Onychoschizia and
damage superficial nail plate) *Thinned nail plate 0.063vs.0.050 cm subjective brittleness
0.059vs.0.030 cm was still present 5
weeks after removal
Cervantes et al, 17 women Chemicals present in After 2 to 5 years of Pterygium inversum unguis *Dermoscopy features RCM: nucleated cells and Upon discontinuation,
201810 Range: 22–57 the gel polish and/or application *Pain when keratohyalin granules at all cases had
the application cutting or filing the level of the subungual complete regression
and/or removal process *Burning sensation extension of the of the nail changes
Hypothesize: hyponychium within 1 to 3 weeks
LED-activated
photoinitiators may
be more likely to
induce pterygium as
compared to UVA
Hwang et al, 1 woman: 61 1*/week for 5 months *Yellowish chromonychia KOH smear and fungus Clinical improvement
201611 *Pincer nail deformity culture negative and no recurrence
*Nail pitting,
*Pseudoleukonychia
*Trachyonychia
UV-induced MacFarlane 2 women UV nail lamps A 15-year history of 1-SCC in situ on the 1-no sign of solar damage to
skin et al, 200913 55 and 48 twice-monthly UV nail dorsomedial aspect of her her face
cancer light exposure right index finger 2- several actinic keratoses
2- 8 times in 1 year for 2-squamous cell cancers on on her face and arms
several years the dorsum of the both hands
Freeman, 1 woman: 70 Manicures and pedicures Over 5 years, the patient 52 actinic keratoses over the
202012 every 2–3 weeks since developed 8 biopsy-proven same period, all except 6
2009 SCCs, which have all were distributed on the
occurred on the dorsal dorsal fingers and feet.
fingers and feet except for a
single lesion on the left
anterior thigh
Source: Reproduced with permission from Elsevier1.
Abbreviations: RCM: Reflectance confocal microscopy; KOH: Potssium hydroxide; HPMA: 2-Hydroxypropyl methacrylate; HEMA: 2-Hydroxyethyl methacrylate; THFMA: Tetrahydrofurfuryl methacrylate;
HEA: 2-Hydroxyethyl acrylate; EGDMA: Ethylene glycol dimethacrylate; MMA: Methyl methacrylate; UA: Urethane acrylates.
introduction of permanent nail polishes containing light- with acetone) and/or chemical components9,10. Mechanical
bonding acrylates, which are inexpensive, durable, and easy to manipulation, using sharp trimmers or nippers to remove the
apply. Household kits make these types of products available eponychium and metal spatulas to push back the cuticle, cre-
to everyone, which in turn increases the risk of allergies7. ates spaces above and below the nail plate and leads to inflam-
(Meth)acrylates are occupational allergens. They are used mation of the nail folds. Nail removers contain solvents that
in a variety of products such as plastics and textiles, as well can irritate the nail folds. Damage to the nail folds and cuticles
as dental and orthopedic materials. For beauticians, (meth) can lead to paronychia. Damage to the hyponychium promotes
acrylates were the most common allergen in artificial nails, pterygium inversum unguis.12 UV curing and related activated
followed by fragrances11. photoinitiators were also possible causes of pterygium inver-
Six of the included articles described ACD (62 cases, sum unguis10. Onycholysis is related to the traumatic separa-
70.5%)1. ACD associated with nail cosmetics are usually tion of the nail plate from the nail bed due to the disruption of
reported in adults and rarely affects adolescents and children. the onychodermal band (Figure 20.1). Efforts to clean under
Nonetheless, there are two pediatric reports of ACD in asso- the nails in an oscillating pattern are characteristic causative
ciation with GNP3. factors.
The risk of sensitization to (meth)acrylates is higher for Over-buffing of the nail plate when removing GNP induces
beauticians and users of home kits than in consumers who fragility and thinning of the nail plate. Nail fragility manifests
attend salons for professional nail polishing4. This could be as breaking nails, longitudinal or transverse fissures, onycho-
explained by the possible contact with (meth)acrylates before schizia, pseudoleukonychia (Figure 20.1), and trachyonychia.
photopolymerization. Acrylates become relatively nonallergic Three articles described GNP-related mechanical nail inju-
after polymerization because of their high molecular weight5. ries (23 cases, 26.1%)1. Data are summarized in Table 20.1. All
Acute ACD signs including vesiculobullous and exudative patients used GNP for a long time (5 months to 5 years). GNP-
dermatitis were described in two cases (Table 20.1). Fissured induced lesions involved pterygium inversum unguis (n = 17),10
painful involvement of periungual nail folds and finger pulp pseudoleukonychia (n = 6), onychoschizia lamellina (n = 5),
was the most common clinical presentation (61 cases, 98.3%). brittle nails (n = 5), thinned nail plate (n = 2), xanthonychia
Lesions were also located on the face (16, 25.8%), the lips (n = 1) (Figure 20.1), pincer nail deformity (n = 1), nail pitting
(2, 3.2%), the forearms (5, 8%), the thighs (4, 6.4%), the feet (n = 1), and trachyonychia (n = 1)1.
(2, 3.2%), and the abdomen (1, 1.6%). Ectopic lesions on the Thinning of the nail plate can be measured using ultraso-
face, particularly the eyelids, cheeks, lips, and neck are caused nography10. Reflectance confocal microscopy revealed nucle-
by passive hand transportation or airborne mechanisms. ACD ated cells and keratohyalin granules in cases of pterygium
was more severe on the dominant hand of beauticians2. It was inversum unguis10.
often accompanied by chronic paronychia. Onycholysis was Improvement was constant after the discontinuation of
present in more than half of the patients (Figure 20.1), and one GNP. All cases of pterygium inversum unguis and pseudo-
case of pyogenic granuloma was reported. leukonychia resolved completely within 1 to 3 weeks, while
Paresthesias were reported in 14 patients (22.5%). Associated regression of pincer nail deformity took more than 4 months
urticaria (1 case, 1.6%), angioedema (5 cases, 8%), and respira- (Table 20.1).
tory discomfort (7 cases, 11.2%) were described. Most patients
reported no history of atopic dermatitis (95.4%).
Ultraviolet (UV) Induced Lesions
The most reported allergens were 2-hydroxypropyl meth-
acrylate (HPMA) and 2-hydroxyethyl methacrylate (HEMA). Most curing lamps emit high-intensity UVA (320–400 nm).
Tetrahydrofurfuryl methacrylate (THFMA) was identified in LED units provide faster cure times and safer use.
80% of cases (Table 20.2). Sensitization to 2-hydroxyethyl acry- The safety of UV nail lamps remains controversial. UV
late (HEA) and ethylene glycol dimethacrylate (EGDMA) was lamps emit 4.2 times more energy than sunlight in the 355 to
also common. ACD developed on average 30 months after the 385 nm wavelength range.13 The total energy exposure per ses-
use of GNP (range: 2 weeks–12 years). About 2.6% of patients sion ranged from 15 to 22.5 J/m2, well above the recommended
with contact dermatitis react to HEMA on patch testing1. exposure limits for field workers19.
HEMA may be a good screening allergen since it is identified Three cases of squamous cell carcinoma (SCC) associ-
in 85.3% of sensitization to acrylates. We suggest testing with ated with GNP frequent use and UV nail lamp exposure were
HEMA first, and if negative, include other allergens (HPMA, reported11,12. Curing of GNP was made by UVA lamps in all
EGDMA, and HEA)1. The concentration of the allergens used cases. The delay between UV exposure and the diagnosis of
for patch testing is important. A too-high concentration may SCC ranged from 11 to 15 years (Table 20.3).
lead to active sensitization, and a too-low concentration may SCCs were localized on the fingers in one case, and the
lead to false-negative results. The concentrations generally dorsum of the hands in two cases. Dorsum of the feet was
established as safe are about 0.1%, 2%, and 10% petrolatum involved in a patient who reported cosmetic nail treatment
for acrylates, methacrylates, and cyanoacrylates, respectively.1 of toenails12. Fitzpatrick skin phototype was III in two cases.
Multiple actinic keratoses were noted in two cases predom-
inantly on the same sites of SCC. There were no signs of
Mechanical and Trauma-Induced Nail Lesions
sun damage on the other photoexposed areas11, 12. Surgical
GNP-related mechanical injury is explained by both GNP removal was performed in all cases (Mohs surgery in two
application or removal processes (mechanical peeling, soaking cases).
Gel Nail Polish and Its Side Effects 199
FIGURE 20.1 Gel nail polish–related mechanical and chemical lesions diagnosed after removing the polish. (a, b) Distal onycholysis encircled
by an erythematous border associated with onychoschizia. (c) Pseudoleukonychia (black arrow) and onycholysis (blue arrow). (d) Xanthonychia.
(Reproduced from Ref. 1 with permission.)
Given the limited number of GNP-related SCC cases, it is

unclear whether exposure to nail UV lamps plays any mean- Conclusion
ingful role in SCC induction. Nonetheless, frequent GNP users
and manicurists should be advised to use high-protection Nail cosmetic use may exceed nail beautification and repre-
sunscreens and to shield their eyes.1 Cumulative exposures sents a way to camouflage unsightly nail abnormalities. The
to UV light may cause ocular toxicity (cataracts, macular principle of managing nail cosmetic problems is prevention
degeneration)1. through education (Table 20.3)1.
TABLE 20.2
Identified Allergens Associated with Gel Nail Polish
HEMA HPMA THFMA HEA EGDMA MMA
Gatica-Ortega M, 2017 2 39/43 (90.7%) 41/43 (95.3%) 31/39 (79.5%) 22/29 (75.9%) 21/31 (67.7%) 7/36 (19.4%)
Ann Sterkens et al, 20208 1/1 (100%) 1/1 (100%) NT 1/1 (100%) 1/1 (100%) NEG
Paolo R and al, 20203 1/1 (100%) 1/1 (100%) NT NT 1/1 (100%) NEG
Gatica-Ortega et al, 20184 3/4 (75%) 3/4 (75%) 3/4 (75%) 4/4 (100%) 3/4 (75%) 1/4 (25%)
Christel Scheers, 20155 1/1 (100%) 1/1 (100%) NT 1/1 (100%) 1/1 (100%) NEG
Le Q et al, 20156 4/4 (100%) 2/4 (50%) NT NT 2/4 (50%) 1/4 (25%)
Dahlin J, 20167 6/8 (75%) NT NT NT NT NT
All records 88.7% 90.7% 72.3% 57.1% 53.7%
Abbreviations: HPMA: 2-Hydroxypropyl methacrylate; HEMA: 2-Hydroxyethyl methacrylate; THFMA: Tetrahydrofurfuryl methacrylate;
HEA: 2-Hydroxyethyl acrylate; EGDMA: Ethylene glycol dimethacrylate; MMA: Methyl methacrylate; NT: Not tested; NEG: negative.
TABLE 20.3
Patient Information on the Safe Use of Gel Nail Polish
Possible adverse events Patient information
Preventing mechanical damage • When clipping, the nails should first be softened by soaking, and the cutting implement should be held
perpendicular to the nail plate to prevent onychoschizia.
• Avoid manipulating cuticles. Trauma may cause Beau’s lines and paronychia.
• Careful trimming of the eponychium as it does not injure the nail folds.
• Do not over buff the nails.
Preventing sensitization For beauticians:
• Workers preferably should be correctly informed about the risk of sensitization to (meth)acrylates and the
most adequate preventive measures early in their career.
• Authorities that regulate cosmetic products should propose more strict regulations, limiting their use to
qualified professionals and banning the indiscriminate sale of domestic kits.
• Lamp maintenance is essential.
• Always change the manicure station’s protective covering after each customer.
Users should:
• Choose safe nail products and licensed nail technicians.
• Never touch the polish, especially while it is still soft.
Avoid contact with any products that have been ‘‘contaminated’’ by acrylates.
• Make sure that acrylates are properly cured.
• Use specific materials for procedures with methacrylates products.
• Use masks and protective eyewear.
• Use gloves. The ethylene-vinyl alcohol–polyethylene gloves offer the most effective protection. However,
these gloves are bulky and inelastic and impair dexterity.
• Latex, vinyl, and nitrile gloves are rapidly permeated by (meth)acrylate monomers, and are thus inefficient
as a sole protection measure, and would require frequent replacement.
Preventing UV induced skin lesions • Limit the frequency and time of nail salon UV exposure.
• Salon operators with LED lights should be preferred.
• Sunscreen protection with a broad spectrum (UVA/UVB) 20 minutes before the procedure is advised.
• Appropriate eye protection is especially important for manicurists who are exposed to UV light daily.
• Special caution is needed for patients with photosensitive disorders.
Gel Nail Polish and Its Side Effects 201
REFERENCES 7 MacFarlane DF, Alonso CA. Occurrence of nonmela-

noma skin cancers on the hands after UV nail light expo-
1 Litaiem N, Baklouti M, Zeglaoui F. Side effects of gel nail
sure. Arch Dermatol. 2009;145(4):447–449. doi:10.1001/
polish: A systematic review. Clin Dermatol. 2022;40(6):
archdermatol.2008.622
706–715. doi:10.1016/j.clindermatol.2022.07.008
8 Jefferson J, Rich P. Update on nail cosmetics. Dermatol Ther.
2 Gatica-Ortega ME, Pastor-Nieto MA, Mercader-García P,
2012;25(6):481–490. doi:10.1111/j.1529-8019.2012.01543.x.
et al. Allergic contact dermatitis caused by (meth)acrylates
9 Shihab N, Lim HW. Potential cutaneous carcinogenic risk
in long-lasting nail polish—are we facing a new epidemic
of exposure to UV nail lamp: A review. Photodermatol
in the beauty industry? Contact Derm. 2017;77(6):360–366.
Photoimmunol Photomed. 2018;34(6):362–365. doi:10.1111/
doi:10.1111/cod.12827.
phpp.12398.
3 Sterkens A, Dendooven E, Lambert J, et al. Hand derma-
10 Stern DK, Creasey AA, Quijije J, et al. UV-A and UV-B
titis from daylight curing “hybrid” gel nail polish. Contact
penetration of normal human cadaveric fingernail
Derm. 2021;84(6):449–450. doi:10.1111/cod.13751.
plate. Arch Dermatol. 2011;147(4):439–441. doi:10.1001/
4 Chen AF, Chimento SM, Hu S, et al. Nail damage from
archdermatol.2010.375
gel polish manicure. J Cosmet Dermatol. 2012;11(1):27–29.
11 Muttardi K, White IR, Banerjee P. The burden of allergic
doi:10.1111/j.1473–2165.2011.00595.x.
contact dermatitis caused by acrylates. Contact Dermatitis.
5 Hwang S, Kim M, Cho BK, et al. Case of various nail changes
2016;75(3):180–184. doi:10.1111/cod.12578
induced by gel polish. J Dermatol. 2016;43(11):1381–1382.
12 Lorizzo M, Piraccini BM, Tosti A. Nail cosmetics in
doi:10.1111/1346-8138.13385.
nail disorders. J Cosmet Dermatol. 2007;6(1):53–58.
6 Freeman C, Hull C, Sontheimer R, et al. Squamous
doi:10.1111/j.1473-2165.2007.00290.x.
cell carcinoma of the dorsal hands and feet after
13 Curtis J, Tanner P, Judd C, et al. Acrylic nail curing UV
repeated exposure to ultraviolet nail lamps. Dermatol
lamps: high-intensity exposure warrants further research of
Online J. 2020;26(3):13030/qt1rd1k82v. Published 2020
skin cancer risk. J Am Acad Dermatol. 2013;69(6):1069–
Mar 15.
1070. doi:10.1016/j.jaad.2013.08.032
21
Nail Cosmetics*
Robert Baran, Nilton Gioia Di Chiacchio, Christel Scheers, Josette André, and Douglas Schoon
The global nail market is expected to reach $15.55 billion in is modeled according to the client’s wishes. The
2024 with a global annual growth rate of 9.5% according to the surface of the nail can be sanded to smooth out any
latest report from Research and Markets (1). Europe remains irregularities (5). The distal nail furrow is cleaned.
one of the preferred markets due to the appeal of its fashion
capitals. This rapid growth can be attributed to recent techno- Emollients used: lanolin
logical advances and the enthusiasm of the young public for • Humectant: propylene glycol, glycerin
nail cosmetics. However, we must remember that this dazzling
• Thickener: sorbitol, magnesium or aluminum
evolution in the nail manicure had its beginnings as a very
silicate
ancient art, as evidenced by discoveries made in Egyptian
tombs dating from 2400 BC. • Perfumes, preservatives, quaternary ammonium
• Fragile nail creams can be applied by massage onto

the nail that has been hydrated with water in order
The Manicure to avoid dehydration. These creams improve the
The manicure is defined as a treatment intended to beautify flexibility of the nail and reduce its fragility. They
the hands and nails. The pedicure concerns the beauty of the mainly contain phospholipids and fatty substances
feet. For the sake of simplicity, we will describe the care of the (Vaseline, lanolin, sweet almond, jojoba, or soya oil),
nails of the hands and feet under the general term of “mani- humectants (glycerin, propylene glycol), or other
cure” (2). active ingredients such as vitamins, panthenol, bis-
Classically the manicure takes place in several stages (2–5): abolol, urea, or lactic acid (3–6). Of fairly identical
compositions, softening creams for cuticles are used
• The use of solvents (2) to remove any traces of between manicures. They make it possible to soften
varnish. the cuticles and prevent the formation of cravings.
Solvents are organic and dissolve the nitrocellulose
of the varnish and oils and counterbalance the Side Effects of Manicures (2, 5–9)
drying effect of the latter (3).
Side effects of the manicure process are essentially mechani-
Current market trends are moving toward solvents cal and linked to too vigorous a manicure at the nail and
that are less aggressive and less odorous than periungual area by cosmetics or due to the fact that cosmet-
acetone (ethyl acetate, alpha butyrolactone) and ics are incorrectly used (see the box on “Side Effects of the
more ecological (e.g. ethyl lactate from corn fer- Manicure”).
mentation and diethyl succinate from sugar cane) Infectious side effects are essentially linked to overly
(See the box on “Solvent Compositions”). aggressive treatment associated with imperfect sterilization of
equipment. Footbaths can promote mycobacterial infections.
SOLVENT COMPOSITIONS Although the current literature cannot confirm a risk of trans-
mission of hepatitis B and C in nail salons, strict disinfection
Solvents: acetone, butyl acetate, ethyl acetate, ethyl lac- measures must be adhered to (7).
tate, diethylsuccinate, alpha butyrolactone. Allergic side effects are related to the classic allergens con-
tained in cosmetics (perfumes, preservatives, lanolin, etc.).
• Lipids: castor oil, sweet almond oil, lanolin derivatives
• Other: perfumes, essential oils, sunscreens, preser-
vatives, dyes, vitamins, etc.
• The nails are then soaked into warm soapy water to * This chapter is based with permission on material in Scheers C, Baran
soften and clean them. They are then cut and filed R, André J, Cosmétiques unguéaux, in: Cosmetologie et dermatologie
in the same direction, perpendicular to the nail plate esthétique, EMC Consulte, 19/07/2020 [50–180-A-10], doi: 10.1016/
to limit onychoschizia (2, 4). The shape of the nail S2211–0380(20)88112, © 2020 Elsevier Masson SAS.
202 DOI: 10.1201/b22897-21

Nail Cosmetics 203
SIDE EFFECTS OF THE MANICURE • Infectious

• Bacteria: Acute paronychia (Figure 21.3), endo-
• Mechanical
carditis (Pseudomonas aeruginosa (Figure 21.4),
• Nail plate thinning and onychoschizia from
Serratia marescens, etc.
excessive sanding (Figure 21.1)
• Viruses: Warts (Figure 21.5), Herpes, Hepatitis C
• Transverse leukonychia and Beau’s lines due to
• Fungal infections: Candida albicans
cuticle aggression (Figure 21.2)
• Mycobacteria
• Distal onycholysis (“roller coaster”) by exagger-
• Allergic: Classic allergens in cosmetics used during
ated cleaning under the free edge of the nail
treatments:
• Chronic paronychia due to cuticle detachment
• Perfumes, preservatives, lanolin etc.
• Weakness and irritation of the nail and peri-
ungual area due to improper use of solvents or
cuticle removers
FIGURE 21.1 (A/B) Thinning and dryness of the nail plate. (C/D) 7 months after treatment with topical ointment. (Courtesy of Dr Nilton Gioia Di
Chiacchio.)
FIGURE 21.2 (A/B) Transverse leukonychia due to mechanical trauma of the cuticle and proximal nail fold. (C/D) 3 months. (E/F) 8 months.
(Courtesy of Dr Nilton Gioia Di Chiacchio.)
Composition of Nail Polishes (4, 10, 11)

Nail Polish
Nail polish was developed in 1920 following the use of lac- CLASSIC COMPOSITION OF NAIL POLISHES
quers in the automotive industry.
• Nitrocellulose
Method of Use • Nitrocellulose film modifier
After the manicure, the nail is degreased, dried, and covered • Plasticizer
with a base coat, two coats of varnish (colored or clear), and a • Solvent—thinners
fixing lacquer coat (10). • Thixotropic agent
• Dyes—pigments
Nail Cosmetics 205
Various • A modifying film: Conventionally a toluene sulfon-

amide formaldehyde type resin (TSFR or Santolite®),
• Nitrocellulose: Main component of the film after evapora- it provides good adhesion and a glossy finish.
tion, it gives the varnish its rigidity but does not allow good Currently other less “allergenic” substances are
adhesion or good flexibility. used such as polyester resins or resins, toluenesul-
fonamide/epoxy resin, acrylate (co)polymers or the
copolymer of phthalic anhydride/trimellitic anhy-
dride and glycols (PTGC) (12).
• A plasticizer: it increases the flexibility of the film:
historically camphor and butylphthalate. Currently
replaced by triethyl citrate, acetyltributyl citrate,
triphenylphosphate. Butyl phthalate classified as
CMR 2 (Carcinogenic, Mutagenic and toxic for
Reproduction) by the European Commission is no
longer used.
• Solvents: they regulate the viscosity and the drying
time: of the alkyl ester type (ethyl, propyl, butyl—
acetate), glycol ether (propylene glycol monomethyl
ether). Thinners (ethanol, isopropanol) also make
it possible to limit the cost price of the varnish.
Toluene, authorized in Europe, is prohibited in the
United States.
• Pigments and dyes: soluble (transparent varnishes) or
insoluble, organic type (e.g. D&C Red 6, 7.34, FD&C
Yellow 5), or mineral (e.g. ferric ferrocyanide, tita-
nium dioxide). The natural nacres formerly extracted
from fish scales for their pearlescence are currently
being replaced by mica-type materials—titanium
dioxide or silicon-titanium dioxide. The scintillating
effect can also be brought thanks to aluminum pow-
ders, bismuth oxychlorides.
• Thixotropic agents: stearalkonium hectorite prevents
the precipitation of pigments by increasing viscos-
ity and good fluidity after shaking the bottle. Small
metallic (nickel) or plastic-coated balls are some-
times added.
• Other substances: sunscreens to limit color degra-
FIGURE 21.3 Acute paronychia after manicure. (Courtesy of Dr Nilton dation (benzophenone 1–3, octocrylene), perfumes,
Gioia Di Chiacchio.) vegetable oils, rosin, plastic or metal glitter, etc.
FIGURE 21.4 (A) Absence of cuticle, slight edema of the proximal nail fold, and dark coloration of the nail. (B) Onychoscopy shows the greenish
coloration, typical of pseudomonas infection. (Courtesy of Dr Nilton Gioia Di Chiacchio.)
incorporating metal particles to be oriented with a magnet

before drying. The organic trend directs producers toward
healthy and environmentally friendly products where sub-
stances suspected of being harmful have been removed, thus
offering a multitude of varnishes that are devoid of them, i.e.
“the big free” (see the box on “The Big Free”).
“THE BIG FREE”

The 3 free: Without toluene, dibutylphthalates,
formaldehyde
formaldehyde, resin formaldehyde, camphor,
formaldehyde, resin formaldehyde, camphor,
paraben, triphenylphosphate
FIGURE 21.5 Wart affecting the lateral nail fold, after manicure.
(Courtesy of Dr Nilton Gioia Di Chiacchio.)
Water-based varnishes, which are difficult to formulate (5),
retain a modest share of the market due to their mediocre stay-
Variants of Nail Polish ing power, still mainly targeting an ecological-minded public
By varying their composition, varnish types are attained or children. They are essentially made up of water and acrylic
adapted to specific situations (5, 10, 11, 13) (see the box on polymers. There is also a recent craze for the incorporation of
“Variants of Nail Polish” below). vegetable substances into the varnish, thus using derivatives of
potato, carrot, wheat, or cassava.
Benefits and side effects that are related to the application of
VARIANTS OF NAIL POLISH nail polish are the following:
• Colorless base, higher resin concentration
Different concentration of solvents and thinners • Benefits
Better adhesion of varnish and protection of the nail • The use of varnish is a sign of elegance and refine-
Fast drying ment (13). It improves the protection, resistance,
• Fixing lacquer (“top coat”), colorless or colored, and hydration of the nail (4). It can also be used
higher concentration of nitrocellulose and plasticiz- for the camouflage of various nail pathologies
ers, UV filters (benzophenone), (e.g. onycholysis, nail plate dystrophy, chrom-
• Different concentration of solvents and thinners onychia) (10, 11).
• Protection of the underlying varnish, flexibility, color • Side effects
effect, or gloss • Keratin granulations (4, 5, 8) may occur and
• Fast drying are explained by surface friability linked to the
• Formaldehyde hardening varnish (max 5%, to be superimposition of new layers of varnish on older
applied on the distal part) ones which were not previously removed.
• Others: silicon, silk fiber, nylon, diamond powder, • The orange coloration of the nail plate, linked to
kevlar, amino acids, calcium, vegetable protein certain pigments, may appear distally. The use of
hydrolyzate (wheat, soy) a protective base reduces this risk (10, 11).
• Smoothing varnish
Allergies usually present as contact eczema and, more rarely,
contact urticaria or swelling of the lips and tongue (pseudo-
To increase opacity and viscosity, silicon, silk fiber, and talc angioedema) (14). Ectopic eczema develops remotely by hand
are used, which attenuate and relieve vertical streaks. Varnish on the eyelids, the lower part of the face (chin, lips), neck, and
vitamins, urea, calcium, and alpha-hydroxyacids may improve décolleté (5). Eczema can sometimes develop symmetrically
appearance, but the action on nail growth has not been dem- by airborne route and is rarer on the nail unit.
onstrated. “Hypoallergenic” TSFR varnish is often replaced The main allergen remains the toluene sulfonamide formal-
by “hypoallergenic” resins (toluenesulfonamide/epoxy resin, dehyde resin (15, 16), but other molecules can also be responsi-
polyester resin, PTGC, etc.), and these components limit the ble such as epoxy resins, PTGC, nitrocellulose, formaldehyde,
risk of allergy. or even metals (nickel, cobalt) (17–19). Psoriasiform-like
Varnishes are no exception to market trends, and we see a periungual contact eczema has been described with harden-
multitude of new products flourish. There are scented var- ing varnishes (20) containing formaldehyde, which are also
nishes to match eau de toilette, thermoactive varnish whose responsible for toxic effects such as paronychia, hyperkerato-
color changes according to temperature or light, and varnish sis under the nail, onycholysis, hemorrhages, etc. (5, 10, 11).
Nail Cosmetics 207
A flexible metallic “paper chablon” is glued and used as a

Artificial Nails guide at the end of the nail. A brush is successively dipped in
the liquid and then in the powder. The mixture thus formed
Indications, Advantages is applied to the initial nail overflowing onto the template
Artificial nails allow one to have more elegant, more resistant, paper to lengthen it. The new artificial nail is molded, filed,
and often longer nails. They can be used on normal nails but and shaped layer by layer. The resin hardens quickly at room
also on short, fragile, or broken nails to enhance their appear- temperature, and the stencil paper is finally removed. The nail
ance. The technologies and materials currently available make thus produced is sanded and filed according to the desired
it an art in its own right, “nail art”, thanks to adapted brushes, shape. It is then covered with varnish. This results in a solid
decals, jewelry, etc. (13). nail extension ideal for the realization of “nail art”. Sculpted
False nails can be used to camouflage a dystrophic nail, nails can be dissolved using acetone.
including partial scarring and anonychia, or to prevent hyper-
trophic regrowth of the periungual tissues during a traumatic
Composition for Polymerizable Gels
event. However, treatment such as this should not be used
in patients with psoriasis or nail lichen due to the risk of a Polymerizable gels are a mixture of acrylic monomers and
Koebner phenomenon (21, 22). polymers, sold ready to use, in the form of a gel that is applied
Nails can be more or less elongated either by modeling with a brush. Two types exist:
directly on the existing nail, using a flexible metal guide paper
(paper chablon) or using glued plastic capsules at the end of the • Light-curing acrylic gels: These gels contain ure-
nail (see further). In the case of acrylic resins, the “sculpted” thanes (meth)acrylates or other derivatives such as
or “shaped” technique on a stencil is preferred. 2-hydroxy ethyl methacrylate (2HEMA), triethyl-
The “shaped” acrylic resin technique (2, 10, 11), initially eneglycoldimethacrylate (TREGDMA), and epoxy
very popular, is gradually losing ground not only because of its methacrylate resins for which polymerization is
unpleasant smell, but also because of the technical know-how obtained by exposure to UV light. They also contain
required. It remains nevertheless interesting due to the price a photo-initiator.
of the materials used. It allows the creation of a solid nail, • Ethylcyanoacrylate gels (less common): In these gels,
suitable for “nail art” and likely to be used on a damaged nail. polymerization is obtained by applying an activator
(N, N dimethylparatoluidine) in a spray or brush.
Composition of the Acrylic Resin Technique
Technique for Photopolymerizable Gel (2, 11)
STANDARD COMPOSITION OF THE This currently popular technique is less smelly and easier to
SCULPTED RESIN TECHNIQUE perform. The nail is sanded, disinfected, and coated with a
Liquid: Acrylic monomer (99%) + stabilizer + suitable primer. If one wants the nail to be elongated, either
accelerator a guide (the paper template) or a capsule glued to the end of
Powder: Acrylic polymer (97%) + initiator (3%) the nail is used (see further). Several layers are successively
Miscellaneous: Plasticizers, accelerators, pigments, applied to the nail each exposed to a UV or LED lamp as a
sunscreens, titanium dioxide base layer, two layers of gel, and a surface layer. The formed
nail is then sanded, filed, and then covered with colored gel
varnish (see further) or a colored gel. Videos of the different
In this technique, the nail is covered with an acrylic resin steps in making photo-cured gel nails are available online.
obtained by mixing a liquid containing a monomer (methyl, An elegant appearance can be achieved by using the nat-
ethyl, or isobutyl methacrylate) with a powder containing a ural colors of the nail (the “French manicure”). Light-cured
prepolymer (polymethyl or polyethyl methacrylate) (3). The nails cannot be removed with acetone and require mechanical
monomer contains a stabilizer (e.g. hydroquinone) and an removal, which represents a serious handicap in the event of
accelerator (e.g. N,N dimethyl-p-toluidine) while the polymer gel allergy.
contains a polymerization initiator (e.g. benzoyl peroxide). The In the gel polish, Shellac or “UV gel manicure” (23) tech-
acrylic resin may also contain plasticizers, solvents, pigments, nique, this system brought to market in 2010 by CND has been
titanium dioxide, and sunscreen. Note that methyl methacry- a dazzling success. It is actually a light-curing gel varnish
late has been banned in the United States since 1974 because intended to be applied to the nails like a classic varnish but is
of its side effect profile. very resistant. This system provides a neat manicure for 2–3
weeks. The color palette is very extensive, and the rendering
is very natural. It is applied in four layers: a base, two colored
Technique for Acrylic Resin layers, and a protective layer, each layer being polymerized by
The nail is sanded and then disinfected. A “primer” (meth- an LED or UV lamp. The evaporation of the solvent reveals
acrylic acid) is used to increase the adhesion of the resin to the small tunnels connected by polymers soluble in acetone, which
initial nail. In view of its low pH, new less aggressive products theoretically facilitates removal compared to photopolymeriz-
or formulations without primers are appearing. able gels. Foils soaked in pure acetone are placed on the nail
for 10 to 15 minutes, and then the residue is scraped off the • Insufficient adhesion between the artificial nail
surface of the nail. To limit the effects of thinning and brittle- and the false nail leads to water penetration and
ness of the nail plate linked to this removal, the gel varnish can surface dyschromia of the nail plate.
be applied to small stickers (“peel off”) previously placed on • There is an increased risk of microbial and bac-
the nail. The assembly will be removed very easily in a single terial infection (e.g. Pseudomonas aeruginosa,
block after 15 days. Serratia marescens) particularly in the event of
In preformed nails or capsules (“tips”) (5, 10, 11), this sys- immunosuppression (26–28). Artificial nails are
tem is made of ABS (Acrylonitrile Butadiene Styrene) ther- to be avoided in the medical environment (see
moplastic resins. These preformed artificial nail plates are further).
available in different sizes and shapes adapted to the natural • An uncomfortable feeling of retraction after
nail. They are glued to the surface of the nail with an ethylcya- polymerization of acrylates has been reported.
noacrylate type glue. They require a normal underlying nail to
• Recent publications have suggested a possible
apply. They are removed with acetone.
carcinogenic risk following the repeated use of
The capsules intended to lengthen the nail are glued to its
UV lamps used for nail styling. In reality, this
distal end and are colorless. They are usually long and are cut
risk appears to be extremely low and limited
to the desired length using guillotine pliers and then filed.
by the safety of the installations, the use of sun-
Their increasing thickness allows optimal locking with the
screens or protective gloves during exposure. As
natural nail. The entire nail thus elongated will then be covered
a precaution, wearing sunglasses is also recom-
by a light-cured gel thus correcting the difference in height
mended (8, 29, 30).
between the initial nail and the nail plate (see previously). The
tips already decorated or to be varnished/decorated cover the • Allergic reactions: Allergic reactions are known (31)
entire nail. Their thickness is constant. They remain popular and increasing in frequency, especially since the
and are purchased as a kit but are not intended to be worn for development of light-curing gels and gel varnishes
more than 2 days. (32). The sale of home kits accentuates this trend
because of the inexperience of users (33). Contact
allergies are essentially due to the persistence of
Side Effects of False Nails (8, 10, 11) unpolymerized and allergenic monomers of (meth)
acrylates in the artificial nail or in the nail dust
Application of false nails is expensive and time-consuming. obtained by sanding. This can be linked to layers of
It takes about 1 to 2 hours to address all ten fingernails, with gel that are too thick, insufficient exposure times to
touch-ups being necessary on average every 2 to 3 weeks lamps, worn UV neon lights or even lamp systems
depending on the natural growth rate of the nail. This regrowth that are unsuitable for the wavelength of the photo-
must be filled according to the technique used, while ensuring initiator contained in the gel (LED versus UV).
a perfect watertight seal. The popularity of these techniques
explains the appearance on the market of kits allowing them Allergic reactions affect clients but also affect manicurists
to be carried out at home for an attractive price. The inexperi- (32). Symptoms may appear between 2 and 4 months after
ence and lack of information of the general public consider- the first applications but sometimes much later (16 months).
ably increases the risk of side effects. Symptoms of pruritus and eczema affect the nail bed and peri-
Side effects can be classified into three groups: those related ungual area, often as a pulpitis. These manifestations may be
to technical errors (mechanical or infectious), those related to accompanied by painful paronychia associated with paresthe-
allergic reactions, and those related to toxic reactions. sias. Onycholysis, hyperkeratosis, and often psoriasis-like nail
dystrophy are common as well as eczema of the arms, face,
• Technical errors (8, 10, 11): Excessive sanding and and eyelids (32, 34).
inappropriate use of a primer weaken the nail and Cases of allergic rhinitis and occupational asthma have
nail plate thinning creates dystrophy (24). This phe- been described (35). A case of cheilitis and lip edema has
nomenon also promotes small periungual wounds also been described associated with the use of gel polish (36).
that increase the risk of sensitization. Gel varnishes Additionally, cases of allergy to dental acrylates (amalgams,
are typically responsible for nail plate thinning (23) dental resins) or orthopedic compounds (cement) associated
occasionally causing pterygia (25). More unusual with the risk of loosening of prostheses sometimes result from
is the association of pincer nails and yellow nails a prior allergy to acrylates in false nails (37). Therefore, wear-
accompanied by punctuated depressions of the nail ing nitrile gloves, changed frequently, is essential and protects
plate (25). against the risk of allergies.
• The excessive length of the nail promotes ony- The cyanoacrylate glues used for capsules or fiber dress-
cholysis or even fracture of the nail plate by lever- ings can be responsible for eczema on the fingertips with nail
age effect. involvement, also sometimes presenting as eyelid eczema. The
• Acrylate monomers have an irritating effect pro- persistence of adhesive residues in the nail leads to a persis-
moting subungual hyperkeratosis and onycholy- tence of the dermatitis (21).
sis, which may be aggravated by the concomitant The most frequently responsible allergens must be sought by
use of UV rays. patch test. Various screening series are suggested since these
Nail Cosmetics 209
allergens do not yet appear in the standard European series appropriate size, nail dressings make it possible to reinforce
(see the box on “Allergens to Screen for by Patch Tests in Case or repair a broken nail and are applied to the nail plate using
of Suspected Allergy to False Nails”) (31, 32, 34, 38). The revi- cyanoacrylate glue then covered with several layers of varnish
sion of standard batteries by the ECDRG will probably soon (4, 21).
incorporate the most frequently found allergen, 2hydroxyethyl Other nail cosmetics include the following:
methacrylate (2HEMA) (32). There are possible cross reac-
tions between different (meth)acrylates but usually no cross • Self-adhesive varnishes: already varnished and
reactions between cyanoacrylates and (meth)acrylates. sometimes decorated, these self-adhesive strips are
Nevertheless, there is often a concomitant allergy to 2HEMA applied to the nail with or without the aid of a heat
and ethylcyanoacrylate (ECA) because of the associated source such as a hair dryer. Their advantage is that
techniques. they can be stuck on and then peeled off easily in one
piece after a few days (“peel off”) (2, 4.5).
• Transfers and jewels (in the form of sequins, pearls,
ALLERGENS TO SCREEN FOR BY
etc.) can be applied to varnish, gel varnish, or false
PATCH TESTS IN CASE OF SUSPECTED
nails (13).
ALLERGY TO FALSE NAILS
• Glycolic acid (70%) or phenol (8%) combined with
False nails in acrylic, UV gel, or gel polish: “Screening trichloroacetic acid (15%) peels seem well tolerated
Batteries”: and could improve nails with surface abnormalities
(trachyonychia, pitting, etc.) (43).
• 2HEMA, ECA (32) • With regard to minerals and vitamins, the benefit of
• 2HEMA, ethylene glycol dimethacrylate (EGDMA), these food supplements are controversial and may
triethylene glycol diacrylate, (TEGDA) (33) improve the fragility of the nail (4, 44), although
• 2HEMA, 2hydroxypropyl methacrylate (HPMA), positive effects have been reported with biotin and
TEGDA, EGDMA, 2hydroxy ethyl acrylate (HEA) cystine (4).
• 2HEMA, HPMA, EGDMA (34)
Capsules or fiber dressing:
• Ethylcyanoacrylate (glue) Nail Cosmetics and Medical Environment

• Tricresylethyl phthalate (capsule) Artificial nails increase the risk of carrying various infec-
• p t butylphenol formaldehyde resin (adhesive) tious agents before and after nail grooming. Nail salon
staff wearing false nails tend to wear their nails longer
and wash their hands less frequently so as not to damage
• Toxic reactions: them. False nails can cause nosocomial infections in hos-
• Severe paresthesias accompanied by pseudo- pitals (e.g. Pseudomonas aeruginosa, Serratia marescens)
Raynaud’s syndrome and permanent nail loss (26–28). Recommendations are needed regarding nail cos-
have been described in the literature. They result metics in the hospital setting (see the box on “Nail Cosmetics:
from a toxic effect of acrylates on the nerve fibers Recommendations for Caregivers”).
(39, 40) reached somewhat easily as there may be For hospitalized patients, fingernail polish is acceptable,
minor wounds around the edges of the nails. although some dark colors may distort finger oximetry mea-
• The products used for false nails are frequent surements only marginally (45). For the same reason in the
causes of accidents and poisonings, most of event of hospitalization, it remains preferable to remove artifi-
which take place at home and of which chil- cial nails beforehand (46).
dren are often victims. Methacrylic acid can be
responsible for poisoning in children but also for NAIL COSMETICS: RECOMMENDATIONS
skin, digestive, or respiratory tract burns. One FOR CAREGIVERS
case of acrylic nails being ignited by the heat of
a burning cigarette resulted in a deep burn and • Wearing non-flaking varnish permitted
amputation of the thumb (41). Cases of acciden- • Nail length less than 3 mm, from the free edge
tal skin burns caused by an exothermic reaction • False nails prohibited
between cyanoacrylate glues and cotton clothing
have been reported in young children (42).
Nail Cosmetics and Salon Safety Measures

Other Nail Cosmetics
The infectious, allergic, or toxic risks incurred by consum-
Nail dressings are among other cosmetic nail techniques uti- ers with regard to manicure treatments and the application
lizing fragments of silk, fiberglass, paper, or linen. Cut to the of nail cosmetics have already been the subject of numerous
publications (7). Practical advice for patients, especially 14. Moran B, Murphy GM. Recurrent tongue swelling:
hygiene measures in salons, has already been formulated. An unusual manifestation of allergic contact dermatitis.
Recently, the ANSM (National Agency for the Safety of Contact Derma. 2009; 60(2):114–5.
Medicines and Health Products) published a practical infor- 15. Warshaw EM, Buchholz HJ, Belsito DV, et al.
mation sheet on the risks and precautions to take when apply- Allergic patch test reactions associated with cosmetics:
ing false nails. Retrospective analysis of cross-sectional data from the
Nail salon workers are also being monitored (47). During North American Contact Dermatitis Group, 2001–2004. J
a routine check, the DGCCRF (Direction Générale de la Am Acad Dermatol. 2009; 60(1):23–38.
Concurrence, de la Consumption et de la Repression des 16. Lazzarini R, Hafner MFS, Lopes ASA, Oliari CB.
Frauds) showed that 43% of professionals did not have the Allergy to hypoallergenic nail polish: Does it exist? An
qualifications required for nail styling activity. Checks also Bras Dermatol. 2017; 92(3):421–2.
showed the use of unauthorized products. A comprehensive 17. Gach JE, Stone NM, Finch TM. A series of four cases of
allergic contact dermatitis to phthalic anhydride/trimellitic
report was recently written by ANSES (Agence Nationale of
anhydride/glycols copolymer in nail varnish. Contact
Food, Environmental and Occupational Health Safety) with
Derma. 2005; 53(1):63–4.
regard to the exposure of professionals to chemicals and their
18. Castelain M, Veyrat S, Laine G, Montastier C. Contact
impact on their health.
dermatitis from nitrocellulose in a nail varnish. Contact
Derma. 1997; 36(5):266–7.
19. Guarneri F, Guarneri C, Cannavò SP. Nail art and
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in the United States. J Public Health Manag Pract. 2014; natal intensive care unit: Did staff fingernails play a role
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Nail Cosmetics 211
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22
Nail Cosmetics for Abnormal and Pathological Nails
Douglas Schoon, Nilton Gioia Di Chiacchio, Christel Scheers, and Josette André
• Method 2 requires less skill and is typically used

Introduction as a colored overlays on the plate.
• Method 3 is the quickest and easiest but least
Medical or surgical nail disorders can sometimes be camou-
durable.
flaged by cosmetic nail techniques. This, however, covers up
the underlying process, and proper diagnosis and therapy are • All will increase the durability of the nail plate and
therefore essential to correct the underlying condition (1). may be decorated with colors, designs, ornaments,
There are limits to the use of cosmetics, such as (meth) and jewels.
acrylic ingredients, in some at-risk patients: those who have • Each type can attractively replace a deteriorated
had a reaction to artificial nails in the past, for example, or nail plate, one reduced by onychophagia, affected
individuals with circulatory disorders, particularly with scar- by splitting for example, or one that is simply bro-
ring or ulceration around the fingertip. Any bacterial or fungal ken—(meth)acrylics can even cosmetically correct
infection should be treated and resolved before attempting to ski-jump nails or the unsightly racket nails.
apply any type of artificial nail. Individuals whose hands are • Sculpting and plastic tips specifically add length beyond
in water for long periods will have difficulty keeping on arti- the free edge and can create the illusion of a longer nail
ficial nails. Psoriasis produces an isomorphic reaction (2), so bed and are used primarily for Method 1 and 2.
artificial nails should be avoided in persons affected by this • Plastic tips require less technical skill to create a
condition, since just nicking the hyponychium or nail folds natural looking nail.
may provoke a Koebner reaction. Lichen planus and lupus ery-
• Natural nail overlays add no length and require lower
thematosus may also precipitate this type of reaction. If the
maintenance while providing a protective coating.
condition is minor or temporary, that is, waiting for hangnails
to heal, then artificial nails are acceptable; however, for poten- • Nail products are applied both in salons and in the home.
tially chronic conditions such as onycholysis or exposed nail
beds, it might be prudent to avoid artificial nails until the con- Since the sculpting technique requires a considerably more
dition is resolved. This will avoid medicolegal problems (3). skill, it is usually to the salon setting.
For the same reasons, an ultraviolet (UV) energy-cured (aka There are three basic types of products used to perform
LED lights) (meth)acrylic based artificial nail product should these services, they share similar ingredients, but feature dif-
never be used in people who are taking photosensitizing medi- ferent chemistries. All three shall be discussed in this chapter.
cations or who are affected by photodermatitis. They are “liquid/powder” (methacrylate based), “UV gels”
[(meth)acrylate based], and “dips” (cyanoacrylate based). Each
of these are part of the acrylic chemical family. In this chapter
the term (meth)acrylates will be used to indicate methacrylates
Artificial Nails and/or acrylates and may refer to these in their monomeric,
There are three major methods for applying artificial nails, oligomeric, or polymeric form.
Method 1 is based on (meth)acrylates and sculptured on a form A typical methacrylate liquid/-based kit contains (4)
or molded on an acrylonitrile butadiene styrene (ABS) or tinite
acetate plastic tips, or applied as thin overlay on the natural nail • Preformed plastic nail tips to serve as a supporting
aka liquid and powder nails. In Method 2 approximately 60% are frame for the new nail
UV cured nail coatings aka gel nails or gel manicures. In Method • Liquid methyla, ethyl, isobutyl, hydroxymethyl or
3 approximately 30% are cyanoacrylate coatings, aka dip nails. hydroxybutyl methacrylate monomer blend contain-
Each is popular for a variety of reasons. ing proprietary blends of other mono-, di-, tri-, and
tetrafunctional methacrylate monomers
• All three methods can correct the coloration of nail • Powdered, spherical polymer made from poly(methyl
plates or beds. methacrylate) and/or poly (ethyl methacrylate) polymer
• Method 1 is superior for building a natural-looking (or a copolymer of both methacrylates) with benzoyl per-
curvature to flat natural nail or correcting the appear- oxide as an initiator and possibly titanium dioxide as a
ance of misshapen nails or lengthening the plate. white colorant or other colored pigments or lake pigments
212 DOI: 10.1201/b22897-22

Nail Cosmetics for Abnormal and Pathological Nails 213
• Stabilizer such as resorcinol, eugenol, thymol, or and nail varnish need not to be used. Various shades of pink
(most commonly) hydroquinone (HQ) or methyl powders are used to hide visible defects in the nail bed and
ethyl hydroquinone (MEHQ) plate and to match the clients natural skin tones.
• Catalyst, such as N-N-dimethyl-p-toluidine, to cat-
alyze the production of free radicals from benzoyl
peroxide in the polymer powder Allergic Reactions
• Plasticizers such as tricresyl phosphate
These may occur 2–4 months, and even as long as 16 months,
• If used, very low levels of solvents to act as clarifiers
after the first application (5). One of the first indications is an
or solubilizers
itch in the nail bed or redness of the soft tissue surrounding
• Soluble dyes to color the (meth)acylate monomer the nail plate. Paronychia, which is usually present in aller-
liquid gic reactions, can be associated with excruciating pain in the
nail area, and sometimes with paresthesia. The nail bed is dry
Metalized nail forms (Figure 22.1) and mylar coated nail forms and thickened (Figure 22.2), and there is often onycholysis
predominate over reusable have fallen out of favor and usually (Figure 22.3). The natural nail plate may appear thinner, usu-
are replaced by preformed plastic tips, which are adhered to ally due to overly aggressive filing techniques (Figure 22.4),
the nail plate. split, and sometimes discolored. It takes several months for
The nail is first thoroughly cleansed by brushing with soap the nails to return to normal. Permanent nail loss (Figure 22.5)
and water and often painted with antiseptic solutions. is exceptional, as is intractable prolonged paresthesia (6–8).
The dried nail is sometimes coated with an adhesion pro- Distant allergic contact dermatitis may affect the face and
moting primer. Though widely used in the past, methacrylic the eyelids (9) and is probably caused by touching the face
acid is now rarely used due to its extreme skin corrosivity. with the hands. The arms and wrist of nail technicians may be
Other reactive adhesion promoting primers are used to react affected if these areas are repeatedly exposed to filing dusts.
covalently with the keratin and the (meth)acrylate, providing Filings may contain small amounts of monomer that has not
increased adhesion to both surfaces, e.g. Bis-GMA (bisphenol yet reacted, since it takes 24 to 48 hours for the enhancement
A-glycidyl methacrylate).1 Methyl methacrylate monomer is to cure fully.
still available, despite its use being specifically prohibited in Technicians should be instructed to wash their hands before
artificial nail products in most US states and Australia. touching the face or eye area. The area involved is usually the
Newer artificial nail formulations no longer require pre- chin, where some technicians tend to rest their heads in their
treatment of the nail with a primer. Applying over a nail tip hands. They should also be warned to avoid skin contact with
with a fresh (meth)acrylate mixture will typically harden at the dust of freshly applied product and to avoid using the prod-
room temperature in less than 3 minutes. The prosthetic nail uct with too high a ratio of liquid to powder.
is shaped and enlarged by repeated applications. The applied A medium dry consistency of the slurry is considered ideal
nail coating can be filed to refine the shape, and as the nail to ensure complete curing of the (meth)acrylate blend. The fil-
grows out, further applications of the (meth)acrylate mixture ings from UV gel nails (discussed later) are also responsible
are added every 2 to 3 weeks to fill in the new growth of nail for skin sensitizations.
plate at the lunula. LED-style UV nail lamps have been designed for use with
Colored polymer powders can recreate the illusion of a UV gels specially formulated to cure with these with more
beautiful nail by using a combination of natural pink color intense UV exposure. Curing can be up to 75% faster when
over the nail bed and opaque white distally for the nail plate’s LED-style UV nail lamps are utilized due to their higher
free ledge. This combination perfectly simulates a natural nail,
FIGURE 22.1 Metalized paperboard template for sculptured artificial FIGURE 22.2 Nail bed and hyponychium thickening from sculptured
nails. artificial nails.
FIGURE 22.3 Onycholysis due to sculptured artificial nails. FIGURE 22.4 Thinning of the nail plate after use of sculptured
artificial nails.
intensity. ED-style nail lamps are designed to continue to pro-

duce constant levels of UV energy for up to 3 years, but then Patch Testing to Identify Reactions
should be replaced since the diodes are soldered to a circuit to Sculptured Artificial Nails
board and can’t be changed. Applying multiple thinner, coats
of products, rather than fewer and thicker coats, is preferred. Patients who are allergic react strongly to the (meth)acrylate
The thicker the coating, the more difficult it is to cure the UV liquid monomer (10) (1–5% monomer in petrolatum or olive
gel. UV penetration is low and the number of photons reach- oil). In the series of 11 patients of Koppula et al (10), 0.1%
ing beyond a depth of 2 mm is greatly reduced, and a complete ethyl acrylate in petrolatum detected 91% of the (meth)acry-
cure cannot be assured if applied too thickly. This is more late-allergic users of artificial nail. These authors proposed
likely to be an issue with heavily colored UV gels. Although the following five chemicals be used as screens: ethyl acrylate,
sensitization to stabilizers such as hydroquinone or butylhy- 2-hydroxy ethyl acrylate, ethylene glycol dimethacrylate, ethyl
droxytoluene is possible, UV gels use acrylate oligomers and cyanoacrylate, and triethylene glycol diacrylate. The pattern
monomers. The molecular weights of oligomers are well about of (meth)acrylate cross-reactivity among the most frequently
500 Daltons, making them much less likely to absorb into the positive (meth)acrylates suggests that a functional group that
skin when compared to monomers which range from 100–400 is a carboxyethyl side group may be requisite for allergic con-
Daltons making the monomeric ingredients the more likely tact dermatitis to (meth)acrylates. Kanerva et al (11) reported
allergen when reactions occur. Also, those from the acrylate that six out of 23 patients who were (meth)acrylate sensitive
family are many times more likely to cause sensitization than were sensitive to ethyl methacrylate, which is consequently a
methacrylates or stabilizers. These systems also rely of 1–3%, significant allergen.
such as ethyl phenyl(2,4,6-trimethylbenzoyl) phosphinate (aka In 2018, the British Association of Dermatologists issued
TPO-L) benzyldimethyl ketal or camphorquinone, or benzo- a warning about 2-HEMA and ethyl acrylate ingredients in
phenone, which can all be sensitizing. artificial nails (12), and in 2019, it was recommended that
Acrylic acid (MW = 72 Daltons) is also sometimes used in hydroxyethyl methacrylate be added to patch testing series.
low levels (<1%), as keratin adhesion promoters and certainly During 2016–2017, 15 UK dermatology centres included
contribute to adverse skin reactions as a corrosive and skin 2-HEMA in the extended baseline patch test series. Patients
allergen. Since UV gels contain oligomers with high molecu- with a history of (meth)acrylate exposure, or who tested posi-
lar weights, they tend to be very sticky and messy, which fur- tive to 2-HEMA, were selectively tested with a short series of
ther increases the risks of overexposure. eight (meth)acrylate allergens. A total of 102 in 5920 of those
the nail plate, Staphylococcus or Candida infection. In fact,

this is a result of improper application and maintenance.
Failure to undergo filling every 2 to 3 weeks may result in
creation of a lever arm that can predispose to traumatic ony-
cholysis or damage to the natural nail. Older clients’ nails grow
much more slowly and make require regular maintenance less
frequently.
Onycholysis (18) is more common with nail extensions that
are too long (lever effect) or with overly aggressive filing/
buffing of the natural nail. It has also been said that the bond
between the sculptured and the natural nail can be stronger
than the adhesion between the nail plate and the nail bed.
There is no evidence that occlusive prosthetic nail interferes
with the nail’s normal vapor exchange. Irritant reactions to
monomers are possible (4). These are manifest as a thickening
of the nail bed’s keratin layer, which can sometimes cause the
entire nail bed to thicken, with or without onycholysis. Still,
FIGURE 22.5 Permanent loss of the nails due to sculptured artificial
nails. without question, the overwhelming majority of cases result
from physical trauma or abuse.
The problem may well not be the (meth)acrylic nail mate-
tested (17%) were positive to 2-HEMA and 140 (24%) to at rials but rather the thinning of the nail due to heavy-handed
least one (meth)acrylate (13). overfilling with abrasives. There is a general tendency to disre-
The powder contains ethyl methacrylate homopolymer or gard manufacturers’ instructions and warnings, which causes
ethyl/methyl methacrylate copolymer, but also may contain the majority of disorders.
small amounts of monomeric methyl methacrylate monomer
and ethyl methacrylate (<0.1%) and up to 2% benzoyl peroxide.
This explains why the powder may in some cases provoke an
allergic patch test reaction (11, 14). Benzophenone and other Contact Urticaria
UV energy absorbers used in nail enhancement may produce
Butylhydroxytoluene has been reported as a cause of non-
eyelid dermatitis (15).
allergic contact urticaria (19).
UV absorbers are often used at low levels (<1%) to protect
the coating from UV-related discoloration, e.g. hydroxyphenyl
benzotriazoles.
Since there are no real monomer-free (meth)acrylate resins,
Removing Sculptured Artificial
an adaptable nail prosthesis made of silicone rubber is some-
times an alternative. Nails and Nail Polish
This “thimble-shaped” finger cover takes nail polish well Acetone is the primary solvent used to remove artificial nail
(16, 17) (Figure 22.6). UV gel nail systems are also used as coating of all types. Usually, 20 to 30 minutes is all that is
prosthetic devices for toes (Dr Robert Spaulding, personal required for (meth)acrylate-based, liquid/powder systems.
communication). Most UV gels are extremely difficult to remove with solvent,
so they are more frequently removed by filing with a course
abrasive. Some rapid remover products sold on the internet for
Non-Allergic Reactions quickly removing nail products in 3–5 minutes typically con-
tain methylene chloride and are sold using deceptive ingredi-
With continued wear, the edges become loose. These must be ent names claiming to be “magic” or “miracle” removers.
filed or clipped and then rebuilt to prevent development of an The use of acetone-free nail polish remover on painted nails
environment prone to bacterial and fungal infection, beneath is not necessarily more desirable. The alternative solvents,
especially methyl ethyl ketone have higher orders of toxicity
and can damage the underlying polymer surface, requiring the
nail coatings to be removed with greater frequency than would
be typically performed. Acetone diluted with 10% water or 5%
glycerin works well for removing colored polish without exces-
sively drying the skin or damaging the underlying artificial
nail coating. Reports have been published of severe and even
fatal cases following ingestion or inhalation of acetonitrile-
containing nail polish and acrylic nail removers because the
acetonitrile is metabolized into cyanide (20–23). Nitroethane
poisoning from artificial fingernail remover has led to cyanosis
FIGURE 22.6 Adaptable nail prosthesis made of silicone rubber. and 39% methemoglobinemia (24). Due to toxicity concerns,
acetonitrile and nitroethane are rarely used any longer for between different nail lamps, including UV wavelength and
removal, if at all. Ethyl methacrylate monomer and polymer irradiance (intensity) produced by different brands/styles.
nails and the UV or photobonded variety may produce severe Because of the wide difference between the many nail lamps
and prolonged paresthesia, even without associated allergic on the market, these systems are best use and properly cured
dermatitis (3), but this is relatively rare. Unfortunately, the when the UV gel is specially formulated to work with a spe-
product the patient was using could have contained methyl cific UV nail lamp—one that emits the correct wavelengths
methacrylate monomer since this ingredient is used in gray at the proper intensity needed for the types and concentra-
market products, but not by mainstream manufacturers; it is tions of the photoinitiator(s) used. The molecular weight of the
often not disclosed in the ingredient listing. oligomeric resins, as well as the ratio of monomers to oligo-
mers, helps determine the UV gel consistency. The chemical
structure of each also plays an important role in determining
UV-Curing Gels (UV Gel Systems— the consistency. When the UV gel is exposed to appropriate
wavelengths of UV (UVA) and the irradiance is sufficient,
Gel Nails Light Curing) polymerization occurs, resulting in hardening of the UV gel.
The word gel applies to the physical form of the product—not However, hardening occurs after only 50% of the oligomer
the product itself. Gels are made primarily from oligomers, and monomers polymerize, therefore hardening does not
which are naturally thicker than monomers, due to their much ensure that UV gel nails are properly cured. Curing p should
higher molecular weight. Monomers are used to adjust/lower exceeds 85% to better ensure the resultant polymers have suf-
the viscosity for improved application ease. UV gel systems ficient durability to withstand to rigors that artificial nail coat-
require no premixing of a powder component and are made ing must endure and to minimize skin exposure to uncured
using either acrylates or methacrylates (approximately 60% of monomers and oligomers contained within the fresh filings
the market, worldwide). created when the nail coating is shaped with an abrasive file.
Cyanoacrylate-based or so-called “no-light gels” are actu- Properly curing nail coatings to exceed 85% of the possible
ally monomers that contain a thickening agent. They comprise polymerization reactions will ensure a significantly lower
about 3–5% of the market worldwide and do not cure via UV, concentration of remaining unreacted monomers, but more
nor do they undergo any photochemical reactions (11). These importantly this higher degree of curing leads to a denser
products cure when exposed to alkaline substances, including structure/network, which impedes migration of residual
moisture since water is a weak base. Polymerization is acceler- monomers to effective trapping them in place so they cannot
ated by exposure to external applied catalyst, typically a ter- contribute to skin exposure.
tiary amine dissolved in a volatile solvent. The term “acryl” gels are UV cured gels that have been
These are typically methyl or ethyl cyanoacrylate and thickened with (meth)acrylate polymer to reinforce the coat-
even though they have a characteristically sharp and irritating and enhance its durability. These can be more difficult to
ing odor, these products release low amounts of vapor, which properly cure because of the tendency of users to apply them
makes both UV cured and no-light gels popular in full-ser- too thickly than can be properly cured given the UV intensity
vice beauty salons and spas seeking to create a relaxing envi- of their nail lamp, potentially leading to under curing near the
ronment. UV gels may also require the use of a nail primer. nail plate.
The thick UV gels are brushed onto the nail plate and cured Marketers sometimes claim that some systems are visible
with via UV. Visible light curing nail systems are impractical light cure, but the photoinitators used absorb and are activated
since the visible light lamps produce large quantities of heat primarily by UV. LED-style nail lamps all produce both UV
and produce an unattractive yellow discoloration of the nail and visible light, but the visible wavelengths are not used to
coating. cure the coatings so it is misleading to refer to such systems as
UV gels often contain urethane (meth)acrylates and/or visible light curing.
epoxy urethane (meth)acrylate oligomers and mono and/or Some individuals with distal fissure or men who bite their
difunctional (meth)acrylate monomers for cross-linking and nails may want more attractive hand. This can be accom-
viscosity reduction, one or more photoinitiators, plasticizers, plished with the use of any types of artificial nail coating.
adhesion promoters, stabilizers, anti-yellowing agents, colo- Each can produce completely natural looking nails with a
rants, and a UVA energy source/unit that is typically referred smooth hard finish that makes the nail more resistant to chew-
to as a “UV nail lamp”. Many of the same types of ingredi- ing. Liquid/powder systems are the preferred way to extend
ents used in two-part methacrylate systems are also found in the length of the nail plate, but UV gels can also be used as
UV gels, but oligomers are not used in two-part methacrylate a tip overlay for individuals who want to extend their nail
systems. plate length. However, cyanoacrylate-based gels do not have
Despite the fact that some products are marketed as being the strength or durability required for extension beyond the
“not acrylics” all two-part liquid/powder systems and UV gel tip of the fingernail’s distal edge. Some companies provide a
systems are based on the acrylic chemistry and use ingredients thicker gel designed for building and sculpting nail extensions.
from the acrylic family of chemicals, which means they con- Some UV gels may also be used as a “sealer” that can also be
tain acrylic functional groups. applied over nail polish, making it more impervious to chip-
The UV gel remains in a semi-solid form until cured under ping, wearing and fading. However, the difficulty in removing
a UV lamp. ED-style UV nail lamps have buttons that trig- the sealer is a consideration when evaluating the usefulness of
ger curing for 30–99 seconds. There are significant difference this technique.
the modes of failure indicate the damage is caused by pry-

Colored UV Gels ing and/or scraping off firmly adhered residual coatings.
Figure 22.7 (Image 1) is clearly the result of upward prying
Liked colored methacrylate powders, colored UV gels are forces. Figure 22.7 (Images 2 and 3) are due to scrapping
sometimes recommended to persons who do not often change forces caused by a wooden implement known as a “pusher”.
polish color or to create nail art designs. They are noted for Figure 22.7 (Image 4) is a lower magnification that shows the
easy application, high shine, and durability. However if nail residual coatings still firmly adhered to the nail plate after the
infection or onycholysis occurs, the permanently colored UV solvent soaking removal procedure is completed. Often the
gel makes detection nearly impossible. Also, colored pigments residual pieces of nail coating remain because of insufficient
and dyes usually block UV penetration, making them more contact time with the solvent remover which results in failure
difficult to cure completely. to sufficiently soften and loosen these firmly bonded areas.
Typically, 15–20 minutes is required for removal in acetone or
other solvent removers. However, UV nail coating designed for
removal every 2 weeks will become even more firmly bonded
UV Gel Polish/Manicure
after 3 weeks or longer of wear. Longer wear times will require
A widely used type of nail coatings called UV gel polish or longer solvent soaking time, up to 25 minutes, as well as more
gel manicures have become very popular. These types of nail gentle removal techniques to avoid nail surface damage.
coatings are used to coat the nail plate with a durable colored Surface nail damage and the resulting visible white spots are
coating capable of beautifully decorating the plates and/or avoidable when sufficient time is allowed to more completely
camouflaging nail defects such as nail bed or splint hemor- soften the UV cured nail coating and gentle removal tech-
rhages. UV gel polishes are unique in that they are designed niques are practiced. Damage becomes more likely because
to be removed and replaced after 2 or 3 weeks and then fol- the nail plates are softer and temporarily more susceptible to
lowed up with a fresh nail coating. Although they duplicate injury from removal implements used after soaking in acetone
the look of nail polish/lacquer/enamel, these nail coatings are or other remover solvent blends. When wearing nail coatings
polymerized by near UV-A (400–350 nm) to result in superior, of this type, users should be warned not to self-remove their
scratch resistance-colored coatings with enhanced durability. nail coatings and to not allow their nails to be filed using
However, UV curve nail coatings are more difficult to remove overly aggressive techniques.
than traditional nail polish formulations—those which form
films exclusively via solvent evaporation, aka “drying”.
Because these are often more difficult to remove, improper
Removing UV Gel Nail Coatings
removal can cause small, roughly round and symmetrical
whitish spots, typically 2–5 mm, to appear on the nail plates Any nail gel coatings slowly embrittle and degrade with con-
surface after removal. When these are found on the surface of tinued UV exposure from tanning beds or even natural sun-
the nail plate immediately following removal of these types of light. Those with formulations susceptible to degradation must
coating, forceable removal of residues of remaining nail coat- usually be removed every 2 to 3 months. Better formulations
ing is the most likely reason. The acetone remover is wrongly are more stable and resistant to these types of continued UV
blamed for dehydrating the nail plate, but these areas are not a exposure, but the colorants used remain susceptible to fading
result of dehydration. The whitish spots may have the appear- and discoloration.
ance of nail granulation caused by medical/health related One good way to remove UV gels is carefully file off the
conditions, however marks these are different and the result upper 75% of the with an abrasive file and remove the remain-
of external physical damage to the surface of the nail plate— der with acetone or specially blended solvent removers.
such as prying, scraping, or otherwise improperly removing Acetone will have no effect on some UV gels, depending on
the nail coatings—forcing the coating to pull out small pieces their composition and degree of curing. These types of UV for-
of the nail plate that were still firmly adhering to the coating. mulation suffer serious disadvantage when compared to more
These areas may also resemble white superficial onychomy- advanced and easily removed UV gel formulations. There is
cosis (WS0); they are not caused by a pathogenic organisms, no basis to the claims that these types of artificial nails are
rather they are the result of surface damage created by overly “safer” or healthier for the nail. In fact, they are no better for
aggressive removal techniques, picking, peeling, or chewing, the nail than any other system. History has shown that nail
etc. When nail plate thinning is observed a likely cause can be technicians’ knowledge and skill are the primary determi-
excessive/repeated filing of the plate. Salon often filed the nail nants for successful application and avoiding nail damage or
plate’s surface to apply the coating, as well as to remove it and other adverse reactions.
again to prepare it for recoat. Depending on the rate of nail
growth, those receiving regular services could have the same
area of their nail plates re-filed more than 12 times before
Removable UV Gels
eventually growing beyond the distal edge.
Shown are several examples of white spots caused by The present trend in UV curable gels is to make products that
improper removal (Figure 22.7). These scanning electron can be removed easily. This usually accomplished by using
microscopy (SEM) images show nail coating residues and sur- an insufficient amount of photoinitiator to lower the degree
face damage magnified between 186–3830 times. Examining of curing and creating a partially cured artificial nail or by
FIGURE 22.7 SEM images show nail coating residues and surface damage magnified between 186–3830 times. Image 1 is clearly the result of
upward prying forces. Images 2 and 3 are due to scrapping forces caused by a wooden implement known as a “pusher”. Image 4 is a lower magnification
that shows the residual coatings still firmly adhered to the nail plate after the solvent soaking removal procedure is completed.
softening the nail coating with excess amount of plasticizers UV-cured (meth)acrylates sensitize some individual in many
or add polymeric substances to make the nail coating more applications including inks, lacquers, composite dental resins,
susceptible to solvents, or some combination of these. These audiological ear molds, and nail cosmetics (27–31). In patients
types of UV generally require 30 minutes soaking in acetone wearing UV-cured (meth)acrylic nails who had perionychial and
to remove them. subungual eczema with fingertips fissuring extending under the
nails (32), Hemmer et al (33) patch tested “hypoallergenic” com-
mercial products. UV curable gels contain potential skin sensi-
tizers, which means that prolonged and/or repeated exposure
Adverse Reactions should be avoided. In contrast to some manufacturers’ declaration,
Like most curable coatings, artificial nails shrink when they there are no “hypoallergenic” products because these continue
are polymerized. to include potential allergens such as (meth)acrylate functional
UV gel enhancement shrinks by up to 18%, which can result monomers, oligomers, and photoinitiators, etc. and therefore con-
in adhesion loss and feel tight on the nail to cause throbbing or tinue to cause allergic sensitization. UV gels and two-part liquid/
may feel warmth below the nail plate. This may lead to tender, powder systems (commonly called acrylics nails) share many sim-
sore fingertips, but usually the condition resolves within a day ilar ingredients but are compositionally distinct enough that they
or two. Adverse nail reactions, even with nail loss (25) and will not necessarily cross react (11, 25). The resistance of dispos-
paresthesia with UV gels, have been observed (26). able latex gloves to penetration by (meth)acrylates is low (34, 35).
Disposable nitrile or vinyl gloves are better alternative since produce allergic changes indistinguishable from dermatitis
their resistance to methacrylates is much higher than latex. caused by so-called formaldehyde nail hardeners. Ectopic
allergic or irritant contact dermatitis may affect the face and
eyelids (36) and large areas of the trunk (37) and disappears
with removal of the cause.
Preformed Artificial Nails Allergic onychia and paronychia due to cyanoacrylate nail
Plastic press-on nails are preformed by injection molding with preparations require some comment (9, 38). After about 3
the thermoplastic resin with the thermoplastic resin ABS and months, painful paronychia, onychia, dystrophy, and discol-
temporarily glued with cyanoacrylate to the nail (Figure 22.8). oration of the nails may become apparent and last for several
They are packaged in several shapes and sizes to conform to months (Figure 22.11).
normal nail plate configurations. Eyelid dermatitis disappears with removal of the allergen.
They come in two types: Shelley and Shelley (39) reported an isolated chronic allergic
contact dermatitis simulating a plaque of parapsoriasis due to an
1. Those that are adhered to the free edge of the nail allergic reaction to cyanoacrylate adhesive used on the fingernails.
plate to act as platform to support artificial nail Not surprisingly, patients react far more often on patch test-
coatings. ing to the adhesive than to the plastic nails.
2. Those that are adhered over the entire nail plate as Suggested allergens for patch testing include:
a temporary application for special occasions, for
example, weddings and high school. • p-t-Butyl phenol resin (1% petrolatum) (40, 41)
• Tricresyl ethyl phthalate (5% petrolatum)
Decorative, preformed nail in chrome or gold plate or with • Cyanoacrylate adhesives (10% petrolatum)
intricate designs (Figure 22.9) may be used in the same way • 5% Methyl ethyl ketones
as a nail coating, but these are not as long lasting. The applica-
• MEHQ or HQ
tion of preformed prosthetic nails is limited by the need for
some normal nail to be present for attachment (Figure 22.10). • The artificial nail itself
When used alone (listed item 2 earlier) it is recommended
that are removed after a few days to a week, as they are not Most cyanoacrylate adhesive formulations contain hydroqui-
very durable and have sometimes caused onycholysis and nail none (HQ) at concentration up to 1000 ppm, but more typi-
surface damage when improperly removed. Since these tips cally 200 ppm.
are adhered by using cyanoacrylate, in some cases they can Since higher levels of HQ are need to prevent premature
polymerization of cyanoacrylate monomers used in artificial
nail products, the European Union has been petitioned by sev-
eral cosmetic associations to raise the allowable limit of HQ to
1000 ppm from a 200 ppm limit in artificial nail system (after
mixing if contained in a two-part system) (42). Therefore, most
investigators perform patch testing not only with cyanoacry-
late glue or nail preparations as such, but also with HQ.
Nail Mending and Wrapping

The purpose of nail mending is to create a splint for a partially
fractured nail plate (Figure 22.12) or one longitudinal split
extending the full length of the nail. The split is first bonded
with cyanoacrylate monomer, then a piece of wrap fabric is
cut and shaped to fit over the nail surface. This is then embed-
ded within the cyanoacrylate monomer and several coats are
FIGURE 22.8 Preformed plastic nail “tips”. applied; conversely, the fabric is applied directly over the crack
and subsequently sealed to the nail with cyanoacrylate mono-
mer or no-light gel. In nail wrapping or “wraps”, the free edge
of the nail should be long enough to be splinted with paper,
silk, linen, or fiberglass and fixed to the plate with cyanoacry-
late monomer (Figure 22.13). The activator for cyanoacrylate
wraps is a catalyst and contains N,N-dimethyl-p-toluidine in
a solvent carrier. Methemoglobinemia with resultant cyanosis
may follow its ingestion (23). DMPT is typically 0.5% of the
formulation and HQ up to 1000 ppm. The ethyl acetate and
trichloroethane in these products do not promote curing but
FIGURE 22.9 Preformed nail in gold plate. are instead solvents.

FIGURE 22.10 (a–c) Different stages for shaping the tips of nails.
Paper is not very effective, but silk wraps are sheer, very
thin, and work quite well. Linen is thicker and offers increased DIP Nail Coatings
strength but inhibits cyanoacrylate penetration to the nail,
thus lowering adhesion, and it does not have as natural of an These types of nail coating utilize highly stabilized, brush-
appearance as other materials on cyanoacrylate resins formulations which are smoothed
Fiberglass combines many benefits of both silk and linen onto the nail plate with a brush and immediately the entire
and is the most universally used. finger is dipped into a small container filled with powdered
In some South American countries, nail technicians use polymerized methacrylate resin, then brushed with an activa-
the fiberglass insulation taken from commercial electrical tor. Typically the same benzoyl peroxide containing powders
wire. used to create acrylic nails are relabeled and marketed for this
Most wrap systems consist of a few basic elements (43): use, even though the benzoyl peroxide provides no value in the
application. The methacrylate powder beads typically range is
diameter from 20–80 microns and act to toughen the coating
• Monomeric cyanoacrylate, polymerizing from mois-
and increase crack resistance. The beads become transparent
ture in the air or in the natural nail’s surface, to form
but remain solid inside coating and block the spread of cracks.
the hard nail coating that is both the base and top
The whitish material adhering to the outside of the beads is the
coats of the nail wrap.
benzoyl peroxide initiator.
• Mesh material, for example fiberglass or silk, is
preferred.
• Activator or catalyst that cuts the hardening time to
seconds. Nail Hardeners and Treatments
There are two main types of products which make nail harden-
See earlier for patch testing patients sensitized to cyanoacrylate. ing claims. In one group the products are modified nail polish
FIGURE 22.12 Nail mending.

FIGURE 22.11 Dystrophic nails due to preformed plastic nails.
containing, among ingredients, nylon fibers, (meth)acrylate show signs of adverse changes. At these concentrations used
resin, and hydrolyzed proteins. They function either as a base products contain less than 12 ppm (0.0012%) free formalde-
coat for nail polish or as a stand-alone treatment. These prod- hyde (46). Companies selling these products generally disre-
ucts provide a protective coating, therefore the implied bene- gard requirements for skin shields, so accidental skin exposure
fits come from the added strength and durability of the coating can occur.
itself, rather than altering the physical properties of the nail Most products never exceed 1.5% methylene glycol since
plate. These products may also consist of polyesters and poly- at higher concentration both the nail plate and the surround-
amides. These nail hardeners are essentially a modification of ing tissue can quickly show signs of adverse changes. At
clear nail polish and the addition of nonfunctional ingredients these concentrations used products contain less than 12 ppm
for marketing purposes, that is, nylon fibers and amino acids (0.0012%) free formaldehyde (46). Companies selling these
or hydrolyzed protein. products generally disregard requirements for skin shields, so
Like nail varnish and base coats, they are applied to the accidental skin exposure can occur.
clean nail plate. Some are designed with a dual purpose and Using a concentration of less than 0.2% methylene glycol
also function as a varnish base coat (44). seems to have little or no positive benefits on the surface hard-
The second type of hardener chemically alters the struc- ness of the nail plate.
ture of the nail. The US FDA allows these products to contain Methylene glycol permanently alters the structure of the nail
up to 5% formalin (International Nomenclature of Cosmetic plate by cross-linking the keratin (47), which can quickly lead
Ingredients [INCI] name: methylene glycol), and kits are to embrittlement since the crosslink density rises over time
required to contain a skin shield to protect the eponychium with continued regular use. Repeated use also allows a deeper
and side walls from exposure (45). migration into the plate, further affecting the bulk properties
It is important to note that until recently, the INCI diction- of the natural nail. Increased cross-link density increases the
ary required manufacturers to call formalin by an incorrect surface hardness of the nail plate, but it also lowers the flex-
name, formaldehyde. Formaldehyde is anhydrous gas that ibility while increasing the strength, resulting in an imbalance
upon mixing with water reacts to form a methylene glycol and called brittleness (48). The property that people are unknow-
residual traces of formaldehyde in equilibrium. Most products ingly seeking is toughness. This occurs when there exists a
never exceed 1.5% methylene glycol since at higher concentra- favorable balance between strength and flexibility. Since the
tions both the nail plate and the surrounding tissue can quickly public doesn’t understand how or why these products work,
FIGURE 22.14 Acute formaldehyde reaction. (Courtesy of P. Lazar.)
FIGURE 22.13 Nail wrapping.
the products are often applied to nails which are already overly
brittle or rigid and therefore not suitable for further harden-
ing. Even on nails which could benefit, these products are fre-
quently misused. The preparations work so well on thin weak
nails that users see an almost instant improvement, which
encourages repeated use and frequently excessive use. After FIGURE 22.15 Longstanding onycholysis due to formaldehyde.
several weeks of success, the nails can eventually become
overly hard and rigid. Continued use can cause splitting,
cracking, and breaking which unaware users can misinterpret.
This will often cause them to continue to use these products
with even greater frequency leading to the problems associ-
ated with over exposure to this ingredient.
Methylene glycol preparations may cause nail changes
including a bluish discoloration (Figure 22.14), which may
turn red, with intense throbbing (49). Resolving hemorrhages
produce reddish-rust or yellow discoloration of the nail.
Methyl glycol can also be responsible for paronychia, ony-
cholysis (Figure 22.15), subungual hyperkeratosis and dryness
of the fingertips, but nail shedding is uncommon. Pterygium
inversum (50) (Figure 22.16) has been observed, sometimes
accompanied by severe pain necessitating systemic corticoste-
roid (45).
Isolated onycholysis and ectopic contact dermatitis, even FIGURE 22.16 Pterygium inversum due to formaldehyde.
associated with hemorrhages of the lips in nail biters (51), have
been reported. Airborne contact dermatitis of the face may In recent years, a new nail hardening ingredient has been
also be seen. introduced which overcomes the objections related to forma-
Formalin (1–2% in water) should be used for patch testing, lin. The ingredient, dimethyl urea is non sensitizing and 2%
but caution is necessary in interpreting the reactions because concentrations in a basecoat preparation does not over cross-
the agent also acts as an irritant. link the keratin. The higher molecule weight and relative
increase in hydrophobicity prevent dimethyl urea from pen- 12. Warning, British Association of Dermatologists, Aug. 9, 2018:
etrating as deeply into the plate as methylene glycol. https://www.bad.org.uk/dermatologists-issue-warning-
This effectively limits the cross-linking action to the sur- about-uk-artificial-nail-allergy-epidemic/; accessed 10 Mar.
face of the plate thereby dramatically reducing the potential 2023.
for overhardening and embrittlement. Further, the greater the 13. Rolls S, Chowdhury MM, Cooper S, et al, Recommendation
cross linking the surface, the more restricted the dimethyl urea to include hydroxyethyl (meth)acrylate in the British base-
penetration will become, essentially creating self-limiting line patch test series. Br J Dematol 2019; 181(4), 811–817.
cross-linking reaction while having the additional benefit of 14. Lane CW, Kost LB. Sensitivity to artificial nails. Arch
being non sensitizing (52). Dermatol 1956; 74: 671–672.
Other alternatives to formaldehyde hardeners are aluminum 15. Guin JD. Eylid dermatitis from benzophenone used in nail
chloride (5% in water) tannin and nail creams with a low water enhancement. Contact Derm 2000; 43: 308–309.
(30%) and high lipid content for minimizing nail fragility. 16. Pillet J. The aesthetic hand prosthesis. Orthop Clin North
Am 1981; 12: 961–969.
17. Beasley RW, de Beze G. Prosthetic substitution for finger-
nails. Hand Clinics 1990; 6: 105–112.
Overall Risk 18. Goodwin P. Onycholysis due to acrylic nail applications.
Clin Exp Dermatol 1976; 1: 1991–192.
Recently nine out of 819 patients showed a contact allergy to
19. Schubert HJ, Lindner K, Prater E. Kontaktallergie im
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The Cosmetic Ingredient + has reviewed 24 artificial nail 20. Turchen SG, Monaguerra AS, Whitney C. Severe cyanide
enhancement methacrylate monomers used to create the two poisoning from the ingestion of an acetonitrile containing
part systems and declared all to be “safe as used”, while recog- cosmetic. Am J Emerg Med 1991; 9: 264–267.
nizing that is was important to avoid direct skin contact with 21. Caravati EM, Litovitz TL. Pediatric cyanide intoxication
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Hydroxyethyl methacrylate monomer is falling out of favor 1988; 260: 3470–3473.
and used much less frequently, as many in the fingernail indus- 22. Rainey PM, Roberts WL. Diagnosis and misdiagnosis of
try blame this monomer for adverse skin reactions. The com- poisoning with cyanide precursor acetonitrile: Nail polish
bination of low molecular weight (130 Daltons) and high-water remover or nail glue remover? Am J Emerg Med 1993; 11:
solubility make penetration into the epidermis more likely. 104–108.
23. Potter JL, Krill Jr CE, Neal D, Kofron WG.
Methemoglobinemia due to ingestion of N,N-dimetyl-p-
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23
Treatment of Nail Fragility in Males and Females
Bianca Maria Piraccini and Luca Rapparini
disorders, rheumatological pathologies (rheumatoid arthritis,

Introduction psoriatic arthritis), cancer, peripheral vascular impairment,
environmental factors (e.g., smoking, alcohol consumption),
Nail fragility, despite being considered a minor abnormality and concomitant medications (retinoids, chemotherapeutic,
and not a proper disease, is a condition that can have psycho- anti-viral agents) (1–5).
logical repercussions on the patient, so it is recommended to
set up a treatment.
Brittle nails are a widespread condition; at least 20% of General Measures
the population is affected, and they are more frequent in the
female sex (male-to-female ratio of 1 to 2.18) (1, 2). • People who perform work activities that put the
The main causes are first and foremost aging and then all nail at risk of microtrauma or repeated contact with
those conditions that promote dehydration of the nail, such aggressive substances (acetone, detergents, dish soap,
as repeated washing especially with very hot water and per- furniture polish, paints) should keep their nails short,
petual use of aggressive detergents and/or solvents; frequent wear rubber gloves with white cotton gloves under-
and repeated immersions in water leads to a loss of much of neath (1), and avoid humid environments as much as
the lipid component of the nail and progressive dehydration of possible, limiting water contact (no more than 3–6
the nail plate, which is greater if the climate is cold and dry, times a day) and moisturizing both hands and nails
facilitating evaporation (Figure 23.1). after each wash (Figure 23.2).
Therefore, the approach to nail fragility must first be based • Cut or better file the nails short after moisturizing
on behavioral measures. To this it is necessary to apply local them (soaking the nails in warm soapy water or pre-
products that keep the nail soft and possibly take amino acid treating them with local products that soften them),
and trace element supplements that support nail trophism and preferring a rounded shape rather than a square
quality, promoting stronger and healthier nail growth. shape (6). The nail should be filed using the tool in
If nail brittleness, despite nutritional or practical strategies, one direction only.
persists or other nail signs are associated, such as altered color • When cleaning nails, avoid the use of sharp instru-
and thickness of the nail plate or spots on the nail, it is advisable ments and never cut the cuticles, as damage to the
to undergo a specialist examination to determine if nail fragil- periungual tissues may promote the entry of micro-
ity is indicative of fungal infections or inflammatory diseases organisms into the skin, inducing paronychia, and a
(eczema, alopecia, lichen planus) and to prescribe appropriate damaged skin is more prone to develop contact der-
treatment. The success rate of treatment is often related to the matitis (7, 8).
correct diagnosis and timely initiation of therapy. In addition • Onychophagia can be a cause of nail brittleness: in
to underlying dermatological disorders, other pathologies must these patients, consider using sorbitol-based chewing
also be sought, including anemia, malnutrition, endocrino- gum and applying a bitter nail lacquer to help disso-
logical disorders (e.g., hyper- and hypothyroidism), depressive ciate the nail-biting habit (Figure 23.3) (9).
FIGURE 23.2 Nail fragility is often associated with hand dermatitis

FIGURE 23.1 Nail fragility: the distal nail plate shows lamellar due to excessive contact with water and detergents, evident as scaling and
onychoschizia and fissures, better seen at onychoscopy. fissuring of the hyponychium and distal pulp.
DOI: 10.1201/b22897-23 225

• Hyaluronic acid increases hydration capacity and

restores normal keratinization, having beneficial
actions on the nail plate, cuticle, and periungual
skin (7).
• Nail polishes are helpful in reducing the permeabil-
ity of the nail plate but should not be removed too
often. It is important to allow the nail polish to dry
completely before resuming manual activities.
• There are specific solutions, such as colorless gels
and polishes capable of creating a water-soluble pro-
tective film on the nail, which can help protect the
nail from external agents, while also increasing its
hydration and subsequent resistance to breakage.
These nail lacquers contain hydroxypropyl chitosan
or HPC (11), silicon-containing nail hardeners based
on silanediol salicylate and Pistacia lentiscus. From
the plant Pistacia lentiscus it is possible to extract
lentisk oil, an aromatic plant resin with active com-
ponents that stimulate the synthesis of hard kera-
FIGURE 23.3 Nail fragility due to onychophagia (nail biting): the nail tins and keratin-associated proteins, increasing nail
plates are typically short and with irregular and brittle distal margin; the thickness and strength (Figure 23.4) (7, 12).
distal pulp is uplifted.
• Artificial nails should not be worn for long periods Dietary Supplements
and avoid too frequent manicures. There is also a Dietary factors play a less important role in nail health: vita-
growing fashion for semi-permanent nail polishes, i.e., min and amino acid deficiencies are rare if the patient has a
those that once applied to the nail remain fixed for 2–3 balanced diet. The vitamins, trace elements, and amino acids
weeks and are therefore composed of substances that important for nail health are iron and zinc, biotin, and sulfur
adhere strongly to the nail plate and make removal dif- amino acids (methionine and cystine). The dietary aspect is
ficult. Nails remain lacquered and beautiful for a long one of the factors that can be most easily corrected, as a suf-
time, but the removal of semi-permanent nail polish ficiently varied diet with an adequate intake of dairy products,
damages them considerably. Removal is usually done vegetables, shellfish, nuts, and legumes can effectively con-
using very aggressive solvents left on for 5–10 min- tribute to maintaining healthy and strong nails.
utes, combined with the use of special files that scrape Taking dietary supplements containing trace elements (iron,
the back of the nail, thus damaging its most superficial zinc), and vitamins (biotin), and amino acids (cystine, argi-
layers and making it more permeable to all substances nine, glutamic acid) can improve nail quality and texture and
with which it will come into contact, including water. facilitate proper nail growth (5).
This range of cosmetic agents is dangerous to the
nail and therefore includes simple acetone, which, if • Biotin (vitamin H) is the main vitamin that can be
used frequently, can still damage keratin, which is the useful in improving nail strength by acting on the
component protein of the nail that is responsible for its synthesis of lipid molecules that produce the binding
hardness and elasticity. Degradation of the keratin fil- between keratinocytes in the nail plate (13). In addi-
aments of the nail plate is responsible for its increased tion to nail fragility, a biotin deficiency may manifest
fragility and decreased strength. Therefore, the use of
an acetone-free nail polish remover (e.g., ethyl acetate,
butyl acetate) should be preferred, and afterward, the
nails should be rinsed and moisturized to minimize
nail fragility (10).
Topical Product Application

• Applying moisturizing topicals several times a day
allows the nail to maintain an optimal moisture level
and remain strong. Lotion, lanolin/petroleum jelly,
olive oil, or alcohol-based humectants such as glyc-
erin and propylene glycol can be used to moisturize
nails. α-Hydroxy acids and urea may also be added to FIGURE 23.4 Cure of nail fragility and improved aspect of the
periungual skin after 4 months of daily topical application of a cosmetic
increase the water-binding capacity of the nail plate (6). topical treatment containing Pistacia lentiscus and hyaluronic acid.
Treatment of Nail Fragility in Males and Females 227
as alopecia, periorificial dermatitis, seborrheic der- 6. Iorizzo M, Piraccini BM, Tosti A. Nail cosmetics in nail
matitis, conjunctivitis, ataxia, hypotonia, ketolactic disorders. J Cosmet Dermat. 2007;6(1):53–8.
acidosis/organic aciduria, convulsions, or candidia- 7. Piraccini BM, Granger C, Alessandrini A, et al. Clinical
sis (8, 14). Food sources rich in biotin are fresh milk, and instrumental objective evidence of the efficacy of a new
egg yolk, meat, fish, seeds, nuts, and sweet potatoes water-based nail-strengthening solution containing Pistacia
(1, 14, 15). The recommended daily dose of biotin is lentiscus and hyaluronic acid applied for up to 6 months
5–10 mg for 3–6 months, preferably taken with food to improve the appearance of weak, brittle nails. Dermatol
to aid absorption (1, 4). Biotin supplementation may Ther (Heidelb). 2020;10(1):119–31.
interfere with assays for free thyroxine (T4), total T4, 8. Cashman MW, Sloan SB. Nutrition and nail disease. Clin
free triiodothyronine (T3), total T3, thyroid stimu- Dermatol. 2010;28(4):420–5.
lating hormone (TSH), parathyroid hormone (PTH), 9. Tanaka OM, Vitral RWF, Tanaka GY, et al. Nailbiting, or
testosterone, estradiol, β-human chorionic gonado- onychophagia: A special habit. Am J Orthod Dentofacial
Orthop. 2008;134(2):305–8.
tropin (β-hCG), ferritin, calcium and other electro-
10. Rieder EA, Tosti A. Cosmetically induced disorders of the
lytes, troponin, and various cancer markers, so it is
nail with update on contemporary nail manicures. J Clin
necessary to suspend biotin intake one month before
Aesthet Dermatol. 2016;9(4):39-44.
undergoing blood tests to avoid falsified tests (16, 17).
11. Chiavetta A, Mazzurco S, Secolo MP, et al. Treatment of
• Iron deficiency can also result in brittle nails and brittle nail with a hydroxypropyl chitosan‐based lacquer,
koilonychia (18). Iron supplementation can be very alone or in combination with oral biotin: A randomized,
effective in improving nail fragility only when ferri- assessor‐blinded trial. Dermatol Ther. 2019;32(5).
tin levels are below 10 ng/mL, but there are no stud- 12. Starace M, Granger C, Carpanese MA, et al. Review of the
ies showing that iron deficiency is strictly correlated literature on the efficacy and safety of a new cosmetic topi-
with nail fragility (1, 4). cal treatment containing Pistacia lentiscus and hyaluronic
• Cystine is a sulfur-containing amino acid involved acid for the treatment of nail plate damages. J Cosmet
in multiple metabolic pathways. Cystine is a disul- Dermatol. 2022;21(11):5514–8.
fide containing two molecules of cysteine and is an 13. Hochman LG, Scher RK, Meyerson MS. Brittle nails:
amino acid that links the protein chains of keratin Response to daily biotin supplementation. Cutis.
(2). It can be helpful in promoting nail growth, hard- 1993;51(4):303–5.
ness, and function. 14. Zempleni J, Wijeratne SSK, Hassan YI. Biotin. BioFactors.
2009;35(1):36–46.
15. Thompson KG, Kim N. Dietary supplements in derma-
REFERENCES tology: A review of the evidence for zinc, biotin, vitamin
D, nicotinamide, and Polypodium. J Am Acad Dermatol.
1. Chessa MA, Iorizzo M, Richert B, et al. Pathogenesis, clini-
2021;84(4):1042–50.
cal signs and treatment recommendations in brittle nails:
16. Rosner I, Rogers E, Maddrey A, et al. Clinically signifi-
A review. Dermatol Ther (Heidelb). 2020;10(1):15–27.
cant lab errors due to vitamin B7 (biotin) supplementation:
2. Dimitris R, Ralph D. Management of simple brittle nails:
A case report following a recent FDA warning. Cureus.
Brittle nails. Dermatol Ther. 2012;25(6):569–73.
2019, 23;11(8):e5470.
3. Gequelim GC, Kubota CY, Sanches S, et al. Perception
17. Almohanna HM, Ahmed AA, Tsatalis JP, et al. The role
of brittle nails in dermatologic patients: A cross-sectional
of vitamins and minerals in hair loss: A review. Dermatol
study. An Bras Dermatol. 2013;88(6):1022–5.
Ther (Heidelb). 2019;9(1):51–70.
4. Iorizzo M. Tips to treat the 5 most common nail disorders.
18. De D, Seshadri D. Nails in nutritional deficiencies. Indian J
Dermatol Clin. 2015;33(2):175–83.
Dermatol Venereol Leprol. 2012;78(3):237.
5. Iorizzo M, Pazzaglia M, Piraccini BM, et al. Brittle nails.
J Cosmet Dermat. 2004;3(3):138–44.
24
Nail Prostheses
Shari Lipner and Kelita Waterton
patients who have experienced the loss of their nails or distal

Introduction segment of their digits. The acrylic nails used for prosthetic
digits may be applied directly to the digit using the polymer-
Hands and nails play a crucial role in social interactions ized mixture as previously described. Patients may also use a
and communication. There are many cultural and societal preformed nail that can be glued or fixed onto a prosthetic or
implications of the hands and fingers, including their use in natural nail bed.9, 10
demonstrative displays of expression, sign language, or sub- Individuals using acrylic resin on their natural nail plate
ject of adornment. The health and functionality of the fingers, or nail bed must be cautioned of potential side effects. The
fingertips, and even fingernails can significantly impact the adhesion between the acrylic nail and the nail plate is stronger
hand’s utility and dexterity.1 Similarly, the toenails serve as than the attachment between the nail plate and the nail bed.
protection for the nail bed and contribute to the health of the This may lead to onycholysis, secondary to injury or during
toe as a whole. Both fingers and toes are subject to injury due the acrylic nail removal process, as well as other onychodys-
to trauma, infection, or other diseases that may disrupt the trophies such as onychoschizia.6, 11
integrity, appearance, and function of the nails.2 While some
patients may require or prefer surgical intervention, espe-
cially following acute trauma, surgery often does not result Dip Powder Manicure
in regaining sensation and utility or achieving aesthetically
Dip powder manicures are one of the newer methods of
pleasing results.3 There are several examples of nail prosthe-
sculpting artificial nails. The material used for this method
ses designed to emulate the structural and cosmetic likeness
is similar to the polymethyl methacrylate material used for
of a natural nail. Knowledge of the risks and benefits of these
acrylic nails.
prostheses is essential for both physicians and patients seeking
It can be applied either directly onto the individual’s natural
options for nail reconstruction.
nails or onto nails with an artificial nail tip for added length.
This mechanism involves brushing a liquid methacrylate
monomer onto the nail and then dipping the nail into a colored
Methods of Nail Prosthesis benzoyl peroxide-containing powder. This process of dipping
the nail after applying the liquid is repeated several times until
Acrylic Prosthesis the desired color, thickness, and opacity are achieved. Once
While the use of artificial nails dates back to Ancient China, the nail is smoothed with a buffer, a topcoat is then applied to
modern-day nail extensions derive from a dentist, Dr. Frederick seal the manicure and create a shiny finish. This mixture hard-
Slack, who used dental acrylic to fix a broken nail in 1957.4, 5 ens quickly and does not require curing with UV light.12 Other
Acrylic nails are temporary, hardened structures that are used techniques, such as brushing or pouring the powder onto the
to lengthen or reinforce the nails. Current techniques involve nail, rather than dipping the nail into the reusable powder, may
the use of liquid ethyl or isobutyl methacrylate combined with reduce the risk of cross-contamination between clients. While
powdered polymethyl methacrylate. The acrylic powder con- this manicure is typically done by a professional nail techni-
tains benzoyl peroxide, which acts as a catalyst and rapidly cian, dip powder kits are also available for purchase. These
polymerizes the product, and hydroquinone, which inhibits kits provide a lower-cost option, while also allowing patients
polymerization and slows down the process. This polymerized to apply the artificial nails at home (Figure 24.1b).
mixture is applied quickly since it hardens within 7–9 minutes.
It is smoothed onto the surface of either the natural nail plate KeryFlex Nail Restoration
or onto an artificial nail tip that is glued onto the free edge of
the nail plate with ethyl 2‑cyanoacrylate adhesive and forms a The KeryFlex nail restoration system, which has been formu-
template for the desired length.4, 6–8 In addition to the acrylic lated to restore the appearance of a patient’s natural toenails,
nail, individuals may opt to apply a multitude of decorative is another option for individuals with toenail loss or dystro-
elements and polish to create the desired look (Figure 24.1a). phy (Figure 24.2). While the product has not been extensively
Though acrylic nails were originally popularized in the studied, it is designed with medical-grade resin that is simi-
cosmetic industry, they have also become instrumental for lar to acrylic but designed with the flexibility to bend. The
228 DOI: 10.1201/b22897-24

Nail Prostheses 229

FIGURE 24.1 (a) Acrylic nails with decorative art; (b) Self-applied dip powder manicure.
FIGURE 24.2 Retronychia of the great toenail (a) before and (b) after KeryFlex application.
restoration system, which includes a bonding agent, resin, and and it does not attach directly to the skin. Nonetheless, it has
a sealant that requires curing with ultraviolet light, must be been used in podiatry to repair partial toenail loss and has
applied to a debrided nail. It is not appropriate for all patients been reported to last at least 6–8 weeks without necessary
since presence of at least 15% of the natural nail is required reapplication.13
230 Tex
exttbook ooff C
Coosmetic
etic D
Deermato
tollogy
Preformed Artificial Nails hand.18 Pistachio shells can serve as a single-use, disposable,
and easily accessible option to help patients with severe nail
Preformed artificial nails or press-on nails, typically made of loss to perform daily activities that require fine movements
acrylic resin, are popular options for natural-appearing nails. with the most frequently used digits.19 Other materials such
These nails may be used to lengthen short or damaged nails as sterilized X-ray films, plastic syringes, and surgical gloves
or to cover the entire nail plate.6 They are readily available have also been used as temporary prostheses to protect the nail
for purchase for patients desiring a temporary nail prosthesis. bed from further damage.20
Users may apply a methacrylate-based adhesive to the inner
surface of the artificial nail, while some nails may be pack-
aged with an adhesive coating. The individual must firmly
press the press-on nail onto the nail plate to secure the attach- Nail Prostheses Attachment
ment (Figure 24.3). These prostheses are intended to be tem- and Fitting Techniques
porary, typically designed to be worn for just a few days. These
nails are easily removed with trauma and because of the strong Cyanoacrylate Adhesive
adhesive materials, traumatic removal of the nail may lead to There are several methods that can be used to attach the pros-
onychoschizia and onycholysis.6, 11, 13 thetic nail to a natural nail bed, nail plate, or prosthetic digit.
One of the simplest techniques of prosthetic nail attachment
Polypropylene Prosthesis is with a cyanoacrylate adhesive.10 This method can be conve-
nient for some patients because it does not involve an extensive
Polypropylene materials may be used for temporary nail reapplication process and can be reattached by a manicurist or
replacement for traumatic fingertip injuries. Sterile, flexible the individual themselves. However, the gradual weakening of
polypropylene plastic obtained from saline bags can function the adhesive may cause an unpredictable separation from the
as an artificial nail while the nail apparatus is repaired.14 The attachment point. This can lead to structural damage to the
material must be cut into the shape of the individual’s nail, skin or prosthetic material.21 A more secure attachment may
fixed under the nail fold, and further secured by sutures.15 After be achieved by lifting the nail folds and inserting the nails into
several weeks, granulation tissue forms; restoring the original the crevices after applying the adhesive.9
shape of the nail and facilitating the healing process.14 Though
temporary, this material has been shown to protect the nail bed
from painful stimuli and encourages repair of the nail bed and Ball-Shaped Insertion
nail matrix as the new nail begins to grow. Polypropylene is a Prosthetic nails that are designed with a ball-like portion on the
low-cost option for patients and can be accessible to physicians inner surface incorporate interchangeability while also secur-
with access to hospital materials such as sterile saline bags.14, 15 ing attachment to a prosthetic nail bed. This method involves a
prosthetic digit that is customized with a spherical depression
Silicone Prosthesis in the silicone nail bed, which allows for the retention of an
acrylic nail with a ball-shaped projection on the inside. Once
Patients with prosthetic digits may opt to have their nails con- the prosthetic nail is customized, additional nails can be pro-
structed with silicone material. The nails can be sculpted into vided to patients so that they may interchange and design the
silicone prosthetics and pigmented to match the individual’s nail as often as desired.22 This method offers an aesthetically
natural nails. Fingernail polish may only last approximately pleasing option for individuals with an amputated digit.
a day. Patients desiring long-lasting painted nails may benefit
from acrylic resin instead.16
Lanced Sheet Technology
Miscellaneous Materials The proposed lanced sheet method utilizes a “tab and slot”
mechanism to fit an artificial nail onto the nail bed. The fab-
In addition to cosmetic and medical developments for nail ricated nail, constructed with polymeric materials such as
prostheses, other miscellaneous objects may serve as func- acrylic, contains flexible metal tabs on lateral sides. The sur-
tional low-cost substitutions. Following an injury in which the geon forms the slots by creating openings in the sides of the
avulsed nail plate cannot be returned to its original position or residual nail that correspond with the placement of the tabs on
is absent, nasogastric or Nelaton catheter splints may be cut the prosthetic nail. The nail is inserted with the tabs placed
into the shape and size of the nail and sutured onto the remain- underneath the surface of the residual nail. Finally, the tabs are
ing nail bed and nail folds. While this temporary replacement bent and inserted into the slots.21
lacks the firmness of substances such as acrylic, it is more ana-
tomically similar to the natural nail plate. It is kept in place for
approximately 3 weeks and serves as protection for the nail Snap-Fit Design
bed.17 Guitar picks and pistachio shells have also been used The snap-fit design is another proposed strategy for nail
as inexpensive options for nail prostheses for advanced nail prostheses. An artificial nail, formed from acrylic materials,
lichen planus and other causes of anonychia. An aluminum is assembled with hooks on either side. The residual nail is
guitar pick, for example, has an ideal weight, durability, and trimmed and shaped to align with the hooks of the prosthetic
flexibility for substitute nails of the first three digits of the nail. As the prosthesis is inserted, the hooks project laterally.
Nail Prostheses 231

FIGURE 24.3 Preformed artificial nails (a) with a methacrylate-based adhesive applied to the inner surface (b), must be firmly pressed onto the nail
plate (c) for secure attachment (d).
232 Text
extbook ooff C
Coosmetic
etic D
Deermato
tollogy
Once the artificial nail meets the distal end of the residual nail,
the physician applies an external force to the hooks, and they Complications of Nail Prostheses
become locked in place.21
Mechanical Damage
Thimble-Type Prosthesis While nail prostheses may be instrumental for cosmetic and
medical purposes, the application and removal process can
Individuals with deformities of the nail or loss of the distal be traumatic to the nail plate. Preparing the nail for a smooth
phalanx may use a simple “thimble” technique that covers the application may involve buffing, drilling, filing, and cuticle
third phalanx. This prosthesis can be easily slid onto the digit removal.26 Removal of the artificial nail can lead to peeling or
once it is modified to attain the best fit. An optimal thimble detachment of segments of the natural nails. This is exacerbated
prosthesis is flexible, thin enough to retain pulpal sensitiv- by improper removal methods, such as biting or peeling the nail
ity, and is designed with realistic curvatures and color of the off, inserting an object between the prosthesis and nail plate,
patient’s natural skin tone. Additional methods to create an or accidental trauma.7 The physical manipulation that occurs
inconspicuous appearance include wearing rings to conceal during these procedures may cause mechanical abrasions, thin-
the margin between the prosthesis and the digit. The proximal ning, fragility, onychoschizia, and onycholysis (Figure 24.4).13
portion of the prosthesis may end at the root of the digit or the For these reasons, individuals should not wear artificial nails
level of the posterior interphalangeal joint.23 on their natural nail plate for more than 3 months consecu-
tively. A month of rest between applications is advised.11
Osseointegration
Contact Dermatitis
Osseointegration originated in the early 1950s by Per-Ingvar
Brånemark, who analyzed the structural and functional inte- Allergic contact dermatitis (ACD) to nail products was first
gration of titanium screw placement in rabbit bone marrow. described in 1937 and to artificial nails in 1955.4 ACD is typi-
Titanium was identified as the most inert and biocompatible cally associated with acrylic materials such as methacrylate,
implant material while 10 times the strength of bone. Once nail adhesives like ethyl 2- cyanoacrylate, or nail polish.
the titanium implant is in place, a translucent nail, made with Patients may present with proximal nail fold erythema and
acrylic material, is screwed into a fixture that was inserted into edema, fingertip tenderness and swelling, and/or neck, face,
the implant.24 This method may successfully restore both the or eyelid dermatitis.4, 11 The acetone in nail polish removers,
aesthetic and function of natural nails.25 methacrylic acid in primers, alkaline substances in nail cuticle

FIGURE 24.4 (a) Traumatic onycholysis and (b) onychoschizia due to improper removal of acrylic nails.
Nail Prostheses 233
removers, and multiple substances in nail hardeners may cause 9. Bhaskaran S, Zachariah GP. Enhancing retention and
irritant dermatitis.4, 27 esthetics of fabricated silicone finger prosthesis using
stump reduction technique and customized acrylic nail: A
unique approach. Natl J Maxillofac Surg. 2022;13(Suppl 1):
Infections
S140–S144.
Bacteria adhere more easily to artificial materials in compari- 10. Arazpour M, Mardani MA, Ahmadi Bani M, et al. Design
son to natural materials. In addition, artificial nails promote and fabrication of a finger prosthesis based on a new method
the growth of bacteria and yeast. Excess moisture that becomes of suspension. Prosthet Orthot Int. 2013;37(4):332–335.
trapped between the false nail and the nail plate can promote 11. Draelos ZD. Cosmetic treatment of nails. Clin Dermatol.
growth of microorganisms. Hand washing and sanitization are 2013;31(5):573–577.
less effective at removing pathogens from artificial nails com- 12. Draelos ZD. Nail cosmetics and adornment. Dermatol Clin.
pared to natural nails.28 There may also be an increased risk 2021;39(2):351–359.
for glove perforations with longer synthetic and natural nails.29 13. Introducing a professional nail restoration system: Keryflex.
Due to the increase in the likelihood of transmitting infections, KeryFlex Nail Restoration System. https://keryflex.com/.
wearing artificial nails are not recommended for healthcare Published Apr 3, 2022.
and food industry workers.27 Furthermore, during the applica- 14. Figueiredo LA, Ribeiro RS, Melo ALB, et al. Polypropylene
prosthesis for the treatment of fingertip injuries. Description
tion process itself, improper sanitization and sterilization of
of surgical technique and results. Rev Bras Ortop.
non-disposable equipment can facilitate the spread of bacterial,
2017;52(6):685–692.
fungal, and/or viral infections between clients in nail salons.12
15. Tos P, Artiaco S, Coppolino S, et al. A simple sterile
polypropylene fingernail substitute. Chir Main. 2009;
28(3):143–145.
Conclusion 16. Buckner H, Michael JW. Options for finger prostheses.
J Prosthet Orthot. 1994;6(1):10–19.
Nail appearance and functionality have significant impact
17. Bayraktar A, Ozcan M. A nasogastric catheter splint for a
on daily life and self-perception. Acrylic nails, dip powder, nailbed. Ann Plast Surg. 2006;57(1):120.
KeryFlex, preformed artificial nails, polypropylene, silicone, 18. Gupta MK, Lipner SR. Guitar pick as a nail prosthesis
and other nail alternatives are suitable options for nail pros- for progressive nail lichen planus. J Am Acad Dermatol.
theses. There are various long and short-term attachment 2021;84(1):e3–e4.
techniques that patients and physicians can consider. With the 19. Gupta MK, Lipner SR. Pistachio nut shell as a nail substi-
wide use of nail cosmetics as a method of prostheses, patients tute to improve function in patients with nail lichen planus.
should be advised of the potential risks of the application and Int J Womens Dermatol. 2021;7(3):353–354.
removal procedures. Nail prostheses can provide improved 20. Guero S. Benefits of an ungual prosthesis in traumatol-
utility and achieve aesthetically pleasing results for patients ogy and reconstructive surgery of the nail. Tech Hand Up
with nail loss or nail dystrophy. Extrem Surg. 2014;18(1):20–24.
21. Elsheikh MEAA, Horowitz ME, Vandersea J, Giladi AM.
Novel approaches to fitting and implanting finger and nail
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nail length on the hand dexterity. J Phys Ther Sci. 2017 a toe prosthesis with paintable and interchangeable nail:
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4. Dinani N, George S. Nail cosmetics: A dermatological per- integrated finger prosthesis with a custom abutment. J Indian
spective. Clin Exp Dermatol. 2019;44(6):599–605. Prosthodont Soc. 2017 Apr–Jun;17(2):212–216.
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among Lebanese women toward hazardous chemicals used control issues. J Hosp Infect. 2001;49(2):139–142.
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25
Assessing the Efficacy of Moisturizers
Whitney Hannon
in this experiment?” and on a more advanced level, “Did this

Introduction instrument really accurately measure the variable claimed
during the experiment?” A checklist of other important ques-
This chapter gives an introductory background to practitioners tions to ask when assessing the performance and validity of an
in cosmetic dermatology who wish to better understand the instrument has been developed by Serup.2
science and data behind efficacy claims for moisturizers. In Besides the aforementioned difficulties, there are other
an age of evidence-based medicine and savvy consumers, it significant but more subtle issues that need to be taken into
is increasingly important to be able to understand, critically account. For example, moisturizers are often complex mix-
evaluate, and summarize the experiments used to evaluate the tures of ingredients that may have interactive properties. In
efficacy of moisturizers. other words, the composition of a moisturizer is more com-
One of the first challenges for the clinician is getting access plex than simply the sum of its independent ingredients.
to information about moisturizer efficacy. Most of the stud- Interactions may occur between water-binding substances3
ies are not published because they are proprietary information. and theoretically also between any of the other ingredients
Information can be requested from companies but can be time- including the vehicle. In addition, it has been observed that the
consuming to obtain. The information that is readily available individual component has different properties when measured
is often incomplete (for example, only available in abstract individually than when measured as part of a combination.4
form) or in difficult or expensive to access journals or books. In summary, the quest to obtain reliable, useful information
Once an article is acquired, the clinician is faced with the sec- on the efficacy of moisturizers encounters three main catego-
ond challenge of understanding a study that is often filled with ries of difficulties: problems with the availability/accessibility
technical jargon and unfamiliar instruments. Once the study of information, problems with the experimental design, and
is deciphered, the third challenge is for the clinician to criti- problems with the measurement technologies. Table 25.1 lists
cally appraise the validity of the information. For example, the specific issues in each of these categories and the implications
clinician needs to ask, “Was the experimental design of this that these problems could have on the interpretation and valid-
study of sufficient quality to warrant trusting the conclusions?” ity of the information. This chapter attempts to assist the busy
Examples of recommended moisturizer study designs are sum- clinician to overcome these challenges by reviewing the litera-
marized by Grove.1 A fourth challenge is that complex instru- ture, translating some of the jargon, and identifying some of
ments are often used to make skin measurements. Therefore, the most useful and comprehensive evidence-based references.
the clinician needs to ask, “Was the instrument used properly
TABLE 25.1
Problems with Moisturizer Efficacy Studies
Issues Implications
Information access Journals/books not easily accessible; full details not published Missing data, publication bias
Experimental design
Patient selection Volunteers May not be representative of consumer population.
Histories not clearly stated, age/sex not always stated Population in unknown; biased population; clinical extrapolation
is difficult
Study size Tends to be small May not have enough subjects to satisfy study objective
(insufficient power)
Controls Often inadequate Cannot account for changes during experiment
Most studies only measured on one side rather than Need to control for variation on different sides of body
contralateral side
Often not stated whether other moisturizers/beauty products Effects may be due to other moisturizers/products
were used
Often studies not blinded and no placebo group Potential for bias
(Continued)
234 DOI: 10.1201/b22897-25

Assessing the Efficacy of Moisturizers 235

Problems with Moisturizer Efficacy Studies
Issues Implications
Materials studied Materials used or concentrations not always stated Cannot compare studies easily; moisturizer effects are
presumably dose-responsive
Range of concentrations often was not studied No information on dose-response
Complex mixtures studied, not broken down into parts so that Unable to separate effects
they could be compared and evaluated
Measurements Not enough time points Gaps in information about time-course
Often did not assess both TEWL and SC at the same time Cannot make conclusions about hydration state
Three-prong approach often not used: panellist self-appraisal, Missing or irrelevant information (for example, not user-
expert grader evaluation and relevant instrumental measures centered enough and/or insufficient data from experts and/or
overreliance on instruments)
Statistics Statistics not always used to analyze data Comparisons have no scientific basis
If statistics used, p values not always stated No knowledge of level of significance
General Not enough studies No verification of findings
Few materials studied Many materials have unknown efficacy
Bioengineering
methods
Operator-dependent Potentially improper use of machines Misleading data
Some studies have no statement of ambient conditions Misleading data
Sources: Hannon W, in Textbook of Cosmetic Dermatology, Fourth Edition, Robert Baran and Howard I Maibach, eds., London: Informa Health Care,
2009. In addition, some information in the original table was derived from the text of Grove GL, in Clinical Safety and Efficacy Testing of Cosmetics, C
Waggoner, ed., New York: Marcel Dekker, 1990, 121–48.
Summary of Bioengineering Techniques Summary of Efficacy Data Based

A variety of bioengineering techniques have been used to on Study Type, Bioengineering
assess the efficacy of moisturizers on the human stratum cor- Technique, and Moisturizer Type
neum. These techniques can be divided into measurements of Gabard8 proposed a useful classification for studies on the
efficacy of moisturizers. He divides the studies into five main
1 Skin surface contour types:
2 Desquamation
3 Elasticity (parallel to skin plane) 1 Single application to normal skin
4 Elasticity (perpendicular to skin plane) 2 Multiple applications of moisturizers over time to
5 Other mechanical techniques normal skin
6 Indirect electrical properties 3 Moisturizer applied to experimentally irritated skin
7 Spectroscopy or thermal transfer (one large irritant insult)
8 Transepidermal water loss (TEWL) 4 Moisturizer applied to experimentally irritated skin
9 Stratum corneum imaging (mild irritant applied repeatedly over time)
10 Optical characterization of skin properties 5 Clinical studies in which moisturizer was applied to
groups of patients with various conditions
The Appendix to this chapter gives details of the techniques,
some of the researchers involved in the development of the To allow evidence-based comparisons, studies can be further
technology, names of different machines, variables measured, divided by the bioengineering technique used to assess the
principles behind the technologies, and their respective advan- moisturizer and types of moisturizers studied. Some of the
tages and disadvantages. more comprehensive evidence-based reviews that include these
Many authors5–6 have reviewed and compared these tech- important variables, and their conclusions are summarized in
nologies. Marks7 took a unique approach by using an arbitrary Table 25.2 and the paragraphs that follow.
scale to compare the reproducibility, sensitivity, and directness Agner9 reviewed the literature in 2002 on moisturizer effi-
of measurement, capability for quantization, standardization, cacy studies and summarized the findings. Studies reported
cost-effectiveness, ease of use, and convenience. were of Gabard study experimental design types 1, 2, 3, 4, and
TABLE 25.2
Selected Evidence-Based Reviews of Moisturizer Efficacy Data
Gabard classification of Bioengineering techniques
Review author Year studies reviewed utilized in studies Moisturizers studied
Agner 2002 1,2,3,4,5 TEWL, electrical conductance, Various proprietary formulations and others
electrical capacitance, laser
Doppler flowmetry,
colorimetry
Hannon 2004 1 Indirect electrical techniques Glycerol, urea, petrolatum, hyaluronic acid, hydrogenated
(capacitance, conductance, phosphidylcholine and others
impedance)
Agache 2006 1,2 Torsional skin elasticity Glycerol, lactic acid, petrolatum
Sivamani 2006 1,2 Mechanical (tribological) Various
Yokota 2006 3,4 TEWL, electrical capacitance, Various proprietary formulations, Dimethicone, xantham
laser Doppler, colorimetry gum, petrolatum and others
Fluhr 2008 5 (psoriasis) TEWL, capacitance, Urea, alpha-hydroxyacids (glycolic acid, lactic acid)
evaporimetry Omega fatty acids
Crowther 2009 1,2,3,4 Confocal Raman niacinamide
microspectroscopy
Bauer 2010 and 5 (occupational irritant hand TEWL, capacitance Various proprietary formulations and barrier creams
updated dermatitis (OIHD))
in 2018
Crozier 2010 2,3,4 TEWL Various proprietary formulations
Greenfield 2012 1,2,3,4,5 TEWL, capacitance, confocal Urea, ammonium lactate, lactic acid, petrolatum, various
(hand eczema and ichthyosis) Raman spectroscopy proprietary formulations and others
Hon 2012 5 (atopic dermatitis) TEWL, D-Squame®, Rosmarinic acid and various proprietary formulations
evaporimeter, stereoimage
optical topometer
Loden 2012 1,2,3,4,5 TEWL Lipids, borage oils, fish oil, petrolatum, sunflower oil,
(atopic dermatitis, ichthyosis) canola oil, urea, glycerin, mineral oil, lactic acid,
ammonium lactate, PCA, various proprietary formulations
and others
Klotz 2015 5 (burn unit) TEWL Aqueous cream BP, bees wax, herbal oil creams,
silicone-based creams, vitamin E cream, paraffin/
petrolatum/mineral oil based products, aloe vera gels
Lindh 2015 5 (atopic dermatitis, irritant TEWL, stratum corneum, Propylene glycol, lactate, ceramide, aluminum
hand dermatitis, ichthyosis hydration chlorohydrate, urea, glycerin
vulgaris)
Beeckman 2016 5 (incontinence associated TEWL Proprietary formulations containing various combinations
dermatitis) of lanolin, petrolatum, glycerin, hydrous wool fat, arachis
oil, oleic acid, and/or dimethicone
Purnamawati 2017 5 (atopic dermatitis, TEWL Natural oils (sunflower, olive, canola, fish), urea, lactic
seborrheic dermatitis, acid, alpha-hydroxy-acids, ceramides, aloe vera,
contact eczema and bisabolol, shea butter, glycyrrhetinic acid, niacinamide,
nummular dermatitis) palmitoylethanolamide, zinc glyconate and squalene
VanZuuren 2017 5 (eczema) TEWL, capacitance, Raman Filaggrin breakdown products, ceramide precursor,
Spectroscopy niacinamide, fatty acids, shea butter and others
Cowdell 2020 5 (skin integrity maintenance TEWL, capacitance Shea butter, glycerin, propylene glycol, aloe vera, various
in older people) herbal extracts, tocopherol, lanolin, and mineral oil
Hebert 2020 5 (pediatric and adult atopic TEWL, capacitance Colloidal oatmeal, ceramides, linoleic-rich plant oils, urea
dermatitis) (to upregulate ceramide production), lactic acid, amino
acids and PCA.
Arifin 2022 5 (atopic dermatitis) TEWL Ceramides, aloe vera, petrolatum, arachis oil (peanut oil)
Kelleher 2022 2, 5 (infant atopic dermatitis, TEWL, capacitance, ATR-FTIR Olive oil, sunflower oil, coconut oil, mineral oil, sesame oil,
infant diaper dermatitis, spectroscopy ceramides, paraffin, various proprietary creams, and gels
infant swimmers)
5. The bioengineering technique used in these studies was pre- Hannon10 reviewed moisturizer efficacy data up to 2004 as
dominantly TEWL. Various proprietary formulations of mois- measured by the indirect electrical techniques (capacitance,
turizers were reported in the studies. conductance, impedance) in detail and identified 20 studies of
Gabard study design type 1 (single application of moisturizer Crowther16 reviewed moisturizer efficacy data in 2009 as
to normal skin). The conclusions are summarized as follows. measured by confocal Raman microspectroscopy for Gabard
Glycerol, urea, and petrolatum were the best-studied sub- study design types 1, 2, 3, and 4. Conclusions were that little
stances. One application of urea, glycerol, petrolatum, hyal- difference was observed in moisturization on day 1. Over a
uronic acid, or hydrogenated phosphatidylcholine was capable 2-week period, use of moisturizers containing niacinamide
of increasing stratum corneum hydration for at least several was associated with increased total skin hydration. Important
hours: urea for at least 6 hours even if washed off, glycerol variables to control included osmotic changes in skin based on
for at least 6 hours even if wiped off, and petrolatum for at moisturizer properties and changes in stratum corneum thick-
least 2 hours (but not if it is wiped off). Water itself had a ness based on different types of moisturizers.
hydrating effect in the short term but eventually resulted in Bauer17 conducted a Cochrane systematic review in 2010
dehydration. The studies had many limitations, especially with on occupational irritant hand dermatitis (OIHD) treatments
regards to controls. For example, many studies did not control including moisturizers and barrier creams. Four random-
for vehicle type (a very important variable) or ingredient inter- ized controlled trials (RCTs) were identified. Bioengineering
actions. Others failed to control for the following complexities techniques for measurements were predominantly TEWL.
associated with indirect electric measurements: for example, Moisturizers studied were various proprietary formulations.
that 1) the capacitance ratio (moisturizer-treated-skin capaci- Of the four identified RCTs, one RCT18 of Gabard type 5 is rel-
tance/untreated-skin capacitance) varies over time depending evant to the current review. This crossover design RCT showed
on type of moisturizer, or 2) electrical readings are not always that during the moisturizer use phase of the study, there were
proportional to the water present depending on the substance, no cases of OIHD. However, in the control phase of the study
or 3) each component of a moisturizer has its own electrical (no moisturizer use), 19 out of 93 participants developed OIHD.
properties that can be a source of false positive results.11 Crozier19 conducted a structured systemic review of the
Sivamani12 reviewed moisturizer efficacy data in 2006 as literature published from 2000 to 2010 on skin care regimes
measured by various mechanical (tribological) techniques and for normal term infants. Nine studies of Gabard types 2, 3,
found that there were limited studies for Gabard type 1 and and 4 were identified. One study by Bartels20 of 64 full term
type 2 experimental designs. Sivamani concluded that the water newborns divided into four groups reported lower TEWL in
and moisturizers had similar effects on the friction coefficient newborns that were treated with a proprietary moisturizer
except the effects of the creams/emollient lasted for hours and compared with those treated with a control of no moisturiz-
the water effects only lasted 5–20 minutes. Important variables ing cream. The other eight studies involved washing products
in studies included the temperature of creams, anatomic loca- only without use of moisturizers and therefore were not of rel-
tion, age of patient, and design of the test apparatus. evance to the current review.
Agache13 reviewed moisturizer efficacy data in 2006 as Greenfield21 reviewed moisturizer efficacy data in 2012 for
measured by torsional measurements of skin elasticity (twist- Gabard type 1, 2, 3, 4, and 5 studies. The Gabard type 5 studies
ometry) for both Gabard type 1 and type 2 experimental study reviewed included the conditions of hand eczema and ichthyo-
designs. The conclusions were based on a limited number of sis. Bioengineering techniques used to assess efficacy were
studies. Some of the results were somewhat contradictory. In TEWL, electrical capacitance, and confocal Raman spectros-
most studies, glycerol and lactic acid had longer lasting effects copy. The following moisturizers were reviewed: petrolatum,
than petrolatum. In one study, glycerol demonstrated increased urea, lactic acid, and ammonium lactate and as well as some
elasticity up to 1 week. Other important variables noted were proprietary combinations.
an increase in skin temperature with increased elasticity. Hon22 reviewed moisturizer efficacy data for atopic derma-
Yokota14 systematically reviewed the literature published titis (Gabard type 5) in 2012. The following bioengineering
between 1992 and 2006 on the efficacy of moisturizers in the techniques were used to assess efficacy: TEWL, D-Squame®,
prevention and treatment of irritant dermatitis on normal skin. evaporimeter, and stereoimage optical topometer. Various pro-
Results were ten studies with Gabard type 3 experimental prietary moisturizers and rosmarinic acid were studied.
design. The studies included outcomes measured by the fol- Loden23 reviewed moisturizer efficacy data for Gabard type
lowing bioengineering techniques: TEWL, electrical capaci- 1, 2, 3, 4, and 5 studies in 2012. The Gabard type 5 studies that
tance, and laser Doppler colorimetry. The studies involved were reviewed included conditions such as ichthyosis and atopic
moisturizers of various proprietary formulations, dimethicone, dermatitis. The bioengineering technique used to assess efficacy
and others, as well as vehicles and controls. Conclusions from in the majority of studies was TEWL. The following moisturiz-
the quantitative analysis were that direct comparisons between ers were reviewed: borage oil, fish oil, petrolatum, sunflower oil,
studies were difficult due to study designs that involved dif- canola oil, urea, glycerin, mineral oil, lactic acid, ammonium
ferent anatomic sites and exposure durations. Two of the most lactate, and PCA as well as some proprietary formulations.
comparable studies, however, by different authors, reported Klotz24 systematically reviewed the published and unpub-
contradictory results. lished literature for randomized and pseudo-randomized con-
Fluhr15 reviewed the literature up to 2008 for moisturizer effi- trolled trials evaluating moisturizers applied to healed skin
cacy data in psoriasis (Gabard type 5 studies). Bioengineering following burn injury (Gabard type 5) up to 2015. The sys-
methods used in the studies were TEWL and capacitance. He tematic review protocol included planned extractions of des-
summarized the known studies for the following moisturizers: ignated primary and secondary outcomes including TEWL.
urea, alpha-hydroxyacids (glycolic acid and lactic acid), and The results were that only one study was eligible for inclusion
omega-fatty acids. in the review (a vitamin E cream study). The vitamin E study
did not show any significant differences between the vitamin E spectroscopy data. One reported study with bioengineering
moisturizer use group and the control group for the outcomes outcomes was for a proprietary cream containing filaggrin
of range of motion, scar thickness, cosmetic appearance, and breakdown products (components of NMF), ceramide pre-
graft size. The included vitamin E study did not report any cursor, niacinamide, fatty acids, and shea butter and showed
bioengineering outcomes such as TEWL. statistically significant clinical improvement for the TEWL,
Lindh25 systematically investigated the effectiveness of capacitance, and Raman spectroscopy outcomes for the mois-
moisturizers in Gabard 5 studies (atopic dermatitis, irritant turizer experimental group over the control group. The authors
hand dermatitis, ichthyosis vulgaris) up to 2015 and identified did not perform meta-analysis on any of the bioengineering
48 studies involving 3262 patients that were eligible for inclu- outcomes, but rather described the findings qualitatively.
sion. Conclusions were that most studies showed that moistur- Bauer30 updated his Cochrane systematic review from 2010
izers as a group had beneficial effects on clinical symptoms. again in 2018 on interventions for the prevention of occupa-
Outcomes included decreased TEWL (range 0 to −12.2 g/m2h) tional irritant hand dermatitis (Gabard type 5). An additional 5
and increased stratum corneum hydration (range +8 to +100 RCTs involving moisturizers/barrier creams were included in
%). Authors also concluded that the review at this 2018 update, bringing the running total to 9
RCTs. Some of the studies reported bioengineering outcomes
Direct comparisons between individual moisturiz- such as TEWL and corneometry. The conclusions of the review
ers are still scarce, but the clinical effect appears to have not changed significantly for this update, namely meta-
be much more well-documented for urea and glyc- analysis involving outcomes is not yet possible due to a very
erin than, for example, propylene glycol, lactate, limited number of studies with considerable data heterogeneity.
ceramide, and aluminum chlorohydrate. Compared Cowdell31 conducted a Cochrane systemic review in 2020 of
with urea studies, glycerin studies were more often Gabard type 5 studies evaluating the efficacy of moisturizers
associated with a high risk of bias. and moisturizer-containing wash products in the maintenance
of skin integrity in older people. Results were 6 studies that
Authors were not able to perform quantitative meta-analysis met the inclusion criteria. Bioengineering outcomes of TEWL
due to differences in study designs and outcome measures. were reported in 2 out of 6 studies and stratum corneum hydra-
They opted to summarize outcomes qualitatively and con- tion (corneometry) in three out of the six studies. The follow-
cluded that “the clinical effect of moisturizers is well-doc- ing ingredients were evaluated: proprietary moisturizers and
umented. Urea-based preparations may be preferable as a moisturizer containing washes/soaps containing ingredients
first-line treatment, but there is an unmet need for well-pow- such as shea butter, glycerin, propylene glycol, aloe vera,
ered comparisons between individual moisturizers.” various herbal extracts, tocopherol, lanolin, and mineral oil.
Beeckman26 conducted a Cochrane systematic review in 2016 Results were for the most part non-significant, and meta-anal-
that included moisturizer efficacy data for Gabard type 5 studies ysis was not possible due to data heterogeneity.
of incontinence associated dermatitis (IAD). There were 13 ran- Hebert32 reviewed many of the most significant moisturizer
domized controlled trials (RCTs) or quasi-RCTs identified includ- efficacy Gabard type 5 studies (RCTs and open label) for both
ing a total of 1316 participants. Conclusions were that the studies adult and pediatric atopic dermatitis in 2020. Authors present
found were not acceptable for meta-analysis due to heterogeneity the study data in easy-to-read tables that include key details
in the participant population, skin care products, procedures, out- about each study including comparisons (ingredients and con-
comes, and measurement tools. Of note, of all the data identified trols), bioengineering outcomes and results. Bioengineering
and reviewed, only one study by Byers27 (n=10) reported a bioen- outcomes reported in many of the studies include TEWL and/or
gineering technique (TEWL) as an outcome. Findings were that corneometry. Moisturizer ingredients studied include colloidal
TEWL was reduced in the skin protectant experimental group oatmeal, ceramides, linoleic-rich plant oils, urea (that upregu-
compared with the soap and water only control group. The fol- lates ceramide production), lactic acid, amino acids, and PCA.
lowing moisturizers were reviewed: various proprietary combi- Arifin33 performed a systematic review in 2022 of Gabard
nations with ingredients such as lanolin, petrolatum, glycerin, 5 (atopic dermatitis) clinical trials with primary outcomes of
hydrous wool fat, arachis oil, oleic acid, and dimethicone. TEWL. The review revealed six articles (n = 270) suitable
Purnamawati28 reviewed moisturizer efficacy up to 2017 for qualitative analysis and three articles (n = 32) with suf-
for Gabard type 5 studies for the following clinical diagnoses: ficiently homogenous data for meta-analysis. The qualitative
atopic dermatitis, seborrheic dermatitis, contact eczema, and meta-analysis showed that atopic dermatitis patients who used
nummular dermatitis. They also reviewed common moistur- ceramides had lower TEWL compared with controls. The
izer ingredients studied in these conditions including natural quantitative meta-analysis did not show statistical signifi-
oils (sunflower, olive, canola, fish), urea, lactic acid, alpha- cance. Authors concluded that this may have been due to sev-
hydroxy-acids, ceramides, aloe vera, bisabolol, shea butter, eral factors: lack of power (n=32) and measurement bias (due
glycyrrhetinic acid, niacinamide, palmitoylethanolamide, zinc to uncontrolled TEWL measurement conditions).
glyconate, and squalene. They also reported relevant bioengi- Kelleher34 conducted a Cochrane systematic review that
neering technique data including TEWL. included moisturizer efficacy data for Gabard type 2 studies of
Van Zuuren29 conducted a Cochrane systematic review in normal infants and Gabard type 5 studies of infant atopic der-
2017 that included moisturizer efficacy data for Gabard type matitis (eczema), infant diaper dermatitis and infant swimmers.
5 studies of eczema. Authors identified 77 studies that met There were 33 randomized controlled trials (RCTs) identified
inclusion criteria. Some of the studies reported one or more that included a total of 25,827 babies. Of these 33 RCTs, 13
bioengineering outcomes: TEWL, skin capacitance Raman RCTs involved the use of moisturizers. Of the 13 moisturizer
RCTs, 11 studies included bioengineering techniques as out-

comes such as TEWL, capacitance, and/or ATR-FTIR spec- Appendix: Bioengineering Techniques
troscopy. The following moisturizers were reviewed: olive oil, for Assessing Moisturizer Efficacy
sunflower oil, coconut oil, mineral oil, sesame oil, ceramides,
paraffin, various proprietary creams, and gels. Despite avail-
ability of the data, the review authors did not attempt data 1 Skin surface contour evaluation (Table 25.3)
extraction or analysis of any of the bioengineering outcomes. 2 Desquamation (Table 25.4)
It is also interesting to note that this systematic review identi- 3 Mechanical bioengineering techniques to measure
fied 11 ongoing studies of baby products (including moistur- elasticity (parallel to skin surface plane) (Table 25.5)
izers) of which nine studies included some combination of 4 Mechanical bioengineering techniques measur-
bioengineering techniques such as TEWL, capacitance, and/ ing elasticity (perpendicular to skin surface plane)
or ATR-FTIR spectroscopy. Future publications will provide (Table 25.6)
additional data for quantitative analysis and hopefully permit
5 Other mechanical properties (Table 25.7)
the meta-analysis of bioengineering outcomes eventually.
In summary, there have been some detailed reviews of mois- 6 Indirect electrical properties (Table 25.8)
turizer efficacy studies that employ bioengineering techniques 7 Spectroscopy or thermal transfer (Table 25.9)
for assessment. More work is needed to fully summarize and 8 Transepidermal water loss (TEWL) (Table 25.10)
analyze the extent of available information. Even when bioen- 9 Stratum corneum imaging (Table 25.11)
gineering outcomes have been reported in studies, they have 10 Optical characterization of skin properties (Table 25.12)
not yet been extracted for possible metanalysis. In addition, as
is evident from the recent large systematic Cochrane reviews, The tables that follow (Table 25.3 through Table 25.12) describe
many moisturizer efficacy clinical trials still do not include each technique, developer/machines, parameters measured/
bioengineering techniques as outcomes. Inclusion of standard- calculated, principles, advantages, and disadvantages.
ized bioengineering outcomes in moisturizers clinical trials
should be encouraged since this could help to reduce the het-
erogeneity of data and permit more meta-analysis.
TABLE 25.3
Bioengineering Techniques for Skin Surface Contour Evaluation
Parameters
Developer/ Measured/
Technique Machines Calculated Principles Advantages Disadvantages
Low-power surface 8× lens magnifier Skin surface Place mineral oil on skin; Can visualize epidermis, Technique has learning curve. Hard to
magnification (35) contour cover with coverslip; epidermal–dermal visualize dry, scaly skin with this
observe skin under low junction and papillary technique.
power. dermis. Easy,
non-invasive method.
Augments naked-eye
observation skills.
Profilometry Perth-o-Meter Skin surface Cast replica of skin in Replica measurements Complex and slow process. The
(Mechanical) (1971)36 contour; silicone rubber is give absolute data. Can application of silicone rubber may
Surfometer (1975)37 roughness measured with a evaluate hydration disrupt the surface; fine lines may be
Surfcom (1979)38 parameter computerized stylus status. effaced when rubber cools; scales
Talysurf (1979)39 instrument, which may be removed from subject.
Anaglypho-graphe produces plots of data. Needs a smooth, even surface (too
(1982)40 Valley and peak profile many hair follicles, scars, tattoos,
of SC flattens with detergents, skin damage, or scaling
hydration. can increase error). Stylus geometry
can introduce errors. Sources of
inter-observer variability are
high-pass filters, low-pass filters and
sampling intervals.41 Expensive.42
Profilometry can identify products
that decrease amount of wrinkles but
does not reveal mechanisms or
safety of these products (irritants,
for example, decrease wrinkling).
Results in 2D only; show
topography in one direction only.
• Acquisition time = 8 minutes
• Accuracy <10–3 mm
(Continued)

Parameters
Profilometry Corcuff (1981)43 Skin surface Cast replica of skin in Gives absolute data; Complex and slow process. The
(optical) contour; silicone rubber is operating time reduced application of silicone rubber may
roughness measured with an optical over mechanical disrupt the surface. Needs a smooth,
parameters; scanner (laser beam). method; non-contact even surface (too many hair
wrinkle sensor; 3D data follicles, scars, detergents, skin
possible; fast damage, or scaling can increase
• Acquisition time = error); also unable to measure soft,
< 1 minute fragile, liquid, high temperature
objects; does not measure in real
time; availability is limited due to
sophistication.
• Accuracy = 10–3 mm
Laser profilometry Gormley (1985)44 Contour; Photographic negative Rapid measurement of Only provides a reconstruction and
with densitometry Barton (1987)45 roughness of skin taken under skin surface relief not an exact image, so smaller
parameters; standard light (oblique without cumbersome features may be overshadowed by
wrinkle illumination with equipment.46 Good for larger ones and omitted from
quantification incident angle of 25°). following clinical analysis (Black 1998). Less sensitive
Shadows formed are progression of scaling in screening normal volunteers. Very
scanned disorders. Most slow acquisition time = 10–30
microdensitometrically accurate of all minutes. Cannot measure soft,
by a computer and gray profilometry techniques fragile, liquid objects and objects at
level assigned. The relief (10–5 mm). Can plot high temperature.
is reconstructed 105 points.
indirectly from gray level
and using appropriate
algorithms, slopes and
roughness parameters of
relief can be calculated.
Proliferometry Altmeyer (1995)47 Surface Calculates a phase image Can determine altitude at • Accuracy = 5 × 10–3 mm
(interference) Lagarde (2001)48 contour from the interference each point. Plots more
Dermatop (Eotech) fringe image projection. points (106) than any
other proliferometry
method.
• Fast acquisition =
1 minute
Transparency De Paepe (2001)49 Thickness, Measures the variation of Measures small plane Very shallow depth of field
(transmission) Skin Visiometer surface absorbance which is area of 1 cm2. Can plot (500 micrometers)
proliferometry SV600 contour related to transparency 105 points. • Accuracy = 10 × 10–3 mm
and therefore thickness • Very fast acquisition =
of the replica according <1 min
to Beer–Lambert’s law.
In vivo image Picton (1976)50 Surface Using video camera, can More objective, Inconvenient
analysis (digital Taylor (1978)51 contour record skin surface quantifiable images Technique less useful for very
image processing) Quantimet (Picton) features directly. Signal (shape, color) than dry skin
Magiscan (Taylor is digitized using a clinic notes. Interactive;
1978) high-speed analog/ can be queried, altered,
digital converter and analyzed automatically
arranged into an array of and rapidly in real time.
picture points. The Permanent record; data
picture points are easily stored. In vivo,
introduced into a digital direct measurement of
image processor that surface possible. Good
interfaces with a for evaluation of low to
minicomputer. Filters moderate dryness.
(mathematical sieves)
can be used to enhance
detail.
(Continued)

Parameters
Scanning Marshall (1983)52 Surface Low-magnification Good for the assessment Not so good for normal skin
microdensitometry contour; photomicrographs are of clinical progression assessment; still needs additional
of roughness taken under standardized in patients with scaling improvements.
macrophotographs parameters light scanned with disorders.
microdensitometer
which records shadows
and highlights and
produces a contour line
similar to profilometry.
Note: Topography measurements can be used to demonstrate changes in amount of wrinkling and state of stratum corneum hydration as noted by attenu-
ation of the relief due to increase in turgor.
TABLE 25.4
Bioengineering Techniques to Measure Desquamation53
Technique References Principles Advantages Disadvantages
Squametry of tape strippings Wolf (1936)54 Tape pressed against skin; Simple, non-invasive, Need to assure clean
Jenkins (1969)55 outermost portion of skin painless, more reproducible, conditions. Tapes not
sticks to tape and keeps objective and consistent than necessarily well
topographical relationship traditional grading systems. characterized in terms of
and desquamation pattern. component properties. Need
Tapes are processed. Scales to precut tape under clean
are sized and counted. conditions; all squametry
Samples stained and viewed techniques are better as a
with microscope (visual screen for dry skin than as a
scoring). quantitative method to assess
skin moisturizers.56
Sticky slide (Miller 1995) Goldschmidt (1967), Prepare slide by coating with More reproducible, objective Prepared slides have limited
Dermatology Lab and adhesive solution and allow and consistent than life due to gradual air
Supply Co organic solid to evaporate. traditional clinical grading oxidation of adhesive
Press on skin, leave on skin systems. Quantification/ surface. Need skill and
for a few seconds, remove standardization of practice to perform. Need
and process. desquamation possible. careful storage and handling
More quantitative than skin to prevent contamination.
scraping because fixed area
is sampled and loss of
material to air currents is
more controlled.
Skin surface biopsy with Marks (1971)57 Cyanoacrylate glue is spread Simple, non-invasive, More difficult to standardize.
microscopy on a flexible plastic slide and painless. Removes more Skill involved.
applied firmly to skin for stratum corneum than
30 sec. Three to five layers pressure-sensitive adhesives.
of corneocytes are detached,
stained, viewed under
microscope, and classified
into one of 5 xerosis
classifications.
D-Squame® (CuDerm Co, Serup (1989)58 Small transparent tape discs Simple, non-invasive, Small disc size prone to
Dallas, TX) analysis using are pressed against the skin; painless; standardized, easy sampling error. May need to
light transmission analysis of discs using light to use. delipidize skin to remove
transmission. scales.
D-Squame® (CuDerm Co, Schatz (1993)59 Small transparent tape discs Chromometry may add Image analysis can be
Dallas, TX) analysis using are pressed against the skin; additional precision. expensive but more
image analysis analysis of discs using image cost-effective machines are
analysis. being developed.60
(Continued)

Bioengineering Techniques to Measure Desquamation53
Technique References Principles Advantages Disadvantages
Adhesive disc squametry Pierard (1992)61 Small transparent adhesive Simple, non-invasive, Small disc size more prone to
combined with Zhu62 discs are pressed against painless. Allows quantitative sampling error. May need to
Chromameter (Minolta) and skin. Corneocytes stained assessments of xerosis. delipidize skin to remove
image analysis D-Squame® and viewed under Eliminates many of scales more effectively.
(see above) or DermTech microscope, and intensity of difficulties involved with Image analysis is expensive/
Smart Stickers™ stain measured with a tape and sticky slides technical luxury.63
combined with Matrix- chromameter. Quantitative because it is specially Extensive, comprehensive
assisted laser resorption xerosis (based on stain formulated and readily skin surface mass fingerprint
ionization time-of-flight intensity). Image analysis available. Three standard database needs to be
(MALDI-TOF) mass reveals number, thickness sizes. Easy storage and use. developed before this could
spectroscopy (MS) and size of squames. Simple, non-invasive, painless be used clinically.
Skin samples taken with sampling; processing of
adhesive disks are analyzed sample is quick high-
via a commonly available thoroughput and highly
analytical chemical sensitive; Developer reports
methodology (MALDI-TOF) “high accuracy” to detect
MS that has been combined skin conditions including
with automated data malignancy and that it could
interpretation using artificial eventually “partially
intelligence (AI). replace” invasive, surgical
techniques such as the skin
biopsy. MALDI-TOF MS is
already reportedly “widely
available” in clinical
laboratories.
TABLE 25.5
Mechanical Bioengineering Techniques to Measure Elasticity (Parallel to Skin)
Technique Developer/Machines Principles Advantages Disadvantages
Extensometry Material constants Extensiometer ® The arms of two strain Can be hand-held. In Strain gauges are stiff,
Thacker (1977)64 gauges are stuck to the vivo measurements and may impose
Gunner (1978)65 skin surface using possible. frictional forces. Some
adhesive tape. By means systems are bulky and
of a lead screw and not convenient for
carrier, a motor and gear clinical use. Technique
combination moves one deforms fiber network
arm away from the other in skin so sequential
at a constant rate, measurements may be
stretching the skin increasingly effected
between the tabs. The by prior
separation of tabs is measurements.
measured with a linear
variable differential
transformer (LVDT)
transducer, and the force
developed in the skin is
measured by strain
gauges attached to the
reduced sections of the
arms. Recoil apparatus
can be installed to
measure extension–time
characteristics of skin
when deforming force is
removed.66
(Continued)

Gas-bearing Dynamic spring rate Hargens (1977) 67 GBE measures Good for quantifying May measure dermal
electrodynamo-meter (DSR) (analogous to displacement of skin in stiffness in surface components as well.
(GBE) Young’s elastic response to a rapidly plane of skin, i.e. SC. Changes perceived by
modulus); loss angle oscillating force placed High degree of trained subjects may
(stiffness, softness, next to its surface. correlation between not correspond to
and compliance) Dynamic stress–strain elastic modulus GBE measurements.
loop appears on measurements and Manual stretching of
oscilloscope, which can visual assessments of skin can change
be analyzed. Application skin by a trained grader. baseline. Thickness of
of moisturizer to the skin Sensitive enough to SC, size, and
surface results in a measure changes in SC geometric
decrease in the DSR and induced by topically arrangement of
a concomitant increase in applied agents or corneocytes, and
the loss angle. mechanical disruption chemical composition
(Hargens 1977). Can differences may
apply small forces. influence
Measurement is direct measurements
rather than implied (Hargens 1977).
from inference, as is the
case with electrical
conductivity or sonic
propagation.
Linear skin rheometer DSR Matts et al (1998)68 Has the same measuring More compact, efficient Not readily available.
(LSR) principles as GBE but with greater inherent Technique deforms
none of the components. accuracy than the GBE fiber network in skin
Instead of a magnet/ and reduced service so sequential
solenoid as in the GBE, requirements. It can measurements may be
there is a force- differentiate between increasingly effected
controlled miniature DC varying degrees of SC by prior
servo, gearing, and lead hydration.69 measurements.
screw. Instead of the
linear variable
differential transformer,
there is a calibrated load
beam. The machine
interfaces with a portable
computer containing
user-friendly software.
Torque meters Torque and phase Vlasblom (1967)70 Disc attached to skin with Sensitive in both Standardization not yet
(disproportional angle-extensibility Finlay (1970);71 adhesive. Weak, constant short- and long-term complete (Salter
strain measurements) (resistance to stretch), Twistometre® torque applied to rotating studies rating hydrating 1994). Technique
viscoelastic properties (Leveque, disc. Movement of disc efficacy. Clear deforms fiber network
L’Oreal); Dermal monitored by rotational correlation between SC in skin so sequential
Torque Meter® sensor. Fixed guard ring extensibility and measurements may be
(Dia-Stron Ltd, delineates area. When severity of dryness. increasingly effected
Andover, UK) distance between disc Measurements made by prior
Barbenel (1977)72 and guard ring is less parallel to skin surface, measurements.
than 1 mm, extensibility so effect of links
reflects SC resistance to between dermis and
stretch. Microprocessor hypodermis are
computes main minimized. Can be
parameters. Immediate used to describe
rotation corresponds to mechanical changes in
immediate extensibility, skin with aging, sun
followed by slow exposure, and
increase corresponding scleroderma (73).
to “creeping” of the Weibull or extreme-
viscous and plastic skin value distribution is
characteristics. more accurate and
sensitive than other
torsion methods (Salter
1994).
(Continued)

Mechanical impedance Point impedance Franke (1950) 74 Impedance head is Can study elastic tissues Technical difficulties
Von Gierke mounted on an or viscous parameters still need to be
(1952)75 electromagnetic actuator in living soft tissue. overcome. Technique
Swept-frequency or shaker, which is driven deforms fiber network
viscoelasto- by a swept sinuisoidal in skin so sequential
meter76 voltage. Corrected force measurements may be
and velocity signals are increasingly effected
inputed into RMS by prior
circuits and then to a measurements.
log-ratio amplifier to
obtain output
proportional to log
mechanical impedance.
Phase angle between
force and velocity signals
obtained via a phase
meter. Phase angle and
log-impedance used as
vertical drive signals to a
multichannel display
multiplexor on an XY
storage display
oscilloscope. Horizontal
drive obtained from
frequency to voltage
converter and log-
amplifier. Thus real-time
plots of log Z vs log of
frequency can be
obtained.
TABLE 25.6
Mechanical Bioengineering Techniques Measuring Elasticity (Acting Perpendicular to Plane of Skin Surface)77
Parameters
Technique Measured/Calculated Machines/Developer Principles Advantages Disadvantages
Suction chamber Stiffness (distensibility, Cutometer (SEM 474 A suction probe is applied More useful for Type of strain measured
(disproportional resilient distensibility, (Courage and vertically on the skin with cosmetological purposes, may be irrelevant to
superficial hysteresis); elasticity Khazaka); Cutometer® a constant pressure. The which aim to measure common practice. May
strain) (relative elastic 580MPA78 amount of skin elevation mechanical properties of still measure mechanical
retraction [RER]) is measured using an epidermis and papillary properties of the deeper
optical system, which dermis. Measurements layers of dermis and
measures the decrease in can be enhanced by use subcutis to an unknown
intensity of an infrared of optical elastography.79 extent; limited in range
beam. The instrument Cutometer® 580MPA was of viscoelasticity;
interfaces with an IBM developed for use on the complex measuring units;
personal computer, and foot. data can be difficult to
standard software interpret; cannot measure
provided allows the viscoelasticity of more
storage of data rigid skin; cannot
concerning important evaluate skin
variables and graphical anisotrophy; seforms skin
display of stress-vs-strain making sequential
and strain-vs-time curves. measurements difficult.
(Continued)

Parameters
Suction chamber Material constants Grahame (1970);80 A suction probe is placed Larger probe is more Correlation of separate
(proportional (stiffness, resilience, Gniadecka, Serup directly on the skin. An useful for medical and parameters of skin
full-thickness distensibility); (Dermaflex A, electronic sensor in the dermatological mechanical properties
strain) hysteresis; elasticity Denmark),81 Serup probe measures the applications, for example with structural elements
(RER) (Dermalab)82 amount of skin elevation in scleroderma and of skin not fully
by measuring the electric chronically inflamed skin; elucidated. Must control
capacitance between the Dermalab can be mounted for numerous biological
skin surface and the with special probes to and environmental
electrode placed in the measure TEWL and skin variables.84 Must avoid
top of the suction hydration as well. repeated measurements
chamber. The data are at same site for at least 1
collected and can be hour due to skin
visualized. Skin deformation.
distensibility and
hysteresis increase
slightly after epidermal
moisturizing.83
Dermagraph Distensibility, Sclerimeter®85 A vacuum probe is placed Good intra- and interrater Not readily available,
relaxation, and Dermagraph86 on skin. Constant vacuum realiability. Able to some anatomic areas
elasticity is applied for 6 sec and measure accurately and more difficult to measure
the amount of aspirated rapidly different areas reliably; normal skin
skin (mm) is measured relevant to patients with more difficult to measure
(distention phase). There scleroderma. reliably. Deforms skin,
is then a 4-sec phase of making sequential
slow relaxation (elastic measurements difficult.
retraction).
Levarometry, Index of deformability; Levometer: Dikstein The skin is attached (using The method is sensitive Not currently
tonometry skin extensibility (1979)87 and Gartstein Perspex disc and double and reproducible. Topical commercially available.
(skin slackness); (1990)88 adhesive tape (Dikstein), applications or Deforms skin, making
biological elasticity Tonometry; Pierard or cyanoacrylate environmental conditions sequential measurements
(1980)89 (Pierard), or vacuum probably do not affect difficult.
(Gartstein) with (Pierard) measurements.90
or without (Dikstein) a Highly discriminating
guard ring) to a between old and young
counterbalanced skin and old female and
measuring rod. Different old male skin.
weights can be applied,
elevating the skin. For
Dikstein’s levarometer,
the rod is attached to a
linear variable differential
transformer, and this
output is recorded
graphically.
Ballistometry91 Coefficient of Tosti (1977)92 Measurement of a drop Non-invasive. Easy to use. Cannot obtain data on
restitution (amount of Ballistometer impact of a body onto the No probes attached to status of stratum
energy returned to the Integrated Dynamic skin skin. Instrument is corneum, as one can
tissue) Rebound Analyzer cheaper than from shear measurement.
(IDRA) PC-based dynamometer. Good for Gives only an indirect
ballistomer93 measuring elastic indication of underlying
parameters in deeper tissue changes.
dermal structures. Can Deforms skin, making
measure differences in sequential measurements
elastic modulus between difficult.
young and old, various
body sites and changes
after pharmaceutical
treatment. Can obtain a
lot of data quickly.
(Continued)

Parameters
Indentometry 94 Skin compressibility Schade (Elastometer, A circular piece of plastic Good for measuring water Not the best method to
1912); Kirk (1949); material attached to a state of ground discriminate between old
Tregear (1965); weighted metal rod is substance–elastin network and young skin or female
Robertson (1969); applied perpendicularly to in dermis; most useful in and male skin.
Daly (1974); Pierard the skin to indent the evaluating edematous Deforms skin, making
(1984); Dikstein skin. The rod is skin conditions and sequential measurements
(1981) counterbalanced so that altered water handling of difficult.
Commercially available the net pressure in the the dermis.
models include: system is a given value.
The measuring rod is
1) Durometer Model
loaded with specially
1700 (Rex Gauge
constructed weights
Company, Inc.,
increasing the baseline
Glenview, IL, USA).
pressure to the desired
2) Indentometer
level (Dikstein 1981). The
IDM 800 (Courage &
rod is attached to a linear
Khazaka, Cologne,
variable differential
Germany) which
transformer, and the
can be connected
output of the deformation
to a multiprobe
adapter CutoMPA 580 curve can be plotted using
(Courage+Khazaka). various methods.
3) Skin ElastiMeter/
Skin FibroMeter
(Delfin Technologies,
Kuopio, Finland).95
TABLE 25.7
Other Mechanical Bioengineering Techniques
Parameters
Measured/ Machines/
Technique Calculated Developer Principles Advantages Disadvantages
Coefficient-of- Coefficient of Rotating wheel Friction of human skin in vivo Good for screening Interpretation of differences
friction devices friction (Teflon Newcastle can be measured by topicals for after-feel in frictional properties
(oiliness/ friction meter); determining how much force is greasiness (96). Some between products are very
greasiness) resolving ground required to drag object across machines are portable. complex. Moisturizers can
glass disc; sliding skin surface; smoother or drier Measurements with increase friction as a result
sled, modified skin theoretically needs less Newcastle machine can of increased contact area.
viscometer force. correlate with sensory Lubricants make skin
scores of smoothness. more slippery.
Scratch-resistance Hardness, Prall (1973)97 A stylus just visibly scratches Can reveal underlying Somewhat invasive.
test softness skin; measure lowest pressure defects not seen at first
load. glance.
Durometer (98) Hardness Durometer model A calibrated gauge with spring Very simple to use, Measurements should be
1700 type 00 (Rex loaded interior that senses portable, hand-held; made in the supine
Gauge) 99 hardness by placing an highly reproducible. position. May be
indentation load on the Good for measuring insensitive in areas with
specimen. It registers linearly scleroderma, decreased subcutaneous
the relative degree of hardness lipodermatosclerosis, tissue.
on a scale of units 0–100. and neuropathic foot
hyperkeratosis.
(Continued)

Other Mechanical Bioengineering Techniques
Parameters
Measured/ Machines/
Technique Calculated Developer Principles Advantages Disadvantages
Microindentometer Pliability, Indentometer Indentation of the SC by a needle One of the few devices Must immobilize area that
hardness (Guibarra, 1979)100 is opposed by the horny layer, available to measure is being measured since
Microindentometer and this force of reaction is pliability and hardness movement or vibration
(Graves, 2002)101 monitored by a force of SC. will alter measurements.
transducer. Needs further
development to eliminate
inertial artifacts.
Acoustic Softness, Tronnier (1952)103 Vibration device in audible range Can be used as predictive Thickness of horny layer,
spectrometer102 hydration level; Potts (1985)104 gives small-amplitude measure. Indirect thickness and tension of
energy loss of Torgalkar (1981) oscillations normal to skin measure of hydration the skin and nature of
viscous surface with second stylus as state. Correlated with underlying tissues can be
component of comparison. Spectrum analyzer subjective assessments sources of error.
skin; elastic can calculate time for shear of moisturization.
modulus waves to travel and degree of
amplitude dampening;
resonance frequency can be
measured. The more SC
hydration, the lower the
resonance frequency. Energy
loss can also be calculated. Can
be used as predictive measure.
Indirect measure of hydration
state. Correlated with subjective
assessments of moisturization.
Viscoelasticity Elasticity, shear Sarvazyan (1990)105 Probe consists of three Allows anisotropic Not readily available.
skin analyzer waves Vexler (1999)106 piezoelectric transducers measurements; compact;
(VESA) propagation (central transmitter with two portable, user-friendly;
(SWP) receivers equidistant on either high accuracy;
side). Transmitter produces a reproducible readings;
tangential oscillatory measurements using this
deformation on the surface of technique do not deform
the skin (SWP) in the acoustic the skin as with
frequency range. SWP is distortion, rotation,
calculated from the time of stretch or suction so
flight of signal to transmitter. sequential measurements
Average reading displayed on are possible; allows
LCD. measurements of upper
skin layers without
influence of subdermis.
Tactile sensor Changes in (Omata 1999)108 Sensor with resonant frequency Simple; allows rapid Significance of correlation
(Venustrom®)107 resonant (Sakai 2000) is pressed and released from the determination of needs further
frequency (Δf) skin at a constant rate. Depth multiple stiffness investigation.
correlate with and pressure are determined parameters; correlated
spring constant allowing hysteresis curve/Δf with firmness
k and stiffness; calculation. (dehydration of skin),
elasticity ratio of acidic amino
acids, and elasticity.
Cohesography Intracorneal Nicholls (1971) After hydrating the SC, there is a Able to assess hydrating Not generally commercially
cohesion Marks (1977) drop in intracorneal cohesion. agents. available (Marks 1982).
measurements Drop follows same magnitude
as flattening in surface contour,
and changes are of same order
of magnitude (Marks 1982).
Reviscometer®109 Resonance RVM600 RRT is inversely related to skin Better able to Sensitivity may differ
running time stiffness. discriminate between depending on anatomic
(RRT) experimental treatments site.
than cutometer.
Measurements most
sensitive on transverse
forearm.
TABLE 25.8
Indirect Electrical Bioengineering Techniques
Low-frequency Clar (1975) 110 Impedance drops with increasing Low frequencies give most Need liquid junction. Electrodes
impedance hydration. Frequency-domain informative data about are occlusive. Long time needed
(frequency approaches examine the response physiological condition of skin for data collection (>20 min).
domain) of skin to sinusoidal stimulating overall because charge carriers Agents other than water can
frequencies. can travel more time before lower impedance. Measurements
field reverses (Salter 1994). are quantitative rather than
qualitative.
High-frequency Tregear (1965)111 Impedance drops with increasing Provides information on deeper Occludes site. Depth of SC not
impedance hydration. Impedance decreased levels of skin; can use dry well defined. Agents other than
(3.5 mHz) with increasing frequency. Higher electrodes. water can affect readings.
(frequency frequency, more skin penetration. Pressure of probe and dermal
domain) irritants can influence readings.
Cannot measure resistance and
capacitance separately at high
frequencies.
Impedance Nova DPM-9003 (Dermal Integrates selected measurements Good for assessing highly Less sensitive for grading the dry
(capacitance Phase Meter) at varying frequencies of the hydrated skin due to low state than the Corneometer.113
calculated) applied alternating current. variability of readings.112 Due Agents other than water affect
Capacitance is calculated from to monofrequency approach, measurements.
the signal phase delay using a subject to less error, less
proprietary chip. Final readout is confounding variables, and has
in arbitrary units related to increased sensitivity and
capacitance. specificity (less false-positives
and false-negatives) when
compared with single-
frequency machines; handling
easy due to small dimensions
and low weight.
Impedance Surface-characterizing Impedance is dependent on tissue Uses the intrinsically more Same disadvantages as with many
(surface impedance monitor hydration, composition, and informative multifrequency electrical methods. Must use
characterizing) (SCIM) (Servo-Med, condition. SCIM measures approach, which is independent probe correctly (perpendicular,
Sweden); impedance magnitude and phase of changes in sweat gland with correct pressure); wait 5s
SkinUp® Beauty Device at 31 frequencies to 5 selectable activity, skin temperature, between repeating measurements
(portable)114 depths. confounding variables. Allows on same site to avoid occlusion.
electrical impedance Measurement failures with wet
spectroscopy of selected layers. surface, dirt. Must perform
measurements under appropriate
ambient conditions (<22°C
and = 60% RH).
Capacitance Corneometer (Courage and Capacitance increases with Easy to operate. Highly Confined to measurement of
Khazaka, Germany) increasing hydration. The reproducible (Black 1998; variation in SC between initial
Portable Skin Hydration Corneometer uses variable Distante 1995). Short and final states (Black 1998).
Sensor Patch (SHSP) frequencies in the low-frequency measuring time (1 s). Poor sensitivity to hydration
(L’Oréal Research & range (40–75Hz); <75 dehydrated Economical (Distante 1995). process taking place in SC of
Innovation Dpt, USP skin; 75–90 skin with tendency to Useful for extremely dry scaly normal skin because optimal
Indicator Solutions and dehydrate, >90 normal skin skin. Information can be range of water content in the SC
AIT) that connects to (arbitrary units) (Black 1998). enhanced and non-homogeneity for the capacitance method is
smartphone app via Near of skin can be accounted for by much lower than for high-
Field Communication using capacitance images for frequency conductance methods.
(NFC).115 example SkinChip.116
Conductance Skicon 100, 200 (Masuda, Uses a fixed frequency (3.5 mHz) Dry electrodes can be used. Single-frequency approach
IBS Co, Ltd) to measure conductance and Correlates well with water subject to more error,
capacitance separately. content of superficial and deep confounding variables,
SC layers. Suitable to assess the decreased sensitivity and
hydration dynamics of the SC specificity (increased false-
induced in the skin. Not positives and false-negatives)
affected by electrolyte-rich when compared with
solutions.117 multifrequency machines (Salter
1994). Current must propagate at
least 5 mm to obtain reliable
values.
(Continued)

Indirect Electrical Bioengineering Techniques
High-frequency Jacques (1979)118 Dielectric probe response (DPR),119 Detects quantitative differences. DPR is not a true hydration
microwave Wavetek 1005 a percentage based on the probe’s Rapid quantification. percentage.
(GHz) response to skin versus a drop of Unaffected by topicals. SC
water. A signal swept several probe depth varies. DPR basic
mHz around a GHz resonates in a unit is useful for comparisons.
cable. Charged grid contacts skin,
water absorbs energy and
produces a standing wave shift,
detection of which is adjusted to
be linearly proportional to
hydration level.
Millimeter Alexseev, Szabo, Ziskin Analysis of reflection of millimeter Good for measuring areas of Not so sensitive for areas of thin
wave (2008)120 (mm) wavelength electromagnetic thick stratum corneum such as skin.
reflectivity waves. Amount of reflection palms in vivo.
depends on electric property of
skin (permittivity). Permittivity
depends on free water content of
skin. Free water content can be
calculated from permittivity
values using skin mode (Alexseev
et al. 2008).
Note: The general advantages of these techniques are that they provide easy to measure, continuous data on skin hydration status and are readily available
commercially.
TABLE 25.9
Bioengineering Techniques Based on Spectroscopy or Thermal Transfer
Fourier-transformed 1970s Beam of polychromatic IR light is In vivo, direct measurement Expensive. Need signal
infrared spectroscopy shone through a zinc or germanium of water. Quantitative, averaging during time when
(ATR-FTIR) selenide crystal applied to skin theoretical relationship site is occluded, since water
(attenuated total surface. Crystal creates 5–20 between measured content changes during
reflectance) reflections, and absorption cycles parameter and water measurements. Depth of
between crystal and skin. Reflected concentration understood. penetration can vary with
beam is detected by Can measure the change in parameters. Bands from
spectrophotometer, Fourier the structure of lipid interfering substances could
transform of beam gives IR lamellae (a determinant of obscure amide bands. IR
spectrum with bands of absorption stratum corneum beam is weak (5–20 μm)
in SC. Ratio of areas of amide I and permeability), carboxylate penetrator. Data only pertain
II bands (peaks) provides relative levels (markers of natural to superficial SC.
SC water content. Amide I at 1645 moisturizing factor levels
cm (Christensen 1977) is (NMF) and filaggrin (FLG)
overlapped by band of protein- expression).
associated water, and thus will
change with protein water content,
whereas amide II at 1545 cm
(Gunner 1981) is not influenced by
water (Black 1998).
(Continued)

Thermal Sensing with Madhvapathy 2020121 The SHS measures the thermal Low-cost production will Data can be sometimes be
skin hydration sensor Foreman (1970s, in properties (conductivity k and allow broad distribution to challenging to interpret
(SHS) vitro);122 Cuono (1988, diffusivity α) of the skin using the both clinicians and patients; because the thickness of the
Magnetic resonance in vitro); Klein (1988, transient plane source (TPS) Measures up to 1 mm epidermis is a variable that
spectroscopy in vitro); Zemtsov technique. The SHS is soft, thin, depth; Do not need to cannot be inferred from the
(MRS)/nuclear (1989, in vivo) wireless and battery free. It can be control application pressure thermal data and can vary
magnetic resonance used on all body locations and in as with conventional considerably between
spectroscopy diverse clinical environments; corneometry; Developer anatomic locations, different
(NMR-S) Transmits to any standard reports that average people and disease states. Still
smartphone using wireless Near repeatability error only 5% experimental. Expensive.
Field Communication (NFC) compared with 14.4% for Limited availability. MRI
integrating with an easy-to-use TEWL-meters and 30% for images prone to motion
custom software application. Corneometers. Gives artifacts. Underlying tissue
Same principles as MRI apply except information about presence may cause data
that the magnetic resonance signal of chemical species as well contamination. Not portable;
is used to construct a magnetic as environment in which heavy measuring apparatus
resonance spectroscopic spectrum. these materials exist and limits measurement to
MRS spectra can be obtained from how this is changing over forearms only.
protons as well as 13C or 31P. 31P time. Quantifies hydration
provides information about in both epidermis and
intercellular pH, tissue turnover superficial dermis.
rate, and tissue bioenergetics (ATP, Metabolic, functional, and
Pi, phosphocreatine). structural information is
possible. May be able to
quantify specific tissue
composition of hemoglobin,
melanin, elastin; more
precise and reproducible
than capacitance or TTT;
one of the few direct
methods; considered a
reference technique.
Near infrared Putnam (1972)123 NIR penetrates deep into skin. Two Gives information on Topical agents may introduce
spectroscopy (NIR) Osberghaus (1978)124 absorption bands are used at 1100 molecular constitution of error. Complicated and costly.
Rigal (1992)125 nm (minimal skin absorbance) and skin. Measures stratum Abrupt relative humidity
NIRS5000 1936 nm (strong absorption band by corneum, epidermal and variations may introduce
Spectrophotometer water molecules). The difference in dermal water. Under certain error.
absorbance at the two wavelengths conditions, exact
is well correlated to clinical scores quantitative relationship
for skin dryness. between IR absorption and
water concentration in the
stratum corneum (Potts
1983). Can be used in
clinical studies with the
fiberoptic probe
(Smartprobe™) to calculate
changes in % relative
humidity. (%RH).126
Permits avoidance of
chemometric manipulation
in data analysis (needed in
most other techniques
used). Direct correlation
with visual dryness
assessment scores. Had
better linear regression for
%RH scores when
compared with conductance
and visual dryness scores
(Kilpatrick-Liverman 2006).
(Continued)

Multiphoton laser DermaInspect® Femtosecond near-infrared (NIR) Non-invasive, ultrahigh Expensive.
tomography Konig, Riemann laser scanning system based on subcellular resolution up to
(2003)113 two-photo excited autofluorescence. 200 μm.1 (Taylor 1978).
Nonlinear induced autofluorescence Compact. More consistent
comes from endogenous results than cutometer and
fluorophores such as NAD(P)H, reviscometer.128
flavins, elastin, porphyrin, and
melanin. Addition of second
harmonic generation (SHG) can be
used to detect collagen.
Fluorescence lifetime imaging
(FLIM) allows 4D imaging (3
dimensions plus time).127
Photo-acoustic Rosencwaig (1977)129 Skin is exposed to IR radiation Can quantitatively measure Not readily available. More
spectroscopy (PAS) Campbell (1979) (heat). Depth of penetration of a in vivo, and no contact technical developments
Simon (1981) periodic heat wave into a solid needed between probe and needed.
depends on its frequency. Radiation skin. Good for investigation
is absorbed by water in the SC at of the horny layer.130 One of
that depth. The superposition of the most depth-sensitive
thermal waves causes periodic methods.
temperature/pressure fluctuations at
the surface of the skin, which can be
detected as sound by a microphone
in a closed photoacoustic cell.
Signal produced depends on both
optical and thermal properties of a
sample.
Optothermal infrared (Frodin 1988)131 Technique derived from By varying the chopper Not possible to determine
spectrometry (OTIS) photoacoustic spectroscopy, based frequency, IT IS possible to absolute values for skin water
on detection of heat generated in a measure at different content.
sample due to absorption of periodic thicknesses of the stratum
monochromatic radiation with a corneum.
wavelength of 1940 nm, a specific
absorption band for water. The heat
is conducted to a sapphire plate in
contact with the skin and
transparent to the radiation directed
to the test area. The plate expands
and is transformed to an electrical
signal by an annular piezo-electric
crystal cemented to the plate’s edge.
Transient thermal Soumet (1986)132 TTT is the property of one body Precise measurements at In vivo repeatability coefficient
transfer (TTT) (Hydrascan exchanging heat with another when different depths is possible; of variation is not as good as
(Laboratoire they are in contact. The skin explores deeper depths than MRI but better than
Dermscan France) temperature is measured. capacitance. Small sensor capacitance. Analytic
A stimulator then generates a size allows measurements variability is not as good as
thermal pulse that propagates on lips, eyes, nails which capacitance or MRI; indirect
through the epidermis to be picked are not possible with either technique; slow data
up by a sensor. The difference in capacitance or MRI. acquisition because requires a
temperature is proportional to water minimum of 10 minutes per
content. The signal is analyzed and depth measured.
processed with electronic and data
processing equipment. A series of
three successive thermal pulses
from three increasing powers
provides hydration measurements
from three epidermal depths.
TABLE 25.10
Bioengineering Techniques to Measure Transepidermal Water Loss (TEWL)133
Machine/Developer Principles Advantages Disadvantages
Evaporimeter Probe with two pairs of humidity Can evaluate products whose mode of Strictly speaking, does not measure
(ServoMed, Sweden) transducers and thermistor measures action is occlusion. Accurate. Convenient skin hydration. Many factors can
the partial water vapor pressure at to use. Inexpensive to operate (Marks affect measurements, and they
two points (3 and 6 mm) above skin. 1982). need careful monitoring.
Rate of evaporation (g/m2/h) Evaporimeter may underestimate
calculated from difference in partial water evaporation rate at high
water vapor pressure between these TEWL (Barel 1995).
points. Probe has surface area
1.13 cm2. Normal TEWL between 2
and 5 g/m2/h.
Tewameter (Courage-Khazaka Same principle of measurement as More recent design; measures probe Strictly speaking, does not measure
Electronic, Germany) Evaporimeter except sensors are at 3 temperature and graphs TEWL over time; skin hydration. Many factors can
and 8 mm above skin, and probe has more complete, somewhat more affect measurements, and they
surface area of 0.79 cm2. convenient, less sensitive to air turbulence need careful monitoring. Newer
than Evaporimeter (Barel 1995). instrument, so less well studied.
Derma Lab® Similar to ServoMed Evaporimeter. Convenient monitoring of evaporative loss Possible additional increased
System with TEWL and Probe is open cylinder placed rates in real time so any undesirable expense and complexity.
computerized evaporimetry perpendicular to skin site. Sensors at influences due to air currents, probe
(Cortex Technology, fixed distances. Can be stand-alone movements are readily apparent and their
Denmark, 1999)134 or equipped with personal computer impact on measurements instantaneously
interface. determined as well as retrospectively
analyzed. Increased reproducibility and
sensitivity.
VapoMeter (Delfin Uses unventilated chamber method of Closed chamber technology allows more Problems with water vapor
Technology Ltd, Finland)135 measurement. mobile, flexible use of instrument. Less accumulation as with all closed
vulnerable to external air movements. chamber techniques.
Self-contained battery powered.
Aquaflux (Biox Systems Ltd, Uses condenser-chamber method of Closed chamber technology allows more Problems with water vapor
UK) (Imhof 2009)Hydration measurement.Portable moisture mobile, flexible use of instrument. Less accumulation as with all closed
patches meter that measures TEWL. Some vulnerable to external air movements. chamber techniques. Somewhat
GPSkin Barrier® (Ye 2019)136 models can also measure Benchtop sensors protected from less mobile than VapoMeter.
temperature and stratum corneum contamination and can maintain Needs further study for validation
hydration that correlates with measurement geometry. on disease states such as atopic
electrical impedance/capacitance Semi‐closed chamber model; Data sent to dermatitis.137
(Corneometer) gold standard. Smartphone via Bluetooth. Correlates
with gold standard Tewameter;
affordable, reliable, versatile; can be
operated by patients.
TABLE 25.11
Bioengineering Techniques to Image Stratum Corneum
Developer/
Technique Machines Principles Advantages Disadvantages
High-frequency Alexander (1979); A (amplitude) mode can measure the Good for whole-skin Difficult to measure water
(20mHz) Muller (1985); thickness of the skin layers. Adaptations visualization. Can quantitatively from images.
ultrasound, machines: to skin need a strongly dampened differentiate epidermis from Motion creates artifacts.
A mode DUB20 (Taberna high-frequency ultrasound detector with dermis in some cases. Can Encoding process can distort
pro medicum, very short impulses produced by ceramic follow aging, sunlight space. Difficult to visualize very
Germany); or piezoelectric polymer transducers in damage, scleroderma, thin sites.
Dermascan C order to detect as many echoes generated steroid atrophy.
(Cortex from as many interfaces as possible. The
Technology, receptors made up of a device protecting
Denmark)138 against emitter overcharge, a wide-band
radiofrequency amplifier, and a detector
of radiofrequency signals. Signals are
viewed on an oscilloscope.
(Continued)

Bioengineering Techniques to Image Stratum Corneum
Developer/
Technique Machines Principles Advantages Disadvantages
High-frequency DUB20 (Taberna In B (brightness) mode, a succession of Useful to measure thickness Difficult to measure water
(20 mHz) Pro Medicum, signal lines in A mode is acquired and and depth of skin cancers. quantitatively from images.
ultrasound, B Germany); reconstructed into a 2D image. B scans Appearance of non- Motion creates artifacts.
mode Dermascan C are oriented in the x or y direction. echogenic band in upper Encoding process can distort
(Cortex dermis may be more space. Information on how
Technology, sensitive marker of aging ultrasound waves carry
Denmark) than skin thickness. information on skin elastic
(El-Gammal Distinguishes skin irritation properties cannot yet be
1993) versus allergic reactions. interpreted. More research
Ultrasound waves needed
theoretically carry
information on elastic
properties.
High-resolution Hyde (1987)139 Conventional MRI equipment adapted to More adapted to visualization Errors introduced by very short
magnetic Querleux and reduce field of view and pixel size using of whole skin. Epidermis T2, chemical shift and
resonance Bittoun (1988)140 surface coils. Small surface can be clearly delineated and partial-volume effect can
imaging (MRI) (Skin Imaging radiofrequency coil to improve the analyzed to an axial spatial overestimate epidermal
Modele, France) signal-to-noise ratio. Bittoun made resolution of 35–70 μm. thickness. Artifacts also caused
further advances by using the device with Able to measure water by motion and spatial distortions
a 1.5T system, obtaining very high- directly and quantitatively in introduced by encoding. Clinical
resolution images of normal skin as well vivo. Can study proton- utility limited by high cost,
as calculations of T1 and T2.141 exchange phenomenon. cumbersome equipment.
Repeated measurements
over time in vivo.
TABLE 25.12
Optical Techniques for Characterization of Skin Properties
Machines/
Technique Developer Principles Advantages Disadvantages
In vivo confocal Petran (1968); A focused spot of light scans the Excellent axial (spatial) resolution Artifacts caused by motion
microscopy/confocal Corcuff (1993); sample. Reflected light in focal (1 μm). Makes horizontal optical and spatial distortions
scanning laser microscopy Tandem plane passes through a pinhole sections. Very good at visualizing introduced by encoding.
(CSLM) Scanning in front of a photo multiple/TV SC. Preserves natural tonicity of Present section thickness that
microscope camera detector. Images skin, hydration of cells, and can be imaged is limited to
(Tracor received are perfectly focused contrast of structures. Possible to 150 μm. Still needs optical
Northern) because almost all reflected measure SC thickness in vivo. improvements to increase
light from above and below the Sharp focused; allows study for signal-to-noise ratio on
plane in focus is blocked. The first time of previously elusive images of inner epidermis.
Nipkow disc has 2000 pinholes stratum lucidum and stratum Optical sectioning is limited
arranged in Archimedean spirals granulosum. Can visualize RBC by transparency of tissue,
and allows lightening spot in capillaries. Excellent scattering and absorption of
scanning and reflected-light reproducibility. Can work in 4D light in the sample, working
formation, which can be space (volume and time) at the distance, and numerical
collected by a TV camera. After microscopic level non-invasively. aperture of the sample.142
computer processing, a volume
representation can be obtained.
In vivo fiberoptic Stratum® (Suihko Confocal microscope adapted for Flexible hand-held system can be Same as CSLM. Intradermal
fluorescence laser scanning 2005)143 study of skin and mucous used on any site including injection of fluorophore
microscopy membranes using fiberoptics mucous membranes. Fluorescein requires some skill.
and fluorophores. Light source sodium is safe for use in vivo.
is a 488 laser. Fluorescein Magnification 1000×. Produces
sodium used as the fluorophore horizontal (en face) images.
(intradermal injection or topical Cellular and some subcellular
skin application) (Suihko 2005). resolution is possible (Suihko
2005). Good for kinetic studies
of substances applied on or into
epidermis.144
(Continued)

Optical Techniques for Characterization of Skin Properties
Machines/
Technique Developer Principles Advantages Disadvantages
In vivo confocal Raman Caspers (1998) In vivo optical method based on Depth resolution of 5
145 Expensive, limited availability.
microspectroscopy (2001)146 inelastic light scatter rather than micrometers; able to measure
absorption (vibrational concentration profiles;
spectroscopy). Skin Raman quantitatively and qualitatively
spectrum are measured; signal accurate when compared with
is analyzed to extract gold standard x-ray
information. microanalysis. Only in vivo
method to analyze skin
molecular composition as a
function of distance to skin
surface with similar detail and
resolution.
In vivo optical coherence Fercher (1988)149 Technique based on the Better resolution than MRI or Expensive; limited
tomography147, 148 (OCT) Huang (1991)150 Michelson principle of high resolution ultrasound; availability; not good enough
inferometry. OCT uses light in resolution to cellular level = resolution to judge grade of
the near infrared range. Gel 10–15 micrometers. Maximum melanocytic tumors; axial
interface couples probe to skin. imaging depth is 1.2–2 mm. and lateral resolution is
Light source (LED) emits a Lateral resolution is 15 inferior to CSLM; allows
broad band light into fiber; micrometers. Real time imaging. visualization of architectural
coupler directs one portion into Fiberoptic systems allow better changes but not single cells.
reference arm. Diverging light access to normally difficult to Only able to image stratum
beams are relayed via both access areas of skin; non- corneum on palms and soles
objectives to the skin probe and invasive so allows monitoring of due to increased thickness.
reflecting mirror. Detector inflammation over time; can
signals are converted from objectively monitor treatment
optical to electrical signals. effect.
Thickness measurements are
calculated using software.
Ellipsometry Jasperson Monochromatic light passes Changes in refractive index can be Topical agents may cause a
(1969)151 through a plane polarizer used to monitor hydration status, change in reflectivity. Very
oriented at 45° with respect to effect of moisturizers. indirect method.
the incidence plane. Polarizer
output is fed into a photo elastic
modulator composed of a piezo
elastic crystal oscillating at a
particular frequency. Output of
the modulator passes through
collimator side of ellipsometer
to skin of interest. Reflected
light goes to telescopic side of
spectrometer and is directed
through a second polarizer to a
photomultiplier tube (PMT).
PMT output and reference
signal enter a lock-in amplifier,
which gives intensity readings
for the ellipsometric parameters.
A computer program calculates
the refractive index. Measures
refractive index.
Skin critical surface tension Jacobi (1949); Droplets of standard liquids Can quantify surface energy Requires some skill on the
(CST) Schneider applied to skin and viewed phenomenon resulting from part of the operator.
(1951); Ginn under microscope. Critical sweat, serum, and emulsion
(1968); El Khyat surface tension can be application as well as
(1996) calculated using Zisman interactions. Can quantify
technique; also can measure wettability.
wettability.
12 Sivamani R, Wu G, Maibach HH, et al. Tribological stud-

Conclusion ies on skin: Measurement of the coefficient of friction, In:
Serup J, Jemec GBE, Grove G, eds. Handbook of Non-
There are multiple challenges facing the clinician who wishes Invasive Methods and The Skin. Boca Raton: CRC Press,
to understand the scientific basis behind moisturizer efficacy 2006: pp. 215–224.
claims, including access to information, understanding the 13 Agache P. Twistometry measurements of skin elasticity.
information, and making sure the study design and technolo- In: Serup J, Jemec GBE, Grove G, eds. Handbook of Non-
gies used are valid. There is an urgent need to perform meta- Invasive Methods and The Skin. Boca Raton: CRC Press,
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studies categorized by study type, bioengineering technique, 14 Yokota M, Maibach HI. Moisturizer effect on irritant der-
ingredients, and clinical population to have more clinically matitis: An overview. Evidence on preventing and treating
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sive bioengineering techniques more profoundly, some text- ers and keratolytic agents in psoriasis. Clin Dermatol 2008;
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26
Anticellulite Products and Therapies
Enzo Berardesca
as well as the interstitial osmotic pressure. These alterations

Introduction induce tissue hypoxia, which results in collagen production
and damaged adipocytes. Anisopoikilocytotic adipocytes are
The term cellulite, first used in the 1920s by Alquier and Paviot, hence surrounded by thickened fibrosclerotic septae; groups
defines a localized lipodystrophic disease which affects more of adipocytes gradually form micronodules and subsequently
women than men. Nodular liposclerosis, edematofibrosclerotic macronodules. Around 85% of postpubertal women suffer
panniculopathy, panniculosis, and gynoid lypodistrophy are from cellulite, independently of their weight. This is due to
some of the other names proposed over the last decades instead the anatomy of the subcutaneous fat, which is constituted by
of cellulite. The pathophysiological aspects of cellulite are still two layers divided by a superficial fascia. The areolar layer is
poorly cleared. Many predisposing factors seem to influence located just underneath the dermis; in this layer adipocytes are
cellulite onset, including gender, heredity, race, body weight, large and arranged vertically. In the lamellar layer, which is the
and age. Hormones and impairment of both microvascular deeper one, adipocytes are small and arranged horizontally. If
and lymphatic circulation are considered the most important weight increases, the lamellar layer enlarges. When cellulite
etiological factors. Cellulite usually develops in particular ana- occurs it is the superficial part of hypodermis that tends to pro-
tomic sites such as lateral thighs and buttocks. The histopatho- trude into the dermis. The areolar layer is thicker in women
logical modifications that characterize cellulite involve the than in men and is under the control of estrogen. Hormonal fac-
different “operational units” of the fatty tissue: the matricial- tors seem to play a significant role in cellulite onset as well as in
interstitial unit, the microcirculatory unit, the neurovegeative its evolution. Cellulite affects predominantly women, appears
unit, and the energy-fatty unit. These alterations are account- after puberty, and worsens during pregnancy and contraceptive
able for the padded and orange peel appearance of the affected therapy; therefore cellulite is greatly influenced by estrogen.
areas and induce irregular body profile. Cellulite represents Estrogen acts on adipocyte increasing lipogenesis and hence
a heartfelt aesthetic problem for millions of women around causing adipocyte hypertrophy and anysopoikilocytosis; it pro-
the world. Various systemic and topical products as well as motes fibroblast proliferation and alterations in glycosaminogli-
numerous medical procedures have been developed to resolve cans and collagen, leading to fibrosclerosis. Insulin, prolactin,
cellulite, very often with poor results and little scientific basis. and thyroid hormones are also involved in the pathophysiology
of cellulite. Furthermore, recent investigations on the adipose
organ have highlighted that adipocytes release several sub-
Etiopathogenesis stances which act in an endocrine or paracrine way as well as
so-called adipokine (2). On the basis of the new knowledge, it
In 1922, Alquier and Paviot were the first to describe cellulite is clear that adipose tissue is not a passive organ but rather a
as a nonphlogistic dystrophy of the mesenchymal tissue, which dynamic organ able to interact with and regulate other cells,
implied accumulation of interstitial liquids. They suggested such as endothelial cells. Cellulite development also depends
that the disorder was a reaction to stimuli of different origin: on predisposing factors such as genetic, nutritional, lifestyle,
infectious, traumatic, toxic, etc. Since then, many contrasting and pharmacological factors. Gender is the most important
theories have been expressed to explain the etiopatogenesis of genetic predisposing factor. On the basis of histological exami-
cellulite, which is currently often considered a physiological nations, Nürnberger and Müller noticed that a female subcu-
phenomenon, especially in Anglo Saxon countries. Among the taneous tissue presents some anatomical peculiarities such
different hypothesis, the theory proposed by Curri has gained as fibrous bands whose course is perpendicular to the skin’s
approval and remains one of the most popular (1). According surface and which could be responsible of the “hill” profile of
to Curri, cellulite begins with alterations of the precapillary the dermohypodermic border, whereas in men the fibrous septa
arteriolar sphincter, as described by Merlen, which induce present a different disposition, more oblique with reference to
capillary ectasia, increased capillovenular permeability with the skin (3). Furthermore, a recent study performed by means
accumulation of interstitial liquid, and consequent intercellular of magnetic nuclear resonance imaging (MRI) has confirmed
edema. Edema provokes fibroblast activation and proliferation, that women with cellulite have constitutional characteristics of
which cause hyperpolimerization of glycosaminoglycans in fibrous interlobular bands, which induce bigger and radial fat
the connective matrix of the subcutaneous tissue. This phe- chambers (4). Caucasian women are more frequently affected
nomenon increases hydrophilicity of the intercellular matrix
DOI: 10.1201/b22897-26 259

by cellulite than Asian or Black women. Genetic influences the orange peel becomes evident only after pinching. On the con-
number and the sensitivity of hormone receptors on adipocytes trary, inactive subjects usually show flaccid cellulite, which is
as well as the tendency to circulatory insufficiency. Nutritional associated with muscular hypotonia. In the edematous form,
factors are very important. As hyperinsulinemia stimulates lower limbs are globally enlarged and patients complain of a
lipogenesis, excessive intake of fats and carbohydrates contrib- sense of heaviness, cramps, and swelling.
utes to cellulite onset and worsening. But although adiposity is
linked to cellulite, MRI has demonstrated that, among women
with body mass index over 30, there are women who do not
manifest cellulite at all. Salt favors hydric retention and alcohol
Noninvasive Techniques to Evaluate Cellulite
stimulates lipogenesis. Sedentary lifestyle contributes to cel- The variety of anticellulite products and professional (surgical
lulite as it is associated with ponderal increase and decreased or not) approaches to treat cellulite is quite huge, ranging from
activity of the muscular pumping in the lower limbs with con- topical products to oral regimens, from manual or mechanical
sequent venous stasis. The muscular pumping activity is also massages, to garments. We can find many strategies to contrast
influenced by the habit of wearing tight clothes and high-heeled the condition, a borderline one with pathology. In general, the
shoes. Among drugs, estrogens, antihistamines, and beta- efficacy of cellulite treatments is often debated and objective
blockers have shown to play a role in cellulite development. studies are needed to claim support. Furthermore, it is very
difficult to investigate cellulite by bioengineering methods.
Classification Thigh Circumference Measurement

On the basis of clinical and histological modifications that This traditional measure indicates the reduction of thigh cir-
occur in the subcutaneous tissue, four stages of cellulite are cumference, which can be due to both the reduction of edema
distinguishable (5). and the effect on the fatty layer. It is recorded on hips, ankles,
and thighs as follows:
Stage I
1 Hip: The tape measure is positioned around the hips,
In the first stage, the patient may be asymptomatic or only putting it finally on the superanterior iliac crest.
manifest a pale and pasty skin. Histologically, we can observe
2 Thigh: The tape measure is placed around the thigh,
a thicker areolar layer, increased capillary permeability, aniso-
marking the site of interest.
poikilocytotic adipocytes, capillary ectasia, and lipoedema.
3 Ankle: The tape measure is placed around the ankle,
exactly above the malleolar bone (7).
Stage II
Clinical alterations are not clearly evident at rest but only Ultrasonography
after skin pinching or muscular contraction we can observe
an orange peel appearance, with decreased skin temperature Ultrasound is used to study the thickness and the quality of the
and elasticity. Histologically, the fibril network, which sur- connective tissue and the edematous component of cellulite.
rounds adipocytes, appears hypertrophic; there is an important Frequencies between 10 and 15 MHz should be chosen for skin
microvessel dilatation, and there are microhemorrhages. examination. With higher frequencies it becomes more diffi-
cult to view in depth (8).
Stage III
Laser Doppler Flowmetry
In this phase, clinical changes are appreciable at rest with the
characteristic orange peel aspect. On palpation, we can notice Laser Doppler flowmetry (LDF) is an optical technique used
small lumps, hypoelasticity, and decreased skin temperature. to evaluate skin microcirculation, which provides informa-
This clinical picture histologically corresponds to anisopoi- tion on blood flow and erythema. The method consists of a
kilocytotic adipocytes encapsulated in micronodules, neofi- Ne-He laser source of 632 nm wavelength applied to the skin
brillogenesis, and dilation of small veins. via a small probe. The incident radiation enters the skin and is
scattered and reflected by nonmoving tissue components and
by mobile red blood cells encountered as the radiation pen-
Stage IV
etrates to a depth of 1 to 1.5 mm. A portion of the scattered and
The clinical characteristics of stage III are more evident; in reflected incident radiation exits the skin and is collected by a
particular there are macronodules due to the agglomeration second optical fiber that carries the light back to a photodetec-
of many micronodules. In this stage, cellulite may be pain- tor where it is converted to an electrical signal. Stationary skin
ful because of the compression of the nerves by the nodules. tissue reflects and backscatters light with the same frequency
According to skin consistency, we can distinguish four types as the incident source, while moving erythrocytes reflect the
of cellulite: hard, flaccid, edematous, and mixed (6). Hard cel- frequency-shifted radiation. The shift increases with increas-
lulite is characteristic of teenagers and young women who reg- ing erythrocytes speed. The LDF extracts the frequency-
ularly practice sport; at rest skin appears firm and compact and shifted signal and derives an output proportional to the flux
Anticellulite Products and Therapies 261
of erythrocytes of the blood flow. LDF is a reliable method for pathophysiological aspects of cellulite. Notwithstanding, only
estimating cutaneous microcirculation (9). a few scientific studies proving their real efficacy have been
published. Methylxanthines such as theobromine, theophyl-
line, aminophylline, and caffeine; β-adrenergic agonists such
Thermography
as isoproterenol and adrenaline; and α-antagonists such as
Anticellulite products are meant to increase local skin blood yohimbine, piperoxan, and phentolamine represent drugs with
flow. By increasing the blood flow, they increase the local skin a lipolytic effect. Among these, topical aminophylline has
temperature. Thermography is an electrooptical method for the been demonstrated to be the most effective, but the best results
imaging of temperature. The current technology used is based are obtained applying aminophylline together with yohimbine
on the detection of the infrared radiation emitted by the skin. and isoproterenol (14). The use of coenzyme A and L-carnitine
A conventional color thermogram uses a spectral color range, may contribute to improve the effects of the aforementioned
where blue is cold and red/white is hot. Intermediary tempera- drugs, as they induce the discharge of free fatty acids. A 2.8-
tures are shown as shades of green, yellow, orange, etc. (10). mm decrease in subcutaneous fat thickness has been observed
after a month of application of a product containing caffeine,
horse chestnut, ivy, algae, bladderwrack, plankton, butcher’s
Plicometry broom, and soy (15). Extracts from Centella asiatica are active
The technique implies the use of the plicometer, a device either on connective tissue or microcirculation, and they are
that allows evaluation of the thickness of cutaneous plicae or commonly used orally and topically. In particular, 60 mg of
folds to calculate the percentage of fat in human body. The Centella asiatica once a day for 90 days induces reduction of
measurement is usually performed on the thigh, on a defined adipocytes’ dimensions (16). Distante et al. have performed a
point which can be determined by measuring the half distance prospective, longitudinal double-blind designed study aimed
between the iliac crest and the center of the knee as reference to test a plant complex on the basis of seed extracts of grape
points. During measurement, the leg is relaxed. All measure- (Vitis vinifera), Ginkgo biloba, Centella asiatica, Melilotus
ments are performed in standard conditions, which guarantee (Melilotus officinalis), Fucus vesiculosus, fish oil, and borage
reliability and suitability of collected data. oil. Data obtained from these trials have demonstrated that the
oral intake of the mixture of plant extracts leads to significant
improvement of cellulite (17). A 4-week oral intake of peroxi-
Magnetic Resonance Imaging some proliferator-activated receptors (PPAR) agonists have
Among in vivo skin imaging methods, MRI (11) is the most demonstrated reduction in subcutaneous fat thickness in mice
recent approach, being of high interest not only for its ability (18). There is no FDA-approved dietary supplement for cel-
to distinguish structures at a submillimeter scale, but also for lulite treatment. The slimming effects of a cosmetic composi-
its ability to describe the physiology of the different skin lay- tion have been recently evaluated showing good efficacy and
ers through the measurement of their intrinsic MR parameters. tolerability (19).
High spatial resolution MRI allows differentiation of the differ-
ent skin departments—epidermis, dermis, and hypodermis— Massage Treatment
offering new and interesting opportunities for the evaluation of
anticellulite treatments. Some authors (4) found that changes in Bayrakci et al. (20) have investigated the effects of mechani-
skin architecture with cellulite can be well visualized by that cal massage, manual lymphatic drainage, and connective tis-
method, pointing out clearly in the images the skin fat layers sue manipulation techniques on cellulite. They have reported
beneath the dermis and down to the level of muscles. Also, the improvement in all groups treated, with a decrease of thigh
diffuse pattern of extrusion of underlying adipose tissue into circumference and fat thickness. This study confirms previous
dermis is clearly imaged and was found to correlate with cel- data obtained by Lucassen et al. (21) who have monitored the
lulite grading. Other researchers (12) applying such a technique effectiveness of electromechanical massage device by ultra-
characterized the topography of the dermohypodermal junc- sound imaging. A “smoothening” of the dermis-hypodermis
tion and the three-dimensional architecture of the subcutane- interface has been observed but the improvement was transi-
ous fibrous septae, giving a clearer frame of skin condition in tory as the result regresses after treatments end.
areas affected by cellulite.
Since methods and guidelines to evaluate clinically and Endermologie
objectively cellulite are lacking, a multidisciplinary group has
been created in order to define a valuable and reliable method- LPG endermologie is an electromechanical handheld massage
ology for this purpose (13). device designed by Louis Paul Guitay, a French engineer and
approved by FDA for cellulite treatment. The machine consists
of two rollers and a vacuum chamber. The rollers rhythmi-
cally fold and unfold skin and subcutaneous tissue while the
Therapies vacuum applies negative pressure. In the few published stud-
ies, the results obtained note that LPG induces fat mobilization
Pharmacological Agents
and redefines body profile. In a recent trial performed on 33
Several proximate principles have been employed topically, sys- women with cellulite grades 1 to 3, treated with LPG twice
temically, or transdermally, in attempt to contrast the different weekly for 15 sessions, Gülec (22) observed a circumference
reduction in all patients but only 15% of the subjects had a Other Food Supplements
reduction of cellulite grade.
While there is no magic pill or supplement that can completely
eliminate cellulite, certain food supplements may help to
Optical Devices improve the appearance of cellulite by targeting specific fac-
tors such as inflammation, fluid retention, and collagen pro-
Velasmooth (Syneron Medical Ltd., Yokeneam, Israel) com-
duction. Here are some food supplements that may be helpful
bines negative tissue massage, radiofrequency (RF), and a
in reducing the appearance of cellulite:
700-nm infrared light (IR). It has been approved by FDA for
the treatment of cellulite. The mechanical massage improves
microcirculation and facilitates lymphatic drainage while RF Collagen: Collagen is a protein that is essential for main-
and IR heat the tissue, thus inducing collagen contraction and taining healthy skin, hair, and nails. Supplementing
neocollagenesis. Improvement is usually obtained after eight or with collagen may help to improve skin elasticity and
more treatments, delivered on a twice-weekly basis. Monthly reduce the appearance of cellulite (29, 30).
maintenance treatment is recommended. Results decline Omega-3 fatty acids: Omega-3 fatty acids are anti-
within 6 months post treatment (23). TriActive (Cynosure, Inc., inflammatory and may help to reduce inflammation
Chelmsford, Massachusetts) combines a 810-nm diode laser, associated with cellulite. They can be found in fatty
contact cooling, suction, and massage. It represents another fish, such as salmon, or taken as a supplement.
FDA-approved device to contrast cellulite and has shown to Green tea extract: Green tea extract is rich in antioxi-
be as effective as Velasmooth in a randomized, comparative, dants and has been shown to improve skin texture
prospective clinical study in which patients were treated twice and reduce inflammation, which may help to reduce
a week for 6 weeks. Bruising was the only reported side effect, the appearance of cellulite.
occurring globally in about 55% of the patients (24). Goldberg Ginkgo biloba: As mentioned earlier, ginkgo biloba can
et al. have investigated the use of a unipolar RF device (Alma improve circulation and reduce inflammation, which
Lasers, Buffalo Grove, Illinois), which delivers a high-frequency may help to improve the appearance of cellulite.
electromagnetic radiation at 40 MHz, inducing heating of the
Gotu kola: Gotu kola is an herb that has been tradi-
tissue. Good results have been obtained with a treatment regi-
tionally used to improve skin health. It may help
men of six every-other-week sessions and benefits were per-
to improve collagen production and skin elasticity,
sistent for the following 6 months (25). More recently, a new
which can reduce the appearance of cellulite.
bipolar RF system emitting variable frequencies, called auto-
matic multifrequency and low impedance (AMPLI) RF, has
been experimented for cellulite in the buttocks in a multicenter
study. Enrolled subjects underwent one treatment per week for REFERENCES
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27
Therapy of Telangiectasia and Varicose
Veins and Their Complications
Charles M. Weddington, Christian R. Halvorson, Robert A. Weiss, and Margaret A. Weiss
The incidence of varicose veins increases with age, and as

Introduction the average age of the United States population grows, so does
the demand for treatment of varicose and telangiectatic veins.
Telangiectatic webs, or spider veins, remain one of the most While 41% of women in the fifth decade have varicose veins,
commonly treated cosmetic disorders in dermatology. The two this number rises to 72% in the seventh decade (9). Statistics
primary treatments used by dermatologic surgeons for these for men are similar, with 24% incidence in the fourth decade,
smaller veins are sclerotherapy and lasers. For larger varicose increasing to 43% by the seventh decade. Six million workdays
veins, dermatologic and vascular surgeons employ a range of per year may be lost due to complications of varicose veins
treatment options, including ambulatory phlebectomy, endo- including stasis dermatitis, cellulitis, and ulceration (10).
venous occlusion and ablation by intravascular radiofrequency
or laser energy, and mechanochemical ablation. The use of
endovenous techniques has expanded significantly in the last
decade, with radiofrequency ablation and laser ablation being Historical Aspects
the most commonly used techniques. Concurrently, recent
The known history of varicose vein treatment dates back to
advancements in sclerotherapy techniques, such as the use of
the first century AD, when Celsus practiced primitive strip-
foamed detergent sclerosing agents, microfoam sclerotherapy,
ping and cauterization. In the second century AD, ligation was
and ultrasound-guided sclerotherapy, have improved the effi-
mentioned by Antyllus, while Galen proposed tearing out the
cacy and safety of the procedure in larger veins as well.
veins with hooks, a precursor to the modern-day technique of
Sclerotherapy, the intravascular introduction of a sclerosing
ambulatory phlebectomy advanced by Swiss dermatologist
substance, is actually endovenous chemo-ablation with subse-
Robert Muller in the late 1960s.
quent fibrosis and concomitant vein wall collagen dissolution.
In 1851, Pravaz attempted sclerotherapy with ferric chloride
The term “sclerotherapy” gained acceptance during the nine-
using his new invention, the hypodermic syringe. The founda-
teenth century. In the United States, sclerotherapy gained wide
tion of modern sclerotherapy can be traced to World War I
acceptance in the early 1990s and is regarded as a highly effective
when Linser and Sicard both noticed the sclerosing effect of
treatment for telangiectasias as well as veins of all sizes (1, 2). It
intravenous injections used to treat syphilis, which often
also serves as an effective addition to surgical techniques such
resulted in vein sclerosis. Tournay greatly refined the sclero-
as ambulatory phlebectomy for saphenous tributaries (3, 4) and
therapy technique in Europe and wrote the gold standard of
endovenous obliteration of refluxing saphenous veins (5, 6).
textbooks. French physicians were leaders in the field of vein
Knowledge of venous anatomy and physiology, principles of
diagnosis and treatment, which evolved into the subspecialty
venous insufficiency, methods of diagnosing venous malfunc-
of phlebology. It was not until 1946, when a safe sclerosant,
tion, uses and actions of sclerosing solutions, and proper use of
Sotradecol (sodium tetradecyl sulfate) had been tested and
compression are essential elements of successful venous therapy.
described, that sclerotherapy began to be seriously studied in
the United States (11).
Another key to the success and acceptance of the treatment
of varicose veins by sclerotherapy was the addition of com-
Epidemiology
pression. The most significant contributions were made by
Bulging varicose veins and unsightly telangiectatic webs European physicians Sigg and Orbach in the 1950s and Fegan in
affect millions of patients. Telangiectases affect up to 50% of the 1960s, who emphasized the importance of combining exter-
women, while larger varicose veins affect up to 40% of the nal compression immediately following injections. Starting in
population (7, 8). In addition to cosmetic dissatisfaction, vari- the 1980s, Duffy promoted the technique in the United States
cose veins may cause significant morbidity including chronic among dermatologists and advocated the use of polidocanol and
stasis dermatitis, ankle edema, spontaneous bleeding, superfi- hypertonic saline as safe and effective sclerosing solutions (12).
cial thrombophlebitis, recurrent cellulitis, lipodermatosclero- The first endovenous obliteration technique utilizing radio-
sis, and skin ulceration on the ankle and foot. frequency was researched and pioneered by dermatologic
264 DOI: 10.1201/b22897-27

Therapy of Telangiectasia and Varicose Veins and Their Complications 265
surgeons as a substitute for ligation and stripping of the greater the termination point of the saphenous veins. Over a decade
saphenous vein (6). Subsequent procedures, including 1320 of experience has shown that radiofrequency or endovenous
nm laser ablation, were also pioneered by dermatologists, and ablation is as effective as the surgical techniques of ligation
these ablative procedures have now become accepted as the and stripping to eliminate saphenous and associated varicose
standard for treatment of saphenous vein reflux (13). Following veins (13, 20).
utilization in Europe in 1998, the technique was made available Previous urticaria or suspected allergy to a sclerosing agent
in the United States in March 1999. Goldman’s first American should serve as a relative contraindication to use of that par-
textbook of sclerotherapy (now in its 6th edition) (14) integrated ticular sclerosing agent. A history of deep venous thrombo-
the world’s phlebology literature, introduced new sclerosing sis (DVT) or previous trauma to the leg (e.g. auto accident)
solutions and validated dermatology’s claim to expertise in should preclude sclerotherapy until adequately evaluated by
vein treatment (15). Several additional textbooks by dermato- Duplex ultrasound. Venous treatment is contraindicated in
logic surgeons have now firmly established phlebology, which a bedridden patient since ambulation is important for mini-
includes the diagnosis and treatment of spider and varicose mizing risks of thrombosis. Similarly, patients under general
veins, within the sphere of dermatology (16, 17). anesthesia for non-related procedures should not undergo
simultaneous sclerotherapy. Severely restricted arterial flow to
the legs necessitates postponement of vein treatment. During
hot summer months, heat-induced vasodilatation and inability
Venous Anatomy and Physiology: The
to comply with wearing of compression hose may also require
Key to Choosing the Right Technique postponement of treatment.
The superficial venous system consists of three primary terri- Pregnancy is no longer considered a contraindication to
tories: the great saphenous vein, the small saphenous vein, and sclerotherapy, and extremely painful or bleeding varices
the subdermic lateral venous system. All these veins contain may be treated even in the last trimester in our experience.
valves. Due to gravitational hydrostatic pressure, sequential Endovenous techniques may be employed to treat refluxing
retrograde breakdown of venous valve function often follows a saphenous veins in pregnancy. However, treatment is typically
leak at one point leading to propagation of a varicosity or spi- postponed since many varicosities and telangiectasias will
der vein (18). Increased diameter between valve leaflets with spontaneously clear within 1–6 months postpartum. Obesity
failure to oppose properly caused by genetically weak venous should be considered a relative contraindication since main-
wall or venous valve structure may initiate these events (8). Calf taining adequate external compression is difficult.
muscle pump pressure plus gravitational hydrostatic forces are
transmitted directly via the incompetent perforating vein or
communicating veins to the surface veins. Venous pressure Treatment Techniques
may reach as high as 300 mmHg in the cutaneous venules with
the patient erect. Transmission of pressure may result in venu- Sclerotherapy (Endovenous
lar dilatation over a wide area of skin including the formation Chemo-Ablation) Techniques
of telangiectatic webs.
General Principles
When present in significant quantity, the volume of blood
sequestered and stagnant in reticular veins and associated A basic principle of treatment is to begin at the largest reflux
telangiectatic webs (particularly of the lateral venous sys- sources and progress to the smallest varicosities. Progression
tem) may cause enough distention to produce symptoms (19). from proximal to distal regions will focus initial treatment
Symptoms are relieved by the wearing of support hose or with on vessels most likely to be proximal reflux sources contrib-
rest and elevation of the legs. Prolonged standing or sitting uting to distal pressure. Sclerotherapy of telangiectasias is
worsens symptoms. The size of the vessels causing moderately approached by combined injection of visibly connected reticu-
severe symptoms may be as small as 1–2 mm in diameter. lar veins, venulectases, and telangiectatic webs or networks.
Sclerotherapy has been reported to yield an 85% reduction in Reticular veins are treated only after all sources of reflux
these symptoms as well as superb cosmetic results (19). from major varicosities have been treated by sclerotherapy
and/or surgery. When no clear feeder vessel is seen or identi-
fied by duplex ultrasound, transillumination (Veinlite, 3Gen,
Dana Point, CA) may be used. Handheld, noncontact devices
Contraindications to Treatment of Spider Veins that project infrared light can also aid in the location and map-
A high rate of recurrence for sclerotherapy is commonly seen ping of feeding reticular veins that may be difficult to see with
when reflux originates at the major saphenous junctions. When the naked eye (VeinViewer®, Christie Medical Holdings, Inc.,
reflux exists at the saphenofemoral junction, this must be dealt Memphis, TN; AV400 Vein Viewing System, AccuVein, Inc.,
with prior to treatment of distal varicosities or telangiecta- Huntington, NY). If an injector is unable to locate an associ-
sias. Since the goal of sclerotherapy and other treatments is to ated reticular vein, then the point at which the telangiectasias
eliminate reflux at its origin, the goal of noninvasive diagnos- begin to branch out becomes the target site to begin injection.
tic evaluation is to reveal the primary source of reverse flow. Injection of telangiectasias is simultaneously performed with
The techniques of endovenous occlusion by radiofrequency injection of reticular veins in the hopes of decreasing the num-
or laser have been developed to address reflux occurring at ber of treatments (21).
Technique of Sclerotherapy
Liquid Sclerotherapy
The American dermatology technique of liquid sclerotherapy
has been described in detail by Duffy and Goldman (12, 22).
The sclerotherapy tray is prepared with the necessary equip-
ment, including a 30-gauge needle bent to an angle of 10–30
degrees with the bevel up, which is placed on the skin so that
the needle is parallel to the skin surface. A 3-cc syringe filled
with 0.5 cc of solution is held between the index and middle
fingers while the fourth and fifth finger support the syringe
against the leg in a fixed position, facilitating accurate penetra-
tion of the vessel (Figure 27.1). The nondominant hand is used
to stretch the skin around the needle and may offer additional
support for the syringe. Magnifying lenses or operating loupes
on the order of 1.5–3× are recommended to aid in cannulation FIGURE 27.1 Position of the hands for sclerotherapy. While the
of the smallest telangiectasias. dominant hand holds the syringe and creates a platform with the 5th digit,
the nondominant hand stretches the skin and acts as a support for the
The initial treatment of telangiectatic webs begins with needle hub so that fine changes in position are permitted.
lowest possible concentration that will cause a telangiectasia
to sclerose over a period of 1–6 months post-injection. This
typically is 0.1% sodium tetradecyl sulfate, 0.2% polidocanol
or compounded 72% glycerin diluted with 1% lidocaine with
epinephrine (1:100,000). When ineffective sclerosis occurs
judged at a subsequent visit, the concentration but not the vol-
ume per site of sclerosing solution is increased. Post-treatment
compression consists of graduated 20–30 mmHg support hose
for 2 weeks for telangiectasia associated with reticular veins
and OTC 15 mmHg compression for telangiectasias only.
Treatment intervals vary between physicians, but allowing 4–8
weeks between treatments allows time for resorption of treated
telangiectasias and therefore helps to minimize the number of
necessary sessions. Typical results are shown in Figure 27.2.
Sclerosing Solutions
Sclerosing solutions have been classified based on chemical
structure and effect: hyperosmotic, detergent, and corrosive
agents (chemical irritants—salts, alcohols, and acid or alka-
line solutions).
Table 27.1 summarizes the sclerosing agents.
Hyperosmotic Agents
Hypertonic Saline
Hypertonic saline (HS) has been a commonly employed solu-
tion (only in the United States) in spite of extreme pain on
injection and relatively low efficacy in vessels over 0.4 mm.
We recommend against using this as a sclerosing solution.
Used at a concentration of 23.4% (HS), a theoretical advan-
tage of HS is its total lack of allergenicity when unadulterated.
HS has been commonly used in various concentrations from
10%–30%, with occasional addition of heparin, procaine,
or lidocaine. Additional agents typically provide no benefit.
Therefore, HS is used either unadulterated or diluted to 11.7% FIGURE 27.2 Typical results following sclerotherapy of telangiectasia.
(a) Treatment with 0.1% STS. (b) Excellent clinical results at 4-month
with sterile water for smaller telangiectasias (23, 24). follow-up.
TABLE 27.1
Comparison of Sclerosing Agents
Concentrations (reduce
Sclerosing concentrations for foamed
solution Category Advantages Disadvantages Vessels treated solution by 50%)
Sodium tetradecyl Detergent May be foamed May cause skin All sizes 0.1%–0.2% telangiectasias
sulfate (STS) Low incidence of allergic breakdown at higher 0.2%–0.5% reticular
reaction when used with concentrations 0.5%–1.0% varicose
Latex-free syringe 1.0%–3.0% axial varicose
Polidocanol Detergent May be foamed May inadvertently be Small to medium 0.25%–0.5% telangiectasias
(POL) Forgiving with injected into arteriole 0.5%–1.0% reticular
intradermal injection without pain 1.0%–3.0% varicose
Hypertonic saline Hyperosmolar Not allergic Ulcerogenic Small 23.4%–11.7% telangiectasias
(HS) Painful to inject 23.4% reticular
Hypertonic saline Hyperosmolar Less painful than HS Relatively weak Small Undiluted–telangiectasias
+ dextrose (HSD) sclerosant Undiluted–reticular
Sodium Detergent None Allergic reactions Small Undiluted–telangiectasias
morrhuate highest Undiluted–reticular
Glycerin (72% Chemical Treats matting Very weak sclerosant Smallest Undiluted to ½
glycerin with irritant Low incidence of strength–telangiectasias
1% lidocaine) pigmentation
Polyiodinated Chemical Powerful for largest veins Avoid in iodine allergic Largest 1%–2% for up to 5 mm veins
iodine irritant patients 2%–6% for the largest veins
(Varigloban)
With hypertonic solutions, damage of tissue adjacent to concentrations of 0.5% and 1.0%, and prior to this was avail-
injection sites may easily occur. Skin necrosis may be pro- able in the United States only through compounding pharma-
duced by extravasation at the injection site, particularly when cies. The detergent-based POL, a urethane compound, was
injecting very close to the skin surface. HS is not one of our originally developed as an anesthetic but was found to have the
favorite solutions for this reason. Injection of hyaluronidase property of sclerosing small diameter vessels after intrader-
into sites of extravasation may significantly reduce the risks mal injection. POL contains hydroxypolyethoxydodecane dis-
of skin necrosis with HS, although this has not been demon- solved in distilled water with 5% ethanol as a stabilizer. First
strated in human clinical applications (24). used as a sclerosing agent in the late 1960s in Germany, POL
is popular worldwide for smaller vessels due to painless injec-
tion and lowest incidence of cutaneous necrosis with intra-
Hypertonic Saline and Dextrose
dermal injection. Lower concentrations of POL were initially
Hypertonic saline and dextrose (HSD) (Sclerodex®, Omega suspected to have a lower incidence of hyperpigmentation
Laboratories Ltd., Montreal, Canada) is a viscous mixture of than HS or STS, but recent clinical trials indicate a significant
dextrose 250 mg/mL, sodium chloride 100 mg/mL, propylene percentage of hyperpigmentation also occurs with POL (25).
glycol 100 mg/mL, and phenethyl alcohol 8 mg/mL. HSD is Australian comparison studies have preferred POL over STS
a relatively weak sclerosant for local treatment of small ves- with increased efficacy with fewer complications (25).
sels, with a total volume of injection not to exceed 10 mL per POL is also available in a 1% foam that utilizes a proprietary
visit, with 0.1 mL–1.0 mL per injection site. HSD is marketed canister device to generate a consistent, low-nitrogen, stable
predominately in Canada. Although a slight burning sensation small-bubble foam which is FDA-cleared for the treatment
occurs, pain is far less than with HS. Efficacy has been seen by of great saphenous vein incompetence (Varithena®, Boston
us in over 5000 patients with excellent results for treatment of Scientific, Marlborough, MA) (26). Notably, compounded for-
telangiectasias and small associated reticular veins. mulations of POL have recently been found to have largely
inconsistent concentrations and impurities, and such non-
branded formulations should be avoided (27).
Detergent Agents
The distinct advantage of detergent agents is the ability to
Sodium Tetradecyl Sulfate
foam these solutions for enhanced efficacy at lower concentra-
tions and for use in treatment of larger varicosities (discussed Sodium tetradecyl sulfate (STS) (Sotradecol®, Viatris,
in Foam Sclerotherapy). Canonsburg, PA; Fibrovein, STD Pharmaceuticals, UK;
Trombovar, Omega Labs, Montreal, Canada) is a long-chain
fatty acid salt with strong detergent properties and is a highly
Polidocanol effective sclerosing agent used worldwide. Approved for use
Polidocanol (POL) (Asclera®, Merz Aesthetics, Frankfurt, in the United States since 1946, it has been popular with vas-
Germany) is the first new sclerosing solution introduced in cular surgeons since the 1960s and first described for use in
the United States since 1946. It was FDA-cleared in 2010 in telangiectasias in the 1970s. A relatively high incidence of
post-sclerosis pigmentation was reported at inappropriately solutions can be used as a contrast agent under Duplex ultra-
high doses (1% STS). More appropriate concentrations for sound, making Duplex-guided treatments easier and safer. An
superficial telangiectasias are 0.1%–0.3%. Other concentra- illustration of the persistence of foam is seen is Figure 27.3.
tions are 0.2%–1.0% in reticular veins or small varicosities Foamed POL has been reported as far more potent on varicose
(1–3 mm diameter), and 0.5%–3% in larger varicosities related veins than the non-foamed of equal concentration (35). Recently,
to major sites of valvular reflux. Recent use of foamed STS combination Polidocanol-Bleomycin foam is being investigated
indicates that half the concentration may be utilized when the as a new potential sclerosant for treatment of venous malforma-
solution is frothed with air (discussed in Foam Sclerotherapy). tions (36). Liquid sclerosant, as opposed to foamed sclerosant,
has been the preferred method for treating smaller veins and
telangiectasia to reduce side effects, but we have found foamed
Sodium Morrhuate
sclerosant to be both effective and safe in smaller veins.
Sodium morrhuate (Scleromate®, Palisades Pharmaceuticals,
Inc., Tenafly, NJ) is a 5% solution of the salts of saturated and
Side Effects and Complications of Sclerotherapy
unsaturated fatty acids in cod liver oil. Approximately 10% of its
fatty acid composition is unknown and use is limited by reports Post-Sclerotherapy Hyperpigmentation
of fatalities secondary to anaphylaxis (15). Although sodium
Post-sclerosis pigmentation is defined as the appearance of
morrhuate is approved by the FDA for the sclerosis of varicose
increased visible pigmentation along the course of a treated
veins, use in treatment of telangiectasias remains uncommon
vein of any size. Initially perivascular hemosiderin deposition and
and cannot be recommended due to the caustic qualities with
not increased melanin production causes this appearance (37).
potential for cutaneous necrosis and higher risks of allergy. This
However, after several weeks to months the hemosiderin is
agent is reserved primarily for sclerosis of esophageal varices.
replaced by melanin. The reason for persistence of pigmenta-
tion is unknown. The incidence of pigmentation is related to
Irritant Agents
The chemical irritants include polyiodinated iodine (very
caustic) and chromated glycerin (very weak) and are believed
to have a direct toxic effect on the endothelium. After injection
of polyiodinated iodine salt, the endothelium near the site of
injection is destroyed within seconds. The corrosive action is
limited due to rapid inactivation by blood proteins. At the sites
of endothelial destruction, the chemical can penetrate further
and diffuse into deeper layers of the vessel wall causing fur-
ther destruction. These agents are not commercially cleared
by the U.S. FDA.
Glycerin without the chromate salt may work primarily
by osmotic injury. A preparation of 72% glycerin diluted 2:1
with 1% lidocaine with epinephrine can be prepared by local
compounding pharmacies. In our experience in over 10,000
patients over the last 5 years, the 72% glycerin solution was
the most effective at eliminating telangiectatic matting and
resistant telangiectasias. It is particularly effective in treating
smaller residual telangiectasias, with a greatly reduced inci-
dence of matting and hyperpigmentation. A commercial glyc-
erin product has been reported to give a lower incidence of
inflammation and subsequent pigmentation in smaller telangi-
ectasias (28). Glycerin cannot be foamed.
Foam Sclerotherapy
Detergent agents such as POL and STS may be mixed with room
air (or other gas) to create a foamed sclerosing solution (29–33).
Typically, air is added at a ratio of one-part solution to 2 to 4 parts
air, which may be equally safe and efficacious. (34) Agitation is
performed by rapid transfer from syringe to syringe via an IV
stopcock or a two-way leur lock syringe connector. The advan-
tages of foamed solutions for treatment of larger vessels include:
(1) by displacing blood in the vein, the highest concentration of
sclerosant is always contacting vessel wall, (2) the total amount
of sclerosant injected is greatly reduced, (3) there is great per- FIGURE 27.3 Foam sclerotherapy. (a) Injection of foam. (b) Persistence
sistence of sclerosant with very slow washout, and (4) foamed of foamed sclerosant at 2 minutes post-injection.
dilution and type of sclerosing agent as well as diameter of tract as the needle is withdrawn. Sclerosing solution may also
treated vessel (38). Pigmentation incidence ranges from 11%– leak out into the skin through the small puncture sites of vessel
30% using HS (18), 11%–30% with POL (12, 39), and up to cannulation. The varicose vein may have a fragile, thin wall,
30% with STS. The incidence of pigmentation may be reduced with the injection causing rapid injury leading to sudden unex-
in varicose veins by expressing the dark, viscous blood thought pected rupture with perivascular accumulation of sclerosant.
to be a liquefied coagulum or intravascular hematoma, which Additionally, injection may inadvertently occur into a small
may accumulate 1–4 weeks following sclerotherapy. For those arteriole associated with telangiectatic varicosities with resul-
patients highly susceptible to pigmentation, such as African tant necrosis and ulceration.
American patients, the use of glycerin as a sclerosant agent is When the dermatologic surgeon recognizes that extravasa-
highly recommended. tion has occurred the risk for necrosis can be minimized by
Pigmentation clears in 70% within 6 months but rarely injecting normal saline in a ratio of 10:1 into the extravasation
persists longer than a year (38, 40). Prior to picosecond laser site. Extensive massage of small subcutaneous blebs to spread
advancements, attempts to hasten resolution of pigmentation the trapped sclerosing agent as quickly as possible will mini-
were mostly unsuccessful as the pigment is dermal hemosiderin mize prolonged blanching of the area. We have found that the
and not epidermal melanin. Bleaching agents, exfoliants such application of topical 2% nitroglycerine paste applied imme-
as trichloroacetic acid or phenol, cryotherapy, various lasers, diately to the suspected extravasation site greatly reduces the
and intense pulsed light achieved limited success (41, 42). The risks of necrosis but will not always prevent it.
Q-switched ruby laser was previously the most consistently
effective for treatment of post-sclerosis pigmentation (43). Our
experience with multiple wavelengths of Q-switched lasers
indicate that ruby, alexandrite, or Nd:YAG Q-switched lasers
Superficial Thrombophlebitis
may be successfully applied to clear the pigmentation more This complication is most commonly mistaken for the normal
rapidly. We now address bothersome post-sclerotherapy hyper- nodular fibrosis (endosclerosis) that occurs with proper sclero-
pigmentation in our practice with picosecond alexandrite laser therapy. After sclerotherapy, a nontender, nonpigmented, non-
utilizing both flat and diffractive lens array handpieces. erythematous fibrotic cord may normally be palpable along the
course of a treated 4–8 mm vein. This frequent finding is due
to a liquefied intravascular hematoma with surrounding vein
wall sclerosis and is not a thrombus. In contrast, superficial
Telangiectatic Matting
thrombophlebitis is characterized clinically by a very tender,
Telangiectatic matting is defined as the appearance of groups indurated, linear erythematous swelling. Incidence of superfi-
of new, fine (<0.2 mm diameter) telangiectasias surrounding or cial thrombophlebitis is quite variable, estimated at 0.01%–1%
replacing a previously treated area in a blush-like manner. A ret- following sclerotherapy (48), although some report that the
rospective analysis of over 2000 patients reports an incidence incidence is higher than typically reported (49). Treatment
of 16% in patients treated with HS and POL (44). Resolution consists of leg elevation and/or compression and regular
usually occurs spontaneously within a 3–12 month period with administration of aspirin or other nonsteroidal anti-inflamma-
70%–80% spontaneous resolution within the first 6 months (45). tory drugs. Extension of superficial thrombophlebitis into the
Matting may also occur as a result of trauma to the leg in deep system is extremely rare, so aggressive anticoagulation is
association with pregnancy or hormonal therapy, or in scars not the usual course of therapy.
around previous sites of surgical stripping. Predisposing fac-
tors include predilection for certain areas of the leg, such as the
medial lower thigh, obesity, hormonal therapy with estrogen,
family history, and a longer history of telangiectasias (44). The
Pulmonary Embolism
relative risk factor for development of telangiectatic matting is Pulmonary emboli probably occur from extension of a super-
3.17 times greater for female patients taking hormonal supple- ficial thrombus into the deep venous system. Evidence of
ments (46). Successful treatment of matting with a pulsed-dye extension from superficial thrombus to deep thrombophlebitis
laser (PDL) is reportedly accompanied by temporary hyper- or DVT should be treated promptly by anticoagulation. The
pigmentation (47). The use of enhanced visualization with a incidence of pulmonary embolism has been associated with
cross-polarized light source (Syris Scientific, LLC, Grey, MA) injection of large quantities of sclerosant at a single site. The
has been found to assist injection of sclerosing solution into incidence is extremely low with less than 1 in 40,000. We have
telangiectatic matting. Treatment is often not required since not seen this complication in treatment of over 20,000 patients.
matting will resolve spontaneously except when caused by a
source of reflux superiorly.
Arterial Injection
This dreaded medical emergency is fortunately extremely
Cutaneous Necrosis/Ulceration
rare. Classic warning signs include immediate intense pain
Cutaneous ulceration may occur with all sclerosing solutions far beyond the normal discomfort at the initiation of injection,
in spite of the most skilled technique. Unavoidably, a tiny although leakage of sclerosant into the arterial circulation may
amount of sclerosing solution may be left along the needle present in an atypical fashion. Continuous intense burning
pain with immediate bone-white cutaneous blanching over perivenous location, energy is applied as the catheter is slowly
an area of several square centimeters is the usual initial sign. withdrawn. This results in collagen shrinkage of the vein wall
Progression to a sharply demarcated cyanosis within minutes accompanied by complete occlusion (19). The efficacy for RFA
is typical for arterial injection. Emergency treatment involves for elimination of reflux is 90% at 2 years (57) with similar
immediate application of ice, attempts to flush the inadver- results at 10 years follow-up (58), a very favorable compari-
tently injected artery with normal saline and/or heparin, injec- son to traditional ligation and stripping with far less morbidity
tion of 3% procaine to inactivate STS, and vascular surgery without the risks of general anesthesia.
consultation for intravenous anticoagulation. Another endovenous technique involves the use of laser
A major clinical problem is that arterial injection may rarely energy. Terms for this technique include endovenous laser
not be accompanied by any pain or cutaneous signs. The atyp- treatment (EVLT) and endovenous laser ablation (EVLA).
ical cases are suspected to arise from arteriovenous malfor- Very similar to RFA, this technique involves the placement of
mations (AVMs), which allow sclerosant to enter the arterial a laser fiberoptic via a small puncture. Wavelengths utilized
system via the venous system (50). This is most commonly include 810 nm, 940 nm, and 980 nm. The primary problem
seen in the popliteal fossa. Arterial injection may lead to wide with wavelengths absorbed by hemoglobin is the requirement
areas of skin necrosis and damage to subcutaneous tissue and for blood for laser absorption (20). This leads to increased risks
muscle which take months to heal. of bruising, pain, and skin burns. A wavelength absorbed by
water only, 1320 nm, eliminates these side effects by contract-
ing the vein with far less heat generation, and has been shown
to provide superior results (59). Accordingly, endovenous laser
Neurologic Events ablation with a wavelength of 1320 nm (CTEV™, CoolTouch
Neurologic side effects are a rare complication of sclerother- Corporation, Roseville, CA) has become our preferred modal-
apy. In a recent review of 10,819 patients undergoing both liq- ity for laser ablation and recently published long-term results
uid and foam sclerotherapy, 97 patients (0.90%) were found have confirmed its superiority over alternative modalities (60).
to experience neurologic events, including speech and visual One developing option for great saphenous insufficiency
disturbances, migraines, cerebrovascular accidents (CVAs), are injectable adhesives that works to occlude and seal the
and transient ischemic attacks (TIAs) (51). In total, there were great saphenous vein (VenaSeal™ Sapheon Closure System,
12 reported CVAs and 9 TIAs, occurring both with liquid and Medtronic, Inc., Dublin, Ireland) (61). With this cyanoacrylate
foamed sclerotherapy, with the majority of symptoms resolv- closure (CAC) system, incompetent great saphenous veins are
ing by the time of discharge. These events are hypothesized to treated with an endovenous cyanoacrylate adhesive, injected
occur secondary to sclerosant particles entering the cerebral under ultrasound guidance without the need for tumescent
vasculature via a patent foramen ovale (PFO), although not anesthesia or postoperative compression stockings. Follow-up
all affected patients have this malformation (51). In a separate data has been promising, with a 92% occlusion rate 2 years
study of 3259 patients who underwent ultrasound-guided foam post treatment (61) and similar results at 36 months post
sclerotherapy, seven (0.21%) experienced side effects includ- treatment (62). Results may be compound-dependent how-
ing visual disturbances, migraines, and chest discomfort, ever, as another system using n-butyl cyanoacrylate has been
all of which resolved by 2 weeks (52). Notably, five of these reported inferior to EVLA (VariClose®, Biolas, Etimesgut,
patients were found to have a PFO. Accordingly, a known Türkiye) (63).
symptomatic PFO is considered a contraindication to foamed An endovenous mechanochemical ablation (MOCA) system
sclerotherapy by the 2nd European Consensus Meeting on more recently cleared by the FDA (ClariVein®, Merit Medical
Foam Sclerotherapy (53). When a TIA or CVA is suspected Systems, Inc., South Jordan, UT) uses a specially designed
during treatment, the patient should be placed on oxygen in the catheter, combining sclerosant infusion with a rotating wire tip
office and transferred to a facility that administers hyperbaric to affect closure without the need for tumescent anesthesia, but
oxygen (54–56). may have a successful anatomical occlusion rate significantly
lower than endovenous RF or laser methods (64).
Modern Minimally Invasive Surgical

Approaches for Varicose Veins Surgical Ligation and Limited Stripping
Endovenous Closure Techniques For larger varicose veins, particularly originating from an
incompetent valve at the saphenofemoral junction, ligation of
When it has been determined by ultrasound that the originat- the greater saphenous vein with short stripping of its proximal
ing point of reverse flow or reflux is the great saphenous vein half in the thigh is the traditional surgical method but has been
or small saphenous vein, endovenous radiofrequency or laser replaced by endovenous ablation by RF or laser. After proxi-
techniques are the treatment of choice. Radiofrequency abla- mal ligation without stripping of the saphenous vein, varicog-
tion (RFA) involves the placement of a catheter within the var- raphy has shown persistent mid-thigh perforator incompetence
icose vein through a small puncture or incision. The catheter in 34%, a patent portion of saphenous vein in 54%, and residual
is threaded up to the saphenofemoral junction typically under or recurrent femoral–saphenous communication in 80% (65).
duplex ultrasound guidance. Following placement of tumes- High ligation combined with sclerotherapy or with varicosity
cent local anesthesia between the vein and the skin and or in a excision was inferior to high ligation and stripping (HLS) of
the saphenous vein (66). The technique of ligation and strip-

ping has been largely replaced by endovenous techniques.
Ambulatory Phlebectomy
This technique, originally described by Robert Muller and
further refined by another Swiss dermatologist, Albert-Adrien
Ramelet, involves the use of tiny incisions through which the
varicose vein is removed by a small hook (67, 68). This safe,
outpatient local-anesthesia technique allows removal of almost
any varicose vein except the saphenofemoral or saphenopopli-
teal junction. Ambulatory phlebectomy is used for primary or
secondary branches of saphenous-related varicosities. Areas
or veins that are resistant to sclerotherapy (axial) are particu-
larly indicated for ambulatory phlebectomy (Figure 27.4).
Risks minimized compared with sclerotherapy are DVT,
post-sclerotherapy pigmentation, skin necrosis, and superfi-
cial phlebitis. In many cases larger varicose veins coexist with
smaller reticular veins and associated telangiectatic webs. It
is reasonable to treat larger varicose veins by various surgical
techniques and follow up with sclerotherapy of the remaining
reticular networks.
Lasers and Light Sources

Improved results with lasers and light sources as treatments
for spider veins have come via longer wavelengths, larger spot
sizes, and cooling to protect the skin. The first report of 1064-
nm Nd:YAG laser indicated that 75% improvement was possible
after a single treatment at 3 months (69). These findings were
confirmed and mechanism of action explained as heat-induced
vessel damage and subsequent fibrosis (70). Other reports also
indicate the effectiveness of a 940-nm diode laser (71). Shorter
wavelengths used in the past, like PDL, are useful on fine leg
telangiectasias, such as telangiectatic matting, especially with
longer pulse durations up to 40 milliseconds. A broadband, FIGURE 27.4 Ambulatory phlebectomy of a large truncal varicose
vein. (a) Before. (b) After AP and endovenous RF occlusion of the great
noncoherent intense pulsed light (IPL) has been reported to saphenous vein. It is important to eliminate the source of reflux into
improve 70% of patients responding with up to five treatments this vein concomitant with the ambulatory phlebectomy of this primary
branch arising from the great saphenous vein.
per region (72). In our practice, the vast majority of laser treat-
ments are performed using 1064-nm Nd:YAG in the millisec-
ond domain on isolated telangiectasias, sclerotherapy-resistant varicosities. A supplemental technique for telangiectasias is
telangiectasias, ankle telangiectasias, and suspected AVMs. laser. These techniques replace traditional stripping and liga-
For fine telangiectasias, we also use 595 nm PDL (especially tion. Clinical evidence demonstrates that primary or secondary
using an elliptical optical spot at 10 milliseconds or longer, branches of saphenous varicosities can be effectively treated
which can be oriented along the long axis of telangiectasia of by foam sclerotherapy, rather than ambulatory phlebectomy.
the leg) (73), and a newer 532 nm laser with variable sequential Larger veins that originate from saphenous reflux require endo-
pulsing (DermaV, Lutronic Co., Korea). Recently, some have venous techniques such as RF or laser ablation, cyanoacrylate
combined POL injection with immediate irradiation by 1064 occlusion, or microfoam sclerotherapy for effective treatment.
nm Nd:YAG long-pulsed laser and found it to be more effective
than POL injection sclerotherapy alone (74, 75).
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28
Management of Hair Loss
Ömer Kutlu and Uwe Wollina
It has been reported that topical minoxidil with 2% and 5%

Introduction can induce hair density by 8.11 hairs per cm2 and 14.90 hairs
per cm2, respectively (6). The maximum clinical effect of
Hair loss also known as alopecia is a common condition in minoxidil was found at one year during 5 years follow-up (7).
dermatological practice. Hair loss can be categorized as either The combination of minoxidil and finasteride has more effect
cicatricial, which involves the permanent destruction of hair on AGA when compared to these treatments alone. This may
follicles, or non-cicatricial. The most common underlying sys- be related to the distinct mechanisms of action of these two
temic factors that contribute to hair loss are nutrition, endo- agents on AGA. Apart from these agents, dutasteride 0.5 mg
crine imbalance, drugs, infections, malignancy, and certain has been approved by some of Asian countries such as Japan
diseases such as systemic lupus erythematosus and anemia (1). and South Korea. The effect of the dutasteride is similar to that
Hair loss may have deep negative psychological effects of finasteride. However, according to the 2022 FEARS data-
on the patients. Hair loss can have significant psychological base, sexual dysfunction and neuropsychiatric side effects are
impacts in many cultures. People experiencing hair loss may approximately 2.5 times more common in finasteride while
feel a loss of self-confidence and fear being stigmatized or musculoskeletal side effects are approximately 2 times more
isolated from their social group. They may also experience common in dutasteride (5). Saw Palmetto extract, which is a
anxiety, unhappiness with their appearance, and depression herbal product that can act as finasteride and dutasteride, can
as a result of their hair loss. In these cultures, hair is often be given as additional treatment in patients with AGA (8).
seen as a symbol of beauty, youth, and vitality, and losing Recently, we reported that intramuscular administration of
it can be deeply distressing for many individuals (2). These 500 mg of DXP once a week for 2 months may improve the
existing problems resulting from hair loss underscore the quality of life of patients with androgenetic alopecia (AGA)
importance of protective measures and effective treatment. by inducing hair growth (Figure 28.1). DXP may serve as an
The treatment options can be prescription medication, lasers, alternative treatment for individuals who prefer not to use topi-
microneedling, platelet-rich plasma (PRP), mesotherapy, and cal minoxidil or hormonal therapy for hair loss. Furthermore,
hair transplant surgery. DXP may be a suitable option for individuals in lower-income
groups due to its affordability compared to other hair loss
treatments (9, 10).
The Management of Non-Cicatrical Hair Loss There have been numerous studies on the potential benefits
of PRP on hair growth, as PRP contains certain growth fac-
Androgenetic Alopecia tors such as EGF, VEGF, IGF-1, and others (11). In a random-
Androgenetic alopecia (AGA) is a progressive miniaturization ized placebo-controlled study, it has been reported that PRP
of the hair that results in baldness in genetically susceptible treatment, when combined with minoxidil and finasteride,
individuals. It is a common condition that involves approxi- can enhance the treatment response (12). The preparation of
mately 73% of men and 57% of women over the age of 80 (3). PRP involves centrifuging anticoagulated whole blood twice
It has been reported that 58% of the male population may have to increase the concentration of platelet granules and growth
AGA between 30–50 years of age (4). Despite the high preva- factors. Although there is no standardization, a centrifuge at
lence of AGA, there are only two agents, topical minoxidil 3000 rpm for 8 minutes may be effective in some commercial
and systemic finasteride, that have been approved by Food and products.
Drug Administration (FDA) so far. Apart from FDA approval Mesotherapy is an injection procedure that involves inject-
agents dutasteride, dexpanthenol (DXP) and PRP are other ing a combination of various substances into the skin. Hair
treatment options in the treatment AGA (Table 28.1). mesotherapy, which includes a mixture of components such as
Considering the pathogenesis of AGA, topical minoxidil vitamins (e.g. biotin, dexpanthenol), amino acids, coenzymes,
increases the VEGF mRNA expression and prostaglandin E2 nucleic acids, hyaluronic acids, finasteride, and minoxidil,
levels in the hair follicle. On the other hand, systemic finas- can be used effectively as an additional treatment for AGA.
teride inhibits 5-alpha-reductase and decreases dihydrotestos- Using a mesotherapy gun can enhance the effect of mesother-
terone (DHT) (responsible for miniaturization of hairs) in hair apy since the device has an additional microneedling effect.
follicles (5). Also, the pressure, depth, and frequency of the injection can
274 DOI: 10.1201/b22897-28

Management of Hair Loss 275
TABLE 28.1
Main Treatment Options in Androgenetic Alopecia
Agents Mechanism of effect Side effects Cautions
Topical minoxidil 2% and Increase VEGF mRNA expression Seborrheic dermatitis, Headaches Hypertrichosis may be a particular
5% formulations and prostaglandin E2 levels Cognitive symptoms, Hypertrichosis concern in women.
After applying the product washing
hands is crucial.
2% solutions may be more suitable
for women concerning
hypertrichosis.
Finasteride 1 mg orally Inhibits 5-alpha reductase type I Sexual dysfunction May be associated with high-grade
Neuropsychiatric side effects prostate cancer and risk of breast
cancer.
Dutasteride 0.5 mg orally Inhibits 5-alpha reductase type I Sexual dysfunction Dutasteride can be found in the
and type II receptors Neuropsychiatric side effects serum after 4–6 months of treatment
Musculoskeletal side effects cessation, therefore, blood donation
and pregnancy are not recommended
during dutasteride therapy.
Dexpanthenol Induces the coenzyme A and ATP Allergic contact dermatitis It is not recommended during
synthesis within the cell pregnancy and breastfeeding.
PRP Secretion of multiple particles from Tissue damage Patients who receive anticoagulant
platelets including dense granules, Nerve injuries agents should avoid PRP treatment.
lysosomes, and α-granules Bleeding
Mesotherapy Growth factors, vitamins, amino Tissue damage Hypersensitivity to any of the
acids, minerals Nerve injuries components, pregnancy, lactation,
Bleeding and receiving anticoagulants are
contraindications.
be adjusted to a standardized rate with a mesotherapy gun. In pediatric patients with limited patchy lesions, high
Another advantage is that the pain is less severe with the potency topical corticosteroids are recommended as a first
mesotherapy gun (Figure 28.2). Combining existing treat- choice (21). Topical calcineurin inhibitors have a limited effect
ments can increase treatment efficacy (Figure 28.3). There are on AA; therefore, they are not recommended (21, 22). Topical
also underused treatment options for AGA that are listed in prostaglandins, such as bimatoprost and latanoprost, could be
Table 28.2 (13–15). adjunctive topical treatments, especially for eyebrows (23).
Carboxytherapy with intradermal and/or subcutaneous Apart from this, topical minoxidil can also be used as adjunc-
microinjections of sterile purified carbon dioxide has obtained tive therapy. However, pediatric patients are prone to develop
good results in some patients (16). hypertrichosis (24). Intralesional steroid treatment is not rec-
Surgical treatment is frequently applied in male patients, ommended in childhood age since it causes pain. However, it
while it is rarely needed in female patients. The FUE (Follicular can be used as an effective treatment in adult patients who are
Unit Extraction) technique is a popular surgical treatment since resistant to topical treatment (25). Intralesional steroid should
the procedure has “no visible scarring” properties at the donor be performed with 0.1 ml of 2.5 to 5 mg/mL of triamcino-
area. In hair transplantation, hair follicles from the occipital lone acetonide intradermally and repeated every 4–6 weeks
region, which are less sensitive to androgens, are transplanted (Figure 28.4). Caution should be taken in terms of side effects
into the frontal and parietal regions. The success of the treat- of topical and intralesional steroids, such as atrophy, telangiec-
ment depends on the density of the hair follicles in the donor tasia, itching, burning, and folliculitis.
area and the experience of the practitioner (17). Contact immunotherapy, such as diphenylcyclopropenone
Cosmetic approaches for AGA are generally preferred in and squaric acid dibutyl ester (SADBE) treatments, can be
female patients. These approaches include the use of camou- used in both adult and pediatric patients. It can be considered
flage products such as hairstyle change, sprays that increase as second-line treatment option in pediatric alopecia areata
hair volume, lotions, wigs, and hairpieces (18). patients with widespread disease (2, 26). Complete treatment
response with contact immunotherapy is seen in approximately
one in three cases. However, a prospective randomized clinical
Alopecia Areata
trial reported that the combination of diphenylcyclopropenone
Alopecia areata (AA) is a common autoimmune, non-scarring, with 0.5–1% anthralin provides >50% improvements in 47% of
chronic inflammatory disease of the hair follicle, affecting patients with chronic extensive alopecia areata (27).
approximately 2% of the population (19). The management of Our current observations suggest that this treatment proto-
AA depends on the age of patients, duration of the disease, and col may be one of the most beneficial options for patients who
extent of the lesions. Topical steroid treatments are the first- do not want systemic treatment and have extensive alopecia.
line treatment options for limited, patchy AA in both pediatric However, the necessity of continuing diphenciprone treat-
and adult patients (20). ment for a long time and the presence of side effects such as
FIGURE 28.2 The pressure, depth, and frequency of the injection can be
adjusted to a standardized rate with a mesotherapy gun.
vesiculation, regional lymphadenopathy, itching, burning, and

eczema may reduce treatment compliance (28).
Systemic treatment is recommended in pediatric patients
above 12 years of age and adults with severe alopecia areata.
Although complete remission is not guaranteed, systemic ste-
roids, cyclosporine, methotrexate, and hydroxychloroquine
have varying success rates in severe AA cases (29).
Steroid pulse therapy is an option for more widespread dis-
eases in children and adults. The pulses can be applied intra-
venous (IV) or orally. In children, either IV dexamethasone
(1.5 mg/kg/day for 1–3 days per month) or IV methylpred-
nisolone (8–30 mg/kg/day for 1–3 days per month) have been
shown to be efficacious. The treatment should be limited to
12 months maximum. The oral option for children is methyl-
prednisolone 15 mg/kg/day for 3 days every other month (30).
Alternatively, dexamethasone minipulses of 5 mg/d on 2 days
per week can be considered. Clinically significant hair growth
is seen on average after 8 months of treatment (31).
In adults, IV methylprednisolone 500 mg/day is given on 3
consecutive days. The outcome after 12 months follow-up was
complete remission 31% and partial remission in 42% (32).
The list of systemic treatment options with their recom-
mended doses for alopecia areata can be found in Table 28.3.
Among systemic treatment JAK inhibitors such as tofacitinib,
ruxolitinib and baricitinib are promising for severe disease.
FIGURE 28.1 Improvement of AGA with only the use of intramuscular In this context, baricitinib is the first FDA-approved systemic
administration of 500 mg of DXP once a week for 2 months. treatment for alopecia areata (33).
FIGURE 28.3 The outcome of a combined treatment of PRP and mesotherapy, which was administered over a period of 8 months, consisting of
6 sessions in total.
pneumatic device setting around the hairline during the drug

infusion, can reduce the risk of developing AE. Numerous
studies reported that scalp hypothermia (<24°C) can be an
effective treatment method in preventing certain types of che-
motherapy-related AE (37). It has been reported that 2–3 ses-
sions per month of PRP treatment can effectively induce hair
regrowth in COVID-19-associated AE (38).
In patients with AE, treatments such as minoxidil, DXP,
and PRP can be used as supportive treatment after the end of
chemotherapy to reduce the period of baldness. Considering
psychological conditions, the use of a wig or head covering/
hairpiece can be offered in particular for women until the hair
regrows (39). Patients should be assured by stating that the
FIGURE 28.4 Intradermal steroid injections to the patches of alopecia current situation will improve with the elimination of the trig-
areata.
gering factor.
Extensive alopecia, nail involvement, and long disease dura-
tion, as well as concomitant atopic conditions, are properties
Telogen Effluvium
that indicate poor prognosis. Considering the chronic and
recurrent nature of the disease, long-term follow-up of patients Telogen effluvium (TE) is characterized by the diffuse loss of
may be necessary (34). In patients resistant to systemic treat- the telogen-phase hairs. Although TE can occur in both gen-
ments, wigs can improve the quality of life. ders, it is more common in women. There are numerous factors
associated with the occurrence of TE (Table 28.4) (40–42).
The management of TE is mostly based on correcting the
Anagen Effluvium
underlying factors. The reassurance of patients with TE is cru-
Anagen effluvium (AE) is abrupt diffuse shedding of hair loss cial to avoid a vicious circle due to chronic stress. Patients pre-
after certain triggering factors such as chemotherapy, severe senting with TE may be stressed that they will lose their hair
infections, radiation, and exposure of toxins such as arsenic permanently. In this context, it should be explained that hair
and thallium (35, 36). This type of hair loss is caused by the shedding can sustain up to 6 months, and by the removal of the
interruption of the mitotic activity of the hair follicles in the responsible factors the problem will be resolved (43).
anagen phase of the hair cycle. Chemotherapeutic drugs are If there are suspicious drugs for TE, discontinuation of the
the most common culprit agents for anagen effluvium. Among drug should be performed for at least 3 months. In patients
these drugs, doxorubicin, cyclophosphamide, and nitrosoureas with nutritional deficiencies, supplements including mul-
are associated with severe hair loss. Hair loss typically starts tivitamins such as vitamin B12 and biotin can be suggested
1 to 2 weeks after the initiation of the offending drugs (37). (44). Certain amino acids may play an important role in hair
There is no definitive treatment for AE. The management of growth. In this context, L-lysine plays an important role in
the AE depends on the elimination of the causative factors. In iron and zinc absorption, while L-cysteine provides viability
chemotherapy-associated AE, hair regrowth starts after dis- and proliferation of the keratinocytes by reducing reactive
continuation of the responsible drugs in most of cases. Some oxygen species (44, 45). For this reason, a supplement contain-
studies have reported that scalp tourniquets, which include a ing essential amino acids such as L-lysine should be preferred.
TABLE 28.2 Some herbal products may also have good results in the
The Underused Treatment Options for AGA treatment of TE. In a placebo-controlled study, it has been pos-
tulated that daily use of lotion containing 0.5% Nigella sativa
Agents Mechanism of action for 3 months significantly improves TE (90% increase in hair
Setipiprant Oral prostaglandin D2 receptor antagonist density) when compared to the placebo (30% increase in hair
Topical cetirizine Inhibits prostaglandin D2 formation density) (48). Khattab et al. reported a single injection of 150 U
Oral minoxidil Increases the VEGF mRNA expression and of botulinum toxin A intramuscularly to the frontalis, occipi-
prostaglandin E2 levels in hair follicles talis, temporalis, and periauricular muscles is approximately
Low-level laser Increases reactive oxygen levels, adenosine as effective as four sessions (every 2 weeks) of mesotherapy
therapy (LLLT) triphosphate production and stimulate certain (Mesoestetic b.prof 018 from Mesoestetic Pharma Group,
transcription factors
Spain) (49).
Topical valproic acid Stimulates beta-catenin levels
PRP treatment is not recommended in acute TE, but it can
be used in chronic TE. Işlek et al. reported that approximately
TABLE 28.3 60% of the patients who received 4 sessions of PRP stated the
Systemic Treatment Options with Their Recommended Doses in treatment as “very effective” (50). Consistent with the litera-
Alopecia Areata ture, we observed that 3–4 sessions of monthly PRP treatment
are beneficial in the treatment of chronic TE developing after
Drugs Recommended doses COVID-19. Further studies are needed for more conclusive
Systemic steroids (prednisolone) 0.4–0.6 mg/kg/day evidence.
Cyclosporine 3–5 mg/kg/day It has been postulated that the use of 100 mg/ml caffeine-
Methotrexate 15–25 mg/week containing shampoo daily for 2 minutes for 6 months may
Mycophenolate mofetil 2 g/day improve hair intensity and hair thickness (51).
Sulfasalazine and mesalazine 3 g/day and 2–4 g/day
Dapsone 100 mg/day
Hydroxychloroquine 200–400 mg/day Trichotillomania
Simvastatin/ezetimibe 40/10 mg/day
Trichotillomania (TTM) is a chronic psychiatric disease char-
Ustekinumab 100 mg/3 months
acterized by recurrent compulsive behavior of pulling out
Tofacitinib 5–10 mg/day
one’s own hair. It occurs more frequently in the pediatric pop-
Ruxolitinib 40 mg/day
ulation, however, it can be seen in any age group. Prevalence of
Baricitinib 2–4 mg/day
the disease extends from 0.5% to 3.4% during the lifetime (52).
Among children, the habit will be lost in the majority of
cases when managed conservatively or with minimal interven-
TABLE 28.4 tion. Adults, however, are more likely to require treatment.
Etiological Factors of the Telogen Effluvium However, there are no FDA-approved drugs for TTM (52).
Factors Explanations Collaboration with psychiatry is essential in treating TTM
since the disease is characterized by psychiatric comorbidities.
Infection COVID-19, HIV, tuberculosis, syphilis, In this regard, Grant JE et al. investigated 530 adults with tricho-
severe fever-related diseases
tillomania and reported that approximately 40% of the patients
Physiological Post-partum, seasonal
had major depression, anxiety, or both (53). Considering the
Drugs Oral anticoagulants, oral retinoids, oral
aforementioned pieces of information, the role of psychother-
contraceptives, beta-blockers, lithium,
valproic acid apy and psychiatric treatment is essential for the management
Psychological stress Depression, anxiety of TTM. Among the types of psychotherapy, the most com-
Systemic diseases Hypo- and hyperthyreoidism, renal mon and effective method is behavioral therapy. For example,
failure, hepatic failure, anemia, a report revealed that one session of habit-reversal training (a
systemic lupus erythematosus type of behavioral therapy) decreased self-reported hair-pull-
Nutritional deficiencies Riboflavin, vitamin D, vitamin B12, ing behavior by 99% (54, 55). Cognitive therapy and cognitive
zinc deficiencies, malnutrition behavioral therapy can also be used in the treatment of TTM,
although they are not as effective as behavioral therapy (56).
It is thought that serum ferritin levels should be above 40 ng/dl in Selective serotonin-reuptake inhibitors (SSRIs) such as
patients with TE. Therefore, an iron supplement can be given fluoxetine and sertralin are the most common treatment
for a couple of months in patients who have low levels of fer- options for the treatment of TTM. However, according to pre-
ritin (44). Both hypo-and hyperthyroidism may lead to the TE. vious studies, the adequacy of the SSRI in terms of the effec-
If there is a thyroid hormone disorder, adjustment of serum tiveness of TTM is unsatisfactory and controversial (55, 56). In
thyroid levels with drugs may improve TE. a placebo-controlled study, a tricyclic antidepressant such as
The use of topical or systemic minoxidil is not recom- clomipramine was found to be an effective treatment for TTM,
mended in acute TE, but it is recommended in the manage- although it is not better when compared to cognitive-behav-
ment of chronic TE (46). In this regard, it has been reported ioral therapy (56). Tricyclic antidepressants are not routinely
that 0.25–2.5 mg daily use of oral minoxidil for 6 months may recommended for pediatric age unless the disease is severe
decrease hair shedding in chronic TE (47). and resistant (57).
N-acetylcysteine is a glutamate modulator that can be used with TA. Apart from triamcinolone acetonide, five out of six
as an effective treatment in TTM in both pediatric and adult patients had also received 5% topical minoxidil treatment (67).
patients (58, 59). Given the mild side effects, N-acetylcysteine There is also a case of successful treatment of hair transplanta-
may be preferable as the initial option of TTM treatment, tion after extensive TA due to ponytail hairstyle (68).
especially in pediatric age. Olanzapine, risperidone, and nal-
trexone are the other agents that can be used alternatively in
the treatment of TTM (60, 61). The duration of treatment with
antipsychotic drugs for TTM is typically 3–6 months due to
The Management of Cicatricial Hair Loss
the potential for adverse events (62). Cicatricial hair loss consists of a group of hair disorders char-
Certain treatment options, including average doses in TTM, acterized by irreversibly destroyed hair follicles resulting in
can be seen in the Table 28.5 (53, 63). fibrous tissue. Cicatricial hair loss can be basically catego-
rized into three classes: neutrophilic, lymphocytic, and mixed
(Table 28.6).
Traction Alopecia
Early diagnosis and onset of treatment is the most critical
Traction alopecia (TA) is hair loss that is characterized by step in disease management in patients with cicatricial alo-
recurrent prolonged tension on the hair follicles. According to pecia since the disease causes permanent hair loss in case of
the severity of the involvement, patch or complete loss of hair delayed treatment. Fibrosis is detected in the histopathological
can be observed. The main reason for TA is due to mechanical examination only in the advanced stages of all cicatricial alo-
trauma. Therefore, certain individuals such as African women, pecias, so it is not helpful for early diagnosis. Therefore, the
Sikh males of Indian descent, ballerinas, and those who wear histopathological examination should be performed from an
tight bonnets or headscarves are prone to developing TA (64). active lesion to aid diagnosis.
Preventive measures that discontinue the exertion of trac-
tion on the hair are the basic approach to treating TA. There
Dissecting Cellulitis
is a lack of studies regarding the treatment of TA. However,
there are some promising treatments that can be used in TA Dissecting cellulitis (DC) is characterized by perifollicular
treatment. In this context, it has been reported that 1 or 2 years inflammation that may eventually progress to discharging
of low-dose oral minoxidil (1.25 mg twice daily) can effec- sinus tract formation. The disease has a chronic and recur-
tively be used for the treatment of TA, including those who rent course and is part of the follicular occlusion tetrad, which
do not respond to the 5% topical minoxidil treatment (65, includes acne conglobata, hidradenitis suppurativa, dissecting
66). Uwakwe et al. reported that injection of 5 mg/mL tri- cellulitis, and pilonidal disease (69). Although many agents
amcinolone acetonide into the frontotemporal hairline at 6–8 are used in the treatment of DC, the results are not satisfactory.
weeks intervals resulted in a good response in all six patients In addition to topical treatments, a variety of other treatment
TABLE 28.5
Certain Treatment Options in Trichotillomania
Drug Mechanism of action Main indications Average doses
Clomipramine Tricyclic antidepressant Obsessive-compulsive disorder, 50–250 mg/day
anxiety, depression
Aripiprazole Antipsychotics Schizophrenia and bipolar disorder 3–15 mg/day
Olanzapine 10–20 mg/day
Risperidone 0.5 mg/day
N-Acetylcysteine Mucolytic, antioxidant Cough, drug hepatotoxicity 1200–2400 mg/day

Naltrexone Opiate receptor antagonist Alcohol and cigarette addiction 50–150 mg/day
Modafinil Central nervous system stimulant Obstructive sleep acne 100–200 mg/day
Topiramate Carbonic anhydrase inhibitor Epilepsy and migraines protections 50–250 mg/day
Dronabinol Cannabinoid antagonist Anorexia, vomiting 2.5–15 mg/day
TABLE 28.6
The Types of Cicatricial Hair Loss in Terms of Types of Inflammatory Cells
Neutrophilic Lymphocytic Mixed
Dissecting cellulitis of the scalp Lichen planopilaris* Acne keloidalis
Folliculitis decalvans Discoid lupus erythematosus Erosive pustular dermatosis
Central centrifugal cicatrical alopecia
Classic pseudopelade
* Includes three types: classic lichen planopilaris, frontal fibrosing alopecia, and Graham–Little–Piccardi–Lasseuer syndrome.
options have been reported in the literature for the manage- cyclosporine, systemic retinoids, mycophenolate mofetil, pio-
ment of erosive pustular dermatosis of the scalp, including glitazon, and hydroxychloroquine can be given as treatment
systemic antibiotics like doxycycline, azithromycin, ciproflox- modalities in all forms of lichen planopilaris. In addition,
acin, rifampin, and clindamycin, as well as systemic isotreti- dutasteride at a dosage of 0.5 mg daily has been reported as
noin, zinc sulfate, dapsone, lasers, photodynamic therapy, an effective treatment for FFA (80). Studies have reported that
and immunosuppressive agents, including biological agents. taking tofacitinib at a dosage of 5 mg twice daily can reduce
However, the success rates of these treatments vary (70, 71). In the severity of lichen planopilaris by 30–94% (81). Baricitinib
cases that respond to treatment, hair regrowth may occur even has also been suggested as a potential treatment option for
if it is not fully restored. Radical surgical resection (scalpec- classic lichen planopilaris and FFA (82). In contrast to cutane-
tomy) and skin grafting has promising results for long-term ous lichen planus oral retinoids (acitretin, isotretinoin) are of
healing in advanced cases (72). very limited value (83).
Recent studies have suggested that sunscreens may be
linked to the development of FFA. While further research is
Folliculitis Decalvans
needed to confirm this link, it may be advisable to discontinue
Folliculitis decalvans is an intense inflammatory form of cica- sunscreen use in patients with FFA (84).
tricial alopecia characterized by inflammatory, perifollicular
papules, and pustules. Yellow-whitish desquamations, follicu-
Discoid Lupus Erythematosus
lar hyperkeratosis, erosions, and hemorrhagic crusts may also
be present. As the lesions progress, cicatricial areas begin to Discoid lupus erythematosus (DLE) is characterized by the
form. Staphylococcus aureus can be cultured from pustules formation of chronic, scaly, and red patches of skin that can
and crusted lesions. Tufted folliculitis, which is characterized lead to scarring on sun-exposed areas of the body including
by the presence of 5–15 hairs emerging from a single dilated scalp. Although rare (occurring in approximately 5% of cases),
follicular orifice, is commonly seen in patients with folliculi- DLE can progress to systemic lupus erythematosus. Therefore,
tis decalvans (73). Since this disease is mostly seen in young it is important to conduct a thorough examination to check for
people, patients may have high expectations. Therefore, it is the presence of SLE in patients diagnosed with DLE (85).
necessary to explain to patients that the aim of treatment is The main goal of treating DLE is to halt the progression
to reduce inflammation as much as possible, and hair may not of the disease and prevent the emergence of new lesions.
regrow in the cicatricial areas. Treatment options include topi- Photoprotection is essential in the treatment of DLE (86).
cal and oral antibiotics, isotretinoin, topical and systemic ste- The first-line treatment options for DLE include high-
roids, dapsone, laser epilation, and surgery. Topical antibiotics potency topical steroids, topical calcineurin inhibitors, and
include mupirocin, erythromycin, fusidic acid, and clindamy- intralesional steroids. Antimalarial agents like chloroquine,
cin while systemic antibiotics include doxycycline, azithro- hydroxychloroquine, and quinacrine are also frequently used
mycin, vancomycin, ciprofloxacin, rifampicin, clindamycin, as systemic treatments (87). Chloroquine and hydroxychloro-
sulfamethoxazole–trimethoprim. Intranasal administration of quine are commonly used antimalarial agents in the treatment
topical mupirocin may reduce S. aureus colonization, which of DLE, but they can cause retinal toxicity. Thus, regular oph-
contributes to treatment success (74–75). thalmological examinations are required to monitor for this
potential side effect. It is also important to note that smoking
can decrease the effectiveness of these medications in treat-
Lichen Planopilaris
ing DLE. Therefore, patients should be advised about the
Lichen planopilaris is characterized by perifollicular ery- impact of smoking on their treatment and encouraged to quit if
thema and hyperkeratosis of the scalp, which leads to fibrotic they are smokers (88). In certain cases of DLE, drugs such as
alopecic areas. Although it can involve any part of the scalp, methotrexate, isotretinoin, dapsone, thalidomide, and biologi-
the vertex and parietal sites are the most commonly affected cal agents may be used as treatment options. However, these
areas. There are three variants of lichen planopilaris: classic are usually considered only when other treatments have failed
LPP, frontal fibrosing alopecia (FFA), and Graham-Little- or are not appropriate for the patient. It is important to note
Piccardi-Lasseuer Syndrome (GLPS) (76). FFA is character- that these drugs have potential side effects and require close
ized by progressive bandlike cicatricial involvement of the monitoring (89).
frontal and temporal hairline. Involvement of eyebrows and
eyelashes is common (77). On the other hand, GLPS is charac-
Central Centrifugal Cicatrical Alopecia
terized by cicatricial alopecia of the scalp along with involve-
ment of non-cicatricial alopecia in areas such as the axillae Central centrifugal cicatricial alopecia (CCCA) is a type of
and pubic region, as well as lichenoid lesions on the body (78). scarring hair loss that starts at the crown or vertex of the
A recent study disclosed that about 2/3 of patients with FFA scalp and spreads outwards. CCCA is more commonly seen
show at least one contact sensitization which might contribute in African American women than other types of cicatricial
to its pathogenesis (79). alopecia (90).
Once a diagnosis of the disease has been made, it is impor- Patient education is crucial in managing CCSA. Patients
tant to explain to the patient that the condition has a progressive should be informed that certain haircare practices, such as
nature, and the goal of treatment is to manage inflammation using hair relaxers, friction-enhancing processes, and expos-
to protect the existing hair. Topical and systemic steroids, ing hair to excessive heat during drying and bathing, may
exacerbate the disease’s progression. It is important to avoid inflammation is the underlying cause of the condition, patients
such practices and to use gentle haircare methods to prevent should be advised to avoid frequent shaving of the hair in the
further damage to the hair and scalp (90, 91). affected area. Additionally, wearing tight clothes that contact
Topical steroids and calcineurin inhibitors are anti-inflam- the neck should be avoided, as this can also induce further
matory agents that can be used in the early stages of the dis- inflammation. It is also important for patients to keep the
ease to help stop hair loss. In addition, a monthly injection of affected area clean and to avoid using harsh hair products or
5 mg/ml triamcinolone acetonide can be administered around chemicals on the scalp (100).
the edges of the affected area for a period of 3–6 months. An effective treatment can reduce keloid formation and scar
This treatment aims to reduce inflammation and stimulate development in acne keloidalis. In the case of mild papulo-
hair regrowth. However, an important point to consider is that pustular formation topical antibiotics such as clindamycin
the choice of treatment will depend on the individual patient’s and antiseptic properties shampoo may be useful treatment
condition and the severity of their symptom (92). It has been options. On the other hand, in the severe presence of the papu-
reported that if the CCSA disease is severe or spreads rapidly, lopustular lesions long-term use of systemic isotretinoin and
systemic agents such as anti-inflammatory antibiotics (e.g. tet- systemic antibiotics such as doxycycline can be given (101).
racycline), hydroxychloroquine, mycophenolate mofetil, and Cryotherapy has been found to be an effective treatment
cyclosporine can be administered. In addition to these treat- method for both early and keloid-phase disease. Intralesional
ments, supplementary products such as zinc, iron, biotin, and triamcinolone acetonide injections of 5–40 mg/mL can reduce
vitamin D can also be given to the patient as part of the treat- scar volume and improve unsightly appearance. In accor-
ment plan (91). Minoxidil 2% or 5% application may be helpful dance with the literature, in our clinical experience, we have
for miniaturized hair and can be added to the treatment plan. If observed that administering steroid injections immediately
the disease progression stops for 1 to 2 years, hair transplanta- after cryotherapy during the same session with a 3-week inter-
tion can be considered as an option (93). val is a highly effective method (102). Lasers such as CO2
laser, 1064-nm neodymium-doped yttrium aluminum garnet
(Nd:YAG) laser, pulse dye laser, and diode laser have been
Classic Pseudopelade
used with various levels of success responses in the treatment
Classic pseudopelade is a self-limiting idiopathic form of per- of the acne keloidalis (103). As in other forms of cicatricial
manent scalp hair loss. Pseudopelade is lymphocytic cicatri- alopecia, surgical treatment options can be considered in cases
cial alopecia, and in this context, folliculitis decalvans, DLE, resistant to medical treatment. In analogy to inverse acne, a
and LPP may be underlying factors. In cases where classic three-step procedure with deep excision and negative pressure
pseudopelade is associated with underlying diseases such as therapy followed by split skin transplantation has been used,
folliculitis decalvans, DLE, or LPP, treatment with steroids, when primary closure seems impossible (104).
hydroxychloroquine, and mycophenolate mofetil can be
attempted, even though there is often resistance to these treat-
Erosive Pustular Dermatosis of the Scalp
ments. There is currently no universally accepted treatment
protocol for pseudopelade. Therefore, treatment plans should Erosive pustular dermatosis of the scalp is a rare, chronic
be tailored to each individual case and regularly monitored for inflammatory condition of elderly patients with a female
efficacy (94, 95). Caution should be exercised when consider- predominance. Clinically, it presents with pustules, purulent
ing the use of immunosuppressive agents in the treatment of crusts, erosions, and ulcerations on actinic damaged skin that
children with pseudopelade. In summary, there is currently no eventually lead to scarring alopecia. Trauma, drugs, and surgi-
universally accepted medical treatment for pseudopelade. If cal intervention account for the development of EPDS (105).
the disease remains stable for at least 2 years, hair transplanta- The treatment options for EPDS can vary depending on
tion may be considered as an option (94, 96). the size and severity of the condition. However, topical and
systemic steroids are typically the first-line treatment options,
as listed in Table 28.7. Combination of the topical antibiotics
Acne Keloidalis
(fucidic acids, silver nitrate) with steroids yields good results
Acne keloidalis is a chronic skin condition that mainly affects (106). Surgical approaches for EPSD treatment are not recom-
the back of the scalp and is characterized by the development mended unless malignancy is suspected (107, 108).
of papules, plaques, and permanent hair loss. The exact cause
of acne keloidalis is unknown, but it is believed to result from a
combination of genetic, environmental, and lifestyle factors It
Conclusion
is considered that the lesions are the result of a chronic inflam-
matory process, which can cause scarring and hair loss in the Hair loss is a prevalent issue that affects people of all ages
affected area. The most frequently affected area is the nape across the world. The choice of treatment for hair loss depends
(97, 98). Patients of African descent have a higher risk for this on various factors, such as the underlying cause of hair loss,
disease. the patient’s gender and age, whether the patient is pregnant or
Patient information is crucial in managing acne keloida- breastfeeding, and their expectations for treatment outcomes.
lis. Acne keloidalis in conjuction with acanthosis nigricans Therefore, the selection of hair loss treatment is often per-
is a red flag for metabolic syndrome. Close cooperation with sonalized to address the specific needs and concerns of each
internal medicine and GP is warranted (99). Since chronic patient. The initial step in managing hair loss is to determine
TABLE 28.7
Suggested Treatment Algorithm in Erosive Pustular Dermatosis of the Scalp
First-line Second-line Third-line
Topical steroid* Topical tacrolimus Oral cyclosporine A
Topical and systemic dapsone
Calcipotriol
Doxycycline
Systemic steroid Photodynamic therapy**
Systemic retinoids (isotretinoin acitretin)
Indomethacin
Zinc sulfate
* High-potent steroid is the preferable.
** Sometimes paradoxically associated with ERPS.
whether it is temporary or permanent. This is a crucial step 12. Alves R, Grimalt R. Randomized placebo-controlled, dou-
in the basic approach to the disease. Temporary hair loss can ble-blind, half-head study to assess the efficacy of platelet-
typically be treated using current suggestions and treatments. rich plasma on the treatment of androgenetic alopecia.
However, in cases of permanent hair loss, it is important to Dermatol Surg. 2016; 42:491–497.
inform patients about this issue and help them to develop real- 13. York K, Meah N, Bhoyrul B, Sinclair R. A review of
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ciclib: Topical cetirizine. J Oncol Pharm Pract. 2021;
27:460–463.
15. Jo SJ, Shin H, Park YW, et al. Topical valproic acid increases
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29
Pigmentation
Dyschromia
Thierry Passeron and Jean-Paul Ortonne
Variations of skin pigmentation are mostly due to quantita- within melanophages or may be free in the extracellular matrix
tive or qualitative defects of melanin pigments (eumelanin and of the dermis.
pheomelanin). However, dyschromia can also result from an Skin lightening or whitening (leukoderma, hypopigmenta-
abnormal increase or decrease of other endogenous pigments tion) is most commonly the result of decreased melanin con-
(hemoglobin, bilirubin) or from the deposit of exogenous pig- tent in the skin (hypomelanosis). Epidermal hypomelanosis
ments (heavy metals, cosmetic tattoos). This leads to a het- may be the result of at least two different pathogenic mecha-
erogeneous group with numerous causes. Although most of nisms: partial or total absence of epidermal melanocytes
the patients will consult for the cosmetic disturbance due to (melanocytopenic hypomelanosis) or even melanin synthesis,
the dyschromia, it is essential to determine the origin of the melanosome biogenesis, transport and transfer and melano-
pigmentary trouble in order to propose the more adapted treat- some transfer despite a normal number of epidermal mela-
ment and if necessary to ask for complementary investigations. nocytes (melanopenic hypomelanosis). Increase of epidermal
turn over can also induce hypomelanosis. Hypo- and hyper-
pigmentation disorders can be inherited or acquired (2, 3).
Dyschromia that results from variation of the hemoglobin
Pathophysiology of Dyschromia content within the skin (diffuse such as in anemia or in polycy-
The color of the skin results from the presence of pigments in themia, or localized such as in Bier spots) can be easily distin-
the epidermis and in the dermis. The melanins (eumelanin, dark guished from other pigmentary disorders as the change in color
brown, mostly produced by dark skin types, and pheomelanin, disappears with pressure (Figure 29.1). Xanthoderma describes
red-fair brown, mostly observed in fair skin types) are the most a yellow to orange macular discoloration of the skin. Jaundice
important pigments in human skin. However, other endogenous and carotenoderma are the two main causes of xanthoderma.
pigments such as carotenoin, hemoglobin, and bilirubin also play Although patients may consult for the cosmetic disturbance, drug
a role in the color of the teguments. Dyschromia can result from and excessive dietary intake of carotenoids and search for under-
a darkening, a lightning, and the occurrence of an unusual skin lying disease must be performed (4). The treatment is etiological.
color (1). Quantitative or qualitative defects in the production or Heavy metals (e.g., iron, silver, copper) and traumatic, medical,
in the deposition of melanin explain most of the pigmentary dis-
orders but abnormal variations of other endogenous pigments and
deposit of exogenous pigments also lead to dyschromic lesions.
In some cases, the dyschromia can also result from an increase
thickness of the epidermis or from a discoloration of the sweat.
An increased amount of melanin in the skin is called
hypermelanosis or melanoderma. A brown hypermelanosis is
caused by excessive amounts of melanin within the epidermis
whereas ceruloderma (or blue hypermelanosis) results from
large amounts of melanin in the dermis. Mixed hypermelano-
sis is characterized by an excess of melanins in both epidermis
and dermis may also occur. Epidermal hypermelanosis may
result from increased melanin production by a quantitatively
normal melanocyte density in the epidermis (melanotic hyper-
melanosis) or by an increased number of epidermal melano-
cytes (melanocytic hypermelanosis). Dermal hypermelanosis
can be due to the production of melanin by ectopic dermal
melanocytes (dermal melanocytosis) or to an abnormal trans-
fer of melanin from epidermal cells to the dermis (pigmentary
incontinence). In this situation, melanin granules accumulate FIGURE 29.1 Bier spots on the arm of a young adult.
286 DOI: 10.1201/b22897-29

Pigmentation 287
or esthetical tattoos are other sources of skin discoloration. An to HQ include inhibition of tyrosinase through the covalent
increased thickness of the epidermis can lead to diffuse, patchy, binding to histidine or interactions with copper at the active
or reticulated light to dark brown hyperpigmentation. The chronic site of tyrosinase, inhibition of DNA and RNA synthesis, and
avoidance of washing can also induce hyperpigmented and some- alteration of melanosome formation and melanization extent.
times keratotic patches. Finally, the discoloration of the skin can-
not only be due to pigment abnormality within the skin, but also
Others
to an abnormal coloration of the sweat (called chromhidrosis or
pseudochromhidrosis). Tranexamic Acid
Tranexamic acid is known as an oral medicine for treating
melasma. The antiplasma activity of tranexamic acid has been
proposed for treating melasma by targeting the vascular com-
Depigmenting Agents
ponent of this disorder (9–11). Oral tranexamic acid should be
Phenolic Compounds proposed at the dose of 250mg 2 or 3 times a day for 3 months.
Safety data for longer duration are missing. Its efficacy is now
Hydroquinone demonstrated in several prospective studies and meta-analyses
Hydroquinone (HQ) is the most popular depigmenting agent (5). (12–15). Unfortunately, the efficacy is transient and treatment
Several studies have established the therapeutic effect of HQ is proposed usually every year. Oral tranexamic acid is pre-
in the treatment of hypermelanosis (6). HQ is still the “gold scribed of label-use and must not be proposed if there is any
standard” of depigmenting agents. The effectiveness of HQ is risk of thromboembolism. Interestingly, a study using histo-
related directly to the concentration of the preparations, the logic analysis of melasma skin before and after oral tranexamic
vehicle used and the chemical composition of the final prod- treatment, showed a significant decreased expression of endo-
uct. Two percent HQ was reported to improve hypermelanosis thelin-1 withing the epidermis. This underlines that tranexamic
in 14%–70% of the patients. However, HQ is most commonly acid probably acts on melasma through a direct on vasculariza-
used at a 4% concentration by dermatologists. At this concen- tion. Tranexamic acid is also proposed by using intradermal
tration, HQ is very effective, but it can have a significant irri- injections, or topically. Data remain sparce and studies with
tant effect. Concentrations as high as 6%–10% are prescribed good methodology are still lacking. Intradermal use seems to
extemporaneously for resistant cases but may be a strong irri- have some efficacy (16–18). They might be proposed if oral
tant effect. Because of the hazard of long-term treatments, use of tranexamic acid is contraindicated. Topical tranexamic
the use of HQ in cosmetics has been banned by the European acid has, at best, limited efficacy (19, 20). The only prospective
Committee (24th Dir. 2000/6/EC). Formulations are avail- randomized trial showed no difference compared to placebo
able only by prescription of physicians and dermatologists. (21). This lack of efficacy of topical formulations is probably
A number of different vehicles can be used for HQ, but the explained by the fact that tranexamic acid should reach the der-
most suitable for the formulation is a hydro-alcoholic solu- mal component of the skin to be active.
tion (equal parts of propylene glycol and absolute ethanol).
A nitro-oxidant such as ascorbic acid or sodium bisulphate Cystamine and Cysteamine
is regularly used to preserve the stability of the formulation.
The acute side effects of HQ include irritant and allergic contact Cystamine and derivatives have been shown to inhibit tyrosi-
dermatitis, nail discoloration, and post-inflammatory hypermela- nase activity as well as the level of tyrosinase protein (22, 23).
nosis (7). These adverse events are temporary and resolve after However, as it reduces eumelanin it increases pheomelanin syn-
HQ discontinuation. Higher concentrations (≥5%) may induce per- thesis. A recent prospective randomized study showed a moder-
sistent hypo or amelanosis (leukoderma en confetti). Exogenous ate but statistically significant superiority compared to placebo
ochronosis is a very rare complication occurring in dark-skinned for treating melasma (24). However, as it reduces eumelanin it
or black individuals after chronic use for several years. This irre- increases pheomelanin synthesis (23). At the contrary to eumela-
versible disorder presents in the form of reticulated, ripple-like, nin, pheomelanin has no photoprotective properties. When phe-
sooty pigmentation affecting common sites of HQ applications omelanin is exposed to UV radiation it produces radical species
(cheeks, forehead, periorbital areas). The lesions are typically (25, 26). More recently it has been shown that pheomelanins
localized on photo-exposed areas. Histological examination of without UVR may promote melanomagenesis by the radical spe-
these lesions shows banana-shaped yellow-brown pigment gran- cies they produce (27). Thus, great caution should be taken with
ules in and around collagen bundles in conjunction with giant-cell such products and in light of the current knowledge it is very dif-
and melanophage-containing granulomas in the upper dermis. ficult to advise their use for treating pigmentary disorders.
The pathogenesis of HQ-induced ochronosis is unknown,
and no effective treatment is available. The mode of action of
Tretinoin
HQ is not fully understood. HQ seems to exert its effect mainly
in melanocyte with active tyrosinase activity. Guidelines and Tretinoin (all-trans retinoic acid—ATRA) has been used in
radical oxygen species arising from the oxidation of HQ induce concentrations from 0.025%–0.1% to treat a variety of pig-
an oxidative damage of membrane lipids and proteins includ- mentary disorders such as pigmented spots of photoaged skin,
ing tyrosinase and depletion of glutathione contributes to the melisma, and postinflammatory hyperpigmentation in dark-
lightening action (8). Other depigmenting pathways attributed skinned individuals (28–31). Erythema and peeling in the
area of application are adverse events of ATRA 0.05%–0.1%. Clinical trials demonstrated that 2% HQ combined to 0.05%–
Post-inflammatory hyperpigmentation may also occur. Topical 1% tretinoin cream and lotions are also effective.
ATRA appears to exert its action by enhancing keratinocyte
proliferation and increasing epidermal cell turnover. However,
Neotone® Cosmetic Products
ATRA, acting on retinoid-activating transcription factors,
interferes with melanogenesis. ATRA does not inhibit mela- This serum combined cosmetic depigmenting agents targeting
nogenesis in skin equivalent or monolayer cultures of melano- melanin synthesis but also the dermal component (i.e., fibro-
cytes, however it enhances the pigmentation of low-melanized blasts and endothelial cells secreted factors). A prospective
melanoma cells and decreases that of highly pigmented nor- randomized trial demonstrated similar efficacy compared to
mal melanocytes after UV irradiation (32). 4%HQ with better tolerance and more homogeneous depig-
mentation (39).
Isobutylamido Thiazolyl Resorcinol (Thiamidol®)
Cosmetic Use of Bleaching Products
Isobutylamido thiazolyl resorcinol is a potent tyrosinase
inhibitor (33). Its efficacy and good tolerance have been dem- This is a common practice in dark-skinned women from sub-
onstrated in several prospective randomized trials for treat- Saharan Africa and a few other parts of the world. The products
ing melasma, but also post-inflammatory hyperpigmentation used include HQ, potent or super-potent topical glucocorticoids,
(34–36). It is one of the only cosmetic depigmenting agent that mercury, salts, and caustic agents such as liquid soaps, hydrogen
demonstrated similar efficacy compared to 4% HQ for treating peroxide, and salicylic preparations. Most users (>90%) apply
melasma (37). the products once or twice daily to the whole body, for months
or years. Side effects, often very severe, include skin atrophy,
delayed cicatrisation, infectious dermatoses (Bacteriae, myco-
Combination Therapies
ses, parasites), acne, dyschromia with a typical pattern, irritant
Combination therapies are widely used for the treatment of and allergic contact dermatitis, prominent striae, ochrono-
hypermelanoses. The purpose of these strategies is to augment sis, poikiloderma of the neck, and perioricular hyperchromia
efficacy by associating active ingredients with different modes (Figure 29.2). Nephrotic syndrome can be observed after the
of action in order to obtain a synergic effect, to shorten the use of mercurial derivatives. The daily use of potent topical
duration of therapy, and to reduce the risk of adverse effects. steroids over years can lead to Cushing syndrome. This prac-
tice is a real health problem, not only in Africa, but in Northern
countries receiving large immigrant communities. A careful
Kligman’s Formula
dermatological examination of patients is helpful to detect the
The most popular combination treatment for depigmenting skin symptoms resulting from this practice (40).
skin is Kligman’s formula. This polytherapy includes 5%
HQ, 0.1% tretinoin, and 0.1% dexamethasone in a hydrophilic
Chemical Peels
ointment. Tretinoin functions as an enhancer of HQ penetra-
tion in the epidermis. Furthermore, tretinoin increases epi- Chemabrasion and peels using various chemicals is another
dermal turnover, thus facilitating melanin dispersion within treatment modality for removal of freckles, actinic lentigines
keratinocytes and also melanin removal from corneocyte and other pigmented spots, melisma, and post-inflammatory
shedding. Dexamethasone decreases the irritation and inflam-
mation caused by HQ and/or tretinoin and melanin synthesis
by inhibiting metabolic activity. This formula demonstrated
efficacy in the treatment of melasma, ephelides, and post-
inflammatory hypermelanosis. Depigmentation occurs rap-
idly, beginning within 3 weeks after twice-daily application.
Unfortunately, the efficacy of this formula depends upon its
stability. Extemporaneous formulation is useful but bears a
strong risk of instability. Recently, a stabilized formulation
containing 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone
acetonide has been launched. Two multicenter, randomized
double-blind controlled trials demonstrated the safety and
efficacy of this combination treatment in patients with mod-
erate to severe melisma (38). After 8 weeks of treatment, a
75% reduction of melasma was found in more than 70% of
the patients. Furthermore, superiority of the formulation over
its three components (HQ, tretinoine, fluocinolone acetonide)
was demonstrated. There are already many variants of the
extemporaneous Kligman’s formula. The suggestion that topi-
cal steroids are not necessary for achieving depigmentation led FIGURE 29.2 Exogenous ochronosis due to chronic application of
to a modification of this formula by removing topical steroids. hydroquinone.
Pigmentation 289
hypermelanosis. Deep peels are avoided in patients with emitting aluminium oxide crystals bears an important risk of
hypermelanosis because of the high risk of post-inflamma- post-inflammatory dyspigmentation. Due to the important risk
tory hyper- or hypomelanosis, scarring, and keloid formation. of PIH along with the risk of relapse, dermabrasion is no lon-
Mainly superficial and medium-depth chemical peels have ger recommended for treating melasma. It has to be used with
been used for the treatment of hypermelanosis, mainly in fair- great care for treating other pigmentary disorders.
skinned individuals.
Glycolic acid is an alpha-hydroxy acid that has an epidermal
Liquid Nitrogen Cryotherapy
discohesive effect at low concentrations. Removal of corneo-
cytes and epidermal upper layer keratinocytes by chemical Melanocytes are particularly susceptible to freezing, and
peeling reduces the epidermal melanin content and improves hence they should be avoided in dark-skinned people because
hypermelanoses. Glycolic acid peels (50%–70%) are becom- of the risk of permanent depigmentation. The freezing agent
ing increasingly popular in the treatment of melasma. They must be applied gently to avoid blistering and skin necrosis.
can be safely used in dark-skinned patients due to a quite low Cryotherapy with liquid nitrogen is commonly used success-
risk of hyperpigmentation (41). fully to treat individual pigmented lesions. Although satisfac-
A few studies have demonstrated the efficacy of chemi- tory results are common, cryotherapy for benign epidermal
cal peels with other depigmenting agents in patients with lesions is problematic because of hypopigmentation, hyper-
hypermelanosis. Complete bleaching of diffuse melasma was pigmentation, atrophy, scarring, and/or frequent recurrence.
observed in patients (30%) treated with glycolic acid 50% Liquid nitrogen cryotherapy has also been proposed for
plus kojic acid 10% and partial blanching in 60% of patients. the treatment of nevus of Ota, delayed nevus spilus, and blue
Serial glycolic acid peels (30%–40%) combined with a modi- nevus. Nowadays laser approaches provide clearly better
fied Kligman’s formula (2% hydroquinone + 0.05% tretinoin + results and cryotherapy should no longer be used for removing
1% hydrocortisone) provided an additional effect to the stan- these hypermelanocytoses. Liquid nitrogen can be proposed
dard topical treatment in dark-skinned patients with melasma. for the treatment of hypermelanoses (actinic lentigos and other
Another study suggested that daily application of 10% glycolic pigmented spots of photodamaged skin) and hypomelanosis
acid lotion and 2% hydroquinone combined with 70% glycolic (idiopathic guttate hypomelanosis).
acid peels every 3 weeks showed some improvement of pig-
mented spots of photoaging in Asian women (42). In contrast,
a split-face prospective study in 21 Hispanic women within
melasma showed no differences in the bleaching effect of 4%
Lasers and Phototherapy
hydroquinone + glycolic peels 20%–30% versus hydroquinone The treatment of pigmentary disorders by lasers is based on
4% alone. selective photothermolysis (45). In order to have selective
Five peelings with salicylic acid 20%–30% at 20-week action, the length of the laser impulsion has to be at least 10
intervals in dark-skinned patients (phototypes V to VI), after times shorter than the relaxation time of the target. This relax-
initial treatment with hydroquinone 5% for 2 weeks, gave good ation time is proportional to the size of the target (but also
results for melasma and other types of pigmentation (43). depends on the shape and the diffusivity of the target). For
The use of trichloracetic 20%–35% followed by hydroqui- pigmentary disorders due to melanin defects the target is the
none hydro-alcoholic 4% solution or tretinoine 0.05% plus melanosome. It is a lysosome-related organelle specific to the
hydrocortisone acetate 1% cream has produced excellent melanocytes within which the melanin is produced. With their
results for hypermelanosis in white patients with higher com- maturation, the melanosomes will be progressively filled with
plexions (41). melanin and be transferred to the surrounding keratinocytes (46).
Resorcinol is used as Jessner’s solution (14 g resorcinol, 14 g The size of a melanosome is about 1 μm. Its relaxation time
salicylic acid, 14 g lactic acid 85%, and enough ethanol to varies from 1 to 10 μs. Thus, the impulsion time of the laser
make up 10 mL) or in Unna’s paste (up to 10% resorcinol plus has to be inferior to 100 ns. The lasers used for pigmentary
zinc oxide and ceisatile) and has also been demonstrated to be disorders are Q-switched, and their impulsion length is from
effective in hypermelanosis with an acceptable rate of adverse 10 to 100 ns, allowing them to target the melanosomes and
effects. most of the exogenous pigments. More recently, picosecond
Peels that combine kojic acid, salicylic acid, and alpha- lasers have been proposed to first treat tattoos but are also now
hydroxy preparations with or without hydroquinone or resor- proposed for hyperpigmentary disorders.
cinol are commercially available (41). Applied every 3 weeks The location of the pigment in the dermis or the epidermis
they do not require neutralization. guides in part the choice of wavelength. Thus, dermal pig-
mentation will be better treated with 1064 nm Nd:YAG lasers
which wavelength could penetrate deeper in the skin tissue.
Dermabrasion
Those lasers are also preferred for dark-skinned people as
Dermabrasion using rotary diamond fraises has been used for they interact less with the melanin of the superficial layers of
the treatment of melasma (44). Although good outcomes have the skin.
been reported by the authors, this technique exposes to a high The type of pigment has also to be taken into consideration.
risk of post-inflammatory hyperpigmentation (PIH), espe- Pheomelanin is a good target for 532 nm Nd:YAG lasers when
cially in Asian and dark-skinned individuals. This limits con- it is a less interesting chromophore for 694, 755, and 1064 nm
siderably the use of this strategy in these groups of patients. lasers (47). The choice of the laser wavelength is even more
Even the more superficial microdermabrasion using a device important for the treatment of tattoos.
All lasers can induce side effects, and patients have to be of the cells (59). These photobiological effects could explain,
clearly informed about the potential risks. If scars are excep- at least in part, the action of the 632.8 nm helium neon laser
tional and are due to excessive fluencies, PIH is the most com- in repigmenting vitiligo. However, clinical data remain poor
mon side effect. PIH is mostly observed in dark skin types. concerning the efficacy of this device in hypochromic disor-
Photoprotection is required before and after the laser sessions ders (60).
to decrease this risk. PIH usually regresses in a couple of weeks
or months. Topical steroid eventually combined with hydro-
quinone could be helpful in the early stages. Leukodermas
are less frequently observed. They are usually transient, but
Surgical Approaches
permanent leukodermas have been reported mainly with 694 Surgical approaches (61) aim to reconstitute the epidermal
nm ruby lasers. The treatment of tattoos leads to more side (and perhaps follicular) compartment of the melanocyte pop-
effects. Cicatricial scars and leukoderma are more frequently ulation of the skin by bringing to the hypochromic lesion,
observed. Patients and physicians have to be aware of the risk after dermabrasion, a new pigmented skin or a suspension of
of paradoxical darkening of tattoos after a first session. Finally, melanocytes, isolated or associated with other epidermal cells
allergic or granulomatous reactions, Koebner phenomenon, such as keratinocytes. For vitiligo such methods are usually
and pseudolymphomas have been also reported. International considered for stable and localized lesions after medical treat-
recommendations have been published concerning the use of ment has failed. However, for piebaldism or to a lesser extent
laser for treating hyperpigmentary lesions (48). for nevus depigmentosus, they are almost the only treatment
Ultraviolet (UV) A and B phototherapies are both widely available.
used in dermatology. UVA radiation includes electromagnetic Several methods are available including punch grafts, blister
waves with wavelengths between 320 and 400 nm. UVB wave- grafts, split-thickness grafts, and autologous transplantation of
lengths are between 290 and 320 nm. It is used with systemic melanocyte suspensions, cultured melanocytes, or cultured
or topical psoralens, which selectively absorbs the radiation epidermal grafts including melanocytes. Grafting of follicular
(PUVA therapy). The main action of PUVA on biological sys- melanocytes to repigment vitiligo leukotrichia has also been
tems is the inhibition of DNA synthesis due to photo-adducts performed successfully (62).
formed between psoralen and pyrimidine bases in the nucleic Punch grafting (1.2–3 mm punch biopsies) is the simplest
acid. PUVA was for a long time considered to be the photo- technique, and grafts are implanted into perforations prepared
therapy of choice, including for hypochromic disorders such as at the recipient sites by different techniques (punch biopsy,
vitiligo. Because of potential side effects, including cutaneous ablative lasers). Minigrafting using small grafts (1.2 mm) is
cancers, many authors now recommend the use of UVB ther- the best technique. The potential side effects include spotted
apy instead (49–52). Prospective studies and meta-analysis have pigmentation, polka dot appearance, color mismatch, a cobble-
now showed that narrowband UVB (NB-UVB) therapy (around stone effect, sinking pits, and scarring. Furthermore, this tech-
311 nm) is superior to PUVA for treating vitiligo (53, 54). nique is time consuming.
The 308 nm excimer lasers have been used in dermatology Split-thickness grafting is obtained by a standard or an
since 1997 (55). The development of 308 nm excimer lamps is electrical dermatome. The main advantage of this treatment is
more recent. At the difference of the lasers, the wavelength is to allow treatment of large areas. Esthetical results are often
not strictly monochromatic and the beam of light is not coher- satisfactory with a homogenous repigmentation. However, this
ent but those systems are much less expensive than lasers. approach may be associated with esthetically unacceptable
Those devices emit a wavelength in the UVB spectrum. The results at the donor site (dyspigmentation, scarring). Adverse
wavelength at 308 nm provides photobiological effects theo- events include miliae-like cyst formation at the recipient site,
retically superior for those devices as compared to NB-UVB, partial loss of the grafts, hematoma formation, and thickening
especially for their immunologic effects. Indeed, 308 nm is of the graft margins.
the most effective wavelength to induce lesions to the lympho- In flip-top transplantation, the epidermis at the recipient site
cyte DNA, and the dose required to induce the apoptosis of is used to form multiple hinged flaps, each covering an ultra-
lymphocytes is clearly lower with 308 nm as compared with thin 1.2 mm graft harvested from the donor site by a razor
NB-UVB (56, 57). However, in vitiligo and more clearly for blade (63).
the other hypopigmentary disorders, the stimulation of the Autologous blisters can be induced in different ways, i.e.,
migration and the proliferation of melanocytes appear to vacuum, liquid nitrogen. The mechanical split occurs at the
have a key role, but fundamental data to compare the respec- dermo–epidermal junction. The recipient site is prepared by
tive photobiological propigmenting properties of the 308 nm dermabrasion, laser ablation (erbium:YAG or carbon dioxide
and NB-UVB wavelengths are still not available. The use of laser), liquid nitrogen, or PUVA-induced blisters, dermatome.
the 308 nm excimer laser and lamps is approved by the FDA The graft (top of the blister) is applied and secured on the recip-
(Food and Drug Administration) for the treatment of vitiligo. ient site. The only adverse event is transient hyperpigmenta-
The 632.8 nm helium neon laser is the first device that does tion at both the donor and recipient sites. The advantages of
not use the UV spectrum to repigment hypochromic lesions, this technique are the absence of scarring and the possibility of
especially vitiligo. Indeed, this laser, which emits a wave- reusing the donor site. Split-thickness grafting and blister grafts
length in the red visible light, has been proven to enhance the have a better success rate than punch grafting (64). These tech-
proliferation and the differentiation of melanoblasts to mature niques are not expensive and can be done in private practice.
melanocytes in vitro (58). It has also been demonstrated that The use of epidermal suspension (melanocytes alone or
this laser acts on mitochondria to increase the proliferation rate combined with keratinocytes) is more recent. Non-cultured
Pigmentation 291
keratinocyte/melanocyte suspensions can be obtained after A siliconated spray could be used to cover the makeup and
trypsinization of a shave biopsy of the buttock or full thick- increase its waterproofing properties, allowing the practice of
ness biopsy of the scalp. Melanocytes obtained from the hair water activities (74).
follicles and interfollicular epidermis as well as keratinocytes, Dihydroxyacetone (DHA) can also be very useful to
are put into a suspension with the patient’s serum for direct decrease the contrast of hypopigmented lesions with the sur-
application to the recipient site without expansion in culture (65). rounding skin. The brown color is due to the chemical com-
The recipient site is prepared with dermabrasion using a der- bination of the DHA with the amino acids of the skin leading
matome or an ablative CO2 or Erbium laser. This technique to the formation of polymeric pigments called melanoidins.
allows treating large lesional surfaces with a small piece of Those pigments remain in the startum corneum until desqua-
skin, as a ratio of 1:5 to 1:10 is commonly used. A prospec- mation of the corneocytes. The coloration appears a few hours
tive randomized double-blind study has demonstrated that epi- after the application of the DHA and progressively fades after
dermal suspension followed by UV (PUVA or Nb-UVB) was 5–7 days (75–77). The main advantages of this are to resist
more effective than UV combined with only dermabrasion and to water and to not stain the dressings. It is used mainly for
serum (66). This technique used to require a specialized labo- the hands and the feet. Concentrations between 2.5%–10%
ratory, but the development of ready-to-use kits now allows it can be used depending on the intensity of the desired color.
to be used by any trained physician. As DHA combines with the amino acids of the stratum cor-
The number of melanocytes (combined or not with kerati- neum, the intensity of the reaction depends on the thickness
nocytes) can be expended in culture before grafting. Applied of this skin layer. Thus, patients should be advised to apply
on vitiligo lesions, it gives satisfactory results in 30%–44% of less quantity on locations with thick stratum corneum such as
patients. Improvement of melanocyte culture conditions and palms, soles, knees, or ankles. The patient would also have to
grafting devices have made possible the transplantation of be informed that the pigmentation produced is not photopro-
autologous cultured melanocytes on large areas (up to 500 cm2 tective against UV.
during one session) of vitiligo involved skin (67, 68). A 95% Micropigmentation could also be helpful, especially for
repigmentation is obtained in approximately 40% of the areas such as lips or nipples in dark skin phototypes (78, 79).
treated areas. However, while the results are usually excellent
for stable vitiligos, active forms lead to failure of the proce-
dure, and careful selection of patients remains crucial (69). All Treatment of Pigmentary Lesions
the techniques involving melanocyte culture and epidermal
reconstruction require specialized laboratory expertise and are Melasma
very expensive. For these reasons, they are not widely used. The gold standard treatment for melasma is topical bleaching
agents (Figure 29.3). A recent meta-analysis confirmed that
Kligman’s formula is the most effective treatment, especially
in its stabilized form (38, 80–84). Peeling and dermabrasion
Camouflaging
can be also proposed but their efficacy is inconsistent, and
Camouflaging has been shown to increase the quality of these strategies frequently induce PIH (46, 85).
life (DLQI) of people using it (70, 71). The use of medical Ablative and nonablative fractional lasers have been
makeup has become progressively more popular and is now reported to improve melasma (86, 87). However, the risk
integrated in many dermatological centers. Cosmetic products of relapse is important and up to 10% worsening has been
with high concentration in pigments allow very interesting and reported with such approaches (88). Moreover, nonablative
esthetical results but require training of the technique (72, 73). fractional laser has been shown to not be superior to Kligman’s
FIGURE 29.3 Melasma before treatment in direct light (a) and UV light (b), and after 3 months of Kligman’s preparation in direct light (c) and UV
light (d).
trio (89). Interesting results have been reported with the 1927 wavelengths in addition to strong UVA and UVB protection is
nm thulium laser (90, 91). However, some PIH were reported mandatory for preventing melasma relapses (109–112).
along with relatively frequent relapses. Prospective random-
ized comparative trials are still required to determine the use-
Vitiligo
fulness of this new device for treating melasma.
Pigmentary lasers such as Q-switched ruby, alexandrite, Many medical or surgical treatments are available for vitiligo,
or Nd:YAG lasers induce almost constant PIH and relapses. but only a few have clearly demonstrated their efficacy in treat-
Q-switched lasers used with low fluencies and repetitive ses- ing vitiligo.
sions have been reported to be effective for treating melasma. Phototherapy (PUVA or Nb-UVB) is the gold standard for
However, when long-term follow-up is performed a constant generalized forms (54, 113, 114). If available, Nb-UVB is pref-
relapse is observed along with up to 20% of worsening of the erable to PUVA, as has greater efficacy with lesser side effects
hyperpigmentation due to PIH (92). Thus, such approaches and better tolerance (53).
can’t be recommended for treating melasma. Picosecond Once-daily applications of topical steroids or twice-daily
lasers do not provide better results as they also expose to con- application of 0.1% tacrolimus or 1% pimecrolimus should be
stant relapses (93–95). used first for localized forms of vitiligo (54, 113, 114).
Intense pulsed light (IPL) has shown some efficacy in Targeted phototherapy with 308 nm excimer lamps and
the treatment of melasma (96–99). The risk of PIH remains lasers is also effective for localized forms, but are more expen-
important but appears to be lower than the one observed with sive (Figure 29.4) (115–120). However, bony prominences and
Q-switched lasers. Topical bleaching preparations, frequently extremities remains extremely difficult to treat (120).
containing hydroquinone, have been used with IPL in order to The data concerning the other therapeutic approaches
prevent PIH (100, 101). Although potentially useful, this asso- including antioxidants or topical vitamin D are more contro-
ciation approach has never been compared to bleaching cream versial (121–131).
used in monotherapy. Combination approaches associating tacrolimus ointment
Increasing data shows that in addition to the increase in or pimecrolimus cream with phototherapy (308 nm excimer
pigmentation, melasma lesions have more elastosis and vasculight or Nb-UVB) have shown their superiority to monother-
larization compared to the perilesionnal skin (102–104). The apy (132–137). Such a synergic effect has been also reported
association of a fixed triple combination cream and a pulsed with the association of topical steroids and excimer laser (138,
dye laser (PDL) with vascular and pigmentary parameters 139–141). Combination approaches are now the gold standard
showed significantly better decrease of the hyperpigmentation treatment for vitiligo (142).
of melasma and reduced the relapses observed after the sum- Recently, ruxolitinib cream (a topical JAK 1,2 inhibitor)
mer (105, 106). Following the same aim of targeting the vascu- has demonstrated its efficacy and good tolerance in treating
lar component of melasma tranexamic acid, an antifibrinolytic limited forms of vitiligo (143). Approximatively 50% and 30%
used to prevent and to treat some hemorrhagic events was also of patients are reaching F-VASI75 (repigmentation of at least
proposed for treating melasma. The combined use of this agent 75% of lesions affecting the face) and F-VASI 90 after 1 year
topically and orally for 8 weeks led to a decrease of the hyper- of treatment. On the body, approximately half of the patients
pigmentation in melasma lesions. Histological examinations achieved at least 50% of repigmentation after 1 year of treat-
showed a decrease in melanin content and in vascularization ment. The tolerance is good with mostly acneiform lesions
(20, 107). Those pilot studies clearly need to be confirmed, but that are mild and transient in all cases. Repigmentation on the
they underline the potential interest of targeting the vascular extremities of hands and feet remains low. In all cases, repig-
component for treating melasma. mentation takes several months and patients must be informed
To conclude, Kligman’s trio remains the gold standard for about the duration of the treatment. Combination with UVB
treating melasma and should be used as the first treatment should provide significant better results as suggested by a short
option. Other options can be proposed if the trio fails to depig- open study (144). Additional studies on the combination of
ment the melasma. In all cases, patients have to be advised topical ruxolitinib cream and phototherapy are still warranted.
about the limitations and potential side effect of the treat- Surgical treatment is a good option for localized or segmen-
ments. However, all the therapeutic approaches do not prevent tal forms that have been stable for at least 3 years (Figure 29.5)
relapses of melasma. After the initial treatment (in most cases (54, 113, 114).
3–4 months of Kligman’s trio), a maintenance treatment has When treatments have failed corrective cosmetics, use of DHA
to be prescribed. Cosmetic depigmenting agents are very use- (dihydroxyacetone 1,3-dihydroxydimethylcetone) or dermopig-
ful for maintenance due to their good safety profile in most mentation (especially for nipples and mucosal areas) can be useful
cases. Preventing triggering factors is crucial. Discontinuation (46, 145). Finally, depigmentation that we would like as perma-
of estroprogestative medications should be discussed, but not nent can be proposed usually for people more than 40 years old,
proposed in all cases, as the impact of their discontinuation after detailed information is given to the patient. Psychological
on the evolution of melasma has been shown to be weak (108). evaluation is also useful. The monobenzylether of hydroquinone
Repetitive friction should be avoided. More importantly, strict (MBEH) causes a permanent depigmentation of the skin that has
photoprotection with clothing, sunglasses, sun avoidance, and been used for generalized vitiligo. However, the side effects that
sunscreens with very good UVB and UVA protection are man- include irritant and allergic contact dermatitis, post-inflamma-
datory. The shorter wavelengths of visible light plays can trig- tory hypermelanosis, leukoderma en confetti at treated sites, and
ger hyperpigmentation of the skin and protection against these hypomelanosis at sites distant from the application areas strongly
Pigmentation 293
FIGURE 29.5 Localized and stable vitiligo lesion (a). Clinical aspect
2 months after epidermal cell suspension graft (b).
results appear inferior to nanosecond laser (151). Depigmentation

therapies should be reserved for limited surfaces, and they should
not be proposed if depigmentation involves less than 50% of the
affected area. In all cases, patients must be clearly informed of
the potential risk of later repigmentation, and photoprotection of
the treated areas should be systematically prescribed.
Thanks to the advances in the understanding of the pathophys-
iology of vitiligo, several new treatment approaches are under
development. Oral JAK inhibitors would be probably the first and
FIGURE 29.4 Vitiligo of the face (a). Clinical aspect after 40 sessions of will be hopefully of interest for widespread and/or active forms
308 nm excimer laser (b), and 18 months after the end of the treatment (c).
of vitiligo (152). However, many other approaches targeting other
pathway should hopefully provide even better results (153).
limit the use of this compound and have prompted clinicians to
explore therapeutic alternatives. Q-switched lasers are as effec-
tive as MBEH with fewer side effects, and should now be pre- Halo Nevus
ferred (Figure 29.6) (146–149). Better results seem to be obtained Halo nevi usually do not require any treatment. However, some
if the vitiligo is active (150). A recent retrospective study demon- patients seek treatment. Some successes have been reported
strated that picosecond lasers are also effective and safe, although with the 308 nm excimer laser (154).
FIGURE 29.6 Extensive vitiligo of the face that did not respond to FIGURE 29.7 Actinic lentigos of the face (a). Clinical aspect 1 month
repigmenting therapies (a). Depigmentation of the remaining pigmented after one session of 755 nm alexandrite Q-switched laser (b).
areas 2 months after one session of 755 nm alexandrite Q-switched laser (b).
Pigmentation 295
Piebaldism the shoulder (Ito nevus) or rarely other parts of the body.
Acquired dermal hypermelanocytosis has also been reported
Piebaldism is a rare autosomal dominant disorder with congeni- (Figure 29.8). Although more frequently observed in Asian
tal hypomelanosis. Most patients have a mutation in the KIT gene people, it affects all races. Ruby, alexandrite, and Nd:YAG
(155). The pigmentary disorder is limited to hair and skin without Q-switched lasers have shown their efficacy. The depth of
neurological, ocular, or hearing defects. The topographical distri- the target pigment leads to the use of longer wavelength. The
bution of the lesions spreading to the anterior part of the trunk, 1064 nm Q-switched Nd:YAG has shown its superiority over
abdomen, extremities, and the frontal part of the scalp is charac- the 755 nm alexandrite (169). Early treatment at a young age
teristic of the disease (156, 157). Unlike vitiligo, these patches are and brown rather than blue lesions are good predictive factors
congenital, stable with time, and do not repigment. Nice results of response to treatment (170, 171). Relapses can be observed,
can be obtained with surgical grafting procedures (158–160). and patients should be made aware of this (172).
Although the literature is poor, Ito nevus and acquired der-
Nevus Depigmentosus mal hypermelanocytosis can also be effectively treated with
Nevus depigmentosus can be effectively treated with graft- the aforementioned lasers.
ing (162, 163). Late recurrences are possible, and the patient
should be informed about this potential risk (164). The 308 nm Poikiloderma of Civatte
excimer laser has been proposed but data are still limited (165).
Laser and IPL approaches are the best treatments for the poi-
kiloderma of Civatte. Both PDL and IPL have shown their effi-
Solar Lentigines
cacy (173–176). However, persistent depigmentation has been
Solar lentigines are effectively treated with topical blanch- reported as a late adverse event, and high fluencies should be
ing cream, liquid nitrogen, Q-switched lasers, and IPL avoided in this fragile location (177). Some authors have sug-
(Figure 29.7). Treatment with Q-switched laser has proved to gested the use of fractional photothermolysis with interesting
be the most effective approach, especially if the lesions are results, but the data remain limited (178, 179).
numerous, but it remains more expensive (166). One or two
laser sessions are sufficient (167). While 694 and 755 nm Café-au-Lait Macules
are usually preferred is most cases, light lentigos are better
treated with 532 nm Q-switched lasers (168). The use of sun- Café-au-lait macules can be treated with lasers and IPL. The
screens and cosmetic depigmenting cream will be advised in response is variable, and recurrences are very frequent. No
all patients to decrease recurrences. If the lesion is atypical, a clinical or histological markers have been determined to pre-
skin biopsy has to be performed to detect a lentigo maligna. dict the response to treatment (180). Thus, the patient should
be clearly informed of those risks. For large lesions, we advise
Pigmented Seborrheic Keratosis a test session on a small area and seeing the patient after one
summer to evaluate the response and the stability after treat-
Thin pigmented seborrheic dermatosis can be treated with ment before treating the entire lesion.
Q-switched lasers and IPL, but shaving, liquid nitrogen, or
ablative lasers are the most frequently used treatments. Nevus Spilus
Q-switched lasers, including ruby and alexandrite, have dem-
Congenital and Acquired Dermal onstrated their efficacy to treat nevus spilus (181, 182). As for
Hypermelanocytosis café-au-lait macules, relapses have been observed. Moreover,
Ota nevi are dermal hypermelanocytosis of the periorbital the risk of melanoma, though rare, is real, and laser treatment
region. Such dermal hypermelanocytosis can also affect should be proposed with caution and a biopsy must done if the
lesion is atypical.
Lentigines and Freckles

Q-switched lasers are effective for treating lentigines, includ-
ing those associated with a genetic disorder such as Peutz-
Jeghers-Touraine syndrome (183).
Freckles can also be treated with laser. As they contain
mainly pheomelanin, the optimal wavelength will be the
532 nm (47, 184). However, due to the constant relapses we do
not recommend the treatment of ephelides.
Becker Nevus
The hair component of Becker nevus responds well to laser
hair removal (Figure 29.9). The hyperpigmentation can also
FIGURE 29.8 Acquired Ota nevus (Hori nevus). be treated with Q-switched lasers, but the response is more
FIGURE 29.9 Becker nevus.
inconstant and recurrences are observed. A test session is

required before treating large lesions. Most of the authors
advise to first treat the hair component, but the sequence of
treatment does not change the final result and the choice mainly
depends on the type of lesions and the preference of the patient.
Pigmentary Mosaicism (Linear

and Whorled Hypermelanosis)
There is almost no data concerning the treatment of pigmen-
tary mosaicism. Blanching products are ineffective, and only
Q-switched lasers have provided some interesting results (185)
(Figure 29.10). However, pigmentary mosaicism is a hetero-
geneous group, and response to treatment is highly variable.
A test session using several wavelengths is required to deter-
minate the optimal laser approach and the risk of recurrences.
FIGURE 29.10 Pigmentary mosaicism of the thigh. A part of the lesion
was chosen for the test session with 532, 755, and 1064 nm Q-switched
Dark Rings lasers (a). Two months after the test session only the area treated with the
755 nm laser showed a nice improvement, in this case emphasizing the
Dark rings under the eyes are a heterogeneous group with importance of testing several wavelengths in such pigmentary disorders.
multifactorial etiologies. Superficial location of vasculature
and constitutional hyperpigmentation are the most frequent
causes. However, dark rings may have other origins such as
Drug-Induced Pigmentation
periorbital edema, PIH, shadowing, loss of subcutaneous Pigmentation induced by drugs (such as cyclines or amioda-
fat, xerosis, and skin laxity (186). A vascular origin is noted rone) can be removed with Q-switched lasers (196–198). The
mainly in fair-skinned individuals, while constitutional hyperpigmentation is usually in the dermis, so 694, 755, and 1064
pigmentation occurs most frequently in dark-skinned patients. nm wavelength should be preferred to Nd:YAG 532 nm.
Dark rings due to constitutional hyperpigmentation can be
treated topically with tretinoin cream, peeling, CO2 laser, or Postinflammatory Pigmentation
surgical treatment (187–190). However, best results are usu-
ally obtained with Q-switched lasers and IPL (191, 192). Only Postinflammatory pigmentation is frequent and can be
cosmetic approaches with makeup can be proposed when the observed after a surgical or cosmetical procedure. Laser treat-
origin is vascular. Skin laxity can be treated surgically, and ments are not a good option for such hyperpigmentation as they
autologous fat injection can be proposed if the cause is loss of can worsen the lesions. Photoprotection and treatment of the
subcutaneous fat. underlying dermatosis, if there is one, is mandatory and could
be effective by themselves. If needed, class 3 topical steroids
alone or combined with 4%–10% hydroquinone can be added.
Pigmentation Due to Hemosiderosis and Siderosis
One of the most common manifestations of this is stasis der- Idiopathic Guttate Hypomelanosis
matitis, but other causes can trigger such hyperpigmentation
(vascular or thrombopenic purpura, post-Kaposi sequelae, iron Idiopathic guttate hypomelanosis is associated with chronic
extravasation). Although the data are still limited, treatment sun exposure (Figure 29.11). Any phototherapy, even focused
with Q-switched lasers and IPL appear to be effective (193–195). treatment with the 308 nm excimer laser or lamp, should be
Pigmentation 297
FIGURE 29.13 Achromic tinea versicolor.
Progressive Macular Hypomelanosis

Progressive macular hypomelanosis (PMH) is a common
skin disorder that is often misdiagnosed (mostly for pity-
riasis versicolor) (Figures 29.12 and 29.13). PMH is charac-
terized by ill-defined nummular, non-scaly hypopigmented
FIGURE 29.11 Idiopathic guttate hypomelanosis. spots on the trunk, often confluent in and around the mid-
line, and rarely extending to the proximal extremities and
neck/head region. There is no itch, pain, or preceding
inflammation. Westerhof et al. suggested the causative role
of Propionibacterium acnes bacteria and thus proposed as
a treatment the application of 1% clindamycin lotion dur-
ing the day, 5% benzoyl peroxide gel at night, and UVA
light irradiation three times a week for a period of 12 weeks
(207). However, phototherapy alone (PUVA or Nb-UVB)
appears also to be effective (208).
Ochronosis
Alcaptonuria is a rare genetic disorder which leads to endoge-
nous ochronosis. Exogenous ochronosis is much more frequent
and is due to the chronic application of hydroquinone. Most
cases are seen in dark-skinned people who seek to blanch their
skin. Discontinuing hydroquinone application is of course
required. Little data are available for the treatment; dermabra-
FIGURE 29.12 Progressive macular hypomelanosis.
sion, CO2 laser, and more recently Q-switched laser have been
proposed (209–211).
avoided. Some isolated successes have been reported with
topical tretinoin, liquid nitrogen, or localized superficial
Dyskeratosis
dermabrasion treatments (199–201). In our practice, super-
ficial Erbium-assisted dermabrasion provides good results. Dyskeratosis, including ictyosis, seborrheic keratosis, derma-
Interesting results have been reported using ablative and tosis papulosa nigra, and confluent and reticulated papilloma-
nonablative fractional lasers (202, 203). tosus of Gougerot et Carteau can lead to hyperpigmentation.
Ictyosis is effectively treated by the daily use of emollients.
The treatment of dermatosis papulosa nigra treatment is simi-
Hypopigmented Striae and Iatrogenic Leukoderma
lar to seborrheic keratosis (cf. upper), curettage, electrodes-
Although quite frequent, those two conditions have no effec- sication, Q-switched lasers, fractional or continuous ablative
tive treatment. Isolated cases have reported some success with lasers have been reported (212–214). The confluent and retic-
the 308 nm excimer laser (204–206). The absence of a group of ulated papillomatosis of Gougerot et Carteau can be treated
control, the weaknesses in the evaluation of the results, and the with topical agents such as tretinoin or vitamin D, but most
need for maintenance sessions should moderate those results. authors agree on the use of minocycline (215–218).
Chromhidrosis and Pseudochromhidrosis

Chromhidrosis and pseudochromhidrosis are rare skin dis-
orders. Chromhidrosis refers to the excretion by the apo-
crine glands of sweat containing lipofuscin pigments, while
the terms pseudochromhidrosis or extrinsic chromhidrosis
are used when the eccrine sweat is colored on the surface of
the skin as a result of the deposit of extrinsic dyes or paints,
or by transformation by chromogenic bacteria. Only few
fungi and bacteria are known to induce pseudochromhidro-
sis. Corynebacteria are responsible for red pseudochromhi-
drosis and Malassezia furfur and Bacillus sp. are the agents
involved in blue pseudochromhidrosis (219). Treatment of
pseudochromhidrosis consists of removing clothes or tissues
responsible for the deposit of the extrinsic dyes or treating the
chromogenic bacteria or fungi proliferation.
Tattoos
Tattoos are inclusions of pigments in the dermis or the hypo-
dermis. Their cause can be traumatic, esthetic, or medical
(marks for radiotherapy). The variety of the color sometimes
leads to the necessity of using several wavelengths. Black pig-
ments can be easily removed by almost all kinds of Q-switched
lasers. Blue and green tattoos will be treated with 755 nm alex-
andrite lasers and red color will be better targeted with 532 nm
Nd:YAG lasers. The quantity, quality, and depth of the pig-
ments in the skin and the individual responses of the patients
account for the variability of results and the potential side
effects sometimes observed.
Many Q-switched have demonstrated their efficacy to remove
tattoos (220). Due to their side effects, the non-fractional ablative
lasers are no longer used. The choice of the laser will be guided
by the color of the tattoos. Amateur tattoos, permanent makeup,
blue-black color, and monochromatic tattoos are good predic-
tive factors of response to treatment (Figure 29.14) (221). For
traumatic tattoos, metal and asphalt origin and large-size pig-
ments appear to be more resistant to laser treatment. A 2-month
delay between each session is usually recommended to allow
elimination of the fragmented pigments and decrease the risk
of cicatricial scars. Gunpowder tattoos should not be treated
with Q-switched lasers as the high energy pulses of laser on the
powder particles creates microexplosions of these fragments,
resulting in cavitation and provoking transepidermal holes and
subsequent scars (222). Recently, picosecond lasers have been
commercialized for removing tattoos. For now, they are still
relatively close to the nanosecond as their pulse duration time
is 500–800 picosec. They aim to induce better fragmentation
of the pigments and thus allow better elimination compared to
Q-switched lasers. Published data provide encouraging results
but prospective comparative randomized intra-individual stud-
ies are still missing, preventing us to draw a definitive conclu-
sion about the real contribution of this technique (223, 224).
Some tattoos (especially cosmetic and yellow tattoos) can
darken or change color after a first session. A test session on
a limited area is recommended. If the tattoo changes color, an
additional treatment eventually, changing the wavelength, usu-
FIGURE 29.14 Blue ritual tattoos of the face (a) almost completely
ally allows removing the remaining pigments. However, abla- removed after only 2 sessions of Q-switched 755 nm alexandrite
tive lasers or fractional nonablative can also be proposed (225). Q-switched laser (b).
Pigmentation 299
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30
Treatment of Keloids
Joshua E. Lane and Tanda N. Lane
Keloids tend to demonstrate a predilection for certain

Introduction anatomic regions, including the presternal area, chest, back,
shoulder, anterior and posterior neck, and earlobes. Many
Keloids and hypertrophic scars represent abnormal wound summarize this predilection as the “cape area.” Areas of
responses. These occur most commonly in predisposed indi- greater skin tension such as the back and chest are common
viduals. Keloids are benign tumors that arise from scar tissue areas for keloid formation. In addition, keloids continue to
and grow beyond the borders of the original scar (Figure 30.1). evolve while hypertrophic scars typically subside (10). Just as
The formation of keloids and hypertrophic scars typically there are clinical differences between keloids and hypertro-
occurs following some form of trauma, whether intentional or phic scars, so too are there characteristic histologic differences
not. This may include surgery, burns, trauma, inflammation, which separate the two entities.
and/or infection. However, some keloids may form spontane-
ously, without any apparent predisposing trauma (1). Keloids
are characterized by scar tissue that extends beyond the origi-
nal dimensions of a wound, while hypertrophic scars maintain Etiology
size within predictable dimensions of the original wound.
A genetic predisposition combined with some form of external
Keloids can thus be differentiated from normal scars and
injury may lead to the formation of keloids and/or hypertro-
hypertrophic scars, the latter being confined to the original
phic scarring in certain individuals. An abnormal response of
dimensions of a wound. A normal scar heals within the con-
the connective tissue following skin trauma occurs. Injury to
fines of the inciting injury. Hypertrophic scars increase in size
the skin may occur in a variety of intentional or unintentional
as an outward growth while keloids are capable of both inward
means (1, 3). Spontaneous keloids develop without a clear-cut
and outward extension.
history of trauma and often favor the chest, upper back, shoul-
Both keloids and hypertrophic scars present a clinical
ders, and arms (Figures 30.1 and 30.2).
challenge in prevention and treatment. Multiple methods of
Another important aspect of keloid and hypertrophic scar
treatment have been reported; however, no single modality is
formation is that of wound tension, which has been implicated
optimal (1–4).
as an instigating factor (1, 11–13). Surgical incisions should
be performed to minimize these forces of tension whenever
possible. Additionally, the use of dermal sutures placed appro-
priately can assist in the reduction of wound tension and in this
Hypertrophic Scars versus Keloids
way help minimize the chance of keloid formation.
Keloids and hypertrophic scars can occur in individuals of all A combination of factors including the nature of injury,
ages and races; however, they are more common with darker- severity, depth, anatomic location, tensional stress, infection,
pigmented skin types. They represent examples of exuberant environmental factors, and genetic predisposition all contrib-
scarring. The incidence of keloids has been reported to be as ute to the potential for and severity of hypertrophic scar and/or
high as 16% in African American individuals (5). Keloids tend keloid formation (14). Evidence of a genetic predisposition for
to be less prevalent in the young and the elderly. The highest keloid formation is demonstrated by its increased frequency in
incidence was reported to range from ages 10–30 (6). Other different ethnic populations, a family history of keloid forma-
reports suggest the average age of patients with keloids at the tion, and its occurrence in twins.
time of initial treatment to be about 26 (7).
Recommendations for ear piercing to avoid keloid forma-
tion have been made based on these trends (8). In one study,
Clinical Aspects
individuals formed fewer keloids following ear piercing if per-
formed before the age of 11 (8). In fact, women with multiple An understanding of both hypertrophic scars and keloids is
ear piercings often demonstrate keloid formation from pierc- essential for accurate diagnosis of keloids. Clinical exami-
ing during puberty or within teenage years, while piercings nation can typically differentiate between these two entities.
performed as an infant did not keloid. Genetic inheritance pat- Hypertrophic scars are confined to the traumatized region
terns have also been reported (9). while keloids extend beyond the initial confines of trauma
306 DOI: 10.1201/b22897-30

Treatment of Keloids 307
FIGURE 30.1 Keloids on the chest with restriction of movement due

to extensive involvement. These are spontaneous keloids and occurred
without any known trauma.
FIGURE 30.2 Spontaneous keloids on the chest wall. No known

surgical or trauma occurred to form these keloids.
(Figure 30.2). This is the primary visual means of differenti-

ating hypertrophic scars and keloids. In areas where stretch-
back scarring can be predicted, hypertrophic scar formation is
often mistaken for keloid formation because of the increased
width of the scar. Occasionally, removal of a keloid results in a
hypertrophic scar which, again, is often confused with a recur-
rence of the keloid. In reality, the distinction may not be as
important, as treatment methods are similar.
Hypertrophic scars typically develop quickly after an incit-
ing surgery and subside gradually over time. In contrast,
keloids often develop more slowly and do not resolve (1)
(Figure 30.3). Hypertrophic scars may be treated with surgical
revision while this may result in additional keloid formation FIGURE 30.3 Hypertrophic scar (a) following a surgical procedure and
keloid (b) resulting from trauma to the left arm.
and/or worsening of the treated keloid.
The size of a hypertrophic scar is usually reflective of the
inciting injury; however, even a small injury can yield a large
keloid (Figures 30.4–30.8). Keloids in areas such as the neck and secondary to hair cut short with resultant inflammation of the
chest can grow to massive size and cause restriction of move- skin from the hair with keloid formation (acne keloidalis nuchae,
ment (Figure 30.1). Those keloids of larger size, and in particular Figure 30.9). Hidradenitis suppurativa can include keloid forma-
those of the chest and back, are difficult to treat. This is largely tion, most commonly involving the axillae and inguinal region
due to the sheer size and the propensity for recurrence. The con- of the groin (Figure 30.10). Keloids can form after severe acne as
stant movement of skin of the chest and back in regular daily well (Figure 30.11). It is important to remember that intentional
motion contributes to this. Treatment of keloids of this size and therapeutic measures such as re-excision, injection, or laser
body restriction prove especially difficult. Keloids may form treatments can themselves cause keloid formation.
FIGURE 30.4 Keloid formation secondary to piercing of the ear in an

adolescent. Piercing was performed at the age of 13.
FIGURE 30.6 Keloid on the right earlobe secondary to piercing of the
ear in adolescence.
FIGURE 30.7 Large pedunculated keloid on the right earlobe. Patient

FIGURE 30.5 Keloid on the posterior ear secondary to piercing of the ear. had piercing performed in adolescence.
FIGURE 30.9 Acne keloidalis nuchae in the scalp secondary to short

haircut.
FIGURE 30.10 Keloid formation in the setting of axillary hidradenitis

suppurativa. Treatment is typically difficult and may consist of topical
and oral antibiotics. The use of CO2 laser as well as some biologics may
offer some benefit.
Histology
Histologic examination of a keloid (and hypertrophic scars)
demonstrates a random array of thick, hyalinized, eosinophilic
collagen bundle deposition (Figure 30.12). This is in contrast to
that of normal skin, in which the collagen bundles are seen in
parallel to the skin surface. Differentiation between hypertro-
phic scars and keloids is also possible. An important histologic
distinction that differentiates keloids and hypertrophic scars is
that a hypertrophic scar remains confined to the site of injury
whereas keloids extend beyond this site. The collagen bundles
FIGURE 30.8 (a, b, c) Excision of keloid on right earlobe with seen in hypertrophic scars are flatter and less demarcated than
transmural excision (dumbbell technique). those in normal skin. Collagen fibers are seen in a wavy pat-
tern. These features are more pronounced in keloids. Occlusion
of microvessels is reported to occur in both hypertrophic scars
and keloids (15). Most scars are accompanied by epidermal
changes, such as a loss of epidermal rete ridges as compared transforming growth factor-β (TGF-β) and platelet-derived
to keloids which demonstrate minimal epidermal changes. growth factor (PDGF). These play a role in modulating con-
Differentiation is typically possible via clinical examination. tractile forces in skin fibroblasts (1). A brief overview of wound
healing assists in the discussion of pathogenesis.
There are three primary phases of normal wound heal-
ing: inflammatory, proliferative/fibroblastic, and matura-
Pathogenesis
tion/remodeling (1, 10). The inflammatory phase consists
The pathogenesis of keloid formation still remains largely of an immediate influx of inflammatory mediators into the
unknown. Recent advances have implicated the role of site involved. A fibrin clot is initiated during this phase.
This occurs by capillary dilation and subsequent delivery of
these mediators. The fibroblastic phase consists of fibroblast
advancement into the fibrin clot with production of new col-
lagen. The maturation phase occurs as the wound matures
via collagen synthesis and degradation (1). A variety of sig-
naling molecules (TGF-β, PDGF, matrix metalloproteinases
[MMPs], tissue inhibitors of metalloproteinases [TIMPs])
regulate this process.
With this basic template of the wound healing process in
place, the faults by which keloids and hypertrophic scars occur
can be demonstrated. Early forms of fibroblasts have been
shown to persist longer in keloids than in normal skin (1). This
persistence of early fibroblasts likely results in increased col-
lagen production. This collagen synthesis is 20 times greater
FIGURE 30.11 Keloid formation secondary to severe acne on the back. in keloids than in normal skin (16). While the dominant type
FIGURE 30.12 Histopathology of normal skin (A–C), hypertrophic scars (D–F), and keloids (G–I). These are shown at 4× magnification (top row),
10× magnification (middle row), and 20× magnification (bottom row). Normal skin has distinct collagen bundles that are predominantly arranged
parallel to the epidermal surface. Evaluation of hypertrophic scars demonstrates less order of the collagen bundles, and keloids are marked by
haphazard arrangement of collagen fibers with random orientation.
of collagen in normal skin is type I, keloids have both types several times per day. This can be useful for smaller scars and
I and III. especially in sites where web formation may occur. The use
Growth factors have shown the most promise in the quest of topical “keloid medications” has not been shown to be any
for keloid pathogenesis. TGF-β promotes fibroblasts to local- better than just massage alone.
ize to sites of inflammation to begin extracellular matrix The use of mechanical pressure is used as both treatment
protein synthesis (1). While this activity is normally turned and prophylaxis. This is commonly seen with pressure ear-
off when repair is complete, dysregulation of TGF-β activity rings used to both treat and prevent keloids secondary to ear
is likely a key factor in keloid production (1, 16). Decreased piercing. Treatment with mechanical pressure takes time and
synthesis of molecules that promote collagen matrix break- may require as long as 6 to 12 months or longer for acceptable
down (MMPs) has also been shown to be a factor in keloid results (1). Additionally, pressure garments should be used 23
pathogenesis (17, 18). Other studies have shown that infrared to 24 hours/day (1). Success in treatment is largely dependent
light can inhibit fibroblast proliferation and activity. How on patient compliance.
this happens is unknown, but it may be why some success Silicon gel sheeting is believed to act by scar hydration,
has been reported with CO2 laser excision of keloids. resulting in decreased capillary flow with subsequent reduc-
tion in collagen deposition from a decrease in circulating
proinflammatory cytokines. Some authors have demonstrated
excellent success rates with silicon gel sheeting, while others
Treatment attribute its success to the occlusive wound effects (26, 27).
Treatment of keloids and hypertrophic scars presents a clini- Silicone sheeting should be worn for a minimum of 12 hours
cal challenge (Table 30.1). As the two entities are similar, per day and for a minimum of 2 months (10). The true “gel”
treatments are also similar. The fact that traumatic injury types of sheeting have been shown to give more consistent
is the typical cause highlights the difficulty of any type of results than the dry “card-like” sheeting.
surgical treatment. Treatment options include a multitude The use of cryosurgery in the treatment of keloids and
of possibilities ranging from noninvasive to invasive. The hypertrophic scars is much like that in treatment of other der-
choice of treatment depends on a variety of factors, including matologic conditions. Cryosurgery utilizes a cryogenic agent
the patient (age, health), location, size, depth, and previous (liquid nitrogen) to induce direct cellular and microcirculatory
treatments. damage. This leads to tissue necrosis and hopeful flattening of
A multitude of topical treatment modalities have been suc- the lesion. The primary risk of this method is hypopigmenta-
cessfully used to treat keloids and hypertrophic scars (19–24). tion of the treatment site. Success rates as high as 74% have
A common technique used at the initial time of diagnosis is been claimed with the use of cryosurgery to treat keloids (28,
gentle massage of the site. Instructions to the patient include 29). It has also been noted that younger keloids tend to respond
a gentle rocking massage for several minutes to be performed better to cryosurgery than older keloids. It can also be used as
an adjunct to initial corticosteroid intralesional injection. The
edema which results from cryosurgery loosens the scar-like
TABLE 30.1 fibers and facilitates easier injection.
Treatment of Keloids and Hypertrophic Scars Topical corticosteroids remain a common first-line treat-
Topical
ment of both keloids and hypertrophic scars. The known
side effect of skin atrophy is harnessed and used to the clini-
Massage cian’s advantage. Similar medications such as tacrolimus and
Pressure pimecrolimus demonstrate some potential; however, these are
Silicon gel weaker than most corticosteroids utilized and thus may be
Cryotherapy most efficacious in anatomic locales where stronger cortico-
Tacrolimus steroids are not possible.
Retinoids
Intralesional injection
Corticosteroid (Triamcinolone acetonide)
Interferon-alpha-2b
5-fluorouracil (intralesional)
Bleomycin (intralesional)
Mitomycin C
Verapamil
Lasers
Pulsed dye laser
Argon laser
Nd:YAG laser
CO2 laser
Oral
Surgical
Radiation therapy
FIGURE 30.13 N-tralig mechanical injector.
FIGURE 30.14 Intralesional treatment of a hypertrophic scar with the

N-tralig mechanical injector.
FIGURE 30.16 (a) Treatment of keloids with CO2 laser. Multiple

treatment sessions were required with (b) resultant improvement and
decreased thickness. Of note, the resultant scars represent hypertrophic
scars, an improvement over the previous keloids.
FIGURE 30.15 Dermajet injector.

lure lock system frequently results in propulsion of the nee-
dle from the syringe. The N-tralig injector utilizes a ratchet-
type mechanism to allow injection of medication into keloids
Intralesional injection remains a mainstay of treatment of and hypertrophic scars (Figures 30.13 and 30.14). Use of this
keloids and hypertrophic scars. The most common and per- device proves especially helpful for firm keloids and initial
haps most useful medication used is triamcinolone acetonide. treatments, where the mechanical force needed to inject is
Triamcinolone acetonide as injected is available in multiple great. Another technique with keloid injection is the dermajet
concentrations. Stock concentrations of 10 mg/mL and 40 (Figure 30.15). This specialized syringe allows one to inject
mg/mL are most often used, while alternate dilutions can be medication without using a needle.
prepared easily by diluting these stock concentrations (30). In all cases, it is important to avoid injecting into the sub-
A common diluent is lidocaine, which offers the added benefit cutaneous fat, as the atrophy that follows is difficult to cor-
of local anesthesia at the injection site. The dose and concen- rect. Injection around or near the eye should also be carried
tration varies based on the size and location of keloid; however, out with caution, as particles from the suspension have been
this may range from 5 to 40 mg/mL. Injecting a medication into shown to cause amaurosis through embolization.
a keloid often represents a physical challenge due to the density Intralesional chemotherapy has also proven useful.
and firmness of a keloid. A basic understanding of Poiseuille’s Fluorouracil is perhaps the most commonly used agent, while
law is important in the delivery of medication. This law defines bleomycin is also used. Often times these are used in a mixture
the volume flow-rate by the pressure difference divided by the with intralesional corticosteroids.
viscous resistance. More succinctly, it determines the resis- The use of retinoids for the treatment of keloids and hyper-
tance to flow. The important point for the clinician is that a trophic scars has been suggested topically; however, they
smaller diameter syringe allows a greater mechanical advan- have also been cited as a potential causative agent when taken
tage for injection. A 1-cc tuberculin syringe with a lure lock orally. Decrease in size of keloids treated with tretinoin 0.05%
tip and 27-gauge or larger needle is recommended. Lack of a topically for 12 weeks has been described. The risk of scarring
FIGURE 30.17 (a, b) Use of CO2 laser to ablate large keloid on the pre-
and postauricular cheek.
was historically of concern following recent treatment with

isotretinoin and acitretin, although this is largely felt to be
untrue at present.
The use of imiquimod 5% cream has been met with
mixed reviews in the prevention and treatment of keloids
(31). Imiquimod is a topical immune response modifier that
stimulates interferon-α (INF-α). This is a proinflammatory
cytokine that increases collagen breakdown. Although there
are conflicting results in the literature, most of these studies
consist of small study groups. Given the favorable results in
many studies and the overall safety profile of imiquimod, it is a
simple and potentially useful adjunctive therapy for treatment
of keloids (32). FIGURE 30.18 Postoperative result after CO2 ablation of keloid (from
Reports of using calcium antagonists to retard extracellular Figure 30.17) at 2.5 months (a) and 4.5 months (b and c). The resultant
surgical scar represents a hypertrophic scar but an improvement over the
matrix production in connective tissue equivalents and intra- previous keloid.
lesional verapamil to treat keloids have also appeared in the
literature.
The use of lasers to treat keloids and hypertrophic scars has pulsed dye laser is a 585 or 595 nm system. Frequency-doubled
been met with some success (Figures 30.13–30.19). A num- Nd:YAG systems have also demonstrated benefit in the treat-
ber of different lasers have been tried but perhaps the main ment of keloids and hypertrophic scars. Pulsed dye lasers have
two that are used most commonly are the pulsed dye laser the benefit of reduction in size and redness of keloids and
(nonablative) and the carbon dioxide (CO2) laser (ablative). The hypertrophic scars as well as normalizing the surface texture
FIGURE 30.21 Surgical excision and CO2 resurfacing of large keloid

on cheek.
FIGURE 30.19 Large keloid on right cheek of a young man (a) and after
CO2 resurfacing (b).
FIGURE 30.22 Use of CO2 ablation to treat a keloid secondary to ear

piercing.
The use of fractional CO2 laser has largely replaced tradi-

tional CO2 laser use, mainly only because it has been more
commonly used for other aesthetic purposes. However, abla-
tive CO2 laser remains an effective mainstay for the treatment
of both keloids and hypertrophic scars. Fractional CO2 treat-
ments are also effective, although by definition not as powerful
FIGURE 30.20 Surgical excision of large keloid.
due to the lesser area and volume being treated. Traditional
ablative CO2 laser is much more capable of dramatic contour
reduction for thicker and more extensive lesions.
of keloids. The CO2 laser is an ablative laser that vaporizes tis- Surgery is commonly used to treat keloids and hypertrophic
sue and can be used to excise keloids (Figures 30.13–30.23). It scars; however, it must be used with caution as this may result
is thought to have an inhibitory effect on fibroblasts. in keloid formation itself, sometimes worse than the initial
FIGURE 30.23 Use of CO2 ablation to remove and recontour keloid on right cheek. The initial keloid (a) was first surgically excised (b) in an effort
to debulk the lesion. Despite the use of intralesional corticosteroids, silicon sheeting, and topical imiquimod, the keloid recurred.
lesion. The risk of anticipated keloid formation from surgical injection of intralesional corticosteroids. More recently,
intervention often warrants adjuvant therapy such as postop- reports of combinations including excision, mitomycin C, and
erative corticosteroid injections. Recurrence of keloids follow- radiotherapy have demonstrated some success. The use of
ing surgical intervention varies from 50% to 80%. Despite the additional lasers such as the 1064 nm Nd:YAG has also been
concern for a keloid returning larger than its pre-surgical size, reported to have some benefit (20, 23).
surgery tends to be an effective modality and especially when
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31
Keratolytic Treatment of Acne
Brigitte Dréno
and closed). This chapter covers widely available topical kera-

Introduction tolytics. Only studies that assessed subjects with acne vulgaris
on the face were included.
Topical keratolytics are agents that dissolve or break down
the outer layer of skin. They loosen and assist exfoliation of
the skin cells. In acne, their target is the comedo, and the
most powerful keratolytics are used topically. These topical
Benzoyl Peroxide
keratolytic agents have long been employed for acne treat-
ment. Acne vulgaris is a chronic inflammatory disease of the Benzoyl peroxide (BPO), a mainstay treatment of mild to
pilosebaceous unit. It results of abnormalities of three main moderate acne for decades, has mainly antimicrobial, anti-
physiological factors consisting of hyperkeratinisation of the inflammatory effects and only mild anticomedogenic effects.
follicle, inflammation where skin microbiome and an anaero- Acting through oxidation and formation of free radicals, its
bic bacteria Cutibacterium acne (C. acnes) play a crucial role, bacteriostatic activity is superior even to that of topical anti-
and finally increased sebum production. Everywhere in the biotics (3). It decreases inflammation by killing polymorpho-
world, acne affects around 80% of adolescents and can persist nuclear leukocytes (PMNs), preventing the release of reactive
into adulthood at a prevalence of 20%. In addition, acne may oxygen species (4). The mild keratolytic activity is probably
lead to permanent scarring and psychological impact, includ- linked to the inhibition of C. acnes. Unfortunately, oxidative
ing depression and anxiety. destruction of the SC may deplete cutaneous vitamin E, result-
Keratolytic have a central role in the treatment of retentional ing in oxidation of surface lipids and proteins; this may predis-
lesions. Shalita et al. state that “the first histologically visible pose to skin dryness and desquamation (5). BPO is absorbed
change in acne is a disruption in the normal pattern of keratini- effectively into the epidermis, particularly by pilosebaceous
zation, resulting in dense, coherent squamae of keratinous mate- units, and converted to benzoic acid, with approximately 2%
rial that accumulate to form a plug in the orifice of the follicle, entering the systemic circulation (6). Its lipophilicity allows it
leading to formation of the microcomedo. Microcomedo is the to enter and accumulate in the lipid-rich pilosebaceous units
precursor of acne lesion, histologically but not clinically visible. and subcutaneous fat (4). It is an FDA Pregnancy Category C
It is well identified now by confocal microscopy. Abnormalities agent, with little known about potential fetal harm or breast
of proliferation, adhesion, and differentiation of the keratino- milk excretion, and positive in the rodent photocarcinogenicity
cytes obstruct the infundibulum of the pilosebaceous follicle. assay. In Europe, it can be prescribed to pregnant women. It is
Recently, it has been identified that C. acnes played a role in the widely available both over the counter (OTC) and by prescrip-
development of the microcomedo both by producing a biofilm tion and comes in different concentrations ranging from 2.5%
which increase its adherence to the keratinocytes and by secret- to 10%. Adverse effects include dryness, peeling, burning,
ing extra vesicles which modulate the expression of filaggrin and redness of skin; phototoxicity (not photo allergy) is rare
and increase the proliferation of keratinocytes (1). Keratolytic and can be avoided by prescribing PBO in the evening, with
agents are thought to function by relaxing the cohesiveness of contact allergy only in 1% to 2% of patients (3). Additionally,
the stratum corneum (SC) layer, which serves as a crucial, life- the water-based formulations may exert less drying, scaling,
sustaining barrier, keeping hydration “in” and harmful foreign burning, and erythema than the alcohol-based formulations.
agents “out.” The mechanism of action does not involve keratin Of note, BPO, an oxidizing agent, can bleach hair, clothing,
lysis as the name implies, but rather disintegration of desmo- and coloured fabrics. It may also inactivate tretinoin if both are
somes and corneodesmosomes that link keratinocytes of the applied concurrently (7); in contrast, adapalene and tazarotene
follicle and bind them to the extracellular matrix, respectively remain stable in the presence of BPO (8).
(2). In this manner, these agents can secondly modulate and The 2.5% formulation is as effective as the 5% and 10% for-
correct abnormal follicular keratinization. Currently many mulations in reducing retentional and inflammatory lesions,
classes of keratolytics exist (Table 31.1). Available in varying while causing fewer adverse reactions than the 10% solution (8).
concentrations and vehicles, they may be specifically indicated Benzoyl peroxide has been combined with other molecules
depending on the type, duration, and severity of acne and the to increase its keratolytic efficacy. In a split-face, double-
sensitivity of the skin and the part of the body (face or trunk). blind trial, a combination of BPO 5% and urea 8% lotion was
Their targets are the microcomedo and the comedo (opened not more efficacious in diminishing acne than BPO 5% lotion
DOI: 10.1201/b22897-31 317

TABLE 31.1
Keratolytics Currently Used for Acne in the United States and Europe
Name Class First introduced Usual concentration(s) (%) Vehicle(s)
Salicylic acid β-Hydroxy acid 1887 No more than 2.0 Bar, foam, cream
Glycolic acid α-Hydroxy acid 1900 <10% Superficial peeling
Benzoyl peroxide Organic peroxde 1920s 2.5, 5.0, 10 Gel, bar
Tretinoin Retinoid 1962 0.025, 0.05, 0.1 Cream, gel
Isotretinoin Retinoid 1979 0.05 Gel
Tazarotene Retinoid 1997 0.1, 0.05, 0.5 Gel, cream
Adapalene Retinoid-like 1996 0.1 Gel, cream
Azelaic acid Dicarboxylic acid 2002 15.0, 20.0 Cream, gel
Sulfur Sulfur 1998 10.0 Bar
Urea Urea 1828 <10% Cream
Resorcinol Phenol 1866 – Peeling
Clindamycin/benzoyl peroxide Antibiotic combination 2009 1.0/5.0 Gel
Erythromycin/benzoyl peroxide Antibiotic combination 2006 3.0/5.0 Gel
Adapalene/benzoyl peroxide Retinoid-like/BPO 2009 0.1/2.5 Gel
2019 0.3/2.5 Gel
Tretinoin/clindamycin Retinoid/Antibiotic 2010 0.025/1.2% Gel
Trifarotene Retinoid RARɣ specific 2019 50 µg/g Gel
alone; the combination took longer to dry and was stickier, are powerful keratolytics, targeting both primary and second-
according to subjects (7). Combination therapy with topical ary prevention of comedones. Retinoids exert their effects
antibiotics and BPO may be more effective than BPO alone. through nuclear receptor families RARs and RXRs (retinoic
Both the clindamycin/BPO and the erythromycin/BPO for- X receptors), subsequently inducing retinoic acid–responsive
mulations have shown superior efficacy when compared target gene expression (16). Both receptor families are ligand-
with either the antibiotic or BPO alone (9, 10). Furthermore, dependent transcription factors and consist of three receptor
the side effect profile (dry skin, peeling, and erythema) of subtypes (a, b, and ϒ), encoded by three separate genes.
combination therapy is comparable to that of BPO alone Although RAR-a is ubiquitous in embryonic skin, RAR-ϒ is
(11). Two multicentre, double-blind randomized studies of the most abundant RAR in human epidermis, cultured kerati-
2813 acne patients with moderate to severe acne compared nocytes, and dermal fibroblasts (17). Since the US Food and
the efficacy and safety of a fixed combination clindamycin Drug Administration (FDA) approved tretinoin in 1971,
phosphate 1.2% and BPO 2.5% with each drug alone and retinoids alone or combined with other agents have become
a vehicle arm, in moderate or severe acne subpopulations. the mainstay of acne treatment. Retinoids act through bind-
Clindamycin-BP 2.5% gel significantly reduced inflam- ing to retinoic acid receptors, altering expression levels of
matory and non-inflammatory lesions compared with each hundreds of cellular proteins affecting multiple pathways
active ingredient and vehicle only in moderate acne at week involved in acne pathogenesis. Retinoids have evolved from
12. Rates of adverse events were low and similar between first-generation agents, such as tretinoin, through chemical
treatment groups and baseline acne severity. This study con- modifications resulting in a second generation (etretinate
firms that the target of this combined therapy is moderate and acitretin for psoriasis), a third generation (adapalene and
and not severe acne (12). tazarotene) and, most recently, a fourth (trifarotene) which
Concerning the combination BPO/erythromycin, no dou- is RARɣ specific (18).
ble-blind study has been performed. Leyden et al. compared Retinoids are a family of compounds that structurally and
clindamycin/BPO and erythromycin/BPO demonstrating sta- functionally resemble vitamin A, an essential nutrient with
tistically equivalent lesion reduction and global improvement, a key role in cellular growth and differentiation. In the skin,
with similar tolerability (13). retinoids exert their effects by binding retinoic acid receptors
In vivo data suggest that the increased efficacy of a BPO/ (RARs) in the cell nucleus with subsequent regulation of gene
antibiotic combination may have an immunological basis as transcription. There are three subtypes of RARs, and the topi-
demonstrated by decreased antioxidant enzyme activities cal retinoids currently approved for acne have differing recep-
in leukocytes after month-long combination treatment (14). tor binding profiles which may translate to clinical differences
Additionally, this combinatory approach may prevent the evo- since the specific RAR subtypes activated dictate the biologi-
lution of resistant C. acnes strains (15). cal response of target cells. The activity of a retinoid depends
on cellular transport, receptor-binding pattern and affinity, and
the genes activated. Recently, bioinformatic data comparing
gene expression in acne lesions treated with a new retinoid tri-
Retinoids: Tretinoin, Tazarotene, Adapalene farotene versus spontaneously resolving acne lesions showed
Topical retinoids encompass a group of powerful comedo- that trifarotene significantly modulates 67 genes that do not
lytic, ant comedogenic, and anti-inflammatory agents. They appear in the spontaneously resolving lesion. These genes are
Keratolytic Treatment of Acne 319
involved in cellular migration, activation of adaptive immu- non-inflammatory acne lesions compared with vehicle by 12
nity, inflammation, and matrix reorganization. Retinoids also weeks. Numerous trials have also demonstrated the efficacy of
inhibit expression of certain genes by down regulating other 0.05% and 0.1% gel tretinoin in mild to moderate acne with a
transcription factors, notably activator protein 1 (AP-1) and decrease of retentional lesions between 30 and 50% according
nuclear factor-interleukin 6 (NF-IL6) (16). Thus, the spectrum to the studies (1). Additionally, tretinoin may bring out the post
of activity of retinoids is large including anti-inflammatory inflammatory darkening that occurs in healing acne of darker-
actions (19). skinned patients (25). Surprisingly, topical tretinoin has poor
Prior to binding with nuclear RARs, retinoids must first percutaneous absorption and does not alter systemic retinoid
bind to intracellular proteins. Cellular retinoic acid proteins levels, which stay constant despite application (5). Side effects
(CRABP I and II) are present in the skin. Intracellular reti- include peeling, erythema, dryness, burning, exfoliation, and
noid concentrations are dependent on CRABP, primarily itching.
type II (16). However, CRABP II is not essential for bio- The addition of some chemical substances or medical
logical retinoid activity as adapalene does not bind to it; devices has been proposed to increase efficacy and decrease
interestingly, it may play a role in retinoid-induced epider- irritation. Thus, addition of polyolprepolymer-2 (PP-2),
mal irritation. Through this genetic regulation, retinoids are localizes drug molecules in upper skin layers, preventing
thought to affect cellular differentiation and proliferation deep penetration (26). PP-2 forms a liquid reservoir of poly-
(20). Experimental studies, some using primary neonatal mer and solubilized drug on the skin surface, slowing per-
mouse epidermal keratinocyte cultures, have confirmed this cutaneous absorption and transcellular cutaneous diffusion,
concordant decrease in keratinocyte differentiation and pro- potentially targeting folliculo-infundibular delivery in the
liferation (21). Retinoids also regulate activity of keratino- process. Clinical trials have demonstrated reduced irrita-
cyte adhesion and cohesion molecules (integrins), resulting in tion as less drug penetrates the skin (26). The microsponge
breakdown and obliteration of the horny plug. Interestingly, delivery system found in 0.1% microsphere gel also helps
C. acnes acts through TLR-2 to stimulate proinflammatory reduce drug release rate and increase drug retention in the
cytokine production (19). The major drawback to topical SC, inhibiting deeper penetration (27). Tretinoin is trapped
retinoids is local skin irritation and acne exacerbation, also within porous copolymer microspheres which selectively
termed “retinoid flare,” which may occur during the first localize to the follicle, releasing tretinoin over time and
month of treatment and last several weeks. This flareup may producing less irritation (than the standard 0.025% cream)
be secondary to release of follicular inflammatory factors due to reduced concentration on the skin (26).
after topical retinoid treatment. Another limiting factor of A study compared the efficacy and safety profile of tretinoin
topical retinoids is the contraindication to their use during 0.05% with adapalene 0.1 and 0.3% and placebo in Mexican
pregnancy. Limb-reduction defects and ear malformations subjects with acne vulgaris. Tretinoin 0.05% and adapalene
have been reported with maternal use of topical retinoids in 0.3% were more effective than adapalene 0.1% and placebo
two papers (22). However, Jick et al., in a retrospective study, in the reduction of both inflammatory and non-inflammatory
did not substantiate this suggestion, and the clinical issue lesions, but the adverse events (topical irritation) were also
remains to be confirmed (23). more important (25).
Two other studies have compared micronized tretinoin
gel 0.05% versus tretinoin gel microsphere 0.1%, with simi-
First Generation of Retinoids lar efficacy in both. Concerning tolerance, the results were
contradictory between the two studies, not permitting any
Tretinoin
conclusions (26).
Tretinoin, the first topical retinoid to be studied, binds with Combination: The alteration in SC integrity incurred during
high activity to all three RAR subtypes and to CRABP, and tretinoin treatment may enhance penetration of other agents
with low activity to RXRs. It is both a comedolytic and anti- such as topical antibiotics (28). Topical retinoid therapy, by
comedogenic, preventing formation of microcomedo (20). weakening the horny layer barrier, may increase skin permea-
Employing the technique of skin surface biopsy, microscopic bility, enhancing penetration of antimicrobial agents. Increased
examination of comedones showed progressive loss of cohe- cell turnover of follicular epithelium enables greater access
siveness and significant alterations in epithelial structure; of antibiotic into the canal that houses C. acnes. A hydrogel
thick keratinous plugs infested with bacteria were transformed containing 1% clindamycin and 0.025% tretinoin was found
into a few wispy layers of keratin with few bacteria. Using to be more efficacious in treating both inflammatory and non-
transmission electron microscopy, it was possible to track inflammatory acne lesions than either agent alone or vehicle
microcomedones with compact, adherent SC morphing into (29). Three other double-blind randomized studies have been
spongy, loosely adherent layers of corneocytes (1). Mills and performed confirming that the combination clindamycin phos-
Kligman, using a cyanoacrylate follicular biopsy technique, phate 1.2% and tretinoin 0.025% decreased significantly more
demonstrated a profound microcomedones reduction in 8 and both retentional and inflammatory lesions in mild to moderate
12 weeks (24). From an immunological perspective, in vitro acne compared with each of the drug used alone (30–32). The
studies have demonstrated that tretinoin down regulates and inflammatory flareup of the first days of treatments was also
decreases surface expression of TLR-2 and CD14 mRNA, less important.
preventing secretion of tumour necrosis factor and IFN-ϒ, as Finally, a BPO 6% cleanser–tretinoin 0.1% microsphere gel
well as production of free radicals (19, 21). Tretinoin cream demonstrated significantly greater inflammatory lesion reduc-
0.025% significantly reduced inflammatory but mainly tion than tretinoin alone (33). However, tretinoin should not
be used with BPO (an oxidizing agent), which can result in initial stages of treatment and demonstrated better tolerability
degradation and deactivation. with respect to erythema and scaling. Finally, one trial com-
pared once-daily tazarotene 0.1% cream and adapalene 0.3%
gel in patients with moderate to severe acne (38).
Topical Isotretinoin Tazarotene 0.1% cream appeared to be more effective and
One multicentric double-blind randomized study (34) has nearly as well tolerated as adapalene 0.3% gel in reducing
compared isotretinoin 0.05% gel with its vehicle. Patients acne lesions and was more effective than adapalene 0.3%
were treated twice daily for up to 14 weeks. Efficacy of gel in reducing PIH. Furthermore, a large clinical trial
Isotretinoin was significantly better than vehicle both for suggests that even short-contact application (<5 minutes),
inflammatory and retentional lesions with low irritation. But once daily for 12 weeks, produces significant reduction in
in a general manner topical Isotretinoin is considered as less both inflammatory and noninflammatory acne lesions (39).
efficacious than other topical retinoids with a low kerato- A multicentre, double-blind, randomized trial found a daily
lytic effect. The efficacy cannot be compared with systemic 5% BPO/1% clindamycin gel–tazarotene 0.1% cream regi-
Isotretinoin. men to be more effective than daily tazarotene monotherapy
in reducing comedo count and inflammatory lesion count,
with a similar, if not slightly improved, tolerability profile
Third Generation of Topical Retinoid (40). Local side effects include itching, burning, irritation,
and erythema.
Tazarotene
Tazarotene, a third generation of topical retinoids, is a topical
Adapalene
acetylenic retinoid indicated in both psoriasis and acne vul-
garis. Currently, only the 0.1% formulation of tazarotene is Adapalene 0.1% or 0.3%, as tazarotene, is a third generation
approved by the FDA for acne and tazarotene is not approved of topical retinoids. It is a derivative of retinoic acid that binds
in Europe for acne. It is primarily used in cases of acne refrac- selectively to RAR-β and -ϒ in vitro but can activate gene
tory to tretinoin and adapalene treatment. expression through all three RARs; it does not bind CRABP
Tazarotene is hydrolysed by keratinocyte esterases to taz- II but increases CRABP II mRNA (16, 18). It has comedolytic,
arotenic acid, its active metabolite. It binds all three RARs antiproliferative, and anti-inflammatory properties which are
but not RXR, activates gene expression only in RAR-ϒ and more important that the first generation of topical retinoids
ϒ. It down regulates AP-1. As tretinoin, it normalizes the (18). Its anti-inflammatory action stems from inhibitory effects
keratinization pattern and decreases coherence of follicular on PMN chemotactic response, free radical production, and
keratinocytes, manifesting both comedolytic and anticom- toll-like R2 receptors expressed by perifollicular monocytes
edogenic properties. Tazarotene also has anti-inflammatory (19). It also inhibits production of leukotrienes by 5- and
properties. In the systemic circulation, tazarotenic acid is 15-lipoxygenase pathways (18, 19). Furthermore, adapalene
rapidly converted to inactive sulfur-oxidized forms, resulting may have a dose-dependent response, with 0.3% statistically
in limited exposure (35). Nonetheless, animal studies have superior to 0.1% in several different measures, while demon-
demonstrated that tazarotene has low systemic absorption strating equivalent tolerability (40, 41). Adapalene’s particle
with no toxic effects even at high topical doses. Additionally, size (diameter between 3 and 10 mm) and its lipophilic proper-
after 12 weeks of normal tazarotene application, serum sam- ties result in optimal follicular duct penetration; furthermore,
ples from 22 subjects demonstrated limited systemic expo- after 5 minutes of exposure, 14-C labelled adapalene applied
sure with most below the quantifiable limit (<0.05 ng/mL) to human skin in vitro demonstrates radio sensitivity in the
(35). Despite little evidence of fetal malformations or spon- pilosebaceous units, with sparse activity in the SC and epider-
taneous abortions, topical tazarotene is an FDA Pregnancy mis. Adapalene demonstrates higher stability than tretinoin in
Category X drug; little is known about its excretion in breast the presence of light, in the dark, and with BPO (8). In a study
milk. Of all topical retinoids in acne treatment, it is the only comparing the chemical stability of 0.1% adapalene gel/10%
one requiring sufficient contraception in women of child- BPO and 0025% tretinoin gel/10% BPO after 24 hours of light
bearing age. exposure, approximately 100% of adapalene remained intact
At the clinical level, a randomized, double-blind, vehicle- versus only 20% of tretinoin (42).
controlled study demonstrated that 0.05% and 0.1% tazaro- At the clinical level, a meta-analysis of five large, random-
tene gels significantly decrease retentional acne lesions and ized trials (900 patients) demonstrated equivalent acne reduc-
produce a higher success rate than vehicle at 12 weeks (36). tion, quicker onset of action (significant at 1 week), and fewer
Moreover, 0.1% gel was significantly more efficacious than side effects in 0.1% adapalene gel compared with that in
0.05% gel, mainly on inflammatory acne. Two randomized 0.025% tretinoin gel (40).
trials comparing tazarotene 0.1% cream to adapalene 0.3% Maintenance therapy: Cyanoacrylate strip data suggests
cream demonstrated tazarotene to be significantly and rap- that application of adapalene 0.1% gel every other day may be
idly more effective in reducing come done and inflammatory effective maintenance therapy in microcomedone reduction,
lesions with no significant difference in side effects at 12 weeks resulting in decreased exposure.
in one study (37). But another more recent study showed that Side effect profile was significantly better in regard to scal-
daily therapy with adapalene 0.1% gel was not inferior to taz- ing, erythema, dryness, immediate and persistent burning,
arotene 0.1% cream in total acne lesion reductions and during and immediate pruritus. Favourable tolerability to adapalene
may be explained by its receptor specificity, neutral molecular is a topical retinoid approved for once-daily treatment of acne;
structure, and lack of breakdown products. it has been studied as treatment for both facial and truncal
Combination: A study testing 0.1% adapalene/2.5% BPO areas of involvement. The genes affected by trifarotene were
combination gel against vehicle and individual monothera- primarily involved in cellular migration, inflammation, and
pies demonstrated combination therapy to have faster onset of extracellular matrix organization and, interestingly, SPP1+
action, significantly greater reductions in all lesion types, and macrophages, a recently discovered proliferative macrophage
no increase in adverse effects compared with monotherapy found in fibrotic tissue (51). Trifarotene was evaluated in a
(43). This efficacy has been confirmed in a double-blind ran- clinical development program that included two large-scale
domized trial in 1670 patients (44). Focusing on subgroups of phase 3 studies and a long-term safety study. The design of the
patients, 0.1% adapalene/2.5% BPO is also well tolerated in the two phase 3 studies was similar and a total of 2,420 patients
black subjects with similar results to Caucasians. No cases of aged 9 years or older were randomized to receive once-daily
treatment related PIH were observed (45) in young preadoles- trifarotene 50 μg/g or vehicle cream. Reductions in facial lesion
cent patients with moderate acne. The combination associated counts were superior in the trifarotene group, with statistically
with systemic cyclins (doxycycline 100 mg/D, lymecycline significant differences in facial lesion counts apparent by week
300 mg/D) can be efficient in severe acne and thus can be an 1 (P<0.001, and truncal acne also significantly responded to
alternative to a contraindication to isotretinoin (46). In addi- trifarotene compared to vehicle. Adverse events were mild to
tion of 0.1% adapalene, the combination 0.1% adapalene/2.5% moderate, and, when present, diminished after the first few
BPO is also able to prevent the occurrence of relapse among weeks of use. The most reported adverse events were sun-
patients with severe acne, and reduces acne lesions during 6 burn (2.6% versus 0.5% vehicle), irritation at application site
months (47). (7.5% versus 0.3%) and application-site pruritus (2.4% ver-
More recently, adapalene 0.3%, was also available in once- sus 0.8%) (52). The third long-term study was an open-label,
daily fixed-dose combination with benzoyl peroxide (BPO) 52-week study (n=453) in moderate facial and truncal acne.
2.5%. Adapalene 0.3%/BPO 2.5% is approved for use for mod- Continued improvement was reported over the duration of the
erate-to-severe acne (48). Weiss et al. first evaluated fixed-dose study up to week 52, with 65.1% facial IGA success and 66.9%
combination adapalene 0.3%/BPO 2.5% in patients with severe truncal PGA success. In addition, 57.9% of patients had both
inflammatory acne and a very high number of lesions at base- facial and truncal clearance of acne lesions.26 As in the other
line (mean: 109–114 total lesions), and reported that adapalene phase 3 studies, the safety and tolerability of trifarotene was
0.3%/BPO 2.5% was superior to vehicle based on lesion count good; adverse events were reported in 12.6% of patients (53).
reduction and IGA success rates Dose-related adverse events
occurred in 19.8% of those in the adapalene 0.3%/BPO 2.5%
group (49). The combination of adapalene 0.3%/BPO 2.5%
Azelaic Acid
with cyclins appears an interesting alternative to isotretinoin,
unfortunately, until now only opened trail have been per- Azelaic acid, a naturally occurring, saturated C9-dicarboxylic
formed. For the first time, this fixed dose is the first one to dem- acid, modifies epidermal keratinization (cytostatic), combats
onstrate to be able both to prevent and reduce the occurrence both aerobic and anaerobic bacteria (reducing P. acnes prolif-
of atrophic scars. Over a 24-week duration (Part 1 of the study eration), and exhibits anti-inflammatory activity (54). This anti-
which employed a split-face methodology to compare ada- inflammatory activity may potentially be mediated through
palene 0.3%/BPO 2.5% vs vehicle), the scar count decreased inhibition of hydroxyl and superoxide radical production by
by 21.7% in patients treated with adapalene 0.3%/BPO 2.5% neutrophils (55). Contributing to its anti-inflammatory proper-
but increased by 14.4% with vehicle, with an approximately ties, in vitro, azelaic acid is an oxygen free radical scavenger,
30% difference between the groups (p<0.0001). Part 2 of the inhibiting hydroxylation of aromatic compounds and arachi-
study was an open-label extension phase for an additional 24 donic acid peroxidation (54). In their review article, Fitton and
weeks during which adapalene 0.3%/BPO 2.5% was applied to Goa describe that azelaic acid in vivo affects differentiation
the entire face. Treatment with adapalene 0.3%/BPO 2.5% was of human keratinocytes by decreasing synthesis of filaggrin
associated with greater rates of success based on scar global (keratin filament aggregating protein) (56). Azelaic acid func-
assessment (clear/almost clear) and excellent reductions in acne tions in a cytostatic, antiproliferative manner on keratinocytes,
lesion counts were also seen. Long-term treatment was safe and affecting both early and terminal phases of keratinocyte differ-
well tolerated, with the most common treatment-related adverse entiation, with primary effects on mitochondria and RER (57).
events being dry skin (4.4%) and skin irritation (4.4%) (50). After application of azelaic acid, 3% to 5% remains on the SC,
up to 10% penetrates into the epidermis and dermis, and 4% is
absorbed systemically (although this can double with gel formu-
Fourth Generation of Retinoids lations). Nevertheless, baseline serum and urine levels are not
altered by topical usage and are primarily dependent on dietary
Trifarotene
intake of whole grain cereals and animal products. It is an FDA
Trifarotene is basically a novel fourth generation locally Pregnancy Category B drug, as animal studies have shown
applied retinoid approved for the first time in the regimens of favourable results; meaningful human studies are lacking.
both face and truncal acnes. This topical retinoid adheres pre- In 2 weeks of topical treatment, 200 mL of 20% azelaic
cisely to RAR-gamma, the epidermis most frequent isoform, acid attenuated tetradecane-induced comedo formation in the
has been approved in October 2019. Trifarotene 50 µg/g cream rabbit ear, a model of follicular epithelial hyperplasia (58).
Azelaic acid has demonstrated significant inflammatory and studied in combination with low doses of isotretinoin (0.5mg/
non-inflammatory acne reduction in numerous studies (59). kg) compared to isotretinoin alone. The pre- and post-treat-
Comparing 20% azelaic acid to 0.05% tretinoin over 6 months, ment analyses of response to MAS and VAS scores, scarring,
one group found statistically equivalent comedone and total inflammatory components at baseline and at the end of treat-
lesion reduction and similar overall improvement. However, ment were statistically significant in favour of combination
tretinoin use led to increased erythema, scaling, and irritation- with a good tolerance (69). In the same manner the combina-
induced discontinuation over azelaic acid (60). Another trial tion with fractional CO2 laser in a split face study demonstrated
comparing 20% azelaic acid with 5.0% BPO demonstrated a a better efficacy than laser alone and a good tolerance (70).
more rapid initial effect with BPO but similar results for global
response, and inflammatory lesion reduction by 4 months.
Azelaic acid demonstrated milder, more transient adverse Sulfur
events than BPO (60).
Despite efficacy as a monotherapy, a large randomized Sulfur, a yellow non-metallic element, is an old ingredient that
trial demonstrated that azelaic acid functions better in com- has many dermatological indications, including but not limited
bination with one of the following drugs: 4% BPO gel twice to acne vulgaris. Once a very common ingredient in acne treat-
daily, 1% clindamycin gel twice daily, 0.025% tretinoin cream ments, sulfur has fallen out of favour, partly due to its pungent
once daily, or 3% erythromycin/5% BPO gel twice daily (61). odour. In the acne area, sulfur is thought to be keratolytic and
Azelaic acid 15% is indicated in rosacea but has no labelling in bacteriostatic. After application to skin, sulfur reacts with
acne. Recently, an hydrogel composite containing azelaic acid cysteine in the SC, resulting in reduction to hydrogen sulfide.
and tea tree essential oil has been tested in vitro. It seems to Hydrogen sulfide is thought to break down keratin and inhibit
have an antibacterial efficacy against Staphylococcus aureus, growth of C. acnes. Sulfur penetrates skin; it is detectable in
Cutibacterium acnes, and Staphylococcus epidermidis (62). the epidermis at 2 hours, throughout the skin in 8 hours, and
completely undetectable by 24 hours. There is no evidence of
systemic absorption in intact skin. Appearing in a variety of
vehicles (lotions, creams, soaps, ointments), it appears to be
Salicylic Acid more efficacious when used in combination with other drugs,
namely BPO and sodium sulfacetamide. Clinical trials have
A core component in many OTC acne treatments, salicylic acid demonstrated that lotions containing sulfur 5% with sodium
(SA) is a widely available topical keratolytic agent. Dissolution sulfacetamide 10% have resulted in reduction of inflammatory
of intercellular cement is further supported by scanning elec- lesions, comedones, and seborrhea (71).
tron microscopy, which has demonstrated marked squamous Rare, transient side effects include dryness, itching, and
cell separation in SA-treated human skin (63). Although vari- malodorous skin. Nonetheless, given a lack of knowledge, it is
ous concentrations exist (0.5%–10%), 2% is the maximum an FDA Pregnancy Class C drug with nothing known regard-
strength allowed by the FDA and European Medicines Agency ing breast milk excretion.
(EMA) in OTC products.
SA is well absorbed as evidenced by numerous studies; its
bioavailability in topical application varies according to dura-
Glycolic Acid and Superficial Peelings
tion of contact (63, 64). In a study comparing medicated pads
0.5% SA in an alcoholic detergent (Stridex) to placebo (pads Glycolic acid, a naturally hydrophilic organic acid (hydroxy
soaked in buffered water), the treatment group experienced a acid), has keratolytic properties targeting SC and is present in
54% reduction in inflammatory acne compared with 29% in many peel formulations due to its desquamating efficacy. In
the placebo group. Reductions of open comedones and total the context of acne, research has been conducted examining
lesions were also significant compared with placebo (65). glycolic acid chemical peels. Various chemical preparations
A 4-week crossover study comparing a 2% SA acne cleanser have been employed, all of which result in a partial thickness
to a 10% BPO wash demonstrated that only patients treated skin injury, or peel (72); the exact mechanism of action may
with the SA cleanser had a significant decrease in comedo- be due to inhibition of ionic bond–forming enzymes involved
nal lesions (66). Like several other keratolytic agents, SA is an in creating sulfated and phosphorylated mucopolysaccharides,
FDA Pregnancy Category C agent, with unknown effects on glycoproteins, sterols, and lipid phosphatides (72). Comedones
breast-feeding. are removed after only two or three peels, and the procedure
As a member of this family, the SA derivative known in the may be repeated every 2 or 3 weeks. Between peels, low con-
literature as 2-hydroxy-5-octanoyl benzoic acid or beta-lipo- centrations of glycolic acid may be used as a daily cleanser
hydroxy acid has also been proposed as an exfoliant and as to prevent occlusion of follicles (73). A randomized split-face
a treatment of acne. The lipophilic nature of C8-LHA and its prospective clinical trial comparing glycolic acid to Jessner’s
relatively slow penetration in the skin afford it an exfoliating solution (salicylic acid, lactic acid, and resorcinol) demon-
effect that is efficient at low concentrations. It appears to have strated significant acne improvement in both after three treat-
antimicrobial, anti-inflammatory, and anticomedogenic prop- ment sessions. Furthermore, glycolic acid was associated with
erties. It targets more specifically the corneodesmosomes (67). significantly less exfoliation than Jessner’s solution, resulting
New chemical peels using 30% SA in polyethylene glycol in more facile makeup application (74). In a similar study com-
vehicle have demonstrated efficacy and safety, with marked paring glycolic acid and SA peels, both were equally effective
reductions in comedones and papules (68). It has also been by the second treatment; however, SA demonstrated greater
sustained effectiveness and a more favourable side effect pro- fixed combinations but always with the same topical drugs, no
file (75). One recent article examines the evidence base that new original molecule has been found. In addition, considering
supports the widespread use of superficial peels in acne. The the mechanism of action of a keratolytic—that is, it dissolves
conclusions were that search of the literature revealed very few or breaks down the outer layer of skin—they are all topical.
clinical trials of peels in acne. Most of these trials included We strongly hope that the near future will provide more rapid
small numbers of patients, were not controlled, and were open advances, based on the power and ease of interpretation of the
label. Notably, no studies of chemical peels have used an acne newly devised in vivo human keratolytic assay. We can hope
drug as a comparator (76). that the development of new galenics will permit a better pene-
tration in the lipophilic environment of pilosebaceous follicle.
Resorcinol
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32
Cosmetics and Moisturizers in Acne Management
Uwe Wollina and Ömer Kutlu
Con: Comedogenicity and Emulgators

Introduction
Topical applied substances may be comedogenic, thus worsen-
Acne is a common chronic disease affecting almost 10 % of ing pre-existent acne or inducing a cosmetic acne. The rabbit
the world-wide population. It usually starts during puberty and external ear canal is an often-used model to investigate the com-
reaches a peak prevalence in adolescents and young adults (1). edogenic potential of various compounds. Histologic evaluation
Neonatal acne and onset of acne in later years of life is possible is necessary to confirm follicular hyperkeratosis and plugging.
but less common. In one study, raw material of isopropyl palmitate, isopropyl
The disease is characterized by inflammatory pustules myristate, butyl stearate, isopropyl isostearate, decyl oleate, iso-
and papules, and comedones (black heads and white heads) stearyl neopentanoate, isocetyl stearate, myristle myristate, and
involving face, neck, shoulders, and trunk. Histologically, cocoa butter have been identified as comedogenic (10).
there is a hyperkeratosis of the follicular infundibulum. The Other studies confirmed a comedonic potential of raw mate-
disease is furthermore characterized by predominance of rial of some more compounds such as propylene glycol-2
pro-inflammatory subtypes of Cutibacterium (C.) acnes, myristyl propionate, acetylated and ethoxylated lanolins, xan-
disturbed production of fatty acids, and release of pro- thenes, monoazoanilines, fluorans, and indigoids contained in
inflammatory cytokines. D & C Red dyes, squalene-monohydroperoxide, and linseed
A disturbed innate immune system with upregulated Toll- oil (11–13). Using this assay, several sunscreen vehicles in the
like receptors (TLR) 2 and 4 and increased expression of early 1980s have been found to be comedogenic (14).
bet-defensin 2 in lesional acne skin contribute to an ongoing A human assay had been developed by Mills and Kligman
inflammatory process (2). (15). Potentially comedogenic substances are applied on upper
The most common type of acne is acne vulgaris. The most back skin of young men with prominent follicular openings
severe type is acne conglobata/acne fulminans. In recent years, under occlusion for 1 months. The degree of follicular hyper-
adult acne became more frequent. There are some differences keratosis and plugging is calculated by fast-setting cyanoac-
between adolescent and adult acne (3). Early and intense treat- rylate glue to remove the follicular contents. Other groups
ment during childhood can improve prognosis and may pre- employed skin biopsies under a stereo microscope (16).
vent adult acne later (4). Recently, reflectance confocal microscopy was used for
Current management of acne involves topical and sys- the early detection of microcomedones. Using this technol-
temic medical drug, laser- and light-based therapies, and ogy, duration of application of test substances could be cut in
cosmesis. half (17).
The rabbit ear assay seems to be more sensitive than the
Mills and Kligman assay.
In the real world, cosmetics containing comedonic sub-
Cosmetics and Moisturizers stances do not necessarily induce comedones on human skin
The role of cosmetics in acne is Janus-faced. From the patient’s (18). This can be explained by differences between assay and
perspective cosmetics are often associated with aggravation of human skin, purified material instead of raw material, and
acne. In a Montenegrin study, 71.2% of adolescents believed final concentration and composition of the cosmetic products.
that make-up aggravates acne (5). A similar perception was There are also ethnic factors, age and sex, and area of applica-
noted among acne patients in Jordan (6). These believes do not tion that need consideration (19–21). Table 32.1 provides an
translate in less common use of cosmetics at all. overview on comedogenic raw material of certain products.
Not all moisturizers are created for inflamed skin. A higher In adult acne, cosmetics have been associated with acne
number of emulsifiers in over the counter (OTC) products can flare-up in 14.3% of patients in a study from New Delhi (22).
even lead to dryness since endogenous lipids are removed Among French adult women, the use of daily make-up was
from the skin barrier (7, 8). slightly more frequent in the adult acne group versus adult
On the other hand, use of moisturizers can support pharma- women without acne (23). In a recent study from Thailand
cological treatment adherence in acne patients—in particular, women with adult acne used slightly more cosmetic products
but not only—when using systemic retinoids (9). than the women in the control group (24). In two Indian trials,
326 DOI: 10.1201/b22897-32

Cosmetics and Moisturizers in Acne Management 327
TABLE 32.1
The Comedogenic Raw Material of Certain Products
Propylene glycol-2 myristyl propionate Isopropyl myristate
Acetylated and ethoxylated lanolins Butyl stearate
Xanthenes Isopropyl isostearate
Monoazoanilines Decyl oleate
Fluorans Isostearyl neopentanoate
Indigoids contained in D & C Red dyes Isocetyl stearate
Squalene-monohydroperoxide Myristle myristate
Linseed oil Cocoa butter
Isopropyl palmitate
43.5% and 40% of adult patients reported aggravation of adult agents such as dryness and irritation. Besides, moisturizing
acne due to cosmetics, respectively (25, 26). A study from Sri sunscreen can be used in the morning (35).
Lanka investigated adult female acne patients. A statistically
significant correlation was observed between cosmetics use
and severity of acne (27).
Pro- and Postbiotics
Probiotics are defined as “live microorganisms which when
Pro: Therapeutic Use of Moisturizers for Acne
administrated in adequate amounts can confer a health benefit
The barrier function of the skin deteriorates for numerous on the host” (36). They are mainly used orally. Postbiotics are
reasons in patients with acne. In addition, various pharmaco- defined as a “preparation of inanimate microorganisms and/
logical treatments such as benzoyl peroxide and retinoic acids or their components that confers a health benefit on the host”
impair the epidermal barrier function by increasing transepi- (37). Postbiotics can be applied topically.
dermal water loss (TEWL) and decreasing the water content Typical bacterial strains used in dermatology are Bacillus
of stratum corneum, respectively (28). In this context, mois- subtilis, Streptococcus salivarium spp. and S. thermophilus
turizers are recommended to support the treatment of acne S244, and Lactobacillus spp. The products exert moisturizing
although there is a Janus-faced nature of these products. effects in the epidermis due to enzymatic activity and have
An ideal moisturizer for acne should be non-irritant and regulatory effects in the local immune system as well (38).
hypoallergenic and noncomedogenic. Glycerin, ceramide, Antimicrobial activity of Lactiplantibacillus (L.) plantarum
lanolin, dimethicone, mineral oils, zinc, hyaluronic acid, and VHProbi® E15 has been evaluated in vitro in agar plate and
botanical extracts are among the common ingredients found agglutination assays against C. acnes. A lotion containing 8%
in moisturizers (29). The application of topical glycerin, one ferment lysate of L. plantarum VHProbi® was applied twice
of the most common humectants, alone can decrease TEWL daily on the face of mild to moderate adult acne patients for 4
by 29% (30). weeks (n = 22). Two-thirds of the participants demonstrated a
It has been found that ceramide is one of the key constitu- decrease of acne lesions at the end of this trial accompanied by
ents of the intercellular lipid membrane in the epidermis that decreased sebum production. The treatment was well tolerated
prevents TEWL. The level of ceramides in stratum corneum (39). Another postbiotic with a beneficial effect on facial acne
is decreased in patients with acne (31). In addition, Kaya is a cell-free culture supernatant (CFCS) of E. faecalis SL-5, a
et al. (2019) reported that circulating levels of ceramide chain bacteriocin with inhibitory effects on C. acnes (40).
length are lowered, in contrast, levels of C16 sphingomyelin
and ceramide-1-phosphate levels are increased in patients with
acne when compared to the healthy group (32). These results
Herbal and Fungal Compounds
may indicate the potential positive effect of the auxiliary
ceramide treatment on acne. Herbal compounds have gained increasing attention as active
While silicon-derived substances such as dimethicone are ingredients of medical and consumer products. An overview
hypoallergenic and non-comedogenic and do not have a bad of possible herbal compounds in topical acne therapy is given
odor, lanolin is a moisturizer with a high risk of allergic con- in Table 32.2 (41–54).
tact dermatitis and has an unpleasant odor (7). Herbals can be combined with physical therapy. In a double-
The beneficial use of moisturizers can contribute to main- blind, placebo-controlled trial 64 adult patients with mild to
taining compliance with the treatment (33–34). The occlusive severe facial acne were randomized to treatment and control
properties of moisturizers prevent TEWL and support the group. In the treatment group, aloe vera gel was combined
skin barrier in patients with acne. Moisturizers can also trig- with ultrasound to improve penetration for 10–15 min, fol-
ger acne due to their comedogenic effect, in spite of their pro- lowed by a soft mask applied for 20–30 min. Patients received
tective barrier effect. For this reason, especially water-based treatment three times a week for 7 weeks. The duration of
moisturizers are recommended for acne patients (7). treatment cycle was 8 weeks. Facial papule count was signifi-
Water-based moisturizers can be used before the use of topi- cantly reduced, whereas no change was observed in the con-
cal anti-acne agents to reduce the potential side effects of these trol group. The local blood circulation was also improved by
TABLE 32.2
Possible Herbal Compounds in Topical Acne Therapy
Herbs Active ingredients Study Reference
Smilax china L. root extract quercetin, resveratrol, and oxyresveratrol are In vitro Joo et al. 2022
inhibitory against C. acnes
Bouea macrophylla Griffth seed inhibitory against C. acnes, inhibits lipid In vitro Poomanee et al. 2022
extract peroxidation
Salix alba extract antioxidative activity due to polyphenols, In vitro Di Capri et al. 2019
anti-inflammatory activity of 1,2-decanediol
Aloe barbadensis extract anti-inflammatory activity In vitro/in vivo Chularojanamontri et al. 2014
Other Lilium plant extracts than Aloe anti-inflammatory, antioxidative activity due to In vitro/in vivo Tang et al. 2022
phenolic acid and flavonoid components
Matricaria recutita extract anti-inflammatory activity In vitro/in vivo Chularojanamontri et al. 2014
Calendula officinalis extract anti-inflammatory activity due to β-farnesene, In vitro/in vivo Chularojanamontri et al. 2014
farnesol, chamazulene, α-bisabolol oxides
A&B
Melaleuca alternifolia extract anti-inflammatory activity due to α- & In vitro/in vivo Chularojanamontri et al. 2014
β-pinene, sabinene, myrcene, α-phellandrene,
α-terpinene, limonene, 1,8-cineole, p-cymene,
linalool etc.
Hamamelis virginlana extract anti-inflammatory activity In vitro/in vivo Chularojanamontri et al. 2014
Butyrospermum parkii (Shea butter) anti-inflammatory activity In vitro/in vivo Chularojanamontri et al. 2014
Kaempferia parviflora rhizome extract anti-inflammatory, inhibitory against C. acnes In vitro/in vivo Sitthichai et al. 2022
due to flavonoids
Palmarosa oil anti-inflammatory, inhibitory against C. acnes In vitro Filipe et al. 2022
Cymbopogon citratus extract lipase-inhibitory activity, inhibitory against C. In vitro Kim et al. 2022
acnes
Azadirachta indica extracts anti-inflammatory, antioxidative activity due to In vitro/in vivo Bhowmik et al. 2010
nimbidin, catechin, gallic acid; antibacterial
due to nimbidin, nimbolide, mahmoodin,
margolone, margolonone, isomargolonone
Cannabis sativa extracts anti-inflammatory, antioxidant, and anti-acne In vitro Martinelli et al. 2022
effects involving either CB1/2-dependent and
independent pathways
Sapindus mukorossi Gaertn. saponins antibacterial activity against C. acnes due to In vitro Wei et al. 2021
oleanane-type triterpenoid saponins
Euphorbia supina extracts antibacterial activity against C. acnes and In vitro/animal study Lim et al. 2018
inhibitory activity on lipase
Rosa davurica Pall. leaves extracts antibacterial activity against C. acnes, In vitro Hwang et al. 2020
downregulation of proinflammatory cytokines
Panax ginseng C.A. Meyer antibacterial activity against C. acnes due to In vitro Hou et al. 2019
hydrophobic fraction panaxynol and panaxydol
combined treatment as demonstrated by a smart mirror intel- salicylic acid, and L-carnitine are capable to reduce surface
ligent facial detection system (55). sebum concentration (8). Topical nicotinamide is also one of
Adverse effects of herbal preparations are often mild and the frequently used products with its anti-inflammatory as well
temporary. However, allergic contact dermatitis has occasion- as its sebo-suppressive effect (58).
ally been observed (56). In a double-blind, randomized, vehicle-controlled trial 60
Polycephalomyces phaothaiensis is an insect fungus. Ethylene adult patients with mild to moderate facial acne were treated 8
extracts containing cordytropolone and stipitalide exert antibac- weeks twice daily with an ointment containing licochalcone A,
terial activity against C. acnes. These compounds also inhibit L-carnitine, and 1,2-decanediol or vehicle only. Surface sebum,
pro-inflammatory cytokines produced by C. acnes (57). C. acnes, and inflammatory acne lesions were decreased (59).
Cleansing of skin is not effective alone but could be part
of a triple approach in acne management with topical drugs,
cleansers, and moisturizers (60). The classical cleansers are
Sebum Absorbants and Cleansers soaps.
Sebum absorbants decrease sebum concentration on the skin Soap is a salt of fatty acids that usually have 12 to 18 car-
surface and exert sebo-regulatory effects on sebaceous gland bon chains and have chemical properties of pH between 9.5 to
activity. Nicotinamide, fullerene, epigallocatechin-3-gallate, 10. The primary ingredients of soap, surfactants, are capable
to solubilize and remove stratum corneum lipids. There are

four types of surfactants: non-ionic, anionic, cationic, and Keratolytic Compounds
amphoteric. The non-ionic surfactants (alkyl polyglucosides,
coco glucoside, lauryl glucoside, and decyl glucoside) have the The most used keratolytics in dermocosmetic products for
lowest skin irritation properties while anionic (sodium laureth acne include ferulic, azelaic, salicylic, pyruvic, phytic acids,
sulfate, sodium lauroyl sarcosinate, or sodium cocoyl isethion- and alpha hydroxy acids such as glycolic, lactic, and mandelic
ate) surfactants are the most common used types of surfactants acid. The highly acidic products such as high concentrations of
(61). Given the effects of surfactants on the skin, the main use glycolic acid (20%–50%) inhibit C. acnes in the pH range of
of soap should be used primarily for non-irritated oily skin. below 5.5. In addition, these products mechanically disrupt C.
The normal pH of the skin is slightly acidic (pH 5–5.5) in acnes cell membrane integrity (78).
contrast to the pH of soaps. The application of alkaline prod- The application of glycolic acid at a concentration of less
ucts can increase the pH of the skin. It has been reported that than 10% has a cleansing and humectant effect. In this regard,
skin pH can be increased by 1.5 to 2.0 units for 4–8 hours after moisturizers containing low concentrations of glycolic acid
washing with soaps (62). can be given to patients with acne (79).
The optimum pH for C. acnes growing is between 6.0 to In a randomized trial (n = 22) with adult female patients
6.5. Prakash et al. (2017) investigated and compared the skin a skin care product beta-lipohydroxyacid (LHA) was applied
pH in 200 patients with acne and 200 age-sex-matched healthy twice daily for 2 weeks. The number of microcomedones
individuals. They found the skin pH significantly increased in decreases as shown by ultraviolet-light video recording com-
patients with acne compared to the healthy control group (63). bined with computerized image analysis (80).
Washing soaps that create a mildly alkaline pH environment in Another trial compared a mixture of cosmetic acids (phytic,
the skin can lead to the growth of C. acne in the skin, thereby, pyruvic, lactic, and ferulic acids 40%) in combination with
can trigger acne (64). Also, the high-level pH soaps may strip or without hydrogen application before. The treatment was
the natural oils of the skin and damage the skin proteins. applied four times with 2 weeks interval. Twenty-four adult
Since the potential negative effect of the classical soaps on female acne patients were included. Severity of acne decreased
the skin, syndet soaps have been developed that are close to the in both groups (81).
skin pH due to the weak organic acids added to their structure. Lastly, it is also well known that 30% salicylic acid, a beta-
Syndet soaps have a less irritant effect on oily skin and may hydroxy acid, can be used safely in patients with acne, in
contribute to the acne management by removing sebum and particular in those who have post-inflammatory hyperpigmen-
maintaining skin moisture (61). tation (82).
Cleanser to remove the sebum excess of oily skin, sebollu- Capryloyl salicylic acid is another option for topical acne
tion (exogenous particles from air pollution found in sebum), treatment (83), but rare cases of contact sensitization have been
and probably reduce C. acnes should not increase pH or desta- reported (84).
bilize epidermal barrier. They need to be non-irritating and
should have a low if any allergen content.
Cleansers based on (a) sodium laureth carboxylate and alkyl Cosmetic Camouflages
carboxalates, (b) tris (hydroxymethyl) aminomethane and
L-arginine, or (c) 5-aminolevulinic acid and peptides have The use of make-up creams and/or powders to conceal color
been tested in mild to modertae acne patients from Asia. It is common among patients with acne. The tinted creams and
is well known that Asian skin seems to be more sensitive to concealers should be oil-free, with non-comedogenic proper-
irritants than Caucasian skin. The trials had been conducted in ties. They should be removed at night to prevent long-expo-
Japan, Korea, and Thailand. These cleansers were well toler- sure-related irritation and acne (85).
ated and reduced inflammatory lesions (31, 65–67). Previous reports demonstrated that the use of make-up and
The effect of facial cleanser can be improved with the use camouflage creams can improve life quality and treatment
of a facial cleansing brush. The combination of brush and compliance (86).
cleanser resulted in a significant decrease of both inflam- Monfrecola G et al. have reported the high tolerability and
matory and non-inflammatory acne lesions after 4 weeks of camouflaging effect of face compact cream including Salix
twice-daily application (68, 69). alba, 1,2-decanediol, soy isoflavones, selective photofilters,
Although regular use of some cleansers can reduce C. and vitamins B3, C, and E. In this study, most of the patients
acnes this does not correlate to a reduction of inflammatory stated that their skin improved after the use of the compact
lesions (70). cream (once daily for 28 days) while none of them stated any
Most trials, however, investigated the effect of a combina- side effects during the use of the cream (87). A broad-spec-
tion of cleansers, moisturizers, and topical drugs like ben- trum sunscreen with tinted properties can also be used as cam-
zoyl peroxide (71–73). In a literature review, 14 articles with ouflage in patients who have post-inflammatory pigmentation.
671 participants had been analyzed on cleansers in acne. The
authors concluded, that with the available data, “it is difficult
to formulate reliable recommendations” (74). Sunscreens
On the other hand, the use of cleansers by patients is very
popular, especially among women, while the selection of OTC Dyspigmentation and post-inflammatory lesions are a condi-
products is often by internet search and not medical advice tion that can be encountered in acne vulgaris, in particular acne
(71, 75–77). excoriée. Certain therapies such as topical benzoyl peroxide,
topical and/or systemic tetracyclines, and retinoids for acne 11. Fulton JE Jr, Pay SR, Fulton JE III. Comedogenicity of cur-
can lead to photosensitivity with even lower levels of ultraviolet rent therapeutic products, cosmetics, and ingredients in the
(UV) light (88–89). Sunscreen creams may be recommended rabbit ear. J Am Acad Dermatol. 1984; 10:96–105.
in such cases as they will prevent dyspigmentation and poten- 12. Valentino A, Fimiani M, Baiocchi R, et al. Acne cosmetica
tial UV-related side effects. In addition, the moisturizing con- e test di comedogenicita’ [Cosmetic acne and a test of com-
tent added to sunscreen may also contribute to the skin barrier edogenicity]. Boll Soc Ital Biol Sper. 1984; 60:1845–1848.
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however, water-based or protection of acne-specific ingredient M. Comedogenicity of squalene monohydroperoxide in the
sunscreens should be used in patients with acne (28). skin after topical application. J Toxicol Sci. 2000; 25:77–83.
14. Mills OH Jr, Kligman AM. Comedogenicity of sunscreens:
experimental observations in rabbits. Arch Dermatol. 1982;
118:417–419.
Unmet Needs 15. Mills OH Jr, Kligman AM. A human model for assessing
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Medical drug therapy of acne, either topical or systemic, may
16. Waranuch N, Wisutthathum S, Tuanthai S, et al. Safety
benefit from adjuvant treatment with moisturizer and herbal
assessment on comedogenicity of dermatological products
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production, and selection of ingredients with a better sus- focal microscopy. J Cosmet Dermatol. 2022; 21:3016–3021.
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terrestrial and aquatic ecosystems. subjects. J Cosmo Trichol. 2015; 2:2.
20. Alexis AF, Woolery-Lloyd H, Williams K, et al. Racial/eth-
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33
Ethnic Cosmetics
Enzo Berardesca
difficulty, whereas colored skin belongs to skin type IV, V, or

Introduction VI, rarely burning, tanning easily. Phenotypically ethnic skin
ranges from brown to black-brown. Clearly, differences in
The market for ethnic cosmetics has been growing in recent skin color are the most striking characteristic in ethnic skin.
years due to increased demand from consumers with diverse skin The color of the skin is due to the combination of four cro-
tones and hair types. Ethnic cosmetics are designed specifically mophores: hemoglobin, oxygenated hemoglobin, exogenously
for people of color and cater to their unique needs, which are produced carotenoids, and melanin. Melanin is the most
often different from those of consumers with lighter skin tones. important pigment for the determination of skin color. The
Ethnic cosmetics brands play an essential role in the mar- increased quantity of melanin correlates with the activity of
ket by offering products that are formulated with ingredients tyrosinase and probably with the level of protease-activated
that work well on ethnic skin and hair. These brands also help receptor-2 (PAR-2) that is involved in melanosome transfer
to promote diversity and inclusivity in the beauty industry by from melanocyte to keratinocyte (2–4). No interracial varia-
catering to a diverse range of consumers and featuring models tion concerning the number of melanocytes has been reported.
with diverse skin tones in their marketing campaigns.
Ethnic cosmetics have become more popular due to the rise
of social media and influencers, who have helped to spread
awareness of the importance of using products that are tailored Stratum Corneum Structure,
to one’s skin tone and hair type. As a result, more consum-
Water Content, and pH
ers are seeking out ethnic cosmetics, and many mainstream
beauty brands are also expanding their product lines to include Stratum corneum is equally thick in black and white skin
more options for people of color. (5, 6). However, the number of cell layers and resistance to
Overall, the market for ethnic cosmetics is expected to con- stripping and other physicochemical insults is still debated
tinue to grow as consumers become more aware of the impor- (7–18). TEWL, skin conductance, and skin mechanical prop-
tance of using products that are designed specifically for their erties have been measured under basal conditions in whites,
unique needs. Hispanics, and blacks to assess whether skin color (melanin
Ethnic differences in skin physiology and reaction to envi- content) could induce changes in skin biophysical proper-
ronmental stimuli are more and more described (1), but not- ties (19). Differences appear in skin conductance are more
withstanding the increasing number of studies, data are often marked in biomechanical features such as skin extensibility,
conflicting. In fact, it is difficult to define and interpret the skin elastic modulus, and skin recovery. They differ in dorsal
cutaneous pathophysiologic phenomena that are not only ana- and ventral sites according to race and highlight the influence
tomical and functional characteristics of ethnic groups but of solar irradiation on skin and the role of melanin in main-
also the result of socioeconomic, hygienic, and nutritional fac- taining it unaltered. Wilson et al. (15) demonstrated higher
tors. Furthermore, skin status may be influenced by climate, in vitro TEWL values in black compared to white skin taken
circadian rhythms, and changes in circulating sex hormones from cadavers. They also found differences in black and white
or stress hormones. Indeed, even though it is well established skin physiology: the TEWL of both races increased with skin
that all humans belong to the same species, many physical dif- temperature. In their own study, they concluded that black
ferences exist among human population. This chapter reviews skin would have a greater rise to achieve the same tempera-
the more consistent differences reported between racial groups ture and therefore a higher TEWL. Since TEWL depends
and their implications in determining different responses after on passive water loss that is theoretically directly related to
use of topical products and in treating skin aging. the ambient relative humidity and temperature (20), then the
increased TEWL in black skin could be associated with an
increase in temperature because it is well established that a
difference in black and Caucasian temperature exists. Most
Skin Color
studies using the forearm, back, and inner thigh (13, 16, 21–23)
According to the classification of Fitzpatrick, Caucasians are show a greater TEWL in blacks compared to whites; however,
generally included in phototypes I to III, having fair complex- other studies don’t confirm these findings (11, 12). Skin lipids
ion, red to light brown hair, tendency to sunburn, and tanning may play a role in modulating the relation between stratum
DOI: 10.1201/b22897-33 333

corneum water content and TEWL resulting in higher conduc- an epidemiological survey aimed to assess ethnic variations
tance values in blacks and Hispanics. Ethnic differences in in self-perceived sensitive skin. They included four ethnic
skin conductance are difficult to interpret in terms of stratum groups: Afro-Americans, Euro-Americans, Hispanics, and
corneum water content because other physical factors, such Asians. Fifty-two percent of the women declared to have sen-
as the skin surface or the presence of hair, can modify the sitive facial skin, but the prevalence of self-reported sensitive
quality of the skin-electrode contact. In all races, significant skin was alike in all ethnicities. Among the sensitive skin
differences exist between the volar and dorsal forearms (19). subpopulation, some slight differences between ethnic groups
These results are in apparent contrast with TEWL recordings. have been noted concerning the cause of irritation or sensiti-
Indeed, increased stratum corneum water content correlates zation. Euro-Americans showed higher reactivity to environ-
with a higher TEWL (24). The data may be explained on the mental stimuli such as cold and wind, and less reactivity to
basis of the different intercellular cohesion or lipid composi- cosmetics, whereas Afro-Americans reacted less to environ-
tion. A greater cell cohesion with a normal TEWL could result mental factors and Asians tended to react to wind, spices, and
in increased skin water content. The acidity of the skin mostly alcohol. Kaidbey and Kligman studied race-dependent cuta-
derives from the fatty free acid content of the skin surface and neous reactivity to topical coal (32). There was a strikingly
the buffer capacity of the skin is due to several mechanisms— different response in the two groups: in whites, the response
one of the most important is the lactic-acid-lactate system. was primarily inflammatory, with development of papules and
According to Berardesca et al. (22), pH values in skin surface, papulopustules in about 2 or 3 weeks, whereas in blacks the
measured on the volar forearm, are similar in black and in inflammatory response was largely absent and, after about 14
Caucasian women, but it decreases after tape stripping only days, an eruption of small open comedones appeared. The fol-
in black subjects. Warrier et al. (11), who measured the pH on licles of white subjects responded early, with rupture of the wall
the cheek, reported a significantly lower pH in black women and outpouring of follicular contents in the dermis, whereas in
than in the Caucasian ones. The results of Fotoh et al. (12) are blacks, the first response was proliferative with production and
quite the reverse: a significantly higher cutaneous pH in black retention of horny cells. That is, in blacks, the skin reacts to a
women compared to the other groups. comedogenic compound with hyperkeratoses rather than with
disintegration of follicles, suggesting a greater resistance to
irritants. Conflicting findings have been reported on the inci-
dence of allergic contact dermatitis in blacks. Kenney reported
Cutaneous Appendages a decreased rate (5% in black patients) (33). Marshall and Heyl
Although the amount of sweat is variable between racial reported that the incidence of industrial contact dermatitis in
groups, with more sweat secretion found in black subjects, the South Africa is less in darkly pigmented blacks (34). Dogliotti
phenomenon does not derive from differences in gland number showed a 7.4% prevalence among Bantus (35). Scott noted
but more likely from differences in density of actively sweat- that contact dermatitis was less frequent in Bantus handling
ing glands (25). Concerning apocrine glands, studies highlight detergents, waxes, and fuels (36). Despite a previous report
that, compared to Caucasians and Chinese, blacks present apo- describing an increased sensitization rate in whites, Kligman
crine glands greater in number and size (25). Evaluating the and Epstein found no significant difference in the two races
sebum quantity present on skin surface, measured on the fore- after testing many topical materials (37). Fisher reported an
head using Sebumeter1, Fotoh et al. (12) showed similar results approximately equal incidence of contact dermatitis in blacks
in all groups in contrast to previous studies that reported sig- and whites (38). Paraphenylenediamine, nickel, and potas-
nificantly higher level of sebum secretion in black people in sium dichromate appeared to be the most common allergens.
comparison with white subjects. In Nigeria, nickel was the most frequent sensitizer, with an
incidence of 12.3% (39) compared with 11% in North America.
In Lagos, the female-male ratio is 1:1, whereas Fregert et al.
recorded a ratio of 6:1 (40). In North America, the ratio is 3:1
Skin Disease and Cosmetic Problems and in Stockholm it is 7:3. Clinically, acute contact dermati-
tis with exudation, vesiculation, or bullae is more common in
Irritation and Stinging
whites, whereas blacks more commonly develop disorders of
Dark skin is generally believed to be more resistant to irrita- pigmentation and lichenification. Hypopigmentation has been
tion (26–28). These differences seem to be modulated by stra- described from contact with phenolic detergents (41), alkyl
tum corneum since its removal by stripping induces similar phenols, and monobenzylether of hydroquinone (42).
responses in different ethnic groups. Stinging may occur in
the nasolabial folds and on cheeks after an irritant (i.e. lac-
Acne
tic acid) is applied. Frosch and Kligman reported that the
most “stingers” were light-complexioned persons of Celtic Acne vulgaris is believed to be one of the most frequent der-
ancestry who sunburned easily and tanned poorly (29). Later, matologic disorders in ethnic patients. Although the acne
however, Grove et al. found no skin type propensity to sting- pathophysiology is the same in all ethnicities, the most dra-
ing; they applied 10% lactic acid to the nasolabial folds and matic difference between black and white skin is the higher
cheek of volunteers and noted that increased stinging was incidence of post-inflammatory hyperpigmentation (PIH)
related mainly to the person’s history of sensitivity to soaps, and keloidal scarring as a result of inflammatory reaction.
cosmetics, and drugs (30). Jourdain et al. (31) have performed Hyperpigmentation occurs as darkly pigmented spots or
Ethnic Cosmetics 335
macules that may persist for months or years after the reso- of each compound. Hydroquinone 5% with tretinoin 0.1% and
lution of acne lesions (43). Therefore, because of the elevated dexamethasone 0.1%, known as the Kligman’s formulation,
risk of important acne sequelae that influence quality of life, represents the most famous association. As long-term use of
clinicians may have recourse to more aggressive therapies to this preparation may determine skin atrophy, telangiectasia,
treat acne in ethnic skin and thereby limit its negative conse- erythema, rosacea-like acneiform eruptions, increased growth
quences. The high rate of PIH has been confirmed in a recent of vellus hair, and perioral dermatitis, FDA has approved a
study including black, Hispanic, and Asian patients (44). PIH modified combination of the Kligman’s formulation, con-
can derive from both acne lesions such as inflammatory pap- taining hydroquinone 4%, tretinoin 0.05%, and fluocinolone
ule or pustules or comedones and skin irritation due to topical acetonide 0.01%. This association has proved its efficacy
or systemic therapy. Keloidal scarring is also considered more without significant side effects in a multicentric safety study
frequent in ethnic skin than in white patients, with an incidence (57). Irritation is the most common acute complication, but
that can be between 5 and 16 times higher (45). Furthermore, in hydroquinone may also induce infrequent allergic reactions,
treating acne in ethic skin, dermatologists must always assess PIHs, and transient hypochromia. Chronic adverse events con-
the cosmetic habits and the use of some over-the-counter (OTC) sist of leukomelanoderma en confetti, exogenous ochronosis,
products. In particular, almost half of acne African American and nail discoloration; these are usually related to prolonged
patients regularly apply greasy hair moisturizers. This custom use of formulations containing high concentrations of hydro-
leads to a special form of acne, the so-called “pomade-acne” quinone (56). Beside OTC bleaching products, ethnic people
(46). This eruption, consisting mainly of comedones on the still employ traditional drugs, transferred from generation to
forehead and temporal area, seems to be a peculiar response generation. An interesting recent screening of some of these
of black skin to topical agents because this reaction can be compounds, used by Nepalese people to treat acquired pig-
detected in black children from 1 to 12 years of age (47). Plewig mentation disorders, has been performed by Adhikari et al.
et al. examined 735 blacks and found that 70% of long-term (58). They have found 53 crude drugs—52 were plant extract,
users of pomades had a form of acne (48). The more elaborate and one derived from a shell called Cypraea moneta. All the
formulations induced pomade acne more frequently and more products tested for the tyrosinase inhibitory activity showed
intensively than simpler preparations such as mineral oil and some efficacy. Extracts of roots of Glycyrrhiza glabra, leaves
petroleum jelly. The distribution of the lesions corresponded of Morus alba, flowering bud of Syzygium aromaticum, fresh
to the area of contact. Comparable data for whites are lacking. peel of Citrus aurantifolia, shell of C. moneta, seed of Punica
According to the previously outlined problems, acne treatment granatum, and fresh peel of Citrus aurantium demonstrated
in dark skin requires a delicate balance between aggressive and the higher activity, some with more than 50% inhibition.
nonirritating therapy. Topical retinoids are considered the first
choice therapy as they act either on the acne itself or on PIH
Exogenous Ochronosis
(49, 50). To reduce their irritating side effect, it is advisable to
start with a low concentration or with alternate-day dosing and Exogenous ochronosis is a bluish-black pigmentation of con-
choose a cream rather than a gel formulation. Among retinoids, nective tissue in the area treated with hydroquinone. The
adapalene 1% cream or gel has been reported to be effective pathogenesis is unknown, but it has been supposed that it
and well tolerated even in patients with dry or sensitive skin derives from the accumulation and polymerization of homo-
(51). Once-daily tazarotene 0.1% cream has also shown to gentisic acid (HGA) resulting from the inhibition of its oxidase
improve acne and PIH in blacks (52). Concerning nonretinoid by hydroquinone. In particular, pigmentation may be induced
acne topical, azelaic acid is often prescribed because of its by the binding of HGA to fibrillar collagen. Exogenous ochro-
low potential of irritation and bleaching effect (53, 54). Severe nosis can occur in pigmented skin as a consequence of the use
forms of acne require early employing of systemic isotretinoin of some topical compounds such as pycric acid, phenol, res-
(55). Skin dryness is the most common side effect of the treat- orcinol, and hydroquinone. Usually, when induced by hydro-
ment and may itself result in PIH but can easily be corrected by quinone (which is a phenolic compound similar to HGA), the
regular application of emollients. discoloration appears within few months of application (59). In
the U.S. population, the condition has been described to appear
in pigmented skin (blacks and Hispanics) after use of topical
Post-Inflammatory Hyperpigmentation
hydroquinone at concentrations of 2% or higher for months or
When acne is under control, therapy can be focused on PIH. years and who have failed to observe sun protection. In these
Hydroquinone remains the gold standard for PIH treatment. subjects, hydroquinone was applied continuously as a bleach-
Its effectiveness is related to its concentration and the stability ing agent to treat dark pigmentation or dark skin discoloration
of the preparation (56). The OTC products available, usually such as melasma or post-inflammatory pigmentation (60).
already used by ethnic patients at time of presentation, contain Nevertheless, exogenous ochronosis is not so frequent in the
1% to 2% hydroquinone but are often inefficacious. In clini- United States as in some African populations and countries.
cians’ prescriptions, the concentration varies from 3% to 5%, This appears to be due to the high concentrations of hydro-
compounded in cold cream or hydroalcoholic base. It is nor- quinone available in skin-lightening products prior to 1984
mally applied once daily and results are appreciable after 4 to in South Africa (average 6% to 8%) (61). Other compounds
8 weeks of therapy, and optimal effects are observed after 6 to capable of inducing irreversible depigmentation, such as tert-
10 weeks of therapy. Hydroquinone is usually combined with butyl alcohol and mercury, were included in skin care products
other proximate principles, exploiting the synergistic action in South Africa up to 1986. Resorcinol, used in some African
countries in cosmetic products for acne, has been also related epidermolysis in a few minutes. Concentration and vehicle
to the onset of exogenous ochronosis. Hydroquinone and resor- are both important to modulate peeling intensity as well as
cinol are also used simultaneously to achieve faster depigmen- the amount of acid delivered and the method of application.
tation (61). Furthermore, alcoholic lotions and vehicle used in To reduce side effects, partially buffered glycolic acid is rec-
lightening and acne products can increase the percutaneous ommended (69). Concentration varies from 30% to 70%. It
absortpion of hydroquinone (62). From a clinical point of view has shown to be effective and safe for the treatment of acne
exogenous ochronosis can classified in three stages (63): in ethnic skin (70). Chemical peeling with a 20% to 30% liq-
uid salicylic acid solution improves acne with a good safety
• Stage I involves erythema and mild pigmentation of profile (71).
the face and the neck.
• Stage II is characterized by appearance of papules
PIH
and mottled pigmentation.
• Stage III includes papulo-nodules and inflammation. PIH may benefit from glycolic or salicylic acid peeling.
Trichloro acetic acid (TCA) 25% and Jessner’s solution have
While low concentrations of hydroquinone inhibit tyrosinase, been used successfully. A full face peeling or alternatively a
higher ones can increase melanin synthesis apparently as con- “spot peel” can be performed. Spot peel is recommended using
sequence of tyrosinase stimulation (64). Melanocytes can be TCA 25% and Jessner’s solution. Improvement is perceptible
involved in the process of ochronosis since it does not appear after three to six peeling sessions. Patients should always have
in areas affected by vitiligo. The role of sun exposure is still been pretreated with topical skin-lightening agents prior to
debated as well (65). Indeed, the condition is often limited to peeling, and topical therapy should be continued for about 4
sun-exposed areas. The treatment of exogenous ochronosis is to 8 weeks (68).
difficult. Generally, it tends to resolve slowly after stopping
the drug. Avoidance of exposure to the causative agent may
Melasma
improve the condition; chemical peels, cryotherapy, and reti-
noic acid have been used with poor results. Melasma is a common complaint of patients with skin
of color, especially Asians, fair-complected African
Americans, and Hispanic women. Once possible causative
Sun Protection factors have been screened, sunscreens, topical hydroqui-
none, and chemical peels remain the treatments of choice.
As mentioned previously, different skin colors are due to Among available chemical peels, glycolic acid and salicylic
the adaptation to different intensities of sun irradiation that acid represent a good tool to reduce epidermal pigmentation
changes with latitude. In the late 1970s, Kaidbey et al. (66) in melasma in ethnic skin. Asians and Asian Americans
demonstrated that 5.7% of UVB are transmitted into the der- respond better to glycolic peels (72) than to salicylic ones
mis in blacks as opposed to the 29.4% in whites. In blacks, whereas the opposite occurs in blacks. Pre- and posttreat-
17.5% of UVA reaches the upper dermis whereas in whites ment with topical bleaching agents is advisable as well as
55.5% penetrates. Antoniou et al. (67) have investigated the daily UV protection.
optical transmission properties of different skin types, dem-
onstrating that, as expected, skin of color is naturally better
protected against damage caused by UVA and also against vis- Acne Scarring
ible and red range of the spectra. They conclude that, because
Nonhypertrophic acne scarring may be improved with a series
of the different relation between UVA and UVB protection
of combined peels with 70% glycolic acid gel and 25% TCA.
among skin types, specific sunscreens should be developed.
Seventy percent glycolic gel is first applied followed by 25%
TCA; at the beginning of the frosting, the peel is neutralized
with a sodium bicarbonate solution (68).
Chemical Peeling
As underlined by Roberts (68), chemical peeling was first Pseudofolliculitis Barbae
employed precisely by people of color. Cleopatra’s habit to bathe
in sour milk can be correctly considered an early employment Excellent results are obtained treating pseudofolliculitis bar-
of α-hydroxy acids as an exfoliating agent. In ethnic patients, bae with series of glycolic or salicylic peels (68).
chemical peeling is useful especially for the management of
pigmentary disorders such as PIH, solar lentigines, mottled
Solar Lentigines and Mottled Pigmentation
dyschromia, and melasma. Acne vulgaris, scarring, and pseu-
dofolliculitis barbae represent other significant indications (68). As in fair complexions, solar lentigines and mottled pigmenta-
tion are a manifestation of aging. Spot peel with a 25% TCA,
applied until a white frost is achieved, represents a good thera-
Acne
peutic option for solar lentigines in ethnic skin. Mottling is
Among α-hydroxy acids, glycolic acid is the one most improved by series of 50% to 70% glycolic acid peels or by
frequently used. Its application on the skin induces 20% to 30% salicylic acid peels (68).
and there were no reported adverse effects (82, 83). Fractional

Skin Aging and Rejuvenation phothermolysis is delivered by a nonablative erbium:glass laser
(1500 nm) and consists in microscopic columns of thermal dam-
Skin Aging age (84). It is an FDA-approved device for treating pigmented
Thanks to progress in in vivo imaging modalities such as ultra- lesions, periorbital rhytides, skin resurfacing, and melasma. As
sound (US) and optical coherence tomography (OCT), differ- epidermidis is protected from injury and melanin is not a target
ences between ethnicities concerning skin structure have been of this type of laser, fractional photothermolysis possesses suit-
recently better investigated. With a 25 MHz US imaging sys- able features to be used in skin of color. Indeed, the procedure
tem, it is possible to measure skin thickness and the subepider- has been described as safe and effective for treating photoaging
mal nonechogenic band (SENEB) that depends on skin aging. as well as acne scarring in ethnic patients (85). Together with
On the other side, OCT imaging supplies a description of epi- photoaging, skin laxity is an important sign of advanced age
dermis morphology. Querleux et al. (73) have reported inter- and is common in all skin types. The demand for an effective
esting data. On the basis of OCT measurements, their study treatment for skin laxity is increasing. Patients with skin of color
has demonstrated that epidermis thickness, taken at the top seek nonsurgical procedures because of their proneness of scar-
of the papillae, does not change with age in all ethnic groups, ring. Radiofrequency (RF) is electromagnetic radiation in the
whereas dermo epidermal junction (DEJ) is influenced by the frequency range of 3 kHz to 300 GHz. It works by selectively
aging process and flattens. This phenomenon concerning the delivering heat energy to the dermis, thus inducing collagen
DEJ is accentuated in Caucasians compared to blacks. It is remodeling and contraction. In their study performed on Asian
therefore deducible that blacks show signs of aging later than patients, Kushikata et al. (86) concluded that RF represents an
whites. This data is confirmed by the measurement of SENEB effective and safe tool to achieve skin tightening in skin of color.
by means of US imaging at 25 MHz; SENEB is thinner in
African Americans than in Caucasians. In blacks, photoaging
appears unusually before the sixth decade. Mottled pigmen- REFERENCES
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34
Changes in Female Hair with Aging
New Understanding and Measures
Paradi Mirmirani, R. Scott Youngquist, and Thomas L. Dawson Jr.
that may occur in genetically predisposed women resulting from

Introduction androgens as well as hormonal changes due to menopause and
potentially other metabolic or extrinsic factors (20, 21). Women
Hair is among the most defining aspects of human appearance with FPHL usually first notice a gradual thinning of their hair,
and often a major initial driver of perceptions of youth and beauty. mostly on the top of their heads, and their scalp becomes more
Ubiquitous hair-related changes in women associated with aging visible (11). Over time, the hair on the sides may also become
are often distressing and met with feelings of anxiety or depres- thinner. The patient may notice that her “ponytail” is smaller or
sion, which can progress to a lost sense of identity (1–5). Women that her longer hair looks “skimpy” at the ends. This thinning of
with alopecia not only face the loss of their hair, but also often scalp hair can vary in extent, but it is extremely rare for a woman
feel isolated and embarrassed to seek care and may be frustrated to become bare on top. With more extensive thinning there may
by misinformation, misdiagnosis, or poor treatment options. be a “Christmas tree” pattern of thinning on top of the scalp with
In both men and women there is an increasing incidence hair loss most notable behind the frontal hairline (Figure 34.1b)
of hair loss with advancing age (6–12). Women may uniquely (22). Miniaturized hairs are characteristic (23).
encounter various hormonal and physiologic changes that
can lead to alterations in the appearance, quality, and quan-
tity of the hair fiber and hair follicle or pilo-sebaceous unit. Senescent or Chronogenetic Alopecia
Androgens, menopausal-related hormonal changes, and age-
Senescent alopecia (SA) is defined as hair thinning that does not
related senescent signals are all biological changes that can
become apparent until after approximately 50 years of age and
lead to significant alterations in the female pilo-sebaceous
in a person with no family history of androgenetic alopecia (8,
unit. Although these changes are complex, our ability to mea-
24, 25). Alternate terms include “chronogenetic,” “late onset,” or
sure changes in hair parameters has improved dramatically.
“age-related” hair thinning. Such hair thinning is often identified
With these improved measures and a better understanding of
as a marker of systemic senescence. In support of this concept,
the complex molecular signals governing hair biology, there
it is observed that patients with progeria, who have genetically
is a greater opportunity to develop pharmacologic and/or cos-
programmed premature senescence, show a phenotype of hair
metic treatments that may specifically benefit women.
loss (26). In reality, senescent alopecia likely frequently coexists
with androgenetic alopecia or FPHL. Clinically, the hair thin-
ning in senescent alopecia is described as being diffuse when
Clinical Manifestations seen in its “pure” form but having both a diffuse and patterned
thinning when seen in combination with androgenetic alo-
Female Pattern Hair Loss pecia (25, 27). Clinically and histologically, there is follicular
Female pattern hair loss (FPHL) is considered the equivalent of downsizing or miniaturization and subsequently the hair shaft
male pattern baldness or androgenetic alopecia (Figure 34.1a) becomes narrower (28). Changes in hair density have also been
(13). There is a reported prevalence of approximately 50% in associated with aging in women with and without perceived hair
Caucasians (14) and a much lower prevalence in Asians (15), loss (29). Interestingly, imaging data supports that women who
Native Americans, and African Americans (16). In both men self-report having thin or thinning hair have significantly less
and women, thinning typically begins in the teens, twenties, and hair and a faster rate of hair loss with age (29).
thirties as a result of androgen-mediated follicular miniaturiza-
tion (14, 17), although the linkage to androgens is less clear in
Telogen Effluvium/Chronic Telogen Effluvium
females than males (18). However, there is increased recogni-
tion that there may be non-androgen causes of hair thinning in Normally, the majority of scalp hair is in the anagen or growth
women that have no counterpart in men (19). Thus, the term phase, with a small percentage of hairs in the resting or telo-
female pattern hair loss has been favored to encompass the clini- gen phase, normally being shed at a low daily rate (100–200
cal phenotype of hair loss in the central and temporal scalp region hairs shed daily) (30). Under certain circumstances a higher
340 DOI: 10.1201/b22897-34

Changes in Female Hair with Aging 341
FIGURE 34.1 Female pattern hair loss. (a) Savin patterns of hair loss (13). (b) Clinical perspective showing diffuse hair loss with preserved frontal
hairline. (From Olsen EA, J Am Acad Dermatol 1999; 40(1):106–109, with permission.)
percentage of hairs cycle into the resting phase, and a sud- shedding that can have a fluctuating course lasting at least 6
den onset shedding, or telogen effluvium (TE), may be noted. months and may continue for 6–7 years (32). Although chronic
Postpartum TE is a commonly observed clinical phenomenon TE is usually self-limiting, the volume of hair typically does
that highlights the impact hormonal changes can have on the not return to premorbid volume and may be a comorbid mani-
hair cycle (31). With age, both the number of hairs in anagen festation of FPHL or SA.
and the duration of anagen may be decreased, thus leading to an
alteration and increase in the number of hairs shed daily (29).
Hair Shaft Changes
Chronic TE is another condition that results in diffuse scalp
hair loss and is typically seen in women in their fourth to The hair shaft is made primarily of keratin bundles that are
sixth decades of life (32). It often presents with an abrupt hair compacted together and surrounded with an outer cuticular
layer to form a rope-like structure that is flexible yet strong. to testosterone, triggers specific genes that then lead to the
Sulfur crosslinks within and between the keratin fibrils pro- gradual miniaturization of genetically programmed hair fol-
vide for the longitudinal strength of the hair. The outer cuti- licles (13).
cle resembles overlapping shingles on a roof and forms the The effects of androgens on the follicle have, for the most
“armor” that protects the underlying hair shaft and provides part, been studied in men under the age of 50. Hence, further
“torsional” strength and resistance to bending (33). The qual- work will be required to define the role of androgens in female
ity and caliber of the hair shaft decreases with age and can hair loss. It has been suggested that the various clinical pat-
significantly affect how the hair is perceived (34). Studies terns of androgenetic alopecia in men and women may reflect
suggest that with age there is increased damage to the fragile quantitative differences in levels of androgen receptor and
substructure (endocuticle) of the hair shaft cuticle leading to steroid-converting enzymes in specific scalp regions at differ-
increased fragility of the hair. As many hair care products ent ages (42).
interact negatively with the hair surface cuticle, various hair There is increased recognition that androgen excess can
care practices that include chemicals and heat can also dimin- occur in patients with various conditions such as metabolic
ish the integrity of the hair shaft (35). Damage or loss of the syndrome, polycystic ovary, and obesity and that these changes
outer cuticle or “weathering” can lead to alterations in the can lead to alterations in the hair follicle (43). Androgen excess
optical properties of the hair (loss of luster) (36), decreased may be a result of changes in sex binding hormones or due to
manageability (“flyaway hairs” and hair tangling), or an increase in peripheral conversion.
hair breakage (37). If breakage occurs, it can happen any-
where along the length of the hair, causing a “shaggy” or
Menopause/Estrogens
“skimpy” appearance and visible and tactilely perceptible
blunt (broken) hair tips. Menopause is defined as either the permanent cessation of
Ultraviolet light can lead to oxidative changes of the hair menses or the lack of menses for 12 consecutive months (44),
shaft, resulting in damage to the hair color (photobleaching) with the major hormonal changes during menopause being the
as well as weathering of the hair structure through changes near cessation of ovarian estrogen production. The definition
including lipid oxidation, disulfide bond cleavage, tryptophan and appreciation of perimenopause remains controversial, but
degradation, protein degradation, and cysteic acid formation recent reviews (45) suggest that hormonal changes begin much
(38–40). The result is an increase in fiber porosity, increase in earlier than previously understood, resulting in symptoms
surface roughness, and decreased mechanical strength. With such as night sweats, mid-sleep waking, and other physiologi-
age and greying, the absence of the natural protective pig- cal changes. Perimenopause, or the transition to menopause,
ments in the hair leads to increased ultraviolet damage includ- spans a variable period of time when estrogen levels can be
ing loss of mechanical strength and an increase in surface erratic before they decrease to the low, stable levels of meno-
roughness (34, 38). pause (45). This transitional phase occurs on average 5 years
prior to the onset of actual menopause but can start as early as
10 years prior (46). While it has been recognized that estrogen
Hair Greying
is an important modulator of hair growth, the details of the
Hair greying is one of the most characteristic changes molecular regulatory pathways have not been well character-
of aging. It is often quoted that, as a rule of thumb, 50% ized. Hair changes, including thinning of the hair shaft, tem-
of people are 50% grey by the age of 50 (28). However, porally equate with the earlier onset “perimenopausal” period
recent epidemiologic studies of men and women of vari- (29), which usually falls in the early 40s but may begin as
ous races suggests a far lower number—only 6%–23% of early as 35 years of age. The mean age women undergo com-
people have 50% grey hair at age 50 (34). Compared to plete menopause is 51; thus women spend about one-third of
people of Caucasian descent, those of Asian and African their life in the postmenopausal period (44). However, if one
descent showed less grey hair (34). The age of onset of hair includes perimenopause, where many of the reported negative
greying is thought to be influenced by genetics. Grey hairs symptoms begin to be reported, the period where a woman
have been noted to have different size (shaft diameter) and lives with the symptoms of menopause may be as much as
mechanical properties and are often perceived as dry and half of her life.
less manageable (41). Estrogen is synthesized in the ovary as well as in a num-
ber of peripheral tissues and acts via estrogen receptors that
belong to a superfamily of nuclear receptors. There are two
estrogen receptors, alpha (ER alpha) and beta (ER beta).
Mechanisms The relatively recent discovery of ER beta has broadened
the range of potential estrogenic target tissues and has also
Androgens
redefined prior concepts of estrogen activity and signal-
Pathophysiologically, androgens mediate and drive the fol- ing. In the human hair follicle, immunohistochemical stud-
licular transformation in androgenic alopecia. There is a ies have shown ER beta to be the predominant receptor (47,
substantial increase in the local, or follicular, transforma- 48). Similar to other estrogenic target tissues, the biologic
tion of testosterone to dihydrotestosterone by the enzyme activity of estrogen in the hair follicle likely depends on a
5-alpha reductase (12). Dihydrotestosterone, which has a five complex interplay of signals that may differ depending on the
times higher affinity for the androgen receptor compared relative distribution and location of the two ERs, as well as
the activity of the peripheral converting enzyme, aromatase

(49–51). Several studies have demonstrated the influence of Efficacy Measures of Hair
estrogen on the murine and other mammalian hair cycle, how- Regrowth in Humans
ever it is clear that the distribution, expression, and biologic
activity of estrogen receptors in murine models may be quite Density
different than in humans (51–57). In vitro studies have shown
Overview
that organ culture of human scalp hair follicles exposed to
estradiol results in decreased growth, whereas cells of the A key weakness in hair research remains to reliably and pred-
dermal papilla responded with proliferation (58, 59). Estradiol icatively measure the effect of aging, hormone changes, or
has also been noted to induce aromatase activity in human treatment on hair quantity and quality. Most methods require
scalp follicles, one possible mechanism by which it may sampling from a small (1–5 cm2) site then extrapolating to
exert biologic activity (60). Since hair growth is influenced the entire scalp. This can lead to significant error, as hairs
by numerous hormones, growth factors, transcription factors, are under differential control across the scalp (29, 42). A fur-
and cytokines, many of which are known to be modulated by ther complication is the non-random, highly irregular pattern
estrogens, it is plausible that an intricate orchestration of these of scalp hairs, making repositioning crucially important and
pathways occurs in response to estrogen. Further clarification mandating a permanent relocation mark (tattoo) for consistent
and study of estrogen effects in different tissues, species, and analyses (68). There are methods utilizing global photography,
genders is ongoing (49, 50, 61). but they suffer from variability resulting from styling, color,
and humidity, among others. Here we review common meth-
ods to measure changes in hair density and diameter, focusing
Senescent Signals
on detecting subject perceptible changes in hair amount from
Although androgenetic alopecia and senescent alopecia share any cause.
many clinical and histologic features, the mechanisms by
which follicular downsizing and miniaturization occur have
recently been shown to be distinct (62). Microarray comparison Direct Manual Hair Count
of age-matched subjects with androgenetic alopecia, senescent Early hair growth studies began in the 1980s and used the
alopecia, and normal controls without hair loss has shown that direct hair count method (69–78). Changes were determined
androgenetic alopecia is associated with altered expression of by counting all vellus, intermediate, and terminal hairs in
genes known to be required for hair follicle cycling. In con- a 1-inch diameter (5.1 cm2) midvertex area. This was labor
trast, the transcriptional profile of senescent alopecia reveals intensive and prone to systematic bias by missing small or
changes in the complex phenomenon of alternative splicing, minimally pigmented hairs. The primary benefit was that
oxidative stress response, and apoptosis, which are character- the hairs most noticeable by subjects were ones most reliably
istic of aging tissues (62). This difference in mechanism has quantified.
significant implications in terms of treatment of hair loss at
different ages. Further characterization of these senescent
pathways may lead to attractive therapeutic targets for treat- Macrophotographic Manual Hair Count
ment of senescent alopecia, but may also prove to be useful In the 1990s, manual hair counting was updated by counting
markers of other systemic senescent processes. dot maps representing hairs present in enlarged color macro
photographs (79–93). This involved clipping all hairs in a
Pigmentation 1-inch diameter area (5.1 cm2) to 1 mm at the anterior edge
of the thinning vertex, with a dot tattoo to maximize reloca-
Much like the skin, the pigment of the hair shaft is derived tion. Photographs must be taken with a dedicated, preset cam-
from melanocytes, which transfer melanin via melanosomes. era system to maintain reproducibility. The photographs are
However, unlike the skin, in which there is continual production enlarged to color transparencies and converted to dot maps of
of pigment, the activity of the melanocytes surrounding the hair visible hairs. This revealed more small or nonpigmented hairs,
follicle is intermittent and is tightly linked to follicular cycling. and was a step forward in precision. However, it is reliant on
Hair pigmentation occurs only during the growth, or anagen, labor-intensive human counting and subject to bias from the
phase, which typically lasts 3–5 years. With each hair cycle, individual counter. Also, exact repositioning remained diffi-
various factors may impact the fidelity of hair pigmentation, cult, increasing the signal-to-noise ratio and adding variability.
and these changes become most notable after the first 10 cycles
or so (63). Hairs with absent pigment are seen as white, whereas
those with a dilution, or a mixture of pigment and white hair, Automated or Semi-Automated Phototrichograms
are seen as grey. Interestingly, white hairs may have increased
Overview
thickness and greater hair growth rate than pigmented hairs
(64). Studies have shown that grey hair is associated with a Macro photographs improved hair count methodology but
decrease in follicular melanocyte population and a decrease manual analysis remained cumbersome and labor intensive.
in melanin content (65). A buildup of reactive oxygen species Hence, digital image acquisition and computational analysis
along with a decreased ability to handle oxidative damage has enabled more sensitive, precise, and time-saving methods
also been implicated in the process of greying (63, 66, 67). using fully or semi-automated systems (68, 94–96).
At baseline, imaging sites are tattooed and the hair clipped. site is identified, tattooed, and clipped as above. The clipped
A water drop is used to minimize light scattering due to scalp hair is dyed black to increase the hair–scalp contrast, com-
flakes or texture. This is essential to enable semi or fully auto- plicating the analysis by counting grey hairs the same as pig-
mated counting of hairs via identification of straight edges. mented hairs. For density and diameter determinations, the
Water has a similar refractive index to hair and so minimizes hairs are colored immediately after clipping. For growth rate
the appearance of nonpigmented hairs. This has the disadvan- and anagen:telogen ratio, the hairs are colored 3 days after
tage of underestimating miniaturized, vellus, or grey hairs, clipping.
but the advantage of biasing to the pigmented, terminal hairs Automated algorithms select color components, reject
which are most likely to be subject noticeable. A baseline artifacts (bubbles and reflections), determine the threshold,
image is acquired as a reference, and at each subsequent visit define the hairs, eliminate the tattoo, and analyze the hair
the probe is repositioned to achieve alignment with the par- from each region. This method is routinely used in clinical
tially transparent baseline image (Figure 34.2). Anagen hair studies for assessing growth-promoting substances as well as
counts can be determined by counting hairs that lengthened to study diffuse hair loss in various hair-related disorders (97,
in images taken 24 hours later. Image analysis algorithms can 99–101).
also be employed to measure hair diameter. TrichoScan has been used extensively and has improved the
speed of analysis, enabling the use of more subjects and assist-
ing in stronger, more powerful clinical designs. However, as
TrichoScan®
with any new method, the precision and accuracy remain con-
TrichoScan is an automated digital phototrichogram tool to troversial. van Neste and Trueb compared TrichoScan to man-
analyze macro scalp images (97–99). It is reported to analyze ual counting and found significant differences between the
multiple hair parameters including density (hairs/cm2), diam- “gold standard” of manual counting and the computer-assisted
eter (pixels converted to microns), growth rate (mm/day), and analyses (102). Further work will be necessary to fully under-
anagen:telogen ratio. TrichoScan combines epiluminescence stand the positive and negative aspects of automated analysis.
microscopy (ELM) with automatic image analysis. Briefly, the As technology improves, so will automated methods.
FIGURE 34.2 Macro-photographic image analysis. Optional imaging parameters available in manual or semi-automated systems.
Canfield EpiLume® beyond the scope of this review, but ample information can
be found on the Dia-Stron company website. Briefly, single
Canfield EpiLume is a macro digital image capture system 4-inch hair fibers are mounted in a holder and rotated while
frequently paired with the Canfield Hair Metrix image analy- in the beam of a laser. This is highly precise and provides
sis system or TrichoScan image analysis to measure changes detailed information on single fibers. In addition to aver-
in hair growth properties, including treatment effects (103). age diameter, it provides fiber shape (ellipticity) and can be
The photographic system leverages a fixed focal camera for applied to multiple sites along the fiber. The limitation is the
imaging scalp sites prepared as above and then images are pro- low throughput relative to the diversity of human scalp hair.
cessed using a validated image analysis system (104). It also requires 4 inches of hair, so about 8 months growth,
necessitating extended clinical trials to measure hair changed
Hair Diameter during the study.
The perception of hair mass or volume (hair amount) is a func-

tion of both density and diameter (105), but careful consider- Optical Fiber Diameter Assessment
ation reveals that changes in hair diameter could be as or more OFDA allows measurement of many hundreds to thousands of
influential than changes in hair density. For example, an 80-μm fibers per sample (107–109). Briefly, 2-mm snippets are cut
hair has almost twice the mass or volume of a 60-μm hair of from each sample, washed, equilibrated, and cast onto glass
the same length because it has approximately double the cross- slides. The slides are read by an optical laser which finds the
sectional area. Therefore in two samples with the same number 2-mm axis and measures the perpendicular. As this technique
of hairs, the one with 80-μm shafts has almost twice the hair allows for measurement of many fibers per sample, it is valu-
amount as the one with 60-μm shafts. To put this in context, able for understanding effects of treatment across larger sites
a 10% drop in density will result in a 10% change in amount, and the effect on the diameter distributions. As it measures
while a 10% change in diameter will result in a 20% change in short segments, it can be used to evaluate the effect of treat-
amount—twice the effect of the same change in density. ment of less than 1 month. Recently OFDA was used to mea-
Hair diameter can be obtained from multiple methods, includ- sure differences in hair diameter in pre- and postmenopausal
ing linear density (106) phototrichogram (94, 95), laser fiber women, demonstrating its utility in human clinical studies
analysis (Diastron®), and optical fiber diameter analysis (OFDA) (Figure 34.4) (29). The limitation is that variability is not deter-
(Figure 34.3) (107). As human hair is variable in diameter even mined along the fiber and no information is gleaned about fiber
across a single fiber, methods have been developed that assess shape or ellipticity. The primary advantages are throughput and
either single points along the fiber or averages for the entire fiber. breadth of analysis (29).
Further, the shape, or cross-sectional area, can be highly vari-
able and account for multiple hair “feel” parameters. All of these
factors must be considered when choosing an optimal method. Combination Measures
As hair quantity is determined by the hair’s density (#/cm2) and
Linear Density diameter (μm), hair loss and growth result from changes
in either or both. Therefore an ideal hair-measuring tech-
The linear density diameter is a calculation based on the num- nology would combine these two measures into a single
ber of fibers in a sample, the length of the sampled fibers, and more descriptive and sensitive “hair amount” metric
an average density for human hair (106). This method provides (29, 105).
an accurate average diameter but does not take into account
variations in diameter along fibers or variations in fiber shape.
Cross-Section Trichometer
Phototrichogram A new device has recently been developed, the cross-sectional

trichometer. This measure captures hairs from a predeter-
Current high resolution phototrichograms can be used to mea- mined area and compresses them into a precise caliper. Care
sure diameter (68). This method enumerates the fibers and must be taken for accurate sample selection, as small changes
counts the total hair area, then calculates the average diameter in the number of fibers have a strong influence. Control of the
of each hair. This method is limited to average diameters as site is accomplished with a 2 × 2-cm dye marker. All hairs
the resolution of current camera technology limits the size of a inside the demarked 4-cm2 area are captured, providing highly
pixel in an image to approximately 1–4 μm. This means many reproducible results. Future work could provide a noninvasive,
hairs must be averaged for accurate and meaningful results. fast, and accurate measure of hair “mass” or “volume,” which
This method also measures hair approximately 1 mm from the would be predicted to be highly relevant to the perceived effi-
scalp and so is useful for measuring the effect of treatments, as cacy in hair loss treatment (105).
newly grown hair is all that is contained in that short fragment.
Hair Weight
Dia-Stron
Hair weight and hair number have been demonstrated to be
The most common method is the laser method using the Dia- valid parameters for assessing efficacy of both minoxidil (17,
Stron device. Description of the full utility of this method is 72) and finasteride. Briefly, a representative site is selected
FIGURE 34.3 Optical fiber diameter analysis showing diversity of human hair shapes. (a) Bundle of hair fibers from Caucasian female embedded
and cross-sectioned. (b) Same bundle of hair fibers examined by OFDA. Arrows represent different populations of hair diameters (108). (Source: With
kind permission from Springer Science and Business Media from Mirmirani P., Fangyi L., Youngquist R.S., et al. Hair growth parameters in pre-and
postmenopausal women. In: Tobin D.J., Trueb R.M., eds. Aging Hair. New York: Springer, 2010, pp. 49–60.)
on the thinning frontal/parietal scalp and all hairs clipped to Global Assessment
1 mm. In subsequent visits, the procedure is repeated. All
the hairs from each collection are manually counted, with Global Macro Photos
pointed versus blunt tipped hairs separated, then each sample While precise technical measures of hair growth are impor-
is weighed. In addition to hair weight and hair count, hair tant for evaluation of pharmacologic intervention, it is also
width and length may be assessed by projection microscopy. important to understand whether technically measurable
While extremely precise, this methodology remains highly changes lead to changes perceptible by the subject and/or
labor intensive. investigator (110–112). These evaluations are based on global,
FIGURE 34.4 Optical fiber diameter analysis of pre- and postmenopausal female scalp hair. Scalp hair collected from 1 cm 2 area of frontal or
occipital scalp (108). (Source: With kind permission from Springer Science and Business Media from Mirmirani P., Fangyi L., Youngquist R.S.,
et al. Hair growth parameters in pre and post-menopausal women. In: Tobin D.J., Trueb R.M., eds. Aging Hair. New York: Springer, 2010, pp. 49–60.)
or whole-head, macro photography and rating using percep- as a reference (93). Generally, investigator assessment time to
tual scales by the subjects and investigators. While it is cru- noticeability falls between technical and self-assessment.
cial to measure perceptible changes, it is extremely difficult Changes can also be evaluated by an expert panel. In this
due to numerous and aforementioned complicating factors. method, standardized color photographs were taken with the
The investigator must tightly control humidity, hair style, hair head in a stereotactic positioning device and then visually
color, background and clothing colors, lighting, camera type graded by trained, calibrated experts (111). Paired baseline-
and magnification, among others. It is also vital to observe and to-post-treatment slides are then independently and blindly
control these features in presentations of hair benefit claims reviewed by an expert panel using vertex and frontal views
and data, as manipulation of any of these facets can lead to (68, 93). Expert graders have much higher sensitivity than
inaccurate interpretation. subject assessments and usually are able to identify effects
sooner. However, the perception of the individual under treat-
ment must remain the ideal, and be the focus of development
Subject Self-Perception
of new therapies.
Patient assessment is measured by administration of a vali-
dated questionnaire based on seven parameters: four on effi-
cacy and three on appearance. These parameters include visible
scalp, hair appearance, hair growth, slowing of hair loss, and
Discussion
satisfaction with the hair appearance and the frontline (93). Complex biologic mechanisms regulate hair growth and char-
Patients may also evaluate changes by reviewing randomized acteristics over the course of a woman’s life. With age, there is a
pre- and post-treatment photographs (68). It is common for waning of many of these functions with an associated increase
self-perception to lag far behind technical assessment, likely in self-perceived thinning (29). Our current understanding is
due to the amount of time required for new hairs to grow to that hormonal controls (including androgens and estrogens) as
a length appreciated by the subject and that the affected area well as age-related physiological changes influence scalp hair
may not be easily visible to the subject. For instance, technical including alterations in hair diameter and density. Prior stud-
effects of minoxidil can be measured in 8–12 weeks, but self- ies have shown that hair fiber diameter increases to 40 years of
perception requires 9–12 months. age, reaches a plateau, then decreases with advancing age (29).
Further, hair diameters for Caucasian women are significantly
higher pre- versus postmenopausal for frontal but not occipi-
Expert Assessment
tal scalp. This suggests that menopausal status and estrogen
Investigators assess subjects using a standardized seven-point alteration affect scalp hair diameter. In contrast, hair density
rating scale (–3 to +3) after referring to a baseline photograph in women decreases throughout teen and adult life, with no
abrupt change near the perimenopausal period. This suggests of hair loss progression (Norwood/Hamilton scale scores for
senescent as opposed to hormonal signals lead to follicular men, Ludwig scale scores for women) and accounting for criti-
dropout and decreased hair density. cal variables such as age, ethnicity, medical conditions, and
Using the combined measure of hair density and diameter, medications that can affect hair biology. The selection of the
hair amount, to more accurately quantify the perception of scalp site is also critical for study outcome. For example, in
hair loss shows that hair amount in Caucasian women peaks at women the effect of FPHL is more pronounced on the frontal
35 years of age. The values are similar at ages 25 and 45, only than on the occipital scalp so studies with measurements from
6% and 5% less than the maximum. However, at age 50 hair the frontal region will likely be more sensitive (109).
amount is 11% less. As the amount of hair changes little from Since the aforementioned objective measurements do not
age 25 to 45, normal loss is less likely to be noticed until after necessarily translate immediately into patient-perceived ben-
the diameter begins to decline in the mid 40s, consistent with efits, subjective perception measures by both patients and
the increased self-perception of hair loss in midlife women. investigators are necessary in treatment evaluation, especially
In addition to density and diameter, other factors affect in pivotal long-term trials, to insure that clinically meaningful
the self-perceived appearance and amount of a woman’s hair benefits have been produced. A self-perceived benefit is the
with advancing age. While several of these reported changes key to successful hair regrowth products.
are subjective, a variety of quantifiable factors contribute. This chapter has focused on describing the fundamental
Nonbiologically regulated factors include length, style, color changes associated with hair loss in normal women with age
(from dying and bleaching), curvature (chemical waving), and and the methods used to objectively quantify those changes.
damage (through breakage and volume) (11, 113). Biologically We have addressed methods for tracking hair density and diam-
regulated facets include density and diameter, color (due to eter, as they are the variables most likely to be noticed by sub-
pigmentation), and curvature. Hair density is a function of fac- jects seeking treatment. Historically, treatment regimens have
tors including anagen:telogen ratio and growth rate. The rela- focused on scalp hair number density as this was perceived to
tive importance of each of these factors on the perception of be the parameter most influencing hair loss. However, recent
hair loss is not fully understood. research is indicating that characteristics beyond density play a
While the methods described in this review are all appropri- crucial role in subjects’ satisfaction with their hair. For exam-
ate for assessing changes in hair growth in humans, no single ple, hair diameter has been found to play a critical and highly
method addresses all questions relating to hair growth proper- influential role in both the perception of hair loss and in the
ties or the efficacy and mode of action of hair loss treatments. efficacy of treatment (6, 10, 105, 109). In another study, grey
Therefore one must always consider the primary objective and hair was found to be a more significant contributor to apparent
utilize an appropriate array of techniques to address the ques- age than hair thinning, and therefore addressing greying may
tion posed. be an important intervention for improving patient satisfaction
The continual rapid advancements in optics and computers (5). Given the importance of these hair characteristics, in the
will continue to improve the study of basic hair biology and next few years new methods must be developed to measure
treatments, increasing both sensitivity and speed. Hair count these endpoints. A final consideration for addressing patient
techniques have progressed from manual counts to macropho- hair concerns is the strong linkage between scalp health and
tography. Recent developments using automated methods have hair quality, and it is likely that measures of scalp health will
increased the capability and sensitivity to monitor hair loss begin to be used to link skin and hair biology (114).
and treatment responses, including measures of density, diam-
eter, growth rate, and anagen:telogen ratio (99). Software and
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49. Ohnemus U., Uenalan M., Inzunza J., et al. The hair fol- 66. Wood J.M., Decker H., Hartmann H., et al. Senile hair
licle as an estrogen target and source. Endocr Rev 2006; graying: H2O2-mediated oxidative stress affects human
27(6):677–706. hair color by blunting methionine sulfoxide repair. FASEB
50. Conrad F., Paus R. Estrogens and the hair follicle. J Dtsch J 2009; 23(7):2065–2075.
Dermatol Ges 2004; 2(6):412–423. 67. Shi Y., Luo L.F., Liu X.M., et al. Premature graying as a
51. Ohnemus U., Uenalan M., Conrad F., et al. Hair cycle con- consequence of compromised antioxidant activity in hair
trol by estrogens: Catagen induction via estrogen receptor bulb melanocytes and their precursors. PLOS ONE 2014;
(ER)-alpha is checked by ER beta signaling. Endocrinology 9(4):e93589.
2005; 146(3):1214–1225. 68. Berger R.S., Fu J.L., Smiles K.A., et al. The effects of min-
52. Stenn K.S., Paus R., Filippi M. Failure of topical estrogen oxidil, 1% pyrithione zinc and a combination of both on
receptor agonists and antagonists to alter murine hair fol- hair density: A randomized controlled trial. Br J Dermatol
licle cycling. J Invest Dermatol 1998; 110(1):95. 2003; 149(2):354–362.
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agonists and antagonists on the mouse hair follicle cycle. J dil solution in male-pattern baldness: Preliminary European
Invest Dermatol 1998; 111(1):175. results. Dermatologica 1987; 175(Suppl 2):42–49.
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gen accelerates hair regrowth in mice after chemother- minoxidil gel and solution formulations in the treatment of
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lates the telogen-anagen hair follicle transition and influ- oxidil. J Invest Dermatol 1990; 95(6):683–687.
ences epidermal cell proliferation. Proc Natl Acad Sci USA 72. Price V.H., Menefee E., Strauss P.C. Changes in hair weight
1996; 93(22):12525–12530. and hair count in men with androgenetic alopecia, after
56. Chanda S., Robinette C.L., Couse J.F., et al. 17beta-estra- application of 5% and 2% topical minoxidil, placebo, or no
diol and ICI-182780 regulate the hair follicle cycle in mice treatment. J Am Acad Dermatol 1999; 41(5 Pt 1):717–721.
through an estrogen receptor-alpha pathway. Am J Physiol 73. Rietschel R.L., Duncan S.H. Safety and efficacy of topical
Endocr Metab 2000; 278(2):E202–E210. minoxidil in the management of androgenetic alopecia. J
57. Moverare S., Lindberg M.K., Faergemann J., et al. Estrogen Am Acad Dermatol 1987; 16(3 Pt 2):677–685.
receptor alpha, but not estrogen receptor beta, is involved 74. Savin R.C. Use of topical minoxidil in the treatment of
in the regulation of the hair follicle cycling as well as the male pattern baldness. J Am Acad Dermatol 1987; 16(3 Pt
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2002; 119(5):1053–10538. 75. Shupack J.L., Kassimir J.J., Thirumoorthy T., et al. Dose-
58. Kondo S., Hozumi Y., Aso K. Organ culture of human scalp response study of topical minoxidil in male pattern alope-
hair follicles: Effect of testosterone and oestrogen on hair cia. J Am Acad Dermatol 1987; 16(3 Pt 2):673–676.
growth. Arch Dermatol Res 1990; 282(7):442–445. 76. Vanderveen E.E., Ellis C.N., Kang S., et al. Topical min-
59. Conrad F., Ohnemus U., Bodo E., et al. Substantial sex- oxidil for hair regrowth. J Am Acad Dermatol 1984;
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61. Thornton M.J. Oestrogen functions in skin and skin append- trial of topical minoxidil and placebo in early male pattern
ages. Expert Opin Ther Targets 2005; 9(3):617–629. baldness. Australas J Dermatol 1990; 31(1):17–25.
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Comparison of gene expression shows two distinct profiles. terone and dihydrotestosterone concentrations in patients
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64. Van Neste D. Thickness, medullation and growth rate of treatment of men with frontal male pattern hair loss. J Am
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47(3):377–385. the efficacy and safety of topical minoxidil and topical alfa-
85. Price V.H., Roberts J.L., Hordinsky M., et al. Lack of effi- tradiol in the treatment of androgenetic alopecia in women.
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genetic alopecia. J Am Acad Dermatol 2000; 43(5 Pt 101. Lopez V., Martin J.M., Sanchez R., et al. Usefulness
1):768–776. of TrichoScan professional in the evaluation of hair loss
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loss. J Am Acad Dermatol 1999; 41(4):555–563. analysis with computer-assisted methods. J Eur Acad
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improves male pattern hair loss in a randomized study in ment of male and female pattern hair loss: A multicenter,
identical twins. Eur J Dermatol 2002; 12(1):32–37. randomized, sham device-controlled, double-blind study.
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97. Gassmueller J., Hoffmann R., Webster A. Topical fulves- 111. Canfield D. Photographic documentation of hair growth in
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158(1):109–115. 113. Draelos Z.D. Shampoos, conditioners, and camouflage
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35
Menopause
Skin and Cosmetology
Rashmi Sarkar, Preethi B. Nayak, and Vivek M. Pai
Elastin
Introduction
Elastin fibres are closely interwoven with collagen fibrils, lead-
Skin is significantly affected by the ageing process, as well ing to recoil after stretching and prevention of overstretching.
as menopause. The changes which occur on the skin during Degenerative changes in dermal elastic fibres occur during
menopause are due to the effects on skin’s individual com- premature menopause in young women.3
ponents.1 Menopause is defined as either permanent cessa-
tion of menses or lack of menses for 12 consecutive months. Elasticity
The major changes that occur during menopause is cessa-
tion of estrogen production by ovaries, and major source of There is progressive increase in extensibility and reduction in
estrogen from conversion of adrenal androgen to estrogen skin elasticity in ageing of skin over the face.3
by the action of aromatase enzyme in peripheral tissues.2
Water
A good amount of water content is required for a healthy skin,
Physiological Changes during Menopause which is dependent on epidermal hydration and cutaneous evap-
Effects of Estrogen on the Structural oration. Dermal glycosaminoglycans decreases with age, these
Component of Skin glycosaminoglycans are associated with high water-binding
capacity and are essential to maintain normal skin hydration.3
Estrogen receptors are seen on skin’s cellular components.1
With changes in structure and functions, the skin becomes
Thickness of Skin
thinner. The quality of skin decreases its efficacy with ageing
due to the synergistic action of time, photo-ageing, hormonal The thinning effect is due to decrease in collagen, water and
deficiency, decline in metabolic activity and environmental glycosaminoglycans, which is seen in the post-menopausal
factors.3 years.3
It is difficult to distinguish between changes which are spe-
cific to ageing and those due to estrogen deprivation, however
Blood Flow
estrogen might lead to accelerated ageing of skin.3
The structural integrity and functioning of capillary blood
vessels are very important for healthy skin. The rich capil-
Collagen
lary network in the dermal papillae is responsible for flush
Atrophy of collagen fibers is a major factor of ageing skin. seen following menopause. Peripheral microcirculation also
Thickened, basophilic clumped collagenous material sugges- decreases significantly at menopause, especially at the nail
tive of partial degradation of collagen, along with significant fold capillaries.3
decrease in quantity of dermal collagen. The ageing of col-
lagen mainly occurs due to decrease in number of immature
Sebaceous Glands and Hair
reducible cross links between collagen molecules and increase
in non-reducible collagen. There is reduction in enzymes There is a decrease in sebum secretion with ageing. Also,
which helps in post-translational collagen processing, reduc- there is increase in facial hair and decrease in pubic/body hair.
tion in fibroblasts which synthesize collagen and vessel supply Estrogen is also important regulator of hair follicle growth and
of skin. Attribute to increase in laxity and wrinkling. There cycles. It is known that androgens have a role in the pathophysi-
is strong co-relation between loss of collagen and estrogen ology of female pattern hair loss (FPHL), but hair miniaturiza-
deficiency, as much as 30% of collagen loss occurs in the first tion in women can also be caused by non-androgen signals as
5 years of menopause.3 well. The hormonal changes of menopause lead to decreased
352 DOI: 10.1201/b22897-35

Menopause 353
growth rate, hair diameter and percentage anagen. Hair density Age-Related Pathological Conditions
is affected by chronological age. The compounded effect of Necessitating Cosmetic Surgery
these changes may lead to a heightened perception of decreased
scalp coverage in middle-aged women. It has been shown that Sun-damaged skin in the elderly may lead to actinic kerato-
the estrogen-receptor pathway regulates the telogen-anagen fol- sis and basal cell carcinomas requiring cosmetic procedures.
licle transition under the influence of estrogens. The length of Pressure sores and contracture formation following debilitation
the hair follicle’s life cycle is increased, owing to the prolonga- is another pathological condition needing aesthetic procedures.9
tion of the anagen phase of the hair growth cycle. Conversely,
with plummeting estrogen levels postpartum, significant loss of Changes in Ageing Faces
hair occurs. Decrease in estrogen levels is known to induce hair
fall, hence hormone replacement therapy/topical estrogens are There is a complex interaction between genetic and environ-
proposed to be used in hair fall.4–6 mental factors leading to ageing changes. Among the extrinsic
factors, sunlight plays a major role. Intrinsic factors of facial
ageing are difficult to control. Although the changes of ageing
Wound Healing differ in different individuals, it follows a consistent pattern. In
As ageing occurs, the skin becomes more fragile and suscep- addition to laxity of skin and ligaments and soft-tissue descent,
tible to trauma, and there is decrease in transforming growth further deflation of the skin envelope seems to occur because
factor (TGF)-β. The estrogen induces TGF-β secretion by of atrophy of the soft tissues of the face.
dermal fibroblasts, and enhance the quality and rate of wound Demas and Braun (2001) outline the signs of the ageing face:
healing.3
• A lined forehead
• Loss of cheek roundedness and deep nasolabial folds
secondary to loss of subcutaneous fat
Menopausal Symptoms
• Drooping of the nasal tissues
The symptoms a women experiences during menopause are • Drooping brows, with a hooded appearance to the
called climacteric syndrome. Climacteric syndrome can be lateral upper lid
classified as physical or psychological in nature. Vasomotor
• Loss of chin definition from submental fat deposition
symptoms, palpitations, headaches, urogenital symptoms,
bone and joint pain, tiredness, disturbed sleep, breast tender- • Sagging neck lines due to loss of platysma muscle tone
ness and skin ageing are the physical symptoms. Depression, • Wrinkling of the skin around the mouth, with thin-
loss of memory, poor concentration, irritability, loss of confi- ning of the lips10
dence and tiredness are the psychological symptoms. Alopecia
and hirsutism seen during menopause are physical symptoms Facial ageing is also associated with bony changes. Tooth loss
that cause significant psychological impact.7 is the major causative factor for bone atrophy seen in the upper
and lower jaws. The loss of alveolar process of bone leads to a
reduction in lower vertical facial height, overclosure of the bite
Dermatological Problems Occurring and pseudo-prognathism.11
More Commonly during Menopause
• Vulvovaginal problems—Atrophic vulvovaginitis, Classification of Management of Ageing Skin
Vaginitis of uncertain aetiology, Lichen sclerosus,
Dysaesthetic vulvodynia. 1. Head and neck
• General dermatological problems—Hirsutism, • Facial peels
Recession of the frontal and frontoparietal hair- • Facial resurfacing
line, Postmenopausal frontal fibrosing alopecia, • Aesthetic cryotherapy
Menopausal flushing, Oral discomfort, Drying of the
• Laser hair removal
skin and Keratoderma climactericum.8
• Blepharoplasty
• Rhinoplasty
Anatomical Changes in Ageing:
• Otoplasty
The Basis of Aesthetic Surgery
• Brow lift
• Face and neck: The facial ligaments attenuation • Facelift techniques
leading to inferior displacement of soft tissue leading • Facial implants
to illusion of deepening, dermal elastin loss, changes
• Facial fat transfer
in underlying fat and connective tissue. Platysma
muscle hypertrophy and weakening of retaining liga- • Facial fillers
ments in the neck • Facial liposculpture
• Body: Body fat redistribution and loss of dermal • Hair restoration
elastin.9 • Radiofrequency—ablative/nonablative
2. Breast Facial Hair Removal

• Breast augmentation
Facial hair removal is a common procedure in younger age
• Mastoplasty group, but elderly women often seek laser hair removal for
• Mastopexy unwanted hair over the face, postmenopause/post-hysterectomy
• Mammoplasty and bilateral oophorectomy. The general paradigm is to treat
patients with light hair or thin hair, and Fitzpatrick skin
3. Abdomen types I–II with radiofrequency technology, 694 nm ruby
lasers or 755 nm alexandrite lasers. Patients with brown and
• Liposuction
medium thickness hair, who are Fitzpatrick types II–IV are
• Abdominoplasty best treated with the 755 nm alexandrite or broad wavelength
spectrum 515–1,200 nm IPL devices. The black hair, coarse
4. Extremities and buttocks texture hair patients with Fitzpatrick Skin Phenotypes IV–VI
• Thigh lift are optimally treated with 800 nm diode or the 1,064 nm
• Buttock lift Nd:YAG laser. The unwanted non-pigmented grey hair is
• Sclerotherapy for leg veins usually targeted using radiofrequency device with epilation
probe.13,14
• Buttock enhancement
• Liposuction of lower extremities and buttocks
Facelift
5. Miscellaneous Facelift surgery remains the cornerstone of facial rejuvena-
• Labioplasty tion and is most durable and a powerful method for cor-
rection of facial ageing. Numerous nonsurgical techniques
have been introduced but have not been able to replace sur-
Facial Peels gical facelift. Surgical techniques differ in the length and
It is a procedure where a chemical agent or a combination of placement of the incision, the extent of undermining and
agents of defined strength are used to cause controlled destruc- dissection and the handling of the superficial musculoapo-
tion of skin layers, leading to surface and texture changes. neurotic system. High intensity focused ultrasound (HIFU)
The important factor in determining peel depth depends on and nonablative radiofrequency are two methods which are
the peeling agent, its concentration, whether rubbed when commonly used nonsurgical facial sculpting methods in
applying, degree of frosting and number of coats applied. ageing skin. Suture facelift/thread lift using barbed sutures
There is an effect on penetration in elderly due to the pres- are nonsurgical method with same efficiency as surgical
ence of actinic damage, photodamage and presence of super- methods.12–14
ficial lesions such as dermatosis papulosa nigra, lentigo and
seborrheic keratoses. The indications of peels in elderly are
Facial Fat Transfers
mainly for photoageing, fine wrinkling, rough textured skin,
skin freshening and rejuvenation, dyschromias and actinic and Fat is an excellent material for adding volume to the face and
seborrheic keratosis.11,12 to provide support but lacks evidence of long-term results and
may require multiple surgical procedures. It is minimally
invasive and has become standard procedure nowadays. The
Facial Resurfacing
transfer of fat to the face will have excellent fat survival due
Resurfacing is broad term and various modalities like; laser to the rich vascularity of face. With proper technique around
resurfacing—ablative, nonablative, fractional lasers, derma- 30–70% of the fat is retained. The cosmetic indications are
roller, dermabrasion and microdermabrasion, ablative and furrows (rhytids, wrinkles), refill of lost supportive tissue and
nonablative radiofrequency and deep chemical peels can be for enhancement of ageing skin.10,12
used. Deep chemical peels (phenol and trichloroacetic acid)
and machine dermabrasion has now been replaced with
Facial Fillers
lasers. The nonablative methods are preferred over ablative,
due to its shorter recovery time and minimal complications. Facial ageing occurs as a result of fat atrophy and bony
But, now with the fractional lasers, ablative is more effec- resorption. The volume loss is usually asynchronous and
tive than nonablative. The concept of resurfacing now works occurs in superficial and deep fat compartments of the face
on the principle of leaving a percentage of skin untreated, leading to contour irregularities. The tear trough hollows
causing rapid re-epithelization and regrowth, leading to appear under the eyes, nasolabial fold deepens, midface flat-
recovery. Resurfacing laser plays a major role in decreas- tens and oral commissures make the mouth have a down-
ing the excessive roughness of facial skin and also helps in turned appearance. Fillers in the skin, subcutaneous tissue
skin tightening. Photoageing, rhytids, moderate elastosis, and supra-periosteal plane reverses the effect of volume loss
acne scars, xanthelasma, epidermal nevi and prevention of on ageing. Facial fillers are divided into temporary, semi-
skin cancer are the other indications of facial resurfacing in permanent and permanent. The choice of filler depends on
elderly.11,12,13 the site and indication.10–12
Menopause 355
Hair Restoration incisions: peri-areolar, umbilical, axillary and inframammary.

Lipo-aspirated fat has also been used for the purpose of breast
Hair transplantation is usually a most sought after procedure by augmentation and reconstruction.14,15
younger age group, but the geriatric age population usually suf-
fer from higher grades of androgenetic alopecia and can be ben-
efited by hair transplantation. Male pattern hair loss and female Liposuction
pattern hair loss both can be treated permanently by follicular It is the most frequently performed plastic surgery operation. In
unit extraction/strip method. In the geriatric age group, pattern women it is usually requested for buttocks, lateral and medial
hair loss will be superimposed by senile alopecia, leading to thigh and in men it is for abdominal or hip area. Previously dry
exhaustion of the donor area. In such situation, artificial hair/ suction under general anesthesia was done, but due to cardiovas-
body hair or other hair camouflage methods can be used.11 cular complications the tumescent technique was later invented.
The liposuction can be done manually or by using a pump. The
Radiofrequency patient is mobile by the first day of operation. Liposuction using
tumescent anesthesia is usually preferred in elderly.11
Radiofrequency (RF) can be used in both ablative and nonab-
lative modes. The benign and malignant lesions which occur
as secondary changes to sun exposure or environmental Sclerotherapy of Leg Veins
changes are treated with ablative radiofrequency. Nonablative Sclerotherapy is the targeted elimination of varicose veins,
radiofrequency creates thermal effects in the dermis with- small vessels and vascular malformations by injection of scle-
out external wounding leading to tissue tightening. Rhytids, rosant into the lumen of the vessel, in order to damage the
wrinkles and other signs of photo-ageing and biological wall of the vessel and transform into fibrous cord. Reticular
ageing can be treated non-invasively using radiofrequency. veins and varicose veins occur due to venous insufficiency,
Radiofrequency energy can be mainly divided into monopo- usually seen in old age. The most commonly used sclerosants
lar and bipolar. Monopolar RF is FDA approved noninvasive are sodium tetradecyl sulfate (STS) and polidocanol (POL).
treatment for periorbital wrinkles (2002) and full face (2004). The sclerosant is diluted to the required concentration with
It shows dual action on collagen with heat disruption of hydro- saline or distilled water. Telangiectasia (<1 mm) treated with
gen bonds, altering the triple helix collagen molecule, lead- STS 0.1–0.2%, venule (1–2 mm) with STS 0.2–0.4%, reticular
ing to collagen contraction and collagen regeneration causing vein (2–4 mm) with STS 0.2–0.4 % and large varicose vein
gradual contraction. Bipolar RF are usually combined with (>4 mm) with 0.4–0.75% of STS. It is carefully injected into
other light-based technologies; FACES (Functional Aspiration the lumen of the vessel with a 30-gauge needle. The quantity
Controlled Electrothermal Stimulation) a combination of bipo- of the injection varies from 0.1–0.5 mL for small veins; for
lar RF and vacuum, electro-optical synergy – bipolar RF and larger vein a larger quantity may be required. Sclerotherapy
optical energies, Polaris WR system – bipolar RF with 900 nm should be given with caution in elderly after adequate exami-
diode. Fractional RF (fractionated delivery of RF energy, with nation and evaluation of co-morbidities.10,12
controlled zones of collagen coagulation in reticular dermis)
and tripolar RF (the three or more electrodes deliver focused
RF current, which simultaneously heats superficial and deep
Psychology of Geriatric Patients Who
layers of the skin) are two other technologies which can be Present for Aesthetic Procedures
used. Nonablative RF technologies help in contouring (face The patients presenting for cosmetic surgery in geriatric age
or any part of body) and lifting of ptotic skin and underlying group tend to be higher functioning and in better health than
structures and providing a good tightening effect.10,12 those who present for removal of a pathological condition. Usually
patients seeking cosmetic procedure will be self-motivated and
would be self-referred but with higher expectations. Internally
Breast Augmentation
motivated patients are more committed to physical changes and
Breast augmentation depends on anatomy of the patient’s hence are better patients. Whereas externally motivated patients
chest, position, cleavage, inframammary fold, skin elasticity, are not only hoping for physical changes of their body, but also
degree of ptosis of breast and breast tissue coverage. There will have a motive to please others and are often dissatisfied
are two categories of breast augmentation: breast enlarge- with the outcome. Postoperative physical attractiveness and
ment through breast stuffing or through filling and shaping the intraoperative reduced pain are both of paramount importance
breast with optimal control of distribution of fill. The second to elderly patients. Expenses of the procedure must be made
method provides long term cosmetic results and minimizes clear in the beginning itself, and patients should also be told
the tissue compromise avoiding re-operation rates. Breast about these procedures not being covered by health insurance.
implants are commonly done to augment and increase the size Pre-operative consultation is a must, with focus on patients’ psy-
of existing breasts. The type of implants can be varied and is chological desires and wellness, as well as whether the patient
selected depending on the amount of breast tissue present and is medically fit for surgery. They should also be assessed for
the pocket of placement, whether sub-glandular or sub-mus- psychiatric diseases or prior dissatisfied cosmetic procedures.
cular position. The different types of implants are smooth tex- If the patients psychological state is difficult to assess or if
tured, microtextured, anatomical, high profile, medium profile patient is unprepared for surgery then a referral to psychiatrist
and saline. The implants can be placed with the following for clearance may be appropriate. Finally, the treating doctor
should spend adequate time with the patient and their prefer- 5. Brincat MP, Muscat Baron Y, Galea R. Estrogens and the
ences should be discussed in detail, and they should be allowed skin. Climacteric. 2005;8(2):110–23.
to choose from other options as well.11,16 6. Bolognia JL, Braverman IM, Rousseau ME, Sarrel PM. Skin
changes in menopause. Maturitas. 1989;11(4):295–304.
7. Blume-Peytavi U, Atkin S, Gieler U, Grimalt R. Skin acad-
emy: Hair, skin, hormones and menopause–current status/
Conclusion knowledge on the management of hair disorders in meno-
pausal women. Eur J Dermatol. 2012 May 1;22(3):310–18.
Youth is a gift of nature, but age is a work of art. With the
8. Wines N, Willsteed E. Menopause and the skin. Aust J
growing desire to look good, age is just a number. Due to civi-
Dermatol. 2001;42(3):149–60.
lization, there is higher level of well-being among individuals.
9. Allen DB. Aesthetic and reconstructive surgery in the aging
Nowadays, there is increase in elderly patients seeking cosmetic
patient. Arch Surg. 2003;138(10):1099–105.
procedures. All patients who will be benefited should be consid- 10. Honigman R, Castle DJ. Aging and cosmetic enhancement.
ered for the aesthetic procedure, but the final decision whether Clin Interv Aging. 2006;1(2):115–19.
to go ahead with the procedure should be made very meticu- 11. Zins JE, Moreira-Gonzalez A. Cosmetic procedures for the
lously. A well planned, well executed procedure will give grati- aging face. Clinics Geriatr Med. 2006;22(3):709–28.
fying results to the patients as well as the treating doctor. 12. Roh DS, Panayi AC, Bhasin S, et al. Implications of aging
in plastic surgery. Plastic Reconstruct Surg Global Open.
2019;7(1).
REFERENCES 13. Brooks AT. Aesthetic anti‐ageing surgery and technol-
1. Raine-Fenning NJ, Brincat MP, Muscat-Baron Y. Skin aging ogy: Women’s friend or foe? Sociol Health Illn. 2010;32(2):
and menopause. Am J Clin Dermatol. 2003;4(6):371–8. 238–57.
2. Lephart ED, Naftolin F. Menopause and the skin: Old 14. Rzepecki AK, Murase JE, Juran R, et al. Estrogen-deficient
favorites and new innovations in cosmeceuticals for estro- skin: The role of topical therapy. Int J Womens Dermatol.
gen-deficient skin. Dermatol Ther. 2020:1–7. 2019;5(2):85–90.
3. Calleja-Agius J, Brincat M. The effect of menopause on 15. Hall G, Phillips TJ. Estrogen and skin: The effects of estro-
the skin and other connective tissues. Gynecol Endocrinol. gen, menopause, and hormone replacement therapy on the
2012;2(4):273–7. skin. J Am Acad Dermatol. 2005;53(4):555–68.
4. Mirmirani P. Hormonal changes in menopause: Do 16. LePillouer‐Prost A, Kerob D, et al. Skin and menopause:
they contribute to a ‘midlife hair crisis’ in women? Br J women’s point of view. J Eur Acad Dermatol Venereol.
Dermatol. 2011;165:7–11. 2020;34(6):e267–9.
36
Microneedles and Cosmetic Uses
Klaus Fritz, Carmen Salavastru, and George Sorin Tiplica
Microneedling is an established and effective method with

low to no side effects and a wide spectrum of indications. Techniques and Indications
The technique intends to achieve minimally invasive per-
forations of the epidermis and/or dermis according to the Rollers and Stamps
needle length and number of passes. By creating thousands There are numerous sterile, single use rollers and stamps avail-
of microscopic channels in the tissue, new collagen produc- able; however, they sometimes have differing quality. Needles
tion is activated as in wound healing; clinically, the skin should be made of solid, stainless surgical steel with a diam-
surface and hypotrophic scars are smoothened. It is easy eter of 150–200 μm, CE marked as a Class IIa medical device,
to perform. arranged on a cylinder or stamp (Figure 36.1).
The needle length is available from 0.3 mm up to 3 or 4 mm.
Those with a needle length up to 0.3 (max 0.5 mm) can be
Scientific Rationale and Terminology used as a home use device; longer needles are for profession-
als, preferably physicians. For the best effects needles should
The objective of skin needling is to induce pinprick micro- be at least 1.5 mm long to penetrate into the dermis or scar tis-
injuries with pinpoint bleeding of the skin. Petechiae on the sue. Beware of poor needle quality in cheap products.
surface indicate the intensity of needling. The microinju- Hollow needles, as used for injections, should never be used.
ries are postulated to induce the wound healing cascade and Electric stamping devices are available, which allow a
release a number of different growth factors which induce cell smooth operation, precise penetration depth adjustment
proliferation. Collagen and elastin are formed as well as new between 0.25 and 2.5 mm, and up to 150 pricks per sec-
capillaries (angiogenesis). Following the pioneering reports (1) ond without scratching or tearing. Quality devices are reg-
on the activation of a wound healing process after subcision, istered medical products at the national authorities, such
Fernandes et al (2–4) described the effectiveness of collagen as the CE mark in the European Union, included on the
induction with microneedles (MNs) and its indications, advan- Australian Register of Therapeutic Goods, ISO13485 certi-
tages and shortcomings. fied, and meet all standards for medical-grade equipment
When needles penetrate the skin, they release thrombocytes in manufacturing, materials, sterile packaging, and more
and erythrocytes, which results in a release of growth factors. (Figure 36.2).
When prick channels close, chemotaxis and electrotaxis are
postulated to initiate an invasion of erythrocytes and leuco-
cytes into the tissue followed by a proliferation of fibroblasts
and a synthesis of elastin, glycosaminoglycan, proteoglycan
and collagen III. In the final remodeling phase, collagen III is
converted into collagen I, resulting in an increased firmness
of the tissue bolstering up the dermis. This collagen formation
helps to smoothen aging skin, scars or stretch marks. Several
treatments are needed, depending on age, depth of scars or
severity of aging.
Advantages are very short or no downtime, very little and
only mild side effects, and very low risks of post inflamma-
tory hyperpigmentation, so it can be used in all skin types
and on all body parts. The disadvantages include bleeding
during and shortly after the treatment, as well as swelling
and redness of the skin (which usually lasts no longer than
1 day).
Due to this mechanism of action, the positive effect after
microneedling is collagen induction which is long lasting, FIGURE 36.1 Dermaroller on parietal area. (Courtesy of Dermaroller
although treated skin is subject to the normal aging process. GmbH/Mitoo Pharma, Wolfenbüttel, Germany.)
DOI: 10.1201/b22897-36 357

• Apply numbing cream, if possible under occlusion.

When treating with longer needles of 1.5 mm and
above, pain management is important!
• Have the relevant medical devices ready: the roller,
stamp or e-stamp with disposable tips (which are
not expired and are CE marked); then an air cooling
device for additional pain reduction.
• In case of drug delivery, prepare sterile active ingre-
dient for application.
• After 15–30 min of numbing remove numbing cream,
disinfect again and start treatment.
• Select areas where to start and to continue.
• With rollers/drums roll in a star-shaped form (four
times per direction) to achieve uniform puncturing
under mild pressure. Reduce pressure over bony
areas; lift roller at the end of the track to avoid
scratching the skin. Stretch skin between your fin-
gers to allow even treatment. Start on frontal area,
roll evenly in slightly varied direction with 10–16
passes for 360° coverage, stretch the skin, and lift
roller when starting a new direction. This results in
160–240 pricks/cm2 (Figure 36.3).
• For stretch marks on abdominal tissue don’t push the
FIGURE 36.2 e-Stamp. roller or stamp into the relatively soft abdominal tis-
sue; it is better to tighten the tissue to be treated. The
more it is stretched, the better and easier the needles
Electric pens allow the clinician to adjust their operating speeds will penetrate. Squeeze the tissue right and left of a
and penetration depths, permitting treatment of large surface stretch mark scar so it runs vertically between your
areas. The disposable needle tips permit treatment of small focal fingers.
lesions such as traumatic scars or upper lip rhytides, which would • With stamps move across the skin in tiny circles,
be hard to treat with a roller drum. Optimal clinical outcomes select a suitable velocity of the stamp.
are achieved when needle depths are adjusted to the specific skin
• Pinpoint bleeding identifies the endpoint of treatment.
location and thickness (5). Stretching the skin helps to achieve
almost full needle penetration (calculate 0.3 mm less than the full • Wipe off excessive blood; have a break if pain or
length of the needle). Without stretching, needles with a length of bleeding becomes annoying.
3 mm penetrate no more than 1.5 to 2 mm (6). • In case of pain or bleeding apply gentle manual pres-
sure first and then ice-water-soaked gauze.
• You may inject droplets of anesthetics with diluted
adrenalin or increase cooling but avoid freezing the
The Use of Microneedling Rollers skin.
or Stamps Step by Step • Continue treatment area by area; calculate about 30
min for a full face.
First Appointment
• After treatment allow the skin to relax; erythema will
• Define the treatable condition such as type of scar first increase, then decrease, mostly after 20–30 min.
(hypotrophic/burn/acne), wrinkle depth, skin laxity, • Clean skin, apply some disinfection and perhaps
striae. some post-treatment such as hyaluronic acid (HA) or
• Exclude contraindications (see further). mild corticosteroid if skin is significantly irritated.
• Instruct patient on effects, duration, and expectation, • Supply patients with disinfection or steroid cream for
as well as potential side effects and what to avoid; home use directly in your office (the pharmacy might
have the informed-consent form signed. be closed or the product unavailable).
• Make a second appointment with long enough time • Recommend sunblocker and recommend use of
for the procedure envisaged. make-up only after 2 days.
• Have the patient come back the next day or call you
in the office or give an appointment for teledermatol-
Second Appointment
ogy consultation to make sure that they are well.
• Start treatment with cleaning the skin area and • Continue a series of treatments every 2 (or, better, 4)
disinfection. to 8 weeks.
Microneedles and Cosmetic Uses 359
FIGURE 36.3 (a) Directions of application: start on frontal area; roll evenly, varying the direction slightly for 10–16 passes in 360°; stretch the
skin and lift the roller when starting a new direction; take 20–30 minutes in total; (b) clinical image. (Courtesy of Dermaroller Gmbh/Mitoo Pharma,
Wolfenbüttel, Germany.)
Exclusion criteria should be • Abnormal skin growths

• Systemic diseases e.g., hematologic diseases with • Dark skin types
bleeding tendency or diabetes mellitus and atopic • Radiation treatment or chemotherapy within the last
dermatitis affecting wound healing year
• Anticoagulants or antiplatelet agents • Inflammatory conditions such as eczema, rosacea or
• Pregnancy or lactation sunburn
• Active bacterial, viral (herpes cold sores) or fungal • Recent treatments such as chemical peels, facial
infection and previous history of frequent herpes waxing or laser
simplex viral infection
• Previous history of hypersensitivity to anesthetic creams
• A history of hypertrophic or keloidal scarring Indications
• The use of isotretinoin within 6 months
The main cosmetic and medical indications for microneedling
In cases of combination with electrical (radiofrequency, RF) include scars (burn, hypotrophic and acne), stretch marks,
devices add as an exclusion criterion: wrinkles, sun damage and lax skin, but the technology is also
reported to improve pigmentation disorders and hair loss.
• Any implantable electronic device (e.g., pacemaker)
Be cautious in cases with Scars

• Photosensitivity
Microneedling is one of the most effective treatments for scars.
• Open wounds In a study before and 6–8 weeks after treatment histological
• Cigarette smokers findings showed a significant increase in the amount of elastic
• Any esthetic procedures on the face within 6 months fibers (7). In a study (8) comparing the effect of four micronee-
before the appointment dlings 1.5 mm to 4 TCA peelings, both groups showed an
improvement, of 68% microneedling to 73% TCA (the differ- times 1 month apart with 1.5 mm microneedling. Six months
ence between both groups was statistically not significant). after the last treatment, the average scar severity had declined
on a 0–6 scarring scale from 4.24 to 2.33. A reduction over
50% was observed in more than two-thirds of the patients,
Grading of Atrophic Scars showing that this method is efficient and safe also in darker
Atrophic scars are graded as follows (9): skin types. After seven treatments every 3 weeks 12 subjects
showed significant improvements according to ECCA (clinical
Grade 1 Macular erythematous, hypo- or hyperpigmented evaluation scale for acne scarring) from 123.3 to 74.16. The
scars histopathological evaluation presented a distinct increase in
Grade 2 Mild atrophy, not obvious at social distances of collagen production and deposition (14).
> 50 cm, or easily covered by facial makeup or beard hair A patient evaluation with rolling and boxcar acne scars
reported excellent (in 20%) and good (in 70%) clinical results
Grade 3 Moderate atrophy, obvious at social distances of
with no side effects. Icepick acne scars could not be improved
> 50 cm, not easily covered by facial makeup or beard
much. The histopathological evaluation presented a significant
hair but able to be flattened by manual stretching
increase of collagen and elastic fibres; both fibre types dem-
Grade 4 Severe atrophy, not flattened by manual stretch- onstrated an improved directionality. The epidermis showed a
ing of the skin thickening of +112% (15).
Thirty Asian patients with atrophic acne scars were treated
Correlating the response rate with the grade of scarring pres- five times (4 weeks apart). The results demonstrated a statisti-
ent, an excellent response rate was achieved in the majority of cally significant improvement of the scar depth after five treat-
patients with grade 2 and 3 scarring. For deeper scars of grade ments. The self-assessment of the patients resulted in “good
4, more aggressive treatment might be needed, such as a two success” in 22 patients (73%) and an “excellent result” in 4
layer treatment starting with 1.5 mm and then a second pass patients (13%) (16), albeit with postinflammatory hyperpig-
with 3 mm needles, or more passes achieving more pricks, or mentation in five patients (Figures 36.5 and 36.6).
more frequent sessions. According to studies all patients toler-
ated the microneedling procedure well and, apart from a tem-
porary erythema and post-inflammatory hyperpigmentation in Burn Scars
only very few patients, no adverse effects occur. Various trials have shown that scars after 1st and 2nd degree
Aust et al. (10) analyzed retrospectively 480 patients with burnings can be significantly improved not just by smoothen-
various indications. Histology after 6 months showed a signifi- ing the texture, but especially due to relaxation of the con-
cant increase of the amount of collagen and elastin and a normal tracture, resulting in improved functionality. Twelve months
collagen pattern, not the parallel pattern typical for scar tissue. after treatment, patients rated the improvement as on average
The epidermis thickened by 40%. Satisfaction was evaluated 80% better than before the treatment. Pigmentation problems,
from 0 to 10 before and 12 months after treatment. For wrinkles, which are often seen with ablative methods, were not observed
satisfaction increased significantly (p ≤ 0.05) from 4.5 to 8.5 (17, 18). After five sessions at 4-week intervals, the lesion
and scars from 3.0 to 7.5. The same result happened with the showed a relaxation of the contracture and an improvement
Vancouver Scar Scale (VSS) and the Patient and Observer Scar in texture and colour with no side effects. Fifty-one patients
Assessment Scale (POSAS). None of the patients reported scar- showed clinical improvement and scar depth rejection by 0.8
ring, hyper-, hypopigmentation or photosensitivity. already 1 to 2 weeks after treatment (19).
Post-Acne Facial Scars Stretch Marks

Facial scarring has always been a challenge to treat. The ideal Microneedling showed similar improvement for this indication
treatment option depends upon the type of scarring. The best as well. Patient satisfaction in a group of 71 patients increased
indications are the rolling and boxcar type of scars; the least significantly from 3.0 to 7.5 (20). Significant improvements in
are icepick scars. Fabbrocini et al. (11) reported on 32 patients stretch mark patients were received also in several other stud-
with acne scars who had received 2 treatments with a 1.5 mm ies (18, 21, 22).
needle length. The treatment was well tolerated by all patients,
with no adverse effects. The same group also reported (12)
Wrinkles, Lax Skin
on 60 patients of skin types 1–6 who were treated 3 times
every 4–12 weeks. In a selected group of patients, scar depth Wrinkles and lax skin are frequent cosmetic indications.
was measured before and 3 month after the third treatment Upper lip wrinkle treatment two times 8 weeks apart with
using Visioscan. The aesthetic improvement of all patients 1.5 mm needles decreased the wrinkles by a factor of 2.3 on
was assessed using the Global Aesthetic Improvement Scale the Wrinkle Severity Rating Scale (WSRS) (23). Two ses-
(GAIS). In most patients, the treatment reduced scar severity sions of microneedling on lax skin of the aging neck achieved
and improved the overall appearance of the skin. Aesthetic significant improvement of the skin condition in 90% of the
improvements were significant. Side effects like hyper- or patients (24).
hypopigmentation were not observed. Pretreatment priming of the skin with antioxidants may also
Another study (13) treated 31 Thai patients with medium to serve to increase gene and protein expression responsible for
dark skin types III–V and medium to severe acne scars 1–4 skin regeneration (25).
FIGURE 36.6 Acne scars after three sessions using Dermaroller 1.5 mm.
MN improved hair parameters when paired with 5% minoxidil,

growth factor solutions, and/or platelet-rich plasma (PRP) topi-
cals, or when introduced to subjects whose hair count changes
had plateaued for ≥ 6 months on other treatments. . . . However,
FIGURE 36.4 Pinpoint bleeding during treatment indicates endpoint.
data are of relatively low quality (27).
Combinations
1. Microneedling with subcision
2. Microneedles for drug delivery
a. Needling + injection
b. Microneedling with hyaluronic acid
c. Microneedling with chemical peels
d. Microneedling with ALA for photodynamic
therapy
3. Needling delivering radiofrequency
1. Microneedling with Subcision

FIGURE 36.5 Acne scars, before treatment.
Gadkari and Nayak (28) showed improvement after subcision in
combination with microneedling in acne scars 6 months after the
Pigmentary Disorders, Melasma, Vitiligo
end of treatment. Garg and Baveja (29) examined the combina-
Ziaeifar et al. summarized in a survey that the combination tion of an alternating treatment with subscision, microneedling
of any type of non-aggressive needing technique with other and 15% TCA peeling for the treatment of atrophic acne scars to
effective therapies (especially topical agents and mesother- a total of six sessions each: 63% patients with grades of severity
apy) yields more promising therapeutic results than single 4 had an improvement to severity 2 and 37% to severity 3. Of
therapy for melasma, dark cycles, and vitiligo as the prototype patients with grade 3 scars, 23% had no scars after treatment,
of pigmentary disorders. However, single needling therapy is 10% improved to severity grade 1 and 67% to severity grade 2.
significantly effective, too (26).
Hair Loss Disorders

2. Microneedles for Drug Delivery
A large review on hair loss found in a total of 22 clinical
studies that microneedling as an adjunctive therapy improved As a drug delivery system, MNs disrupt the stratum corneum,
hair parameters across genders and a range of hair loss types, forming channels when used as a pretreatment before the
severities, needling devices, needling depths of 0.50–2.50 mm, application of active ingredients. (Fractional ablative lasers
and session frequencies from once weekly to monthly. Across 17 similarly have been proposed to effectively deliver drugs
investigations totaling 911 androgenic alopecia (AGA) subjects, across the stratum corneum.) The MNs are a new technology
to enhance transdermal delivery of high-molecular-weight

drugs and have been shown experimentally to increase the
skin permeability by orders of magnitude in vitro for a range
of drugs that differ in molecular size and weight. Needle
diameters should not be too big, in order to produce a hole
which is as small as possible to exclude bacteria and other
foreign particles, and skin thickness and MN length are cor-
related with skin permeability. Transdermal vaccination using
biodegradable MNs is a rapidly progressing field of research
and applications (30).
a. Needling + Injection
There are drums of MNs in the market (e.g., the “Roller jet”)
which are used to evenly inject active ingredients such as HA
into the superficial skin layers. The device includes a roller
mounted on an axle, a container that can hold up to 1.5 mL,
and 15 needles positioned in the roller. The container is acti-
FIGURE 36.7 Penetration of MN effect and HA without damage to
vated when the roller is in sliding motion on the skin and con- stratum corneum or epidermis.
tent is pushed from the container through the needles in a
controllable way, so that each needle injects the same amount
of material into the same depth in the skin. Exactly the same d. Microneedling with PRP
amount is injected by each needle and up to 500 injections
can be done in just 3 minutes. For different applications The same rationale would apply to MN delivered PRP.
various designs are available with different needle length Microneedling platelet-rich plasma is said to increase the immune
(1.5–3.5 mm) and thickness (25–33 G). The effect of such response because of the high concentration of the patient’s own
devices is based rather on an even distribution of microdrop- growth factors. Platelet-derived growth factor (PDGF) initiates
lets in defined tissue depth than on the wound healing activa- all wound healing. PRP contains several growth factors, includ-
tion following the needle irritation, as in the other real MN ing PDGF, transforming growth factor-beta 1 (TGF-beta 1) at
treatments. high levels, and vascular endothelial growth factor (VEGF).
b. Microneedling with Hyaluronic Acid e. Microneedling with ALA for

Photodynamic Therapy
Among the drugs used to treat stretch marks, scars and reju-
venation, HA is very popular and effective. It can be traced 5-aminolevulinic acid (ALA) for topical photodynamic ther-
histologically even deeper in the dermis than the needle pen- apy (PDT) shows a limited penetration into the skin, mak-
etrates, which means that some diffusion happens in the tissue, ing it difficult to treat deep skin neoplasias, such as nodular
in addition to the delivery into the skin (7). An immediately basal cell carcinoma. Microneedles (MNs) help to increase the
visible effect, due to the water binding effect of HA, increases amount and depth of drug penetration (32). MNs have been
the patient’s acceptance of microneedling. It helps to wait sev- developed with lengths up to 900 μm to avoid penetrating into
eral weeks for the newly induced collagen. The combination of vascular and nerve regions without stimulating pain receptors
both provides a faster and longer lasting result than each one as (33). The MNs can also be produced with a drug coating on
a monotherapy (Figure 36.7). their surface, to facilitate delivery, or hollow, to promote the
delivery through channels (34).
The use of MNs rollers for enhancing penetration of topical
c. Microneedling with Chemical Peels ALA has been described with a higher formation of PpIX in
Sharad (31) compared a microneedling treatment to a combi- deeper skin regions when MNs are used, compared with topi-
nation with 35% glycolic acid peeling for treatment of acne cal application in animal models (35, 36). The PpIX fluores-
scars in dark skin, which showed postinflammatory hyperpig- cence intensity showed 5-times higher at 0.5 mm on average
mentation. The combination was more efficient in improving compared with cream in the in vivo tumor mice model (37).
hyperpigmentation than microneedling only. Microneedling is Solid MNs have been commonly used for skin pretreatment
regarded as a simple, low-cost method, also safe for Indian before conventional PDT, promoting a good PDT response for
skin types (III–V). actinic keratosis (38).
A combination with four sessions of MN + 20% TCA-Peel
compared to phenol peel showed significant improvements
by both (75% vs. 69%) but no significant differences; since a
Safety Considerations
TCA-peel is less aggressive than a phenol peel, this shows that
microneedling increases the penetration of active ingredients Normal reactions of the skin include moderate pain, transient
into the skin and their effectivity (8). or prolonged edema (11, 12), or erythema of 1–12 hours (13,
39). Rarely skin infections happen (14). In skin type > 3 pig-
mentation disorders (dys-, hypo- or hyperpigmentation) can
appear but are rare, especially compared to ablative skin treat-
ments like lasers, deep peelings or dermabrasion (11, 12).
Pain can be significantly reduced by topical numbing creams
and air cooling. Pain during the procedure can occur despite
a topical anesthetic cream, depending on needle length and
individual sensitivity; post-operative pain is low (8).
Micropores close after 10–15 minutes (40), so the risk of
skin infection is considered very low. In studies measuring
transepidermal water loss (TEWL) (41) the authors concluded
that micropores close after about 2 hrs in vitro; in vivo this
probably occurs more rapidly.
Compared to the use of injection needles significantly fewer
microorganisms (Candida albicans, Pseudomonas aerugi-
nosa, Staphylococcus epidermidis) penetrated through the FIGURE 36.8 Treatment tip for microneedling radiofrequency. (Courtesy
of Viol.)
MN lesions than through the puncturing channels of a conven-
tional 21-gauge needle.
The use of devices with longer needles, greater pressure
exercised during the treatment, and the use of hollow needles
or reuse of sterilized needles, which are no longer as sharp as
initially, definitely increase the risk of side effects.
Melanocytes do not show any alteration or change in num-
ber after microneedling (7).
Using topical active ingredients and/or special vitamin
preparations before and during MN treatment may cause side
effects (42) such as allergic reactions, irritation (vitamin C is
acidic), prolonged erythema or pustules.
Patients developed granulomas after topical vitamin C
serum during microneedling.
Be sure not to apply cosmetic products before MN therapy
because MNs increase the penetration of all ingredients into FIGURE 36.9 Mechanism of action for microneedling radiofrequency,
showing coagulation zones below the epidermis. (Courtesy of Lutronic
the skin, and some might even start to have systemic effects. Medical Systems Germany GmbH, Hamburg, Germany.)
Only drugs permitted for intradermal injection are safe with
MN treatment!
The RF types to be distinguished are unipolar, monopolar and
bipolar RF. Unipolar RF flows uncontrolled into tissue gaps,
whereas the monopolar RF flow goes from a positive electrode
3. Microneedling Delivering to the grounding electrode, which makes it more targeted and
effective. Bipolar RF is limited in penetration depth (penetra-
Radiofrequency (43, 44)
tion depth = approximately half the distance between elec-
Microneedling initiates tissue reaction mechanically. If RF trodes) and less effective, but also shows fewer side effects (43,
is emitted in addition, the tissue reaction can be increased 44). An elegant way of conducting heat into deep tissues is not
(Figures 36.8 and 36.9). to let the RF act from the outside via the epidermis, but to let
The basis of RF therapy (300 MHz–3 KHz) is to generates it act through the MNs to penetrate the epidermis into the der-
electromagnetic energy between two electrical poles by cur- mal tissue at variably determinable depths of 0.5–4 mm (45).
rent, which causes oscillation in the water molecules of the Various devices use disposable single-use treatment tips
target tissue and (depending on the tissue resistance) results in consisting of an array of 25–49 coated or uncoated MNs that
tissue heating. In terms of physics, the principle of treatment is allow to set a penetration depth of 0.3–0.5–1-2–3-4 mm into
based on Ohm’s law. This heat development is independent of the skin, delivering RF energy to create controlled coagula-
chromophores, unlike with laser beams. tion zones through the dermis. Software allows a constant
The aim of the application of RF is to vaporize and to coag- energy delivery independent of individual tissue impedance
ulate tissue and to promote a thermally induced collagen for- with enhanced volumetric heating mode. Insulated MNs are
mation, which allows skin tightening via the dermis. RF can coated, so thermal energy is generated only from the tip of the
even penetrate to the deeper fat tissue and there lead to apopto- needle. Insulated MNs have a relatively small thermal effect,
sis and thus fat cell degradation and circumference reduction. which causes bleeding issues, and requires increased power or
The effect of RF treatment depends on the parameters used multiple passes to increase the therapeutic effect.
such as energy density, exposure time, polarity of the radio- Uncoated needles deliver RF all along the needle, which
frequency, surface cooling and the method of application (45). results in full hemostasis. Epidermal damage depends on the
pulse duration. Because of the different conductivity of the skin Acne Vulgaris
tissue, a teardrop-shaped thermal effect minimizes the dermal
damage of the epidermis and maximizes the thermal effect of In studies with mild acne, 47% reduction of lesions has been
the dermis. This occurs up to an RF conduction time of 300ms, achieved by bipolar RF and optical energies, in particular a
showing that with an appropriate pulse duration, uninsulated reduction of sebaceous gland size and perifollicular lympho-
MNs can be both effective and safe in skin treatment (46). cyte infiltrations.
The variety of penetration depths and MNs allows multilayer
treatments according to the indication. Deep dermal fractional Teleangiectasia and Vessels—Rosacea and Melasma
heating occurs without epidermal wounds. Neocollagenesis Two different types of RF waveforms are available: one (con-
replaces collagen but needs time; the degree of neocollagen- tinuous wave; CW) non-selectively denatures or coagulates the
esis depends on the energy levels. The punctiform pinpoint skin tissue with a single long pulse to treat skin laxity, wrin-
coagulation resulting from MN RF, limited to 10–20% of the kles, pores or scarring. The other (pulsed wave; PW) selec-
total area, results in less injury, much faster healing, and far tively stimulates tissues with high conductivity by irradiating
less serious side effects compared to fractional ablative lasers. RF in the form of multiple short pulses, so it can be applied to
The predominant amount of energy is initially released at the treat lesions like rosacea or melasma.
point of contact and decreases with distance from the elec- In the case of rosacea, the conductivity with blood is high,
trode. It leads to punctiform superficial ablation, including so treatment with PW is effective improving facial redness.
coagulation, and in the wider environment to a biostimulating In melasma PW stimulates and improves factors that affect
effect, resulting on the long term formation of new collagen. melanocyte activity, such as disrupted basement membrane,
Risks—especially pigmentation in darker skin types—are increased vascularity, senescent fibroblasts and others. For
thereby minimized (43, 44). such indications and this specific pulsed RF waveform, it is
According to studies from Hantash et al. (47, 48) HSP important that needle depth is adjustable from 0.3–4.0 mm.
72 expression rapidly diminished after day 2 while HSP47 A needle depth of 0.3 mm targets the papillary dermis just
expression increased progressively through 10 weeks. below the basement membrane of the skin.
Reticular dermal volume, cellularity, HA and elastin content
increased. RT-PCR studies revealed an immediate increase
Fractionated Microneedle
in IL-1b, TNF-a and MMP-13 while MMP-1, HSP72, HSP47
Radiofrequency and Drug Delivery
and TGF-b levels increased by 2 days. There was a marked
induction of tropoelastin and fibrillin, as well as procolla- Treatment with fractional RF plus stem cell conditioned medium
gens 1 and 3 by 28 days post-treatment, proving a significant in three sessions at 4-week intervals showed clinical improvement
wound healing response and an active dermal remodel- on physician’s global assessment and patient satisfaction scores
ing process with new collagen by 10 weeks posttreatment, on both the RF-only side and the combination with stem cells.
demonstrating for a profound neoelastogenesis following RF Stem cell conditioned medium provided a synergistic effect on
treatment of human skin. improvement of skin roughness, which was statistically signifi-
cant (p = 0.05). Histologic examination revealed marked increase
Indications in dermal thickness and dermal collagen content (52).
Three sessions of intradermal RF at intervals of 4 weeks (1134-
Parameters depend on the indication and target layer in the kHz frequency, 12-W power, 26-G electrode size) combined
skin. For smoothing of the epidermis as in striae, superficial with autologous PRP for striae distensae showed 5.3% excellent,
ablation using bipolar fractional radiofrequency is sufficient. 36.8% marked, and 31.6% moderate improvement in Asians (53).
In order to achieve a deeper tightening effect, deeper needle
penetration (length) is needed and/or monopolar (especially
Acne Scars and Striae
unipolar) RF.
Significant improvement could be demonstrated in all skin
Skin Rejuvenation types and different types of acne scars and striae. Acne scars
belong to the most frequent and best responding indications
For medium deep targets bipolar RF can be combined with (47, 48, 53–55) (Figures 36.10 and 36.11).
broadband light, vacuum or diode lasers to reach deeper struc-
tures, showing improvement in sagging of the skin (eyelids, Combinations
cheeks, chin and upper neck) with an increase in epidermis
thickness and a 28% improvement in collagen fibers (49, 50). Microneedling plus RF can be combined with other technolo-
gies or medication.
Skin Tightening of the Lower Face, Hypertrophic scars were treated with triamcinolone using
fractional ablative RF combined with an acoustic pressure
Jawline and Neck Region
ultrasound module to enhance delivery of the triamcinolone.
Subjects were treated with a fractional insulated RF MN sys- Complete resolution was seen after one session in patients with
tem in one to three sessions at intervals of 4 to 12 weeks. The scars on the nose and mandibular area and on the neck and on
physician, the blinded investigator and the subjects rated the the knee after four sessions (15,56).
clinical outcome as highly improved. Sufficient pain manage- Striae distensae improved better when treated with using
ment should be provided (51). retinoic acid 0.05% (55).
Slight oedema, irritations, punctiform bleeding as well as

Practical and Safety Aspects slight itching are symptoms to be expected.
Before MN RF treatment the same procedures apply as for a MN
treatment. Consider as additional preoperative pretreatment: For Post-Treatment
• Use cold and moist compresses or air cooling
• Commence herpes prophylaxis 1–2 days in advance
and continue over 7 days • Clean and disinfect facial skin
• Oral antibiotics casn be indicated in patients at risk • The extent of postoperative wound care depends on
the total area removed, the number of ablation points
• Use topical anaesthesia over 60 minutes before
and the energy intensity used
• Limit size of the area to be treated because of absorp-
• After 1 or 2 days there is usually hardly anything left
tion risks
to be seen
• Air cooling (for the room) helps to reduce pain and
• Finally, sunlight should be strictly avoided in order to
oedema
avoid postoperative hypopigmentation
• Additional anxiety-relieving drugs can be helpful
• In cases of doubt concerning a patient’s skin reac-
tion, skin type or tendency to scars carry out a trial
treatment on small area first Complications
• Perform the first treatment in lower parameters for The first symptom that may indicate an onset of complications
energy strength, number of passes and layers, paris the marked increase in pain, which can result from bacterial
ticularly in the eyelids and neck, and especially for infections, especially with staphylococci and Klebsiellae, as
patients who had previous surgical lifting well as fungal and viral infections, as after laser ablation. If
in doubt, prescribe a broad-spectrum antibiotic with an anti-
mycotic agent and take tests for microbiology and resistance
to medication.
In dark skin patients the risk to induce pigmentation disor-
ders with MN RF is significantly lower than with lasers, but
in patients at risk use hydroquinone 2% and sun cream as pre-
treatment for 2–4 weeks.
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37
Cosmetic Cryotherapy
Rodney Sinclair
Texas, U.S.) that, through an appropriate nozzle, emits an open

Introduction spray of liquid nitrogen (Figure 37.1). In general, the nozzle
size is chosen according to the size of the lesion; however a
Most dermatologists and dermatologic surgeons limit them- “D” nozzle will be suitable for most benign lesions. The flask
selves to warts and keratoses. Some also treat skin cancers. should be two-thirds full to ensure an even flow of cryogen.
Many are unaware of the diverse range of conditions, patho- Overfilling the flask can lead to the valve icing over. The
logic and cosmetic, amenable to treatment with liquid nitro- nozzle is held 1 cm from the skin surface at a 90° angle and
gen. Cryosurgical treatments, when applied correctly to the centre of the lesion is sprayed until an ice ball forms that
appropriately selected patients, produce excellent cosmetic encompasses the lesion and the desired margin. The “desig-
results, which justifies a description of these techniques in a nated ice field” may need to be marked out with a suitable pen,
cosmetic dermatology text. As liquid nitrogen is freely avail- as freezing blurs lesion margins. Once the ice field reaches the
able and cheap, and can be used without local anesthetic, it desired size, freezing is stopped temporarily to allow palpation
is often thought of as “low-tech” and unable to compete with of the ice ball to ensure that the lesion is entirely frozen. Once
the newest lasers. On the contrary, cryosurgery is the equal of satisfied of adequate ice formation, the spray of liquid nitrogen
high-tech alternatives for therapeutic efficacy and aesthetic out- may recommence and continue for the appropriate treatment
come for a wide range of conditions. Despite these advantages, time. During this time, the ice field size should remain con-
cryosurgery tends to be underutilized. Cryosurgery developed stant, with the spray of liquid nitrogen adjusted with the trigger
as a dermatological treatment modality about a century ago, on the spray gun appropriately. If more than one freeze-thaw
with the first cryogens being liquid air and compressed carbon cycle (FTC) is needed, then complete thawing should occur
dioxide snow (1). The following is a description of the specific before the next cycle. This usually takes longer than 60 sec-
cryosurgical techniques for treatment of an array of lesions onds. This can be assessed by palpation between the finger
seen by the cosmetic and dermatologic surgeon and describes and thumb again for the presence of an ice ball as well as wait-
the steps to be taken to achieve good cosmetic results. ing for the disappearance of the frozen-white surface appear-
ance. Lesions greater than 2 cm in diameter are generally
best divided into overlapping treatment fields to ensure that
Technique and Terminology the timed spot freeze technique adequately treats all parts of a
large lesion (Figure 37.2). Using only one treatment field may
Various methods have been devised in the use of cryotherapy not adequately freeze the deep margins at the periphery of a
of lesions. large lesion. The open spray technique is extremely versatile
and can be used for most easily accessible lesions. Variations
1. Open spray freeze technique (Timed spot freeze do exist: the paintbrush method involves spraying starting
technique) from one side of the lesion and moving up and down across
2. Cotton-tipped dipstick freeze technique (Applicator the lesion, and the spiral method, where treatment starts in
technique) the center of the lesion and moves outward in ever-increasing
3. Closed spray freeze technique (Cryoprobe method/ circles (2). These two techniques are particularly useful for
Contact cooling) larger lesions and when a light, superficial freeze is desired.
4. Semi-closed freeze technique (Chamber/ Hyperpigmentation may complicate the treatment of some
Thermocoupler method) lesions. Hyperpigmentation is particularly common in people
5. Semi-open freeze technique (Cone/Confined spray) with Fitzpatrick type III and IV skin. Although usually tem-
porary, it may take 3 to 4 months to resolve. In general, before
6. Tweezers/Forceps
embarking on this treatment in people with darker complex-
7. Intralesional Cryotherapy ions, a small test should be performed first.
Hypopigmentation is generally only seen after large doses
of liquid nitrogen are applied to the skin, for example, in the
Open Spray Freeze Technique (Timed Spot)
treatment of skin cancer. In very fair people, this may go unno-
The spot freeze technique involves the use of a liquid nitrogen ticed. For patients with an olive complexion, to prevent a sharp
spray gun (Brymill Cryac Gun, Owen Galderma, Fort Worth, demarcation between the hypopigmented treated area and
368 DOI: 10.1201/b22897-37

Cosmetic Cryotherapy 369
FIGURE 37.2 Bowen disease: showing method of freezing successive

2-cm overlapping circles to ensure uniformity of treatment of the whole
lesion.
therefore not recommended. Decanting a small amount of liq-

uid nitrogen into a separate new disposable container for each
patient treatment is preferred. Dipping a cotton bud into the
flask of a spray unit leaves behind cotton fibers that will even-
tually block the nozzle and lead to uneven flow of cryogen.
Closed Spray Freeze Technique (Cryoprobe)

Various types of cryoprobes are available; the choice
of probe depends on the type and site of the lesion (4).
Cryoprobes may be attached to the liquid nitrogen spray
guns and are cooled by the stream of nitrogen. The probe
is applied directly to the lesion. A thin layer of Vaseline or
similar gel may be used on the tip of the probe to facilitate
FIGURE 37.1 Liquid nitrogen cryosurgery cryogun, with multiple contact with the lesion and release of the probe on thawing.
interchangeable nozzles to regulate spray. As cooling occurs through conduction of heat from the skin,
comparatively longer periods of freezing are required with
surrounding normal pigmentation, “feathering” may be per- this technique. Once the ice forms, the probe and lesion is
formed. This involves spraying the border of the ice field to ice gently retracted to prevent further injury to the surrounding
formation to produce mild hypopigmentation that reduces the tissues. Direct pressure on a vascular lesion can also be used
contrast with untreated skin. A better cosmetic outcome may to empty the lesion and produce a greater fall in temperature,
be achieved when treating lesions within a single cosmetic unit but the amount of pressure will influence the depth of freeze
by light spraying the entire cosmetic unit. Because any depig- and lateral spread.
mentation so produced will be permanent, it is better to pro-
ceed cautiously when deliberately lightening the skin. Semi-Closed Freeze Technique
(Chamber/Thermocouple Device)
Applicator Technique (Cotton-Tipped Dipstick) To treat malignant lesions, a temperature probe coupled to
The dipstick technique involves dipping a cotton wool bud into a digital thermometer that can read 10 to 75°C can be used.
a cup containing liquid nitrogen and firmly applying the bud to Local anaesthetic is injected into the lesion, and a temperature
the lesion until a narrow halo of ice forms around the bud. This probe is inserted into the estimated depth of the lesion. Usually
method is most effective with a cotton bud slightly smaller than a metal or styrene cone is used to concentrate the freeze. The
the lesion to be treated and the cotton bud is home-made using liquid nitrogen is sprayed into the cone until the desired tem-
loosely wrapped cotton wool around the wooden orange (or perature is reached, usually –50 to –60°C. The process can be
satay) stick. This holds more liquid nitrogen than prefabricated repeated until the desired destruction is achieved.
cotton buds. Pressure applied to the skin facilitates lower tem-
peratures as a wider area comes into contact. The pressure can
Semi-Open Freeze Technique
also be used to empty vascular lesions leading to a greater fall
(Cone/Confined Spray)
in temperature. As adenovirus is capable of survival within
liquid nitrogen and other viruses may potentially survive and A polycarbonate plate with holes, neoprene cones, or otoscope
cross-contaminate one’s store of nitrogen (3), redipping is specula can be used to restrict the sprayed LN to the target
lesion. As the LN is confined to the lesion itself, it spares the formation. Ice crystals do not form until temperature –5
surrounding epidermis. This technique allows faster freezing to –10°C. The ice damages organelles (mitochondria and
compared to the open spray technique (5). endoplasmic reticulum) and further concentrates electro-
lytes intracellular. The rate of thawing also influences the
degree of damage, with long thaw times being associated
Tweezers
with greater damage due to the accumulation of intracel-
Frozen forceps or tweezers can be used to treat benign pedun- lular electrolytes. Rapid freezing and slow thaw maximize
culated skin lesions. The freezing is transferred from the for- tissue damage to epithelial cells and is most suitable for the
ceps to the filiform lesions without affecting the surrounding treatment for malignancies. In addition, repeat FTCs pro-
epidermis. Its use is limited to treatment of superficial skin duce more tissue injury than a single freeze and thaw. The
lesions. This technique allows sparing of surrounding tissue minimum temperature needed for destruction is cell-spe-
compared to open spray freeze. cific. Cryosurgery causes selective destruction of different
cell or tissue types, depending on the temperature reached.
The collagen-containing connective tissue types are more
Intralesional Cryotherapy resistant to cryodamage than the epidermal cell types, espe-
A thick, curved needle attached to a cryogen unit is passed cially melanocytes and deeper epidermal cell layers. Mild
through the skin lesion. The main advantage is that it allows freezing causes dermoepidermal separation. Keratinocyte
for treatment from within the centre of a skin lesion compared destruction requires a minimum temperature of at least
to open freeze spray. This makes it more invasive compared –30 to –40°C, while melanocytes are much more sensitive,
to other freezing techniques. It is mainly used to treat keloids dying at –4 to –7°C. This fact is the reason for the result-
and larger tumors. ing hypopigmentation following cryotherapy on darker skin
individuals. Repigmentation often occurs with migration
of melanocytes from the edge of the frozen zone or from
undamaged melanocytes within hair follicles. Fibroblasts
Mechanisms of Action produce less collagen after a rapid thaw. Therefore, a rapid
The mechanism of lesion destruction is similar for all cryo- thaw may be more suitable for the treatment of keloids or
gens and can be divided into four phases: benign lesions in areas prone to scarring.
1. Heat transfer
2. Cell injury
Vascular Stasis and Occlusion
3. Vascular stasis and occlusion
4. Inflammation Cold temperatures lead to vasoconstriction and endothelial
damage. At –15°C, endothelium is damaged and platelet
aggregation, along with microthrombus formation, leads to
ischemic necrosis of the treated tissue in succeeding hours.
Heat Transfer A reflex hyperemia lasting minutes to hours also occurs,
appearing as a purplish discoloration at the edge of the
The rapid freezing of skin lesions depends on a quick transfer
defrosting lesion.
of heat from the skin to a heat sink, for example, liquid nitro-
gen. The rate of heat transfer is dependent on the temperature
difference between the two, in this case 36 to –196°C.
Inflammation
Over the next 24 hours, inflammation develops in response
Tissue Injury
to cell death and further contributes to the destruction of the
On application of the cryogen, the initial event is extracel- lesion. Significant edema may occur, especially where the
lular ice formation. This commences at –10 to 15°C. The skin is loosely attached to underlying tissues, for example, the
transformation of water into ice leads to loss of water from dorsum of hand and around the orbital region. Histological
the extracellular compartment. This concentrates the extra- changes first become apparent 30 minutes after cryotherapy.
cellular solutes and sets up an osmotic gradient across the Eosinophilia and vacuolation of the cytoplasm appear initially,
cellular membranes. The movement of water across mem- and the entire cytoplasm becomes homogenized over the next
branes is exacerbated by mechanical compression from few hours. This is accompanied by nuclear pyknosis. There is
extracellular ice crystals that damages the cell membrane. separation at the dermoepidermal junction, resulting in blis-
The movement of water out of the cell leads to an intra- ter formation. At 2 hours, edema, focal capillary damage, and
cellular concentration of solutes. This damage is mostly isolated microthrombi are seen; at 5 to 8 hours, there is seg-
reversible. Irreversible damage is due to intracellular ice mental necrosis of blood vessels. There is initially a wet exu-
formation and is dependent on the rate of cooling and the dative wound, nature’s own biologic dressing, followed by a
minimum temperature achieved. The faster the cooling and dry eschar and, usually within a month, a well-healed hypopig-
the lower the temperature, the greater the intracellular ice mented scar.
oiliness of the skin and hastened the resolution of comedo-

Lesion Selection nes and papules as well as improving depressed pitted scars.
This was superseded by cotton-tipped applicators dipped
Accurate diagnosis is essential to determine duration of the in liquid nitrogen, which has also been used for larger acne
freeze required. An appropriate biopsy of the lesion should be cysts. Better results and better control can be achieved with
performed if there is any diagnostic uncertainty. If a punch the open spray techniques (9). Small inflammatory papules
biopsy specimen is taken from the centre of the lesion, infor- require a 2- to 5-second single FTC, while the large cystic
mation regarding the thickness of the tumor will also be lesions of acne conglobata may require a 15- to 20-second
gained. Vast experience in the treatment of numerous and var- single FTC, depending on their size. Open spray liquid nitro-
ied skin lesions by cryosurgery has been accumulated over the gen has also been used as an alternative to dermabrasion and
past 30 years since this treatment was popularized by Zacarian laser resurfacing for diffuse scarring (10). The skin surface
for skin neoplasms (6,7). Much of this experience is summa- is divided into squares, each about 4 cm on a side. Using the
rized in Tables 37.1–37.4, while that pertaining to skin cancer paintbrush technique, each segment is frozen for between 5
can be found elsewhere (8). and 15 seconds, depending on the depth of the desired peel.
Areas of hypertrophic scarring may require longer freezes
because of the relative cold insensitivity of collagen, while
Vascular Lesions areas around the eyes, where the skin is thin, only requires
5- to 10-second single FTCs. If more than one treatment
Spider nevi require only a light freeze. A 5-second single FTC is planned, 1 month is the suggested interval between ses-
is usually ample. Cryosurgery is a good alternative to fine sions. Of the patients so treated, 95% were reported to have
wire diathermy for people with pale complexions, especially had good or excellent results, which were similar to those
for diffuse lesions with more than one feeding vessel. Diffuse achieved by superficial dermabrasion, with the advantage of
telangiectasia, such as that associated with rosacea, can also their use in the presence of active acne. Pigmentary changes
be treated with good results and is a substantially cheaper are often seen in ethnic patients and care should be taken
alternative to the use of a pulsed dye laser. Pyogenic granulo- when using this technique on darker skin (11).
mas also respond well (Figure 37.3). Cryosurgery is also use-
ful for palliation of HIV-associated Kaposi sarcoma. Small
individual lesions (and a 3-mm margin) can be treated with a
15- to 30-second single FTC, with an 80% complete response.
Cryoprobes are useful when treating venous lakes, since they
Sun-Damaged Skin and Facial Peeling
allow the operator to empty the lesion during treatment, which Solar keratoses, solar lentigines, solar elastosis, sebaceous
leads to lower tissue temperatures and higher cure rates. A sin- hyperplasia, colloid milium, and the fine wrinkles of solar
gle 10-second FTC is usually sufficient. aging are all within the realms of unsightly sun-induced lesions
There is a great variation in the size and depth of cavernous amenable to cryosurgery. These lesions occur on highly visible
and capillary hemangioma, and this is paralleled by the varia- sites, such as the face and hands, and may cause patients’ dis-
tion in freeze times required. For small thin lesions, a single tress. Cryosurgery is an excellent option for limited disease.
5-second freeze may suffice, while for larger lesions a 30-sec- Many clinicians ignore sebaceous hyperplasia; however, a sin-
ond double FTC will be required. Experience in the treatment gle 5-second FTC will often make these lesions disappear. The
of these lesions allows the operator to better judge the length same applies to solar elastosis, solar lentigo, and many solar
of treatment required. keratoses. For widespread changes, full-face cryopeels can be
used for effective depth-controlled removal of actinic kera-
toses, pigmented lesions, and seborrheic keratoses. Healing
Acne
begins immediately and is usually complete within 10 days.
The first treatment to be advocated for acne was a solid car- The skin is left smoother, pinker, and tighter, and the results
bon dioxide slush that acted as a peeling agent to reduce the are equivalent to those of a chemical peel; however, there is
TABLE 37.1
Suggested Treatment Regime for Disturbances of Pigmentation and Melanocytic Lesions
Lesion Technique Time, number of FTCs Margin Sessions and interval Response
Melasma OS Uniform ice formation × 1 Feathering 4–6 weekly according to response Moderate
Idiopathic guttate OS 5 sec, × 1 1 mm 4–6 weekly according to response Moderate to good
hypomelanosis
Tattoos OS 30 sec, × 2 1 mm 4–6 weekly according to response 54% improved
Freckles P Uniform ice formation, × 1 Feathering Usually only single treatment required Variable
Lentigo simplex OS or P Light, × 1 Feathering Usually only single treatment required Good
Solar lentigo OS or P 5–10 sec, × 1 Feathering Usually only single treatment required Good
Abbreviations: OS, open spray technique; P, cryoprobe technique; FTS, freeze-thaw cycle.
TABLE 37.2
Suggested Treatment Regime for Vascular Lesions and Nevi
Time, number
Lesion Technique of FTCs Margin Sessions and intervals Response
AIDS-related Kaposi sarcoma OS 10–30 sec, × 2 3 mm 3 at 3 weekly intervals 80% improved
Venous lake P 10 sec, × 1 1 mm Usually only single treatment Excellent
Cherry angiomas P 10 sec, × 1 1 mm Usually only single treatment Good
Angiokeratoma of Mibell OS or P 10 sec, × 1 1 mm 3 at 2 monthly intervals Good
Angiokeratoma of the scrotum OS or P 5–10 sec, × 1 1 mm 3 at 2 monthly intervals Good
Spider nevus P 10 sec, × 1 1 mm 3 at 6 weekly intervals Good
Capillary hemangioma P 5–30 sec, × 2 1 mm 2–4 at 8 weekly intervals Excellent
Cavernous hemangioma P 5–30 sec, × 2 1 mm 2–4 at 8 weekly intervals Excellent
Pyogenic granuloma P 15 sec, × 1 1 mm 1–2 at 4 weekly intervals Excellent
TABLE 37.3
Suggested Treatment Regime for Cysts, Tumors, and Nevi
Time, number
Acne cyst OS or D PB to peeling 5–15 sec, × 1 – 2–3 at monthly intervals Good to excellent
Milia P Ice formation × 1 1 mm Usually only single treatment Good
Myxoid cyst P or OS 30 sec × 2 1 mm 1–3 at 8 weekly intervals 86% improved
Syringoma P Ice formation × 1 1 mm 2–3 at 1–2 monthly intervals Good
Trichoepithelioma P Ice formation × 1 1 mm 2–3 at 1–2 monthly intervals Good
Trichilemmal cyst OS Ice formation × 1 1 mm 2–3 at 1–2 monthly intervals A minority respond
Steatocystoma multiplex OS Ice formation × 1 1 mm 2–3 at 1–2 monthly intervals A minority respond
Skin tag OS or forceps 5–10 sec, × 1 1 mm Usually only single treatment Excellent
Hidrocystoma OS or P Ice formation × 1 1 mm 2–3 at 1–2 monthly intervals Small: good
Large: poor
Dermatofibroma OS or P 30 sec × 1 2 mm 1–3 at 1–2 monthly intervals 90% improved
Seborrheic keratosis OS or D or P Ice formation × 1 1 mm Usually only single treatment Excellent
Sebaceous hyperplasia OS or P 5–15 sec × 1 1 mm Usually only single treatment Good
Chondrodermatitis nodularis helices OS or P 15 sec × 1 2 mm 2–3 at 1–2 monthly intervals 15–20% improved
Verrucous nevus OS 5 sec × 1 1 mm Up to 5 at 1–2 monthly intervals Excellent
Hyperkeratosis nevoid of the nipple OS 20 sec × 1 1 mm Up to 5 at 1–2 monthly intervals Excellent
Acrokeratosis verruciformis OS 5 sec × 1 1 mm Several at 6–8 weekly intervals Excellent
Dermatosis papulosa nigra OS or P Ice formation × 1 Nil Several at 6–8 weekly intervals Excellent, but may
depigment
Benign lichenoid keratosis OS 5 sec × 1 1 mm 2–3 at 6–8 weekly intervals Good
Adenoma sebaceum OS 5–20 sec × 1 1 mm 3–6 at 3 weekly intervals Satisfactory
Abbreviations: OS, open spray technique; P, cryoprobe technique; FTS, freeze-thaw cycle; D, dipstick.
TABLE 37.4
Suggested Treatment Regime for Various Other Conditions
Time, number
Keloid OS or P or IL 15–30 sec, × 1 1 mm 5–10 at 4–8 weekly intervals Variable
Acne scar OS Face 5 sec, × 1 1 mm 1–3 at 4–8 weekly intervals Good to excellent
Back 5–15 sec, × 1
Rhinophyma OS 30 sec, × 2 Entire nose 4–6 at 8 weekly intervals Satisfactory
Xanthelasma OS 5 sec, × 1 1 mm 2–3 at 4–8 weekly intervals Satisfactory
Alopecia areata D 2–5 sec, × 1 Nil 4 at weekly intervals Satisfactory
Porokeratosis plantaris OS Ice formation × 1 2 mm 2 at 2 weekly intervals 90.5% improved
discreta
Elastosis perforans OS 10 sec, X 1 1–2 mm 2 at weekly intervals Excellent
serpiginosa
Abbreviations: OS, open spray technique; P, cryoprobe technique; FTS, freeze-thaw cycle; D, dipstick; IL, intralesional technique.
then frozen with the open spray and a B or C nozzle for 10

to 20 seconds depending on size and thickness. Repeat treat-
ments at three to four weekly intervals are generally required.
For recalcitrant lesions a double freeze thaw should be used.
Filiform or digital warts are finger- or frond-like warts and are
most common on the face, neck, and scalp (Figure 37.4). Each
lesion should be sprayed with a fine “needle” to ice formation
plus 10 seconds of continued spray. Treatment may need to
be repeated after 2 to 4 weeks. The likelihood of recurrence
is dependent on the number of lesions, the user, and the tech-
nique used. With a gentle technique cure rates are estimated
around 64.4%, and this is increased with more aggressive
treatment (12). Aggressive treatments are more likely to lead
to increased side effects. A less aggressive approach should be
used where skin and subcutaneous tissue are thin (13).
Seborrheic Keratosis
Flat lesions can be effectively treated with a 5-second single
FTC (Figure 37.5), but as keratin insulates the underlying epi-
dermis from the cold, large hyperkeratotic lesions may still
survive 30-second double FTCs. A recent pilot study examin-
ing 25 patients with SK treated with cryotherapy versus curet-
tage found that 60% of patients preferred cryotherapy and
rated their cosmetic outcome as better with cryotherapy (14).
The main pitfalls of treatment are the induction of permanent
alopecia, if hair-bearing areas are treated, and the induction of
transient hyperpigmentation. It is for that reason that dermato-
sis papulosa nigra occurring on pigmented skin is best treated
cautiously, and preferably with a test patch of a single lesion.
FIGURE 37.3 Pyogenic granuloma (a) before and (b) after cryospray.
Rhinophyma
Cryosurgery has been used to treat rhinophyma (15). However,
greater control of the depth of the ice field, so it can be adjusted in our hands, it has proved to be less effective than dermabra-
to accommodate localized lesions (10). sion or serial shaving. However, there have been a number of
case reports detailing successful methods for treating rhino-
phyma. In one case report a patient was treated with two or
three FTC over a number of sessions using the paintbrush
Viral Warts
method. Sessions were spaced fortnightly and combined with
These are due to the human papillomavirus. On different the use of spironolactone to reduce sebum excretion and pore
body sites, warts often show different morphologic types. The size (16). Thirty-second double FTCs are recommended and
cryosurgical treatment scheduled will vary with the site and can often be performed without anesthesia, or solely with
type: common warts are mainly seen on hands, fingers, and EMLA cream. Multiple treatments are required but are well
knees. For flat lesions, a single FTC using the open spray for tolerated. For mild cases, cryosurgery can still be considered
10 seconds is generally sufficient for an initial treatment. For as an inexpensive option with low risk and low morbidity that
hyperkeratotic wart, it is often best to pare the keratosis prior has shown some success.
to freezing. Periungual warts often require multiple freezes
with gradually increasing dose. The spray should be directed
laterally to avoid overfreezing the nail matrix and to prevent
Tattoos
pterygium. Plane warts are smooth, small, flat-topped papules
most commonly seen on the back of the hands and around the Good results have been seen after cryosurgery of tattoos in
mouth. They are often multiple and can Koebnerize. Each wart up to 50% of cases (Figure 37.6) (17). However, newer tech-
should be frozen individually using the open spray with an E tip nologies including Q-switched nano-and pico lasers are the
for 3- to 5-second single freeze. Plantar warts (verrucas) typi- preferred option for tattoo removal since cryotherapy can
cally occur on weight-bearing areas of the sole. Prior to cryo- leave the patient with skin discoloration and ink retention
surgery, they should be pared to remove excess hyperkeratosis, (18). Cryotherapy provides complete, rapid, and cheap tattoo
FIGURE 37.4 Filiform wart of upper lip (a) before and (b) after fine FIGURE 37.5 Large seborrheic keratosis of right cheek (a) before and
“needle” cryospray. (b) after cryospray.
removal and for some patients desperate for the treatment intralesional cryotherapy is clearly inferior to keloid excision
there is no affordable alternative (19). followed by brachytherapy, but for small primary keloids,
intralesional cryotherapy can improve keloid appearance in
certain patients (27).
Keloids
Many cryosurgeons disappointed by the apparent poor
Complications
response of keloids to liquid nitrogen abandoned this form
of treatment. Various techniques had been tried, including Inflammatory morbidity, inevitable side effects, and compli-
prophylactic and intralesional cryotherapy, with some suc- cations are difficult to separate with this modality of treatment
cess. Results varied between 20 and 75% scar reduction (28). Table 37.5 shows some of the well-known complica-
(20–24). The incidence of hypopigmentation in intralesional tions of cryosurgery. Some degree of pain is universal, but its
cryotherapy is lower than in contact cryotherapy (25). A pro- intensity is extremely variable. Syncope can occur if the pain
spective clinical trial published in 2010 examined surgical is severe, and many prefer to treat patients (particularly young
excision with postoperative radiotherapy versus cryotherapy men) lying down. During the freeze time, pain is felt as burn-
with intralesional steroids. The study revealed that while suring, and during the thaw phase, when pain is commonly worse
gery with cryotherapy and intralesional steroids had more than during the freeze, it is felt as throbbing. The periungual
side effects and a higher recurrence rate, it was still a good region and the temples are the most persistent. Headache is an
choice for new, small keloids (26). A prospective trial pub- occasional sequela after treatment of sites close to bone, such
lished in 2018 examined the effectiveness of intralesional as the forehead, temple, or scalp. Immediate hemorrhage,
cryotherapy versus surgery followed by either intralesional if occurs, is often prolonged, but can usually ultimately be
steroid injection or brachytherapy. The trial was terminated stopped with pressure alone. This can follow by performing
prematurely due to poor results in the intralesional cryo- biopsies immediately prior to treatment but can also occur if a
therapy group. The study showed that for resistant keloids pedunculated lesion is manipulated while frozen, and cracks.
Edema is the product of acute inflammation. Pronounced

idiosyncratic edema may occasionally occur after short
freezes. Edema is often more severe around the eyelids and
lips (Figure 37.7). The edema can be partly inhibited by a
single application of a potent topical steroid immediately
following treatment (29), and if severe edema is anticipated
then systemic corticosteroids can be used. Temporary hyper-
pigmentation is common in people with an olive complexion
and may last 2 to 3 months. Careful sun protection following
treatment may reduce this risk. For patients with Fitzpatrick
types III and IV skin, even temporary hyperpigmentation may
be unacceptable, and treatment of a small test area is recom-
mended. Hypopigmentation is virtually universal following
tumor doses of cryosurgery, owing to the exquisite sensitiv-
ity of melanocytes to cold, and can occur unpredictably fol-
lowing lower doses. In pigmented skin, this will lead to an
unacceptable cosmetic result; however, in fair-skinned people
this is usually not a problem and can be dealt with by feather-
ing. Any loss of pigmentation is permanent, but because the
texture of the underlying skin is normal, it can be effectively
disguised by cosmetics. Feathering is a technique described
to minimize the contrast between normal and hypopigment
skin. It involves a light spray around the outer margin of the
ice field after the treatment. Alopecia will follow large doses
of liquid nitrogen, and occasionally occurs at lower doses in
an unpredictable fashion. Like pigment loss, any hair loss is
usually permanent, and so cryosurgical treatment of lesions
in the scalp and beard areas is generally only considered for
small lesions. Scarring and wound contraction do not occur if
the duration of the freeze after ice formation does not exceed
30 seconds but can occur with higher doses (30). This is due
FIGURE 37.6 Tattoos (a) before and (b) 4 months after liquid nitrogen to the relative resistance of fibroblasts and collagen fibers to
spray. cold, which leads to the preservation of the fibrous tissue net-
work, which then acts as a scaffold on which wound healing
occurs. Cartilage is similarly cryoresistant, allowing lesions
TABLE 37.5
on the ears and nose to receive full 30-second double freezes
Side Effects of Cryosurgery of liquid nitrogen without distortion of normal tissue contour
Immediate (31). Sensory impairment following cryosurgery has been
Pain described in both the patient and the operator (32). Touch,
Headache pain, and cold sensations are all reduced and may take as long
Hemorrhage as 18 months to recover. The extent of sensory impairment
Edema and blister formation is more pronounced with longer freeze times. Although this
Syncope may be of advantage for repeat treatment of lesions or if anal-
Delayed gesia is desired, patients must be warned of this complica-
Infection tion if sensitive areas such as the fingertips are being treated.
Hemorrhage/blood blister Neuropathy has been described when treating tumors on the
Excessive formation of granulation tissue side of the neck, near elbow or knee, and on the side of the
Prolonged but usually temporary finger. This is temporary, persisting usually for 3 to 6 months.
Hyperpigmentation Contraindications to cryosurgery generally relate to intercur-
Milia rent illnesses such as those listed in Table 37.6. Cryosurgery
Hypertrophic scars should not be carried out on neoplasm of uncertain behav-
Alteration of sensation/Nerve damage ior. A clinical or histopathological diagnosis should be made
Prolonged and usually permanent prior. Relative contraindications arise with certain lesions
Hypopigmentation where the cosmetic result would be more favorable with dif-
Alopecia ferent treatments, such as the beard areas or in patients with
Atrophy pigmented skin, or in sites where wound healing may be slow,
Ectropion such as the pretibial region. Cryosurgery can still be used on
Notching of the eyelids, ear, or vermillion border. all these lesions as long as the operator acknowledges that the
cosmetic outcomes will be diminished.
“A level of knowledge permitting an adequate understand-

ing of the diagnosis and the pathophysiology of the condition
to be treated must be a prerequisite. This is to be combined
with a degree in skill in dermatocryosurgical procedures to
allow the selection of those methods necessary to carry out
the treatment plan. These skills must be acquired. There are
no shortcuts (7).”
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cosmetic usage for treatment of disease is sometimes difficult. 2008;74:S28–S36.
Many pathologies cause little functional impairment but cause 12. Khaled A., Romdhane B., Kharfi M., et al. Assessment of
psychological morbidity through their perceived unpleasant cryotherapy by liquid nitrogen in the treatment of hand and
appearance. To dismiss these disorders as trivial or unworthy feet warts. Tunis Med 2009; 87(10):690–692.
13. Kandamany N., Ahmad M. Cool it! The judicious use of
and merely of cosmetic significance is to deprive the patient
liquid nitrogen for viral warts is important. J Plast Reconstr
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Aesthet Surg 2010; 63(2):e204.
there are few published data that specifically address how to
14. Wood L.D., Stucki J.K., Hollenbeak C.S. Effectiveness of
perform the actual treatment. This is because experienced
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cryosurgeons will be able to judge the treatment required on the
atoses. JAMA Dermatol 2013; 149(1):108–109.
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38
Botulinum Toxins
Doris Hexsel and Ana Carolina Krum dos Santos
motor neuron in the treated muscle, resulting in therapeutic

Introduction and cosmetic actions. It selectively inactivates these nerve ter-
minals by blocking the release of acetylcholine, producing a
The cosmetic use of botulinum neurotoxin type A (BoNT-A) temporary and ultimately reversible blockade of cholinergic
on the upper face was first reported by Carruthers and transmission (8). In the neuromuscular junction, the blockade
Carruthers in the late 1980s (1). The first studies of the cos- of the release of acetylcholine promotes a different spectrum
metic use of BoNT-A were published in the early 1990s, and of action (9) varying from muscle relaxation to muscular palsy,
approximately 10 years later its use was approved by the Food depending on the subtypes and doses used.
and Drug Administration (FDA) in the United States, and Different formulations of BoNT-A are available world-
similar authorities in other countries. This represents one of wide, which are neither identical nor interchangeable. Botox®
the most important contributions to the approach of the aging (Allergan, Inc., Irvine, California) is the trade name for ona-
face in recent decades. botulinumtoxinA (ONA) (10). ONA is also known as Vistabel®
Easily applied by experienced physicians, BoNT-A injec- or Vistabex® in Europe. Dysport® (Galderma, Lausanne,
tions are now perhaps the most frequently used cosmetic pro- Switzerland) is the trade name for abobotulinumtoxinA
cedure. In the United States, BoNT-A injections were the most (ABO), which is also known as Azzalure®. Xeomin® (Merz
frequently performed cosmetic procedure from 1995 to 2010, Pharmaceuticals, Frankfurt, Germany) is the trade name for
and the one that increased at the greatest rate over time (2). incobotulinumtoxinA (INCO), also known as Bocouture®.
Their popularity and success among physicians and patients Table 38.1 shows the principal characteristics of the main
can be related to their consistent positive results and safety commercial preparations of BoNT-As.
(3,4), besides being a fast, minimally invasive (5), and low-risk
procedure. Botulinum neurotoxin type A is now a recognized
treatment for a wide spectrum of conditions characterized by Reconstitution, Handling, Dilution,
relative over activity of one or a few muscles (m.). BoNT-A
injections are effective in the treatment of localized hyper-
and Dose Equivalence
hidrosis, and recent publications report their effectiveness in Available BoNT-A preparations are usually stored in a refrig-
other dermatological conditions. The relative simplicity of erator and reconstituted with isotonic sodium chloride (0.9%
the procedure and the low rates of side effects or significant saline solution) with or without preservative (5) prior to their
complications make this procedure increasingly attractive for use, except incobotulinum toxin, which does not require
cosmetic use. refrigeration.
Although botulinum neurotoxin type B may be cosmetically The manufacturers of the commercial preparations of
used and although there are varied botulinum toxin brands, BoNT-A recommend their use within the first 4 or 8 hours
this chapter discusses only the BoNT-A main preparations, after reconstitution, depending on the product, to ensure that
such as Botox®, Xeomin®, and Dysport®. the potency of the drug is maintained and to prevent the pos-
sibility of contamination of the vials. Manufacturers recom-
mend storing BoNT-A in the refrigerator no longer than 4
hours after reconstitution. However, studies support the safety
Pharmacology and Mechanisms of Action
and efficacy of BoNT-A when the product is reconstituted up
Clostridium botulinum produces an exotoxin that is consid- to 15 days (11) and 6 weeks before the injections (12,13). No
ered the most poisonous of all poisons (6). It is an anaerobic, signs of microbiological contamination were verified (11,13).
gram-positive bacillus that forms spores, and its strains are Reconstitution of BoNT-A in smaller rather than larger vol-
grouped into one of the eight serotypes: A, B, C, D, E, F, G, umes of saline solution is preferable. For cosmetic purposes,
and H (7). a higher concentration allows a low injection volume, which
The currently available serotypes A and B result from permits more precise placement of the neurotoxin. Tables 38.2
modification of the protein structure and have been used for and 38.3 show the most common regular dilutions of Botox®/
a variety of medical and cosmetic indications. Botulinum Vistabel®, Xeomin®/Bocouture®, and the recommended
neurotoxin causes a temporary chemical denervation of the equivalent doses for Dysport®/Azzalure®.
378 DOI: 10.1201/b22897-38

Botulinum Toxins 379
TABLE 38.1
Comparison of Different Commercial Preparations of BT Available in the Majority of Countries
Botox® Vistabel® Dysport® Dysport Azzalure® Prosigne® Xeomin®
100 U 50 U 500 s.U 300 s.U 125 s.U 100 U 100 U
Active substance BT-A complex BT-A complex BT-A complex BT-A complex BT-A complex BT-A complex BT-A neurotoxin
(925 kD) (925 kD) (150 kD)
Suggested equivalence NA NA Between 1:2 Between 1:2 Between 1:2 1:1 1:1
for cosmetic uses and 1:2.5U and 1:2.5U and 1:2.5U
(relative to Botox)
Mode of action: target SNAP 25 SNAP 25 SNAP 25 SNAP 25 SNAP 25 SNAP 25 SNAP 25
protein
Pharmaceutical form Lyophilized Lyophilized Lyophilized Lyophilized Lyophilized Lyophilized Lyophilized
powder powder powder powder powder powder powder
Reconstitution 0.9 % NaCl 0.9 % NaCl 0.9 % NaCl 0.9 % NaCl 0.9 % NaCl 0.9 % NaCl 0.9 % NaCl
solution solution solution solution solution solution solution
Storage before dilution 2–8°C or 2–8°C 2–8°C 2–8°C 2–8°C 2–8°C 25°C
Storage after dilution 24h/2–8°C 24h/2–8°C 4h/2–8°C 4h/2–8°C 4h/2–8°C 4h/2–8°C 24h/2–8°C
Shelf life (unopened) 36 months 36 months 24 months 24 months 24 months 36 months 36 months
Shelf life reconstituted Up to 24h Up to 24h 4–8h 4–8h 4h 4h Up to 24h
depending on depending on depending on
country approval country approval country approval
Auxiliary substances albumin albumin albumin albumin albumin gelatin 5 mg, albumin 1 mg
0.5 mg/vial 0.5 mg/vial 0.125 mg 0.125 mg 0.125 mg dextran sucrose 4.7 mg
NaCl 0.9 mg NaCl 0.9 mg lactose lactose lactose 25 mg, and
2.5 mg 2.5 mg 2.5 mg sucrose 25 mg
pH-Wert 5–7 5–7 5–7 5–7 5–7 5–7 5–7
Toxin protein load in 5 ng/100 U 2.5 ng/50 U 5 ng/500 U 5 ng/300 U 5 ng/125 U 4–5 ng/100 U 0.6 ng/100 U
dose-equivalence
range
TABLE 38.2
Regular Dilutions of 1, 2, and 2.5 mL for Botox®, Vistabel®/Bocouture®, and Xeomin® and Equivalent Dilutions to Achieve a 1:2.5 U
Equivalence for Dysport®/Azzalure®
To achieve equivalence
between Botox/Vistabel If the vial of 100 U If the vial of 50 U The vial of 500 U The vial of 300 U The vial of 125 U
or Xeomin/Bocouture and (Botox or Xeomin) (Vistabel or Bocouture) of Dysport should of Dysport should of Azzalure should
Dysport/Azzalure of is usually diluted in is usually diluted in be diluted in be diluted in be diluted in
1:2.5 U 1 mL 0.5 mL 2 mL 1.2 mL 0.5 mL
1:2.5 U 2 mL 1 mL 4 mL 2.4 mL 1 mL
1:2.5 U 2.5 mL 1.25 mL 5 mL 3 mL 1.25 mL
A dose-equivalence of up to 1:2.5U between Botox® or dose-equivalence and showed greater diffusion for Botox®
Xeomin® and Dysport® is adopted by the most experienced compared to Dysport®. These studies confirmed that, regard-
physicians in the use of both products and is supported by ing the toxins, diffusion is a dose-dependent effect rather than
recent studies (14,15). This dose equivalence is also inferred related to intrinsic characteristics of each product (19).
by comparing controlled studies that aimed to establish the In 2013, an expert panel of French aesthetic physicians and
optimal dose for glabellar area (16–18). Such studies dem- biologists established a consensus on the clinical equivalence
onstrated comparable results and optimal effects in treating in efficacy and safety of Botox® and Xeomin®. They concluded
glabellar wrinkles using doses of 20U of Botox® (16) and both neurotoxins are clinically equivalent in terms of efficacy
50U of Dysport® (17,18). Hexsel and cols showed that injec- and safety, and that 1:1 conversion ratio can be used between
tions of Dysport® and Botox® at the dosing ratios 2.0:1.0 them (20).
U demonstrated similar field effects in both muscles and In 2015, a study (21) presented similar results for the fields
sweat glands. However, injections at an equivalence ratio of of muscular effect (WSS and ECMAP) between Dysport® and
2.5:1 U (Dysport®:Botox®) showed minimal differences but Xeomin® over time and larger FAE for Dysport® compared
greater efficacy measured by diameter and area of the field with Xeomin® at the 2.5:1 equivalence. The authors suggested
of anhidrotic effect for Dysport® when compared to Botox® that a lower dose equivalence between Dysport® and Xeomin®
(15). Another study from Hexsel and cols tested also the 1:1 could be established, such as 2:1.
TABLE 38.3
Regular Dilutions of 1, 2, and 2.5 mL for Botox®, Vistabel®/Bocoture®, and Xeomin® and Equivalent Dilutions to Achieve a 1:2 U
Equivalence for Dysport®/Azzalure®
To achieve the equivalence
between Botox/Vistabel or If the vial of 100 U If the vial of 50 U The vial of 500 U The vial of 300 U The vial of 125 U
Xeomin/Bocouture and (Botox or Xeomin) (Vistabel or Bocouture) of Dysport should of Dysport should of Azzalure should
Dysport/Azzalure of is usually diluted in is usually diluted in be diluted in be diluted in be diluted in
1:2 U 1 mL 0.5 mL 2.5 mL 1.5 mL 0.62 mL
1:2 U 2 mL 1 mL 5 mL 3 mL 1.25 mL
1:2 U 2.5 mL 1.25 mL 6.25 mL 3.75 mL 1.56 mL
TABLE 38.4
Contraindications, Precautions, Contraindications for BoNT-A Injections
and Recommendations Pregnancy and breastfeeding
Contraindications and/or limitations for BoNT-A are listed Active infection in the proposed area
in Table 38.4. Pressure at the site before and after treatment, Neuromuscular transmission disorders (myasthenia gravis, Eaton-
application of cold, and the use of small syringes and fine-gauge Lambert syndrome, Rooke syndrome)
needles can reduce pain and bruising at the injected sites (22). Hypersensitivity to components of the BT-A injection solution (BT-A,
human albumin)
Hexsel and cols (23) presented a safe, economical, and effective
Medication that influences neuromuscular transmission such as quinine,
tool to cool the skin for analgesic purposes. It is a single-use calcium channel blockers, penicillamine, aminoglycoside antibiotics,
disposable balloon filled with a frozen solution of 10%–20% pancuronium, galamine, tubucurarin succinylcholine
isopropyl alcohol in water that is effective in reducing pain, Medication that interferes with coagulation (e.g. acetylsalicylic acid,
ecchymoses, and hematomas in common dermatologic proce- anticoagulants, vitamin E) and coagulopathies
dures. It is safer and more cost-effective than other tools (23). Candidates with unrealistic expectations, unrealistic fears of the toxin,
Injections should be symmetrical regarding doses, muscles, psychiatric disorders such as psychosis, mania, body dysmorphic
and areas. This is important for the natural balance of the disorder, and eating disorders.
facial structures and to avoid asymmetries. Exception includes Source: Wollina U, Konrad H, Am J Clin Dermatol 2005; 6(3):141–50.
evident asymmetries, such as those caused by facial palsy.
Since the results are expected for 4 to 6 months, treat-
ments are usually repeated twice a year, for maintenance of lines (26,28,29). The main cause of these wrinkles is the mus-
the results. A period of 15 to 59 days for touch-ups should be cular action (28); they are thus considered “expression lines.”
respected. It is important to avoid more than one touch-up The direction of facial wrinkles and lines is usually perpen-
and respect the minimal interval of 3 to 4 months between dicular to the direction of the muscle fibres. The muscles of the
treatment sessions, due the risk of inducing the formation of upper face are intricately intertwined. In this area, location,
antibodies. However, there is evidence of little resistance to muscle anatomy and muscle mass, as well as the way patients
BoNT-A in the cosmetic use (24). When BoNT-A is injected use their muscles, vary greatly between individuals (30).
adjunctively to some surgical procedures, such as a facelift, A 2015 study (21) showed thicker and thinner muscles pre-
blepharoplasty, and laser resurfacing, some physicians prefer sented similar wrinkle severity scores at baseline. However,
to inject it in the postoperative period (25). thicker muscles presented more severe wrinkles than thinner
The dose to be injected depends on the target muscle and muscles 28 days after the injections. Authors suggest thicker
can vary from patient to patient, and from one application to muscles may need higher BoNT-A doses to achieve similar
another, according to the patient’s needs, muscle mass and results of thinner muscles (21).
activity of the target muscles, gender, and number of previous The frontalis m. has quite a variable anatomy and function-
treatments. The suggested doses by the consensus groups for ing, being responsible for raising the eyebrows, thus causing
Dysport® (26,27) and Botox® (28) are informed in Table 38.5, the horizontal forehead lines. Besides being important in
according to the area to be treated. the facial expression, aged people also use these muscles to
Patients should read and sign an informed consent form before amplify the visual field. Muscles controlling the frown include
application, and photographs should be taken before all cos- the corrugators m. and the orbicularis oculi m., which move
metic procedures, in order to evaluate the results. Photographs the brow medially, while the procerus m. and the depressor
must be taken at rest and also with contracted muscles. Makeup supercilli m. pull the brow inferiorly. The orbicularis oculi m.
should be removed and the skin cleansed before application. is divided into three parts, the orbital, the preseptal, and the
pretarsal portions.
Upper Face Glabellar Lines

Cosmetic indications for the upper face include the treatment Glabellar lines (Figure 38.1) are interpreted as presenting neg-
of glabellar lines, forehead lines, brow lifting, and crow’s feet ative feelings, such as sadness, anger, and frustration (16,31).
TABLE 38.5
Suggested Total Doses of Botox® or Xeomin® and Dysport® in Different Cosmetic Treatments
Botox® or Xeomin® Dysport®
Facial indications Average total dose (U) Average total dose (s.U)
Glabellar lines 12–40 30–70
Forehead lines 8–25 20–60
Crow’s feet 12–30 30–60
Infraorbital rhytids 1–4 2–5
Bunny lines 4–8 10–20
Drooping nasal tip 2–6 5–10
Repeated nasal flare 1–4 10–20*
Perioral area 1–5 4–12
Mentalis/dimpled chin 4–10 10–20
Depressor angulis oris 4–8 10–20
Gingival smile 1–4 5–10 [48]
Masseteric hypertrophy 15–40 60 for Caucasians and 120 for Asians
Platysmal bands 60 Maximum dose 50 per side
Décolleté wrinkles 50–100* 75–120
* Doses suggested by the present author. Not defined by consensus.
FIGURE 38.2 The five-point technique for glabellar lines.

FIGURE 38.1 Glabellar lines. Muscles involved: corrugators and procerus.
preference (26). Repeated injections of BoNT-A for glabellar

A variety of different injection techniques and doses have lines were shown to be safe and efficacious, and no loss of
been reported over the years. One or two injection sites may effectiveness or cumulative adverse effects is reported (33).
be used on the belly of the procerus m. This muscle can be The eyebrow is a mobile structure elevated by frontalis m.
treated with a single injection in the midpoint of an imaginary and depressed by brow depressors (orbicularis oculi m., cor-
“X” formed by lines joining the inner brows and the contra- rugator supercilli m. and procerus m.). Botulinum neurotoxin
lateral inner canthus (26). If the frontalis m. is not treated, the type A treatment for glabellar lines causes an elevation of the
middle to lateral portion of the eyebrows will be slightly raised medial and lateral brows (34) (Figure 38.3a and b), leading
by the opposing elevator action of the frontalis m. (26) The to a desirable arched shape and elevation of the brows (29). It
conventional injection technique involves the observation of was observed that the ideal brow shape in women is the lateral
the medial aspect of the eyebrow, while the patient frowns. and medial elevation, instead of medial elevation only (29),
BoNT-A is slowly injected into the belly of each corrugator whereas the rectilinear brow pattern is preferable for men.
m., taking care to maintain the needle 0.5 cm from the upper However, excessive elevation of the tail of the brows is unde-
orbital rim and internal to the midpupillary lines (26) (see sirable by the majority of the patients.
Figure 38.2). The needle should be positioned perpendicularly
and advanced slightly within the muscle fibres in a vertical
Forehead Lines
direction toward the hairline (32).
The total doses of Botox® (28) for glabellar lines range from When treating the frontal region, it is important to preserve
12 to 40 U, and from 30 to 70 s.U of Dysport® (26). The doses at least some muscle movement, as the frontalis muscles are
should be adjusted based on wrinkle severity and on patient responsible for facial expression and lifting of the eyelids and

FIGURE 38.3 (a) Original position of eyebrows, before treatment. (b) The same patient, showing changes in brow position and shape, after treatment.
eyebrows. Since the frontalis m. are also responsible for facial and previous treatment with BoNT-A may lead to a decreased
expressiveness, multiple injections of small doses of BoNT-A duration (28).
are used in this area to create only a weakening of the muscle
instead of a total paralysis, preventing brow ptosis and allow-
Bunny Lines
ing the patient to maintain some movement (32,34–37), espe-
cially in the upper part of these muscles. Besides, injection This is the most common indication of the middle face. The
points should be high on the forehead and small doses are rec- levator labii superioris m. and nasal m., as well the medial por-
ommended for the first treatment (32). The total dose varies tion of the orbicularis oculi (39) are involved in these wrinkles.
from 8 to 25 of Botox® (28) or Xeomin® and 20 to 60 s.U of Nasal wrinkles, called “bunny lines” (Figure 38.6), are treated
Dysport® (26). with low doses of BoNT-A (40). These lines may become more
pronounced after BoNT-A injections for the treatment of gla-
bellar and periorbital wrinkles. The injection must be applied
Periorbital or Crow’s Feet Lines
in the high lateral nasal wall, below the angular vein, avoid-
The wrinkles radiate from the lateral canthus outwardly and ing injections near the nasofacial groove in order to prevent
laterally, and are perpendicular to the direction of the muscle relaxation of the levator labii superioris m. which may lead to
fibres of the orbicularis oculi m. (32) (Figure 38.4a). upper lip ptosis (40,41). The recommended dose is 1 to 4 U of
The total doses used to treat crow’s feet lines range from Botox® (28) or Xeomin® and 5 U to 10 s.U of Dysport® (27)
6 to 15 U/side (28) of Botox® or Xeomin® and 15 to 30 s.U/ injected intradermally in just one point 1 cm above the upper
side of Dysport® (26) (Figure 38.4b). These doses are gener- lateral part of nostril on each side. The treatment may be less
ally distributed over two or three injection sites (34), although effective in patients who recruit these muscles excessively or
sometimes four to five sites are needed (Figure 38.5). A study have had prior rhinoplasty (40).
showed no difference in safety and efficacy when the same
dose was injected in one or three points in periocular area (38).
Nasal Tip Droop
All the injections must be performed at least 1 cm laterally to
the lateral orbital rim. The depressor septi nasi m. is a small muscle located in the
Infraorbital rhytids (Figure 38.6) can be treated with external inferior base of the nasal septum, which contributes
intradermal injections of 0.5 to 2 U/side of Botox® (28) or to the nasal tip lowering, aggravating the nasal tip ptosis that
Xeomin® and 1 to 2.5 s.U/side of Dysport® (27), 3–4 mm usually occurs with aging. Injections are done at the base of
below the eyelid. It increases the palpebral aperture and thus the columella (40). Injection of 2 to 6 U of Botox® (28) or
widens the eyes. It is not recommended for patients having Xeomin® and 5 to 10 s.U of Dysport® (27) perpendicular and
dry eyes, prominent eye bags, scleral show, or morning eyelid deep in a single site at the junction of the columella and the
oedema (27). upper lip can result in partial, very discrete lifting of the tip
of the nose.
Middle Face Repeated Nasal Flare

Whereas the duration of the effects of BoNT-A injections in Some people present dilated or rhythmic contractions of the
the upper face is about 3 to 4 months or longer, sometimes 6 to nostrils on certain occasions, which may cause embarrass-
8 months, (3) the duration in the middle and lower face is about ment. Injections of BoNT-A are indicated on each side in the
2 to 3 months. Technique and doses, individual differences, lower nasal fibres above the lateral nasal ala (40).

FIGURE 38.4 (a) Crow’s feet wrinkles before treatment. (b) The same patient after treatment with botulinum toxin, showing residual wrinkles, which
may be treated with adjunctive treatments.
FIGURE 38.6 Injection sites for the treatment of infraorbital rhytides

and bunny lines.
which is desirable for this area (42,43). A recent study showed

the safety and efficacy of full-face injections of BoNT-A also
for the lower face indications (3).
Due to the low doses used to treat the lower face, it is rec-
ommended to inject lower face together with upper face. Care
should be taken not to inject all areas in the lower face because
of the increased risk of the accumulated effects and doses in
this area, increasing the risks of side effects.
Most of the muscles of the lower face are functionally related
to the mouth and lips (43). In the lower face, BoNT-A is use-
ful to treat a series of conditions, including perioral wrinkles,
masseteric hypertrophy, “peau-d’orange” chin (mentalis m.),
FIGURE 38.5 Superficial injections of botulinum toxin type A for the marionette lines (depressor angulis oris m.), as well as gingival
treatment of crow’s feet wrinkles. and asymmetric smile.
Perioral Area
Lower Face
Photodamage, hereditariness, cigarette smoking, loss of deep
Lower doses of BoNT-A than those usually used in the upper structures and volume, sleep positions, orthodontic deformi-
face are recommended for the lower face. Such doses permit ties, and dynamic components, like playing a musical instru-
muscle relaxation, instead of paralysis, of target muscles, ment that requires embouchure, or even whistling, have been
thought to cause this aesthetic problem (40,44). Fine vertical of the chin (Figure 38.7b), with good results (Figure 38.7c)
lip rhytids are also caused by repetitive action of the orbicu- (42). Consensus recommendations for Dysport® suggest super-
laris oris m. Tiny doses of BoNT-A produce localized mic- ficial injections be performed to obtain satisfactory results
roparesis of the orbicularis oris m., reducing dramatically (27). Total doses of 4 to 10U of Botox (28) or Xeomin® and 10
perioral lines and also giving a pleasant pseudoeversion of the to 20 s.U of Dysport® (27) are recommended.
lip, with enhancement of the vermilion contour (40). The depressor angulis oris m. is responsible for lowering the
To define the injection points, the patient is asked to pucker, corner of the mouth; this worsens the nasolabial fold, producing
and the adjacent areas of muscle contractions are marked. It is the called “marionette” lines and thus giving a negative expres-
recommended to inject low doses and superficially, above the sion to the patient (Figures 38.7b and 38.7c). These muscles can
vermilion ridge, in the area of muscle contraction adjacent to be treated with injections of BoNT-A at the border of the jaw
the creases, away from the oral commissures and Cupid’s bow. bone, at a point on an imaginary line descending from the naso-
Injections of 1 to 5 U of Botox® (28) or Xeomin® and 4 to 12 labial fold. The total dose ranges from 2 to 4 U/side of Botox®
s.U of Dysport® (27), divided among 4 to 6 injection sites, are (28,46) or Xeomin® and from 5 to 10 s.U/side of Dysport® (27).
recommended. Side effects for this area are dose-dependent Lower lip dysfunction can be caused when the injection is too
(45), and higher doses are associated with a higher frequency medial and high, reaching the depressor labi m. (22).
of side effects when treating this area (3).
Gingival Smile
Mentalis and Depressor Angulis Oris
Gingival display is defined as the difference between the lower
Mentalis m. cause wrinkles giving the chin a dimpled or “cel- margin of the upper lip and the superior margin of the cen-
lulitic” aspect (Figure 38.7a). These muscles can be treated tral incisors (47). Excessive upper gum exposure occurs when
with one injection in the midline or two injections in each side more than 3 mm of gingival is exposed when someone smiles
of the insertion of these muscles at the point of the prominence and is called “gingival smile.”

FIGURE 38.7 (a) “Cellulitic” chin before treatment. (b) Treatment of mentalis m. with 3 U of BoNT-A on each side. (c) Same patient after treatment
of the mentalis m.
Most authors consider the gingival smile a consequence of causes, as in the case of certain types of surgery on the face
excessive retraction of levator labii superioris alaeque nasi m., or accidents; a third type of facial asymmetry can be idiosyn-
but levator labii superioris, zygomaticus major, zygomaticus cratic or familial, in which a muscle on one side of the face can
minor, levator anguli oris, orbicular oris, and risorius muscles be comparatively stronger or weaker than its partner muscle on
are also involved. A classification based on area of gingival the contralateral side of the face (55).
exposure—anterior, posterior, mixed, and asymmetric— BoNT-A can also be used to treat lesions or muscle
permits a better therapeutic approach (48). hypertrophy resulting from surgical procedures or trauma,
BoNT-A injected into the levator labii superioris m. causes a in order to achieve better cosmetic and functional results.
slight to moderate drop of the upper lip, reducing the anterior Usually BoNT-A injections are performed on the unaffected
gummy exposure. Doses should be adjusted according to the side of hemi paresis, treating the hyperkinetic muscles (25).
degree of gum exposure (48). The total dose suggested by the Application of BoNT-A in the healthy side of the face can
consensus for Botox® use is 1 to 4 U, but doses as high as 8 U improve its symmetry at rest and during facial motion, espe-
may be appropriate for some patients (28). A study reported cially when smiling, speaking, or exposing the teeth (57).
the efficacy of 4 to 6 U of Botox® to treat gummy smile (49). BoNT-A can provide a simple, noninvasive, and safe way of
The consensus for the use of Dysport® does not state doses for correcting obtrusively distracting asymmetry (55).
this indication (26). The total doses of 5 to 10 s.U of Dysport®
to treat anterior gummy smile and maximum dose of 2.5 s.U
Asymmetric Smile
of Dysport® on each side to treat posterior gummy smile are
suggested (48). Duration of effects were reported to last from The most common cause of asymmetric smile is related to
3 to 5 months (48). Results are less satisfactory in middle-aged depressor labii inferioris m. hyperkinesis or weakness. The
and older patients, as this causes slight vertical elongation of total doses are variable according to the patients and muscles
the upper lip (46). to be treated. The toxin is injected into the belly of the hyper-
kinetic muscle. The results become evident in less than 5 days
and the effects last 4 to 5 months after the first treatment. In
Masseteric Hypertrophy
subsequent treatments, it is recommended to reduce the doses
The hypertrophy of masseter m. is a rare, asymptomatic prob- and the results are usually longer (55).
lem of unknown cause. It can be uni- or bilateral and may also
be related to bruxism. Usually it begins during infancy and
may determine a squarer shape of the face.
Platysmal Bands and Décolleté Wrinkles
BoNT-A can safely be considered as a non-invasive drug
treatment for patients with masseteric m. hypertrophy (50). Its Platysmas m. are a pair of flat muscles that originate in the
effectiveness is noticed as early as 2 weeks after injections and subcutaneous of the upper thorax, ascend laterally to the
reached a peak effect in 3 months. Injections are performed 1 lower face, cross the neck, pass behind the mandibular angle,
cm below and above a reference line drawn from the tragus of and insert into the cutaneous muscles around the mouth (58).
the ear to the corner of the mouth. About 44% of patients would Platysmal bands are the result of the repeated and strong con-
complain of reduction of mastication strength (51). Although a tractions of these muscles.
previous study (52) showed that 6 months after the injections Platysmal bands are better visualized when the patient
the facial contour gradually returned to the original shape and shows the lower teeth. In this indication, BoNT-A should be
volume, Lee and cols reported that masseters treated with injected at various points along the length of the bands, at dis-
BoNT-A maintained significant volume reduction 24 weeks tances of 1–2 cm. The maximum suggested dose of Botox®
after treatment (53). The patients can be treated again every 3 (28) or Xeomin® for platysmal bands is 60 U and the consen-
to 4 months, if needed. However, there are reports of retreat- sus for Dysport® establishes the maximum of 100 s.U (27).
ment each month until there is no palpable movement of the However, the risk of complications with high doses can exceed
muscle on clenching the teeth (54). Doses can vary from 15 to the potential benefits. Goldman and Wollina reported the
40U of Botox® (28) or Xeomin®, and up to 60 s.U of Dysport® injection of three to four sites with 5 U of Botox® or Xeomin®
(27). Usually, higher doses are used in Asians (27,28). or 15 s.U of Dysport® on both sides of the medial portion of
the platysma m. for the attenuation of the platysmal bands and
elevation and redefinition of the angle of the mouth (59).
The main platysmal bands are chosen to be treated in
Facial Asymmetry
each session (usually two to four bands) (40). This results in
Facial asymmetry is a frequent complaint and can result from improvement of the appearance of the bands and fine wrin-
many different causes, which determine whether it will be kles. In older people, it can reduce wrinkles and bands in cases
a temporary or a permanent condition (55,56). Asymmetry where surgical lifting is contraindicated or when there are
occurs when one of the bilateral muscles is comparatively postsurgical residual wrinkles (39). Greater benefits are seen
stronger or weaker than other. Three basic types of facial in patients with apparent bands upon contraction, good elastic-
asymmetries have been described and result from different ity of the skin, and minimal fat deposition in this area (60).
causes: the acquired facial asymmetry is the result of a medi- Cutaneous wrinkles in the décolleté area can be classified as
cal or physical episode, for instance, a cerebral vascular acci- dynamic wrinkles, static wrinkles, and combined wrinkles. They
dent; facial asymmetries can also be the result of iatrogenic result from several factors, such as photoaging (main cause),
intrinsic aging, contraction of the pectoralis major m. and lower Although BoNT-A can be used in combination to surgical
part of the platysmal bands as well as sleep position. Botulinum procedures, it has been shown that the combination of non-
toxin relaxes the underlying muscles, improving these wrinkles surgical therapeutic modalities provides improvement of facial
(58). Doses of 2–5 U of Botox® or Xeomin® and 7.5–10 s.U of skin texture, pigmentation, tone, and wrinkles, as well as an
Dysport® can be used at each injection site in a V-shaped tech- improvement in facial contour (67), significantly increasing
nique, being four to six sites per side. The total dose of 50–100 patient satisfaction (68,69).
U of Botox® or Xeomin® and 75–120 s.U of Dysport® (27) is
used, improving décolleté wrinkles in selected patients in about
2 weeks (61).
Hyperhidrosis
Hyperhidrosis (HH) is a condition characterized by intense
sweating in one or more areas of the body (70), mainly affect-
Adjunctive Treatments
ing axilla, palms, soles, face, thigh, and inguinal area (70–72).
Facial wrinkles are the result of a combination of many causes. HH may cause significant physical, emotional, and/or social
Different therapeutic applications have been used throughout discomfort for patients, having a considerable impact in their
the years to give the face a youthful appearance. The com- quality of life (73).
bined use of BoNT-A with different cosmetic procedures such HH occurs due to the exacerbated perspiration of the eccrine
as fillers, lasers, light sources, and Subcision® may improve sweat glands, which are distributed over almost the entire
the results and their duration, when compared to the same body surface. There is a high density of these glands in some
techniques used alone, producing a more polished and refined areas such as the soles of the feet and the forehead, followed
result (62) (Figure 38.8a and b). by the palms and cheeks (74). The function of apocrine and
The aesthetic improvement in moderate to severe glabel- apoeccrine glands in HH is unknown, but they are believed to
lar and forehead lines can be effectively achieved with neu- play only a minor role in the pathophysiology of the condition
rotoxin alone. However, the result is better when combining (72). Sweating is controlled by nerve fibres that, anatomically,
BoNT-A with hyaluronic acid fillers (63,64). Botulinum toxin are distributed through the sympathetic nervous system (75).
minimizes muscle contraction, allowing the filler to remain in HH can be primary, which is idiopathic, or secondary to
place longer than when injected alone. Both frontal and glabel- various causes. The main causes of secondary HH are high
lar areas are considered dangerous areas for fillers injection. temperatures, physical exercise, fever, anxiety, fear, other
In the perioral area, dermal fillers can be combined to psychological symptoms, thyrotoxicosis, lymphoma, cancer,
BoNT-A to treat volume losses, a key component of perioral hypoglycemia, nausea, neurological lesions, and some drugs,
aging. Resurfacing techniques can also be used in combination such as neuroleptics, antidepressant agents, and anxiolytic
with BoNT-A in this area (65). The adjunctive use of fillers agents. In both cases, HH can be focal or generalized. Primary
into lip margin can be also useful in gingival smile treatment HH is a relatively common disorder, and it is usually localized
(40). Fractional therapies are also useful. and symmetrical (70).
For décolleté wrinkles, BoNT-A can be combined with other The diagnosis is clinical and the criteria for focal forms of
techniques, such as peels, lasers, and surgical lift (58). A study HH are (71): bilateral and relatively symmetric; impairs daily
showed that patients may be treated with several nonablative activities; frequency of at least one episode per week; age of
lasers immediately after BoNT-A injection without loss of effi- onset less than 25 years; positive family history; cessation of
cacy or other apparent untoward effect (66). focal sweating during sleep. Some tests are used to visualize

FIGURE 38.8 (a) Before and (b) after lip augmentation with hyaluronic acid filler and botulinum toxin in the peri-oral area, including the orbicularis
oris m. and depressor anguli oris m.
(starch–iodine or Minor’s test) and quantify (gravimetric test) safe and showed statistically significant quantitative reduction
the sweating. These tests are the most widely used for the visu- of sweat production (93).
alization of the active sweat areas (76). Hexsel and cols. pro-
vided suggestions to perform the Minor’s test and presented a
Microdosing for Oily Skin, Acne, and Rosacea
new scale (Sweating Intensity Visual Scale) to better evaluate
and interpret Minor’s test results (76). Besides these methods, BoNT-A reduces the production of sebum by sebaceous glands
the Hyperhidrosis Area and Severity Index (HASI) has been by proposed mechanisms of blocking acetylcholine release in
developed to assess the HH taking into account not only the sebocytes and inducing paralysis in the arrector pili smooth
amount of secretion, but also the size of the secreting area muscle of follicular units since arrector pili contraction is
(77). Transepidermal water loss measurement has also been needed for sebum secretion. It also reduces pore size (94–96).
referred as a rapid, practical, and reliable technique for quanti- Dosing of 8–45 units is diluted, generally 1:4 to 1:5 solution
fying palmoplantar sweating (78). (97). Topical anesthesia is mandatory. Application is per-
Several treatments are used for HH and most of them formed at 1 cm intervals, intradermally, in a grid-like fashion,
cause significant adverse effects (64) or have limited efficacy forming small blebs (98). Reduced sebum production is gener-
in severe cases (75). Available treatments for HH include ally seen in up to 4 weeks and lasts for 4–6 months (94,99).
topical, medical, and surgical treatments. The Canadian Action in rosacea is proposed by modulation of other neu-
Hyperhidrosis Committee developed guidelines that provide ropeptides, such as substance P, the calcitonin gene-related
a recommended course of therapy for patients with different peptide (CGRP), and the vasoactive intestinal peptide (VIP)
focal hyperhidrosis based on the severity of disease, which is (100,101). BoNT-A reduces flushing, persistent erythema and
evaluated through the Hyperhidrosis Disease Severity Scale telangiectasias in this group of patients, with technique and
(HDSS) (75). duration of effect similar to acne treatment (102–110).
Botulinum neurotoxin type A is an irreversible inhibitor
of acetylcholine release from the presynaptic membranes of
neuromuscular junctions, preventing the release of this neu-
Complications and Side Effects
rotransmitter on the postganglionic sympathetic fibres that
act on the sweat glands (71). Since apocrine, eccrine, and The complications and adverse effects of the use BoNT-A are
apoeccrine glands respond to cholinergic stimuli, subcutane- usually transitory and, in most cases, technique-dependent
ous injections of BoNT-A into the sweating regions result in (35). There are isolated few reports of systemic adverse effects
complete cessation of sweating from all gland types (79). So after BoNT-A injections with the use of doses larger than those
far, no anatomical differences in sweat glands have been dem- usually recommended for cosmetic purposes (111).
onstrated between hyperhidrotic patients and control groups. The most common injection-related side effects are pain,
But after BoNT-A treatment morphological alterations in the transitory oedema, erythema, hematomas, and ecchymoses
glands’ ducts have been noticed (80). (35,111). Common technique-dependent complications include
Botulinum neurotoxin type A in the treatment of focal eyelid ptosis, asymmetries, and excessive brow elevation.
hyperhidrosis is considered fast, safe, and efficacious, and In the lower face, the most common complications are
rarely produces significant side effects (81). The application is related to high doses or erroneous application of BoNT-A.
usually intradermal because it targets the sweat glands, which These can cause undesirable paralysis of the musculature,
are located 2.5 mm below the skin (72). A recent study (82) resulting in asymmetric smiling and complications due to the
showed that the field of anhidrotic effects (FAE) does not vary incompetence of the sphincter function of the mouth (111).
significantly when the same doses in different dilutions and Some symptoms appear as a consequence of lip movement
depths are injected on the back of patients suffering from com- difficulties, as in swallowing, speaking, smoking, whistling
pensatory hyperhidrosis. This study also showed that areas of or playing wind instruments, involuntary biting of the tongue,
more intense sweating, like the midline of the back, needed lip paresthesia, filter disappearance, and difficulties in specific
twice the doses to achieve similar size of the FAE (82). These lip movements, such as spreading lipstick with the lips and
results supported the previous findings of the present author, involuntary dribbling during speaking (35). Thus, caution is
who stated that brand, usual dilutions, and depths are less required for musicians who play wind instruments, profes-
important in the size of the FAE or “diffusion” than dose and sional singers, speakers or actors because of the chance to have
amount of sweating of the treated areas (83). difficulties with lip proprioception after treatment.
Ideal doses have been focus of discussion, aiming to obtain The most common complications in the treatment of the
more efficacious and lasting results. Table 38.6 lists some of neck are dysphagia and difficulties in flexing the neck and
the published articles with the proposed doses for the treat- nodding (112).
ment of axillary, inguinal, and palmar HH. The average dura- In some focal forms of hyperhidrosis, some transitory
tion of effects is also reported. compromising of the adjacent musculature can occur (113).
Although some reports refer multiples treatments do not Patients who perform minutely detailed activities with the
interfere in the duration of effects (91), Lecouflet and cols hands, such as artisans, pianists, and others, deserve special
suggest an increase in the duration of efficacy of botulinum attention (113). Residual areas of hyperhidrosis and asymme-
injections with the repetition of injections (92). Glogau have tries are also reported with the use of BoNT-A.
described the use of topical applications of BoNT-A in treat- In microdosing, inadvertent use of higher doses may lead to
ment of axillary hyperhidrosis. This technique appeared to be muscle paralysis, especially in the midface (99).
TABLE 38.6
Proposed Doses for the Treatment of Axillary, Inguinal, and Palmar HH
Authors HH area Study design Patients Treatment Results Duration
Heckmann (71) Axillary R, DB, PC, 145 200U (ABO) unilaterally vs. Similar reduction in 26 weeks for
(2001) multicenter placebo sweating with 200 U and both groups
Placebo-treated side received 100 100 U doses.
U after 2 weeks
Naumann and Lowe Axillary R, DB, PC, parallel 320 50 U (ONA) vs. placebo Response at week 4: 94% 16 weeks
(84) (2001) group (active group) vs. 36%
(placebo)
At week 16: 82% (active)
vs. 21% (placebo)
Galadari (85) (2003) Axillary Case series 15 125 U (ABO) 93% of the patients 1–6 months
showed anhidrosis after
1 week
Hexsel (72) (2004) Inguinal Case series 26 100 U (ONA) Improvement showed for 6–8 months
60 and 80 U can be used to treat inguinal HH for first
less severe cases time
Lowe (86) (2007) Axillary R, DB, PC, 322 50 or 75 U (ONA) or placebo 75% of the subjects with 6–7 months for
multicentre, Retreatment if HDSS score of 3 or at least 2-point the active group
parallel-group 4 and at least 50 mg of improvement in HDSS
spontaneous resting axillary sweat score at week 4
over 5 minutes in each axilla vs. 25% from placebo
Talarico-Filho (87) Axillary DB, R, prospective 10 50 U (ONA) on one side and 150 U Sweat rate decreased 260 days for
(2007) (ABO) on the other 97.7% (ONA) and ONA and 290
99.4% (ABO) days for ABO
Gregorious (88) Palmar Open label 36 100 U (ONA) per palm Significant improvement 6.2 months
(2010) and (assessed by gravimetry)
plantar Plantar HH: marginal
improvement in 12
patients and worsening
in 24
Frasson (89) (2011) Axillary R, SB, bilateral 10 50 U (ONA) vs. 2500 U of BoNT-B Both treatments were 6 months
paired (contralaterally) effective: reduction in
sweat weight.
BoNT-B more effective
than ONA
Dressler and Adib Axillary DB, intra-individual 51 First: 100U (ONA) bilaterally Both doses had similar 3–4 months
Saberi (90) (2013) comparison Then: Direct comparison 100 U effects
unilaterally vs. 50 U
contralaterally; 50 U bilaterally
(extension period)
Abbreviations: R, randomized; DB, double blind; SB, single blind; PC, placebo-controlled.
Knowledge of the anatomy of the facial muscles as well as

Other Recent Indications the use of proper technique are mandatory to reach predict-
able results and avoid complications. Differences between
Studies have shown the effects of BoNT-A in other condi- products and patients must be considered in all BoNT-A
tions or diseases, such as depression (114–117), Raynaud’s treatments.
phenomenon (118–120), Hailey–Hailey disease, hidradenitis BoNT-A treatments have greatly developed and increased in
suppurativa, Pompholyx, Darier’s disease, and inverse psoria- the last few years with new potential uses. It is nowadays one
sis (110,121,122), among others. Further studies are needed to of the most performed minimally invasive procedures for skin
establish effective doses and safety. rejuvenation.
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39
Soft Tissue Augmentation
Joanna Dong and C. William Hanke
scaffolding, and loosening retaining ligaments. Current trends

Introduction in modern rejuvenation are to achieve a natural appearance
through volumization, repositioning, and improvement of skin
In the past several decades, minimally invasive aesthetic quality through multimodal treatment. Fillers and biostimula-
procedures have steadily overtaken surgical procedures in tors provide a key therapeutic to volumize age-related or HIV-
the global aesthetic market. Now, injectables account for the associated hollowing of the face, to improve atrophic scars
majority of the non-invasive aesthetic treatment market in the from trauma or acne, to augment existing facial structures, to
United States. This remarkable growth has been attributed diminish static rhytides, and to improve skin quality by stimu-
to advancing technology that create a more natural aesthetic lating neocollagenesis.
result with minimal adverse effects, patient desire for less Treatment of the face with soft tissue augmentation may be con-
downtime after aesthetic procedures, and social media aware- ceptualized by anatomic region: upper face, midface, and lower
ness that destigmatizes these procedures. face. It is important to note for all anatomic indications of facial
Soft tissue augmentation is a mainstay of the aesthetic arma- filler use, combination aesthetic treatment in conjunction with
mentarium that plays an important role in the multi-modality neurotoxin injections and energy-based devices provide the most
treatment of aging. effective overall results compared to facial fillers alone [2–4].
Several injection techniques have been described and are
utilized by injectors based on personal preference, anatomic
Historical Perspective situations, and filler choice. The main techniques are serial
puncture, depot, linear threading, cross-hatching, and fanning.
Multiple types of fillers have been utilized in soft tissue aug- Further, needle (most commonly 23 g–32 g) or cannula (most
mentation since the early 1900s, from autologous fat injections commonly 21 g–25 g) may be utilized in any anatomic loca-
to the repurposing of liquid silicone for cosmetic injections. The tion. Studies comparing cannula and needle use demonstrate
first filler to be introduced in the United States for aesthetic use that all cannulas of larger bore than 27 g are safer than corre-
was medical grade silicone in the 1960s. However, use of unreg- sponding needle sizes in terms of intraarterial penetration [5].
ulated adulterated forms of silicone led to severe complications, Overall, intravascular occlusion incidence was less likely with
including necrosis, foreign body granuloma, and migration; sili- cannula use compared to needle use, though this difference
cone has since fallen out of favor in modern aesthetic use [1]. In diminished with increasing years of injector experience [6].
the 1990s, the Food and Drug Administration (FDA) issued a
warning against injectable silicone use as soft tissue augmen-
Upper Face
tation. Bovine collagen was developed in the 1980s and after
FDA approval, marketed as Zyderm and Zyplast in the United The forehead, glabella, brow, and temporal fossa of the upper
States. Collagen dominated the aesthetic filler market until third of the face is amenable to filler augmentation.
newer fillers without need for pre-testing and with more favor- Static rhytids of the forehead and glabella can be directly
able safety profiles were developed. Since the early 2000s, the treated by low volume (0.1–0.2 mL per rhytid) serial puncture
number of approved facial fillers in the United States, Europe, injection in the superficial dermis. Forehead contouring with
and Asia has grown rapidly, with an expansive assortment of fillers may be indicated for restoration of age-related hollow-
filler material, crosslinking technology, and biostimulatory ing of the middle third of the forehead. Deep supraperiosteal
action. This chapter will discuss current injectable fillers which injections via cannula or depot needle injections can be placed
include hyaluronic acid (Belotero, Restylane, Juvederm, RHA, horizontally along the forehead hollow, around 2 cm above the
Revanesse), calcium hydroxylapatite (Radiesse), poly-L-lactic periorbital rim, with proper massaging post-injection. Given
acid (Sculptra), and polymethylmethacrylate (Bellafill). the proximity of the supraorbital and supratrochlear vessel
bundle coursing vertically along the forehead, the least vol-
ume necessary to achieve the effect should be used, around a
maximum of 0.4 to 0.6 cc across the entire forehead to prevent
Indications and Injection Technique
vascular occlusion [7].
Aging of the face is the result of a complex interplay of cutane- Eyebrow contouring and shaping can be achieved with
ous laxity, decreased muscle tone and adiposity, loss of bony minimal filler at the lateral aspect of the brow in cases where
DOI: 10.1201/b22897-39 393

neurotoxin provides insufficient lifting effect. Filler can be or dark shadowing. This is caused by a combination of genetic
injected with cannula or needle in the subdermal and/or supra- predisposition toward fat pad herniation, orbital retaining liga-
periosteal plane deep to the brow and lateral to the mid-pupillary ment weakening, and volume loss. Of note, treatment of the
line to avoid the supraorbital artery; this can improve age- medial cheek can itself correct tear trough deformities to some
related brow ptosis and upper eyelid hooding. An aesthetically extent and if indicated, should be performed prior to targeting
desirable brow arch (“Anastasia” shape) can further be achieved the tear trough directly. Typical injection technique is using
by filler injection into the apex of the eyebrow at the temporal needle (29 g to 32 g) with bolus or cannula (25 g) microdro-
crest [8]. Low volumes (<0.5 cc per brow) should be injected to plets with entry point around 2 cm inferior to the infraorbital
avoid overcorrection, as there is a high risk of filler migration or rim and lateral to the mid-pupillary line. If needle is used,
persistent eyelid edema with excess filler volume [9]. filler should be placed in the supraperiosteal layer with the
Temporal fossa hollowing and wasting is commonly seen in point of the needle touching bone. Low volumes should be
the aging face or in HIV-associated lipoatrophy. The temples used, around 0.2 to 0.5 mL per side per treatment session, err-
are the most common indication for soft tissue augmenta- ing on the side of undercorrection. This anatomic region has
tion of the upper face and a natural focal starting point for high propensity towards filler migration if overcorrected [17].
the “upper and lateral face first” treatment approach to maxi- Filler augmentation of the nose, termed a “liquid rhino-
mize filler effect [10]. Multiple injection techniques have been plasty,” can address aesthetic concerns that would otherwise
proposed, the most common of which is a single supraperios- require surgical rhinoplasty. Indications include correction
teal depot injection of filler “one up one over” from the lat- of a dorsal hump, nasal tip underprojection, nasal deviation,
eral supraorbital tubercle [11]. Injection technique in the more and alar rim collapse. This is an anatomic region of especially
superficial subcutaneous fat plane is largely avoided as the high risk as injection of the nasal region has resulted in the
superficial temporal artery and vein and the temporal branch highest incidence of blindness in recent years. This is because
of the facial nerve all run more superficially in this anatomic the vessels of the nose directly anastomose with the ophthal-
region. A maximum of 1 cc should be injected in each temple mic artery system and retrograde embolization of filler can
in a single visit to prevent compression of superficial temporal travel upstream to occlude the ophthalmic artery [18]. Caution
artery. should be exercised regardless of needle or cannula use. Many
variations of techniques have been described to prevent intra-
vascular injection, including small bore needle (27 g to 32 g)
Midface
with bevel down and large bore cannula (22 g to 25 g) with
In the midface, the medial cheeks, lateral zygomatic cheeks, entry point in the infratip lobule or dorsal hump [19–22]. All
tear troughs, nose, and the nasolabial fold extending to the oral injections should be performed in the midline in the avascular
commissures can be treated for volume restoration or lifting supraperichondrial or supraperiosteal plane.
effect. The goals for treatment in these areas are for improve- Deep nasolabial fold (NLF) creases are a combination
ment of eyebags or hollows, dark infraorbital shadowing, age of aging and genetic phenotype predisposition. Correction
or disease related volume loss of the cheeks, and inaesthetic of temple, medial cheeks, and lateral cheeks should first be
prominence of the nasolabial fold. undertaken as this is often more effective to soften this crease
The anatomic underpinnings of midfacial aging are the most due to superolateral vector lift. The NLF can be directly
complex of all structures in the face and therefore, strategies treated with cannula or needle in the superficial subcutaneous
of rejuvenation should be tailored accordingly. The medial and fat plane. Deeply set pyriform fossa can additionally be treated
lateral cheeks have deep fat compartments (lateral suborbicu- by a needle bolus injection directly on the supraperiosteum
laris oculi fat, medial suborbicularis oculi fat, and deep medial with needle tip touching bone to avoid intravascular injection.
cheek fat) and superficial fat compartments (infraorbital fat,
middle cheek fat, medial superficial cheek fat, and nasolabial
Lower Face
fat). Midface volume loss is hypothesized to be a combination
of age-related deep fat compartment loss (more so than super- Crucial anatomic regions to an aesthetically rejuvenated
ficial fat compartment loss), bone resorption, genetic predis- appearance of the lower face are the lips, marionette lines
position to nasolabial fold prominence, and soft tissue descent (melolabial folds inferior to the oral commissures), chin, and
with age-related waning of retaining ligamenture strength that jawline.
results in midface grooves [12–14]. Therefore, efficient volume The lips are one of the most technical areas to sculpt and
restoration of the medial and lateral cheeks with the minimal contour with soft tissue augmentation. It consists of preserv-
necessary filler involves first injecting the deep fat compart- ing and appropriately enhancing its cosmetic subunits (cupid’s
ment and subsequently volumizing the lateral aspects of the bow, white roll, philtrum, tubercles, and vermillion borders)
superficial fat compartment to induce an “up and out” vector as well as maintaining ethnically sensitive ratios between the
of midfacial lift [15]. Both the deep and superficial fat com- upper and lower lip (1:1 to 1:1.6 in Caucasians and 1:1 in Blacks
partment can be injected via needle depot injections or with and Asians) [23–25]. Numerous injection techniques have been
cannula fanning techniques. For efficiency of entry points, a popularized including with 25 g cannula (entry point at four
single site has been described by which a 1.5 to 2 inch (38 to 50 sites: upper right, lower right, upper left, and lower left vermil-
mm) cannula can access a majority of the midface [16]. lion border near the oral commissures), threading with small
The tear trough is the infraorbital area that commonly bore needle (30 g to 32 g) horizontally along the lips, or serial
causes aesthetic concerns with age-related hollowing, grooves, puncture with small bore needle in vertical columns along the
Soft Tissue Augmentation 395
lips [26,27]. All injections should occur in the subcutaneous fat Many of the current hyaluronic acid (HA) products and
or submucosal layer, taking care not to inject too superficially calcium hydroxylapatite are commercially premixed with
to prevent the Tyndall effect. Caution should be observed to lidocaine to reduce intraoperative discomfort. Lidocaine can
avoid intraarterial injection of the superior and inferior labial further be added to poly-l-lactic acid or any commercial HA
artery labial artery. product without lidocaine to provide anesthetic effect. As the
Marionette lines are the static creases of the melomental filler or biostimulator with lidocaine is injected, subsequent
folds that are created by the interaction between the jowl fat injections are infiltrated into areas that are already numb.
compartments and the mandibular ligament with aging. This However, the initial stick still requires anesthesia for patient
creates a striking downturn of the oral commissures. Common comfort. Topical anesthesia is a mainstay of pre-injection pain
injection technique is use of needle (27 g to 30 g) or cannula prevention given its ease of use, as long as 30 to 60 minutes
(22 g to 25 g) in the superficial to mid subcutaneous fat depth, of numbing time is blocked out by the patient and the physi-
targeting the anteroinferior prejowl sulcus up to the lateral cian schedule. Various anesthetic mixtures (benzocaine/lido-
lower cutaneous lip. Placement of filler at the modiolus and caine/tetracaine, lidocaine/tetracaine, lidocaine alone) have
the lateral upper cutaneous lip can upturn the oral commis- been safe and efficacious in providing sufficient pain relief
sures and improve the marionette lines. prior to soft tissue augmentation injections [29]. Application
The jawline and prejowl sulcus are integral to rejuvenation under occlusion may provide an even greater anesthetic effect.
of the lower face. As the mandible resorbs with aging, the Topical ice packs can provide a similar anesthetic effect to top-
jawline extending from the ghonial angle to the chin loses its ical anesthesia mixtures, are relatively inexpensive, and do not
youthful smooth lines, contributing to an aged and sagging require a prolonged pretreatment icing period [30]. Injectable
appearance. It is recommended to correct lateral structures anesthesia (lidocaine with or without epinephrine) is less com-
first, such as the ghonial angle, prior to injecting the prejowl monly used during a filler injection visit as it can distort facial
sulcus as this can reduce the amount of product necessary anatomy and volumize the subcutaneous space. However, it
overall. Depot or threading needle (27 g or 28 g) injection can can be utilized in small volumes in specific cases to provide
be used in the supraperiosteal layer. Cannula (22 g to 25 g) maximal relief from discomfort. An intramucosal block of the
injection is in the mid subcutaneous fat layer. Use of a com- mental nerves and alveolar nerves can provide total anesthesia
bination of needle and cannula can augment multiple planes for lip filler without distorting anatomic architecture. If can-
of depth, if necessary. Gender-sensitive care should be taken nula is to be predominantly used, 0.1 to 0.2 cc of lidocaine
in sculpting the jawline, as the masculine jawline is more with epinephrine can anesthetize each planned entry site to
angulated at the ghonial angle compared to the feminine jaw- ensure patient comfort with the needle introducer and cannula
line [28]. Often correction of prejowl sulcus is performed at puncture.
the same time as correction of marionette lines. The facial Needle and cannula size can additionally play a role in
artery courses over the jawline anterior to the masseter and patient injection comfort. Up to 30% of young adults express
caution should be exercised in this region. needle fear and needle phobia, to the point of hospital and
Age-related bone resorption can lead to a recessed chin that is physician avoidance [31]. Intuitively, the smaller the needle or
deficient in 3-dimensional projection and/or in length and width. cannula bore size, the less discomfort patients will feel. The
The chin also contributes key anatomic markers of masculinity difference between 30 g and 32 g in terms of injection dis-
(squared and wide chin) and femininity (tapered and thinner comfort is perceptible to patients [32]. Therefore, the small-
chin). Augmentation of the chin can be technically complex, est bore needle compatible with choice of filler or anatomic
as different angles and locations for injection can contribute to region should be used. Further, repeat injections with the same
length, width, and anterior projection. With cannula use (22 g to needle leads to blunting and needle deformation that makes
25 g), injection depth is typically in the deep subcutaneous fat subsequent injections more painful and less precise. It is rec-
layer and product can be fanned to correct contour irregulari- ommended to consider changing to fresh needles after every
ties. Needle injections (25 g to 27 g) with depot technique can five injections in the subcutaneous fat and every three injec-
better access the less vascular supraperiosteal layer. tions with bone contact [33].
Other Sites
Soft tissue augmentation of areas off the face, including the
Hyaluronic Acid (HA) Fillers
neck, décolletage, upper arms, thighs, and buttocks will not be HA is a member of the glycosaminoglycan family and a
discussed in this chapter. natural component of the extracellular matrix in human con-
nective tissue. The HA molecule is identical across all spe-
cies and lacks a protein component, thus it has little to no
potential for immunologic reaction in humans. Over years
Pre-Injection Preparation/Anesthesia
of aging, sun exposure, or disease-associated hollowing, the
Pain management is of utmost importance during every cos- amount of endogenous HA in the skin decreases, reducing the
metic visit for soft tissue augmentation. Even if the cosmetic skin’s water-binding capacity and turgor, ultimately leading
outcome is a success, patients with excessive discomfort dur- to skin wrinkling, sagging, and loss of hydrated sheen. HA
ing cosmetic procedures may report dissatisfaction and are filler is composed of repeating disaccharide units stabilized
less likely to return for subsequent treatments. with cross-linked hydroxyl groups that absorbs 1000 times its
molecular weight in water to improve skin turgor, volumize, treat. G’ is a measure of the elastic properties of the HA gel.
and restore hydration. HA gels come in pre-packaged syringes In general, the higher the G’, the greater the lift capacity of a
and do not require refrigeration. This ease of packaging, bio- filler, however this does not always correlate across products
compatibility, and the availability of commercial hyaluroni- that utilize different crosslinking technology. Exact G’ mea-
dase, the reversal enzyme for HA, makes HA filler the soft surements of branded products have been published and vary
tissue filler of choice for facial rejuvenation. across rheologic laboratories[36,37]. For purposes of this chap-
While native HA behaves more as a fluid and undergoes ter, HA fillers and appropriate uses will be conceptualized as
high rates of turnover within the skin (half-life of 24 to 48 low, medium, and high lifting capacity (Table 39.1). Correction
hours), commercial HA filler is chemically modified with of the upper face will call for medium to high lifting capacity
covalent crosslinking to produce cross-linked HA that is resis- fillers due to the thickness of the skin and the predominance
tant to enzymatic degradation and therefore lasts longer in the of supraperiosteal injections. The malar and zygomatic cheeks
skin (several months) [34,35]. The type of cross-linking and require medium to high lifting capacity depending on the vol-
the concentration of cross-linked HA in a formulation impart ume restoration that is required. Low G’ fillers should be used
varied characteristics in the degree of hardness, amount of for tear troughs given the natural thinness of the skin and the
lift, duration of effect, and resistance to degradation by heat or propensity for lumpiness and overcorrection. The nose has
enzymes that are seen across different branded formulations natural overlying stiff sebaceous tissue and requires high G’
of HA filler. filler to provide effective contouring. Correction of chin, pre-
Table 39.1 lists the plethora of HA filler products available in jowl sulcus, and jawline necessitates high G’ filler, especially
the United States market. While HA fillers are FDA approved for the supraperiosteal injection plane, as maximal projection
for treatment of specific anatomic units, in the hands of expe- is necessary in this region. Medium G’ filler can be used for
rienced injectors with knowledge of filler properties, many fill- marionette lines as natural dynamic movement is prioritized.
ers can be appropriately used off-label in multiple sites. The Lip filler should be soft and malleable, with low to medium
elastic modulus (G’) has traditionally been used by injectors G’. Low G’ filler that does not produce a Tyndall effect (blue
to compare the stiffness and lifting capacity of different fill- discoloration of superficially placed HA filler) should be used
ers, which determines the anatomic regions each product can for direct correction of fine rhytids such as on the glabella
TABLE 39.1
Current FDA-Approved Hyaluronic Acid Fillers with Categorization of Lifting Capacity
Brand name (U.S.) First FDA approval Current anatomic indication Lifting capacity (G’)
Restylane 2005 Moderate to severe facial rhytides and folds High
Lip augmentation
Restylane Silk 2014 Lip augmentation Low
Perioral rhytides
Restylane Lyft 2015 Moderate to severe facial rhytides and folds High
Cheek augmentation and midface contour deficiencies
Dorsal hand
Restylane Refyne 2016 Moderate to severe facial rhytides and folds Low
Restylane Defyne 2016 Moderate to severe deep facial rhytides and folds Medium
Restylane Kysse 2020 Lip augmentation Low
Upper perioral rhytides
Restylane Contour 2021 Cheek augmentation and midface contour deficiencies Medium
Juvederm Ultra XC 2010 Moderate to severe facial rhytides and folds Low
Lip augmentation and perioral area
Juvederm Ultra Plus XC 2010 Moderate to severe facial rhytides and folds Medium
Juvederm Voluma XC 2013 Cheek augmentation High
Chin augmentation
Juvederm Volbella XC 2016 Lip augmentation Low
Perioral rhytides
Undereye hollows
Juvederm Vollure XC 2017 Moderate to severe facial rhytides and folds Medium
Juvederm Volux XC 2022 Moderate to severe loss of jawline definition High
Belotero Balance 2011 Moderate to severe facial rhytides and folds Low
RHA Redensity 2021 Moderate to severe dynamic (vertical) perioral rhytides Low
RHA 2 2017 Moderate to severe dynamic facial rhytides and folds Low
RHA 3 2017 Moderate to severe dynamic facial rhytides and folds Medium
RHA 4 2017 Moderate to severe dynamic facial rhytides and folds High
Revanesse Versa+ 2017 Moderate to severe facial rhytides and folds Medium
Revanesse Lips+ 2020 Lip augmentation Low
and perioral region (e.g. Belotero, RHA Redensity, Juvederm augmentation in 2015 and for jawline contouring in 2021. CaHA
Volbella XC, Juvederm Ultra XC, Restylane Silk). Suggested is a non-allergenic bioceramic that is identical to the primary
injection patterns for HA fillers are depicted in Figure 39.1. mineral constituents found in bone and teeth. CaHA has sev-
HA fillers have an average duration of 6 to 12 months. The eral properties that make it an important tool in facial recon-
duration of effect is influenced by the specific crosslinking touring, including lack of allergenicity, long-lasting effects, and
technologies used across brands, with the Vycross technol- high elasticity. Radiesse contains microspheres of CaHA, 25
ogy in Juvederm products perhaps contributing to the longest to 45 μm in diameter, in a soluble carboxymethylcellulose gel
duration prior to enzymatic degradation. However, the poten- carrier, which acts as both a soft tissue filler and biostimulator
tial cost of more long-lasting HA fillers is their propensity of neocollagenesis. After the CaHA is injected, the gel carrier
for inflammatory nodules and hypersensitivity reactions that is phagocytized, leaving behind CaHA microspheres to act as
persist for longer. Beyond the inherent properties of HA filler, a scaffold for autologous collagen synthesis [38–40]. As time
other factors can contribute to duration of effect, such as the passes, the CaHA microspheres are gradually broken down via
presence of progressive disease-associated wasting or an indi- normal metabolic processes into calcium and phosphate ions
vidual’s metabolic activity. and are removed by the renal system. New tissue deposition
and collagen proliferation in combination with the slow break-
down of the CaHA are responsible for the prolonged effects of
Radiesse, often 12–18 months. There is no reversal agent for
Calcium Hydroxyapatite (Radiesse)
CaHa and removal of material can only be done by procedural
Injectable calcium hydroxylapatite (CaHA), also known as extraction or awaiting natural metabolic breakdown.
Radiesse® (Merz Pharmaceuticals GmbH, Frankfurt, Germany) Currently, CaHA is widely used for pan-facial (most com-
was first used in 2002 and initially approved by the FDA for monly temple, cheeks, prejowl sulcus, chin, and jawline)
vocal fold insufficiency, oral/maxillofacial defects, and radio- volumization, contouring, and biostimulation, as well as
graphic tissue marking. In 2006, it was approved for treatment rejuvenation of non-facial sites (neck, décolleté, upper arms,
of moderate to severe facial wrinkles and for HIV lipoatrophy. thighs, buttocks, and abdomen). It is not advisable to use
Most recently, Radiesse received FDA approval for dorsal hand CaHA in hyperdynamic areas like lips and upper cutaneous
FIGURE 39.1 Possible treatment areas of the upper face (blue), mid face (green), and lower face (red) with hyaluronic acid (HA) filler. Supraperiosteal
placement with needle is indicated in large dot in lighter color tone. Straight line with arrows indicate cannula pathway with small dot suggesting entry
point. Wavy line with arrows indicate injection of fine line rhytids, injected at superficial dermal depth. Forehead, temple, nose, pyriform fossa, chin,
and jawline are injected at supraperiosteal depth. Cheeks, tear troughs, and brows are injected at supraperiosteal or subcutaneous fat depth. Nasolabial
fold, marionette lines, lips, and preauricular region are injected in the subcutaneous fat and supramuscular depth.
lip or in areas of high risk for vascular occlusion such as gla- session. Maintenance injections after the first year can be per-
bella and nose. Skin testing is not required prior to injection. formed on a yearly basis.
Commercially available CaHA, Radiesse®, is sold as a white, Needle or cannula can be used for injection of CaHA depend-
sterile, semisolid gel in a 1.3 mL syringe without lidocaine or ing on anatomic region and the dilution used. CaHA should be
as Radiesse®+ in a 1.5 mL syringe premixed with 0.3% lido- injected slowly in either an anterograde or retrograde fashion
caine. Initial adoption of CaHA into the pan-facial and pan- into the subcutaneous fat or supraperiosteal planes using a 22
body rejuvenation armamentarium was limited by concern for to 25 g cannula or 27 to 30 g needle. Gentle massaging of
generalized lumpiness after injection due to the thickness of any irregularity or nodularity should be performed immedi-
the product or longer-term granulomatous nodule formation. ately after injection, especially if more concentrated CaHA is
The rates of nodularity were as high as 6.5% in multiple stud- used. Injectors should be cognizant of vascular danger zones
ies, and injections into the lips were considered the highest risk and use extreme caution given the increased risk of emboliza-
areas [41,42]. The advent of dilution and hyperdilution injection tion in these areas and the lack of reversal agent for CaHA.
techniques led to more popular use of Radiesse and its applica- As with other soft tissue fillers, a plethora of techniques have
tion across multiple anatomic regions. Current consensus sug- been described including linear retrograde, tunneling, thread-
gests diluting Radiesse+ (with lidocaine) 1:1 for face, hands, ing, serial puncture, fanning, and cross-hatching, and often the
abdomen, cellulite, striae, and acne scars, and hyperdiluting technique utilized is guided by personal preference and loca-
1:2 up to as high as 1:6 for neck, arms, legs, décolletage, and tion being treated. Overcorrection is not recommended.
buttocks [43]. In general, more concentrated CaHA prioritizes Areas of volume loss well suited for treatment with
volumizing and contouring while more diluted CaHA priori- Radiesse and their associated injection techniques are shown
tizes biostimulation and improvement of skin texture. More in Figure 39.2.
dilute CaHA is easier to inject superficially without concern
for nodularity or irregularity. Dilution should be performed
with lidocaine or lidocaine in combination with normal saline
PLLA (Sculptra®)
to assist with patient comfort with injections.
Treatment intervals can be around one to three sessions in Injectable poly-L-lactic acid (PLLA) has been used worldwide
the first year, with follow-up every 3 to 4 months after each since the 1990s as a pure collagen biostimulator to improve
FIGURE 39.2 Possible treatment areas of the upper face (blue), mid face (green), and lower face (red) with CaHA (typically diluted 1:1) for pan-
facial rejuvenation. Needle depot placement is indicated in large dot in lighter color tone. Cannula or needle threading placement is indicated by
straight line with arrows in darker color tone. Small dot in darker color tone is suggested cannula entry point. Temple, jawline, and zygoma injected at
supraperiosteal depth. Other regions are injected at subcutaneous fat depth.
age-related volume loss or HIV or disease-related lipoatrophy injection (cheeks, preauricular areas) and fanning, depot, or
in the long-term. Injectable PLLA is composed of 40 to 63 retrograde linear threading technique for supraperiosteal
μm microparticles of poly-L-lactic acid, a synthetic polymer injection (medial maxillary area, zygomatic area, temples,
of lactic acid from the alpha-hydroxy-acid family that has been prejowl sulcus, chin). Prior to injection, the mixed product is
used in medicine in the form of absorbable sutures (polygla- typically drawn into 3-mL syringes and a 25 g needle or 22 g
ctin 910) for decades [44]. PLLA was first approved in 1999 blunt tip cannula are often used for all injection locations and
in Europe (New-Fill®, Biotech Industry SA, Luxembourg) planes. Clumping of the mixed product is common so larger
for soft tissue augmentation of scars and wrinkles. In 2004, bore needles and cannulas are recommended. Post-treatment
injectable PLLA was approved in the United States (Sculptra®, massage should be performed immediately after injection and
Galderma Laboratories, Fort Worth, TX, USA) for the treat- the patient should continue self-massages for several days after
ment of HIV-associated lipoatrophy. In 2009, it received treatment. Commonly the “5–5-5” rule is employed for post-
further FDA approval for the correction of shallow to deep care instructions to the patient (self-massage 5 times per day, 5
nasolabial fold contour deficiencies and other facial rhytids minutes each time, for 5 total days after injection).
under the brand of Sculptra® Aesthetic. As with injection of CaHA, the same understanding of
Injectable PLLA as a pure biostimulator differs from other facial anatomy and associated safety considerations to avoid
facial fillers such as HA in that it does not directly fill in lines or injection into vasculature or nerves is necessary with PLLA
depressions. It creates the appearance of immediate volumiza- injections.
tion due to the hydrostatic effects of the injected suspension, Figure 39.3 illustrates common areas of volume loss and
but this disappears within a few days as the suspension fluid associated site-specific injection techniques recommended by
is absorbed. The long-lasting effects of injectable PLLA are the authors when treating with injectable PLLA.
seen in the months that follow as the microparticles degrade, It is important to counsel patients that the immediately
inducing a fibroblastic host response and de novo collagen syn- observed effects will fade over the following days as the
thesis, resulting in gradual correction of the volume-depleted injection fluid is absorbed. Moreover, overcorrection must be
areas caused by lipoatrophy or age-related changes. Cosmetic avoided, because as outlined previously, injectable PLLA is
benefits in treated areas last for 2 years or more [45]. a progressive collagen-stimulating product that will gradu-
PLLA is currently used for pan-facial (temple, lateral brow, ally volumize over the following weeks to months. Injectable
cheeks, preauricular region, jawline and prejowl sulcus) reju- PLLA requires multiple treatment sessions (on average three
venation, acne scar treatment, and off-facial rejuvenation of to four) in the first year with one to two vials per treatment ses-
the neck, décolletage, arms, abdomen, buttocks, and thighs. sion at 4 to 6 week intervals to restore volume. Maintenance
Injectable PLLA is biocompatible, biodegradable, and immu- sessions can be performed on a yearly basis thereafter.
nologically inert, thus no skin testing is required. Reconstitution
practices is the key to appropriate and effective use of PLLA.
After its original FDA approval, Sculptra initially called for a
Polymethylmethacrylate (PMMA; Bellafill)
reconstitution volume of 3 to 4 mL with sterile water for injec-
tion. However, later clinical trials and consensus recommen- Bellafill® (Suneva Medical, San Diego, CA, USA), previously
dations in the United States and Europe have established the Artecoll® and Artefill®, as FDA approved in 2006 for the cor-
modern reconstitution technique of 9 mL for facial injection rection of nasolabial folds and in 2014 for acne scars, follow-
(typically 8 mL sterile water for dilution and 1 mL of lidocaine ing earlier use in Europe and other parts of the world in the
with or without epinephrine) to reduce incidence of papules 1990s. It is a suspension containing 20% PMMA suspended
and nodules [46,47]. The safety and efficacy of immediate in 80% bovine collagen and lidocaine. Bellafill is the only
use after reconstitution with this volume has been established permanent injectable filler currently on the U.S. market. Once
in a clinical trial of 80 subjects for correction of nasolabial injected, it can only be removed by surgical or procedural
folds, such that in 2021, the FDA approved an updated label for extraction. The bovine collagen provides initial correction and
Sculptra Aesthetic to include this higher dilution and immedi- is degraded over several months, leaving behind the PMMA
ate use procedure [47]. In this study, Sculptra Aesthetic was microspheres. Given the bovine component, pre-treatment
reconstituted with 8 mL of sterile water for injection and 1 mL skin testing is necessary. Sensitivity to bovine collagen and
of 2% lidocaine, shaken vigorously for 1 minute, and no stand- animal derivation as well as granulomatous reactions to a per-
ing time was allowed prior to injection [47]. Previous to this, manent product remain areas of concern. In terms of the latter,
reconstitution was recommended to be performed at least formulation changes to Bellafill from precursor PMMA prod-
24 hours prior to injection, which was often impractical in the ucts (Arteplast®) has decreased the overall adverse event rate
clinical setting. For treatment off the face, current consensus to 0.11% of syringes [49].
guidelines recommend a hyperdiluted volume of 16 mL (14 mL
of sterile water for injection and 2 mL of lidocaine with or
without epinephrine) [48].
Injection technique should ensure full and even coverage of
Safety and Complications
the treatment area and in the deep subcutaneous fat or supraperi- Common adverse events immediately after injection of all
osteal layer to prevent visible papules or granules. Depending soft tissue augmentation products include erythema, swell-
on injector comfort and experience with different techniques, ing, and ecchymoses in the days following treatment, which
we recommend the fanning technique for deep subcutaneous can be mitigated by immediate pressure following injection
FIGURE 39.3 Possible treatment areas of the upper face (blue), mid face (green), and lower face (red) with PLLA for pan-facial rejuvenation. Needle
depot placement is indicated in large dot in lighter color tone. Cannula or needle threading placement is indicated by straight line with arrows in
darker color tone. Small dot in darker color tone is suggested cannula entry point. Temple and jawline injected at supraperiosteal depth. Zygoma and
preauricular region are injected at subcutaneous fat depth.
and periodic post-op icing. To alleviate tenderness associated Vascular occlusion and tissue necrosis is the most feared
with swelling in the days that follow treatment, acetaminophen complication of filler or biostimulator injection. Vascular
is preferred over NSAIDS to prevent worsening of bruising. occlusion can occur via direct injection of filler or biostim-
Patients may also note asymmetry or nodular lumps after ulator into a vessel causing an embolism or by hydrostatic
treatment which can be largely avoided by careful injection compression of a vessel due to high volume of product placed
technique and post-injection massage. Dysesthesia and anes- nearby. Early recognition is key. Patients often report immedi-
thesia can occur immediately after inadvertent nerve trauma ate exquisite pain upon injection into a vessel. Discoloration
by the needle or cannula, direct injection into the nerve, or due can occur within minutes or hours thereafter, starting as a live-
to lidocaine contained in the injected product. Nerve injury doid blush and eventually progressing to a violaceous reticu-
is rarely permanent and can take time to resolve. An initial lated ecchymosis, often in a clear vascular distribution. If
acute hypersensitivity can be evident by exaggerated swelling caught late, tissue necrosis will be evident. Ophthalmic artery
to the injected area, most commonly after lip injection with occlusion leading to partial or total blindness is a devastat-
HA filler. This should resolve after several days and can be ing consequence of filler or biostimulator embolism in a ves-
attenuated more quickly with short courses of antihistamines sel that closely anastomoses with this artery. While vascular
and oral steroids. occlusion of any facial area can theoretically cause this com-
Longer-term complications include infection with bacteria, plication, the majority of documented incidences were due to
fungus, or mycobacterium, herpes simplex reactivation (espe- injection in the nose, glabella, forehead, and nasolabial fold.
cially after lip filler); delayed biofilm or abscess formation; for- HA filler carried the most risk, followed by calcium hydroxyl-
eign body granuloma formation; or severe immune reactions. apatite. From 2015 to 2018, one incidence of blindness due to
Management of these delayed complications have been exten- PLLA was reported [18].
sively reviewed in published consensus guidelines [50,51]. Injection technique and understanding of anatomy can be
In short, combinations of antimicrobials, intralesional triam- key to preventing vascular complication. Products without
cinolone, and immunosuppressants can be used to mitigate a reversal agent (PLLA, CaHA, PMMA) should largely be
these complications. avoided in high-risk areas, such as forehead, glabella, nose,
and pyriform fossa. Aspiration prior to injecting with a nee- 12. Rohrich, R.J., Y.J. Avashia, and I.L. Savetsky, Prediction
dle may be helpful. A slow injection rate with retrograde of Facial Aging Using the Facial Fat Compartments. Plast
or anterograde technique is also helpful. Use of cannula Reconstr Surg, 2021. 147(1s–2): p. 38s–42s.
has been shown to carry less risk of intravascular injection 13. Boehm, L.M., et al., Facial Aging: A Quantitative Analysis
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occlusion after filler injection involve warm compresses, Surg, 2021. 147(2): p. 319–27.
rebreathing into a paper bag, ocular massage (if ophthalmic 14. Galadari, H. and S.H. Weinkle, Injection Techniques for
artery occlusion), high-volume hyaluronidase injections, oral Midface Volumization Using Soft Tissue Hyaluronic Acid
aspirin, heparin, hyperbaric oxygen, and systemic steroids. Fillers Designed for Dynamic Facial Movement. J Cosmet
Hospitalization may be considered to achieve these treatment Dermatol, 2022. 21(3): p. 924–32.
measures [50,52]. 15. Salti, G. and R. Rauso, Facial Rejuvenation with Fillers:
The Dual Plane Technique. J Cutan Aesthet Surg, 2015.
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40
Chemical Peels
Philippe Deprez
Main types of peels: Alpha hydroxy acid peels are

Introduction mostly used for this exfoliation purpose.
Action mode: The activity of AHA on the corneo-
Various peeling formulas are currently available, many of cytes seems to be secondary to an action on ionic
them resulting of a more or less adequate combination of charges, to the inhibition of enzymes involved in the
chemicals whose aim is usually to peel the skin and induce a formation of ionic links. For example, AHAs could
skin rebuilding, an architectural restructuration. Some peels compete with sulfates and phosphates at the level of
consist of strongly destructive solutions, able to dissolve the sulfotransferases, phosphotransferases, or kinases,
full skin thickness; others are simply stimulating solutions involved in the formation of sulfated or phosphory-
with little destructive power; their application can induce a lated mucopolysaccharides, glycoproteins, sterols, and
nearly invisible skin desquamation. The difficulties of peels lipids. This could produce a lower quantity of electri-
procedure, the results, the inconveniences, and the side effects cally negative groups on the surface of keratinocytes
are often directly linked to the depth reached by the acids. and corneocytes and lower the adhesion forces with
Not much will be said about pre-peel skin conditioning in amines or basic aminated acids (electrically positive).
this chapter, breaking a quasi-dogma. Indeed, there is a pos-
sible way to do peels that makes this pre-peel strict condition- Basically, AHAs penetrate between cells, unsticking the
ing not often necessary. I just use peeling formulas that usually proteins responsible for corneo-desmosome adhesivity (it is
penetrate evenly and that dramatically slow down the imme- a non-covalent, electric link) and allowing the cells to sepa-
diate post-peel inflammatory reaction, mainly responsible rate from each other, inducing desquamation. Since there is
for postinflammatory hyperpigmentation (PIH). The rest is a no strict chemical reaction during this process, AHAs are not
question of good indication (don’t go too deep if not necessary) much consumed and have to be neutralized. Rinsing with a
and the practitioner’s ability or experience. basic solution stops their action.
Pre-peel conditioning is principally used when a quite deep
chemical peel has to be done on a phototype IV to VI: in this Clinical signs: Irritative erythema is usually the
case, molecules are used to equalize the acid penetration only visible sign.
(glycolic acid, tretinoin), to speed up epidermal regeneration Desquamation: Roughly, no desquamation is
(pre-peel tretinoin does that but immediate post-peel tretinoin clinically seen.
has a contrary effect; vitamins). Pre-peel conditioning is also Risks and Problems: Globally, this is not a risky
necessary to induce melanocyte sedation and lower the risk of depth. Main risks are a higher sensitivity to sun dur-
ing some days and a higher risk of skin infections.
post-inflammatory hyperpigmentation. Many other molecules
Neutralization is the main problem: if too early, it
can be used during pre- and post-peel periods.
gives no result; if too late, it could induce more side
effects. We will see later that this problem can be
avoided by using specific slow-release and self-neu-
Depths of Peels tralizing AHA mixtures.*
I usually consider seven depths of peels, as seen in Figure 40.1.

Depth 2—Intraepidermic Peel: VHS
Depth 1—Exfoliation: VHS The peel solution penetrates deeply into the epidermis, remov-
ing more cells; nevertheless, it does not touch any part of der-
The most superficial peel consists of simple exfoliation of stra- mis or the basal layer. The final touch of the skin is still more
tum corneum dead cells: it gives a good skin cleansing, a touch hydrated than in the case of simple exfoliation (depth 1). After
of better hydration. This “hydration touch” results in reality the peel, living keratinocytes are suddenly directly exposed to
of skin damage: the peel has removed the protective stratum air, sun, pollution, and dryness. They react, synthetizing more
corneum layer and the fingers are now directly in contact with TNFa (inducing a faster transformation of keratinocytes into
superficial keratinocytes. Keratinocytes are living cells (only
the most superficial layers are near to death), containing more
water than stratum corneum cells. * Easy Phytic Solution.
DOI: 10.1201/b22897-40 403

FIGURE 40.1 Graph showing the various possible depths of peel.
corneocytes) and sending a message to the basal layer in order

to stimulate basal layer turnover and substitute the removed
cells with new ones. At the same time another message reaches
the fibroblasts, responding by stronger synthesis of all the der-
mal intercellular matrix.
Intraepidermic peels (depth 2) give better results than depth
1 peels and can be used for treating superficial epidermal
melasma and many keratinization problems.
Main types of peels: Alpha hydroxy acid peels, alpha

ceto acids, trichloracetic acid (TCA), resorcine
peels, and salicylic acid can be used.
Action mode: We have roughly seen how AHAs
work. TCA is a proteocoagulant chemical. When in
contact with proteins, it coagulates them, modifying
their tridimentional structures in a way that does not
allow their normal function. All membrane proteins
are therefore damaged, making the keratinocytes
unable to survive. In the same time, intercellular
proteins are also coagulated.
Clinical signs: More clearly visible erythema can be FIGURE 40.2 Erythema: intraepidermal peeling.
seen, but no white pinpoints appear yet (Figure 40.2).
Desquamation: Can look like very thin dandruff.
skin has to be perfectly calculated, in relation with the skin
Risks and problems: Intra-epidermic peels are
permeability. The TCA application technique has to be per-
usually not dangerous. Nevertheless, cases of post
inflammatory hyperpigmentation (PIH) have been fect for even penetration. Resorcine and salicilyc acid are
seen, making prevention of this side effect nec- phenol derivatives, not widely used out of the United States.
essary when the skin is known to be sensitive. Treatments of large surfaces using phenol derivatives are sus-
Neutralization of AHAs remains the main problem pected to potentially induce toxic reactions. TCA and AHAs,
since it must be done following strict rules (neutral- on the other hand, are not toxic products.
ization has to be done when an erythema appears—
it is always irregular erythema—and in any case,
Depth 3—Basal Layer Peel: HS
before any sign of protein coagulation that would
appear as skin frosting points). It is difficult to fore- This is a very interesting peel level, since it is easily reached
see the right moment for an ideal neutralization. and gives good results. Stratum corneum cells are com-
pletely removed; keratinocytes are largely damaged up to
With TCA, no neutralization can reverse the proteinic coag- the level of basal layer keratinocytes (depth 3 in the graph)
ulation; therefore the total amount of TCA applied on the (Figure 40.3).
Chemical Peels 405
Risks and problems: Basal layer peels are usually

not dangerous peels. The application technique is
important since a perfect protocol is very secure. If
the peel application is a little bit too strong, basal
layer peeling can nevertheless give the start to a
vicious cycle of inflammation based on free radicals
liberation that induces cells damage, etc. If we allow
this inflammatory vicious cycle to begin, mela-
nocytes could react and cause post-inflammatory
hyperpigmentation (PIH). Cases of PIH have been
seen, making the control of this post-peel inflamma-
tory vicious cycle necessary. No herpes prevention
is necessary. Problems are mainly linked to too-
strong melanocyte stimulation, without adequate
treatment, or to an irregular application, too-deep
application, or infectious rebounds in cases of acne.
Pre-peel skin conditioning can be used from this
point if the peel used does not penetrate evenly or
does not control the post-peel inflammatory reac-
tion. Using Easy TCA peel, no pre-peel conditioning
is necessary. Except in cases of deep scratching and/
or strong local infection, no scar is to be anticipated
from this peel depth.
FIGURE 40.3 Before and after four sessions of Easy TCA (Skin Tech),
one peel every week, basal layer depths.
Depth 4—Grenz Zone Peel: HS
Epidermis is nevertheless not completely destroyed since This is a very interesting peel level, easy to perform, not very
many keratinocytes—less damaged by UVs—are living in painful for the patient, with a low level of risk and pretty good
deep epidermal papillae; skin regeneration is fast and easy. results. Stratum corneum and a large part of keratinocytes
Basal layer peels can be used as serial peels for treating are destroyed. Acids penetrate slightly into the more super-
skin aging (Glogau 1–2), fine lines, epidermal melasma, kera- ficial layers of papillary dermis, eliminating abnormal cells
toses, and acne (from black dots up to papule-pustule acne). from epidermis (treatment of lentigines, keratoses), eliminat-
Together with a good control of melanin synthesis (blending ing many keratinocytes excessively charged in melanin and
bleaching cream*), a TCA basal layer peel can treat many melanocytes producing the melanine (melasma). Grenz zone
cases of melasma. If attention is paid to adequately clean (German, meaning border area) peel also directly stimulates
the skin (remove black dots, open microcysts, etc.) and if the the superficial coats of papillary dermis, allowing a strong col-
patient applies disinfecting creams and creams limiting sebum lagen and elastin deposit into the Grenz zone. These Grenz
production, than we can treat active acne, usually without zone peels, together with basal layer peels, are the depths of
antibiotics.† peel I use the most frequently.
Main types of peels: AHAs should not be used at this Main types of peels: TCA is the must for these
depth since this is the border after which AHA’s side depths. AHAs are not used because of their irregular
effects are prone to appear, are difficult to treat, and are penetration, making their use risky for Grenz zone
inconvenience for the patient’s social life. TCA repre- peels. Resorcine and salicylic acids are difficult to
sents the best choice for this depth, if the right concen- use for reaching exactly the Grenz zone. Phenol
tration, formula, and post-peel care are selected. should be kept for other indications.
Action mode: We have seen (see depth 2) the TCA Action mode: We have seen the TCA action mode.
action mode: keratinocyte destruction induces a TCA coagulates keratinocyte proteins and also der-
basal layer strong reaction, dramatically stimulating mal proteins, inducing a wider skin “frosting.”
the turnover of basal cells. Clinical signs: No more pinpoints of frosting, but
Clinical signs: TCA coagulates proteins and its “frosting clouds” are seen, together with a diffuse
entry through the domes of papillae induces a spe- erythema (Figure 40.4).
cific proteinic coagulation; dermal protein coagula- Desquamation: Desquamation looks like a strong
tion points occur, clinically appearing as little white sunburn, easy to live with if the skin is fair. Nevertheless,
marks (white pinpoints) called “frosting points.” dead skin becomes dark brown on darker phototypes
Desquamation: Looks like a sunburn desquama- (Figure 40.5).
tion, allowing a social life in the majority of cases. Risks and problems: The patient’s social life, espe-
cially dark phototype patients, can be difficult for a few
days. At the same time, the risk of PIH becomes higher,
* Skin Rebirth® making “pigment synthesis sedation” quite interest-
† See www.estetik.com, peelings, treatment tips. ing before and after this peel depth. PIH prevention
FIGURE 40.6 “Frosting clouds”: Easy TCA Grenz zone peel.
FIGURE 40.4 Basal layer peeling: frosting points.

FIGURE 40.7 Frosting of Unideep papillary dermis peel.
5 peel is able to treat many skin defects such as lentigines,

solar keratoses, melasma, freckles, and fine lines. Negative
limits are that since a papillary dermis peel is not able to treat
real wrinkles or skin sagging. When strictly respected, this
depth is safe regarding scarring: scars should never appear
when a peel is strictly limited to the level of papillary dermis.
Main types of peels: AHAs, Salicylic acid peels,

alpha keto acids, and resorcine are not good choices.
Phenol sometimes has been used to perform a depth
5 peel, but the related (cardiac, renal, hepatic) toxic-
ity makes me avoid its use at this depth. TCA peel,
if correctly applied, remains the master choice for a
safe and efficient papillary dermis peel.
Action mode: The TCA action mode has been
described previously.
FIGURE 40.5 Desquamation after Easy TCA up to Grenz zone. Clinical signs: After application, frosting clouds
progressively or rapidly become a pink-white uni-
form frosting that can progressively or rapidly turn
is mandatory if the patient is phototype Fitzpatrick
into a pure white frosting (Figure 40.6).
4 or more, or works outside in a sunny environment.
Infections are uncommon at this depth, since the
immune system is still widely valid. Herpes prevention Why progressively or rapidly? Passing from clouds to even
is not yet obligatory, except in special cases of frequent, frosting is progressive when we use relatively low concentra-
recurrent herpes attacks. Other problems are the same tions, as Unideep* (23% w/w) (Figure 40.7). This concentra-
as for basal layer peels. tion allows the doctor to stop his (very safe) application as soon
as the desired frosting appears. Conversely, an even pure white
frosting rapidly appears when using higher TCA concentra-
Depth 5—Papillary Dermis Peel: S tions, like 35% or 40% (w/w). In this case, it is not possible
Depth 5 peel is the dividing line between secure and insecure
depths. Here we reach positive limits in the sense that a depth * See www.skintech.info
Chemical Peels 407
to stop the TCA action. It can be compared to initiating an Another risk comes from the fact that not every peeling solu-
artificial fire: we know how big the firecracker is, but we are tion is able to evenly penetrate the skin. Simple TCA-in-water
not sure about the final result of the spectacle. Nevertheless, solutions irregularly penetrate the tissues and can give uneven
when the fuse is inflamed, it is impossible to stop it or modify results: some areas are too deeply treated (causing local ery-
the course of future events. Identically, to believe that it is pos- thema, pigmentations, depigmentations, infections, scarring).
sible to undo (by neutralization) what TCA has done is a deep The real action of TCA being largely hidden during the
misunderstanding. Frosting appears as pink-white as long as application process, damage can occur that the practitioner
the acids did not coagulate the blood vessel proteins. When cannot see immediately and hence cannot correct. Therefore,
acids have been strong enough to coagulate the well-defended the concentration of the peeling solution and, more important,
perivascular area, blood cannot pass beyond the top of the der- the total amount of TCA applied on the skin during a period of
mal papillae, close to the epidermis basal layer, and frosting time, has to be strictly calculated before application. No neu-
tonality passes from pink-white to pure-white. tralization of TCA is possible, as will be explained later.
At the same time as the acids penetrate dermis, they coag- When using a simple TCA-in-water solution, skin condition-
ulate proteins, sticking epidermis to dermis, and the sign of ing is mandatory for four main reasons: to allow a more even
“epidermal sliding” appears. This sign will last for a while and penetration, to allow a deeper penetration and hence a better
disappear when dermal edema is strong enough for tenting the result, to keep melanocytes in rest and limit the occurrence of
epidermis over it. PIH, and to stimulate the basal layer turnover and facilitate
post-peel skin regeneration. Mixtures of AHAs, tretinoine,
Desquamation: Is quite important, as it looks like a and hydroquinone are often used for this purpose.
snake changing its skin and lasts from about 6 days
to 8–12 days (usual TCA in water solution, phar-
macy made) (Unideep peel, SkinTech) (Figure 40.8). Depths 6–7—Reticulary Dermis Peel: QS–D
Social life is usually possible during the first eve- (Range is from “QS”—the risks largely depend on many
ning, but not from the next morning. Days 2 to 6 parameters, controllable or not, to “D”—it is always dangerous
are days of reclusion, during which skin will largely to perform such a deep peel, but it can be done in some cases.)
peel in more or less dark plaques, in relation with Reticular dermis peel is a kind of Holy Grail of peeling; this
the phototype.
depth of peel allows treating nearly every pigment problem: it
Risks and problems: The most immediate risk
tenses the skin and removes wrinkles. Nevertheless, thick and
consists of infections: viruses, bacteria, and myco-
oily skins are not the best candidates for a reticular dermis
ses find the skin totally open and without defenses.
peel since these skins resist very well to the action of acids.
It is easy for them to penetrate and locally prolifer-
ate. It is therefore mandatory to prevent viral infec- Unfortunately folds usually resist the action of deep peels.
tions using herpes prevention (valacyclovir i.e., 3–4 Very often, we have to discuss with the patient the choice
days before and 4–5 days after peel). Bacterial and between two therapeutic options: surgical lifting or deep peel-
mycotic infections can be avoided by strict control ing. At Hera Clinic (Empuriabrava, Spain), our first guide is
of medical hands and material cleanliness as well a simple decision table (Table 40.1). Naturally, this has to be
as by avoiding any other source of iatrogenic infec- adapted to the specific skin and situation. The global meaning
tions. The patient has to be aware to wash his hands is that we will not recommend a phenol peel to a patient with
before any contact with his skin (like scratching), to thick sagging skin and no sun aging problem. Conversely, we
avoid direct contact with mammal or non-mammal will not recommend surgery to a patient with thin skin, with-
pets, and to call the doctor for any question or incon- out sagging but with important pigment or sun aging problems.
venience that could arise. Scratching the skin after The quest for the Holy Grail is a risky trip, as also is deep retic-
papillary dermis peel usually induces infection. ular peeling. Not only does the selected peeling solution have
Non- or badly treated infections could induce PIH, to be perfectly adapted to the doctor’s and the patient’s aims,
depigmentation, or scarring. but also the application technique and post-peel care have to
be totally professionally done. Full-face reticular peel is a very
aggressive treatment that leaves no room for improvisation.
Any mistake can cause scarring, and pigmentary problems are
TABLE 40.1
Problems and Preferred Treatments
Problem Preferred treatment
Pigmentary problems Peelings
Sagging skin Surgery
Pigmentary and sagging 1/surgery wait 6 months 2/phenol peel
Thick skin Surgery
Thin skin Peeling
FIGURE 40.8 Desquamation day 4 after Unideep papillary dermis.
frequent. Nevertheless, reticular peels are pearls in the right an immediate pure-white frosting, without passing
hands and the right circumstances. through a pink-white one). After the typical papil-
lary dermis frosting, the tonality quickly will shift
Main types of peels: Two main molecules are used to a grey-white or grey frosting.
for reaching this depth: TCA and phenol. I really
appreciate concentrated TCA for performing focal It is possible to reach this depth by applying various acids
deep peels, for deeply treating lentigine and kera- concentrations; nevertheless, I have always felt more com-
toses less than 1 cm in diameter (Only Touch, for fortable using less concentrated products, but applying more
example, is a 45% w/w TCA), but I would not be coats. Indeed, when we are using proteocoagulant products,
keen to use it for large areas, as a full face peel. the final result depends on the total amount of active acid
In this case, phenol seems to be better; its activity molecules that have been able to interact with skin proteins.
depth can be better kept under control and the results A very strong and aggressive peeling solution could induce a
are definitively better, even at similar depth as TCA. superficial thick coagulation, only letting pass the acids at the
Phenol seems to have a better “rebuilding effect” on level of higher skin permeability, which could induce irregu-
the skin than TCA. My best phenol peel is actually lar results and local overpeeling. When using a progressive
Lip and Eyelid Formula (SkinTech), which is an oil
application technique, we can always decide to apply no more
of phenol, penetrating slowly into the skin, which
acid on the higher permeability areas and keep applying on the
limits its general toxicity (giving the liver, lungs,
areas where we did not see the desired frosting appear. Doing
and kidneys more time for detoxifying it) and allows
that has allowed me to have zero overpeels in the last 20 years.
a longer contact time between phenol and the skin
proteins, inducing a potential larger protein coagula-
tion and hence a better result (Figure 40.9). Desquamation: Desquamation is huge, always forc-
Action mode: Phenol is proteolytic or proteocoagu- ing a social retirement of 7–8 days. Dead skin layers
lant, depending on the concentration. Higher concen- should be left in place as a natural protection and only
trations are proteocoagulant and lower concentrations extracted at around day 6 or 7, as long as this extraction
are proteolytic. For peeling purposes, the best con- is easy and atraumatic. Phenol peel can be used under
centration range is 40%–60% (w/w). Nevertheless, a complete 24-hour occlusion, inducing a maceration
many substances can interfere with its action and of the upper coats of the skin. During occlusion, skin
speed up or slow down its penetration. These sub- melts (in open techniques, skin usually dries) and has to
stances are described at greater length in (1). be protected by using, i.e. Bismuth subgallate powder.
Clinical signs: Acids reach reticular dermis after From day 5 or 6, sterile petrolatum jelly can be applied
having largely coagulated papillary dermis, show- on the dead skin to help with desquamation. Occlusion
ing a pink- or pure-white frosting (depending of causes the phenol peel to be deeper and more efficient.
the concentration, an aggressive peel will develop TCA occlusion does not have the same result.
Risks and problems: Histologically, there is only
one reticular dermis, situated between papillary der-
mis and subcutaneous tissues. However, with peels,
we have to consider that we face two different depths.
Into the more superficial reticular dermis, overall at the face level,
we still can find keratinocytes (mainly at the level of hair roots
and sebaceous glands—sebocytes are phenotypically differenti-
ated keratinocytes, able to undifferentiate into normal keratino-
cyctes when necessary to repair the skin). Superficial reticular
dermis still has material to rebuild the skin. Deep reticular dermis
is empty of this reservoir but contains big fibroblasts, also dif-
ferentiated to be able to synthetize a thick bundle of collagen that
will stick to the neighbor fibroblast. In addition, they are consid-
ered contractile nonmuscular cells, able to contract when neces-
sary. They are one of the main things responsible of the scarring
process: when these cells are strongly stimulated during a self-
maintained inflammatory vicious cycle, scarring can appear.
Problems: All possible side effects can appear when

using deep peeling. Pigment problems are frequent
since deep TCA kills melanocytes and phenol can
make them impotent, unable to synthesize melanin.
As a result, many cases of unaesthetic depigmenta-
tion have been seen in the past. A new formulation
FIGURE 40.9 Frosting of Otp +/− desquamation secondary to intraepidermic
(Lip and Eyelid Formula, SkinTech) seems to be
peel. (Abbreviation: Otp, Only Touch Peel.) much safer in this regard, since it induces mainly
Chemical Peels 409
TABLE 40.2
Possible Side Effects
Locoregional side effects Regional side effects General side effects (phenol)
Insufficient results Larynx oedema Symptoms occurring rapidly
Post-inflammatory Long-lasting face oedema Neurological problems: Headaches, acouphens, hypoacousy,
hyperpigmentations paresthesies, muscle hypotony, stupor
Melanotoxicity (up to porcelaine skin) Dynamic wrinkles resurgence Digestive problems: Nausea, Vomiting, Pain in belly, diarrhoea
Demarcation line Cardiovascular problems: Arrythmias, asystoly
Erythema Symptoms occurring later
Telangiectasies Nephropathy
Not even complexion Hepatopathy
Scars (+ ectropion or entropion) Hemoglobinury, Methemoglobinury
Prurit
Scratching lesions
Bacterian, viral, mycotic surinfections
Acne, milium grains
Conjunctivitis
Iritis, opacification of cornea
Post peel pain
Sun sensibility
Dilation of pores
Petechies, purpura
PIH, which is easy to treat, other than “porcelain Frosting events have some kind of invisible inertia; they are
skin,” which cannot be treated. Table 40.2 summa- not immediately-appearing phenomenon; proteocoagulation
rizes many of the possible side effects. will continue going on during the neutralization process. It is
therefore very risky to apply too much of the phenol derivative
or TCA acid on the skin, thinking that it will be possible to
neutralize it after seeing a frosting to appear. That is the best
About Acid Neutralization way to cause overpeeling. To try to neutralize TCA after see-
Acid neutralization is a recurrent problem. Why neutralize? ing a frosting could be compared to trying to stop an arrow just
What to neutralize? How to do it? When to do it? Together with before it touches the target. In addition, neutralizing a proteo-
dermatological use of AHAs appeared the notion of neutraliza- coagulant acid will never reverse the potential damage caused
tion; pre-existing peels (i.e. phenol derivatives and TCA) had not to cellular proteins or matrix proteins. When an acid combines
been and could not be neutralized since proteocoagulant mole- with amino acids into a protein, it is transformed to a salt that
cules definitively interact with skin’s proteins and combine with sticks to this amino acid and modifies the volumetric, tridi-
them, forming a kind of conglomerate that cannot be separated. mentional, proteinic appearance.
As a result of this interaction, non-AHA acids are largely and This is why a safe behavior is to rub on the skin the right
automatically neutralized and trapped into destroyed proteins amount of acids to get the desired frosting, without any neu-
in which tridimentional structures have changed, inducing the tralization. Remember that only a few seconds are necessary
well-known sign of “frosting.” Neutralization of proteocoagu- for proteocoagulant acids to pass through epidermis: that is
lant acids is therefore impossible after their action has begun. At why phenol induces a skin anesthesia only 12 seconds after its
a maximum we could neutralize an eventual floating excess over application!†
the skin, before this excess can penetrate the skin. We have also seen that AHAs have a very low proteocoagu-
Is this even really possible? This idea of neutralizing pro- lant power; they do not easily combine with proteins. Their
teocoagulant acids (as is TCA) is in reality extremely tricky natural neutralization by the skin can only be done by using
since we have to introduce a time scale in our discussion: the the skin buffer potential, which is too slow-acting. Without
appearance of a frosting is a signature of past events. The frost- neutralization, pure, non-partially neutralized AHAs would
ing that we see right now does not represent what is actually eventually burn the skin.
happening, but what happened into the skin some time ago.* We cannot neutralize an acid by adding water to it. When we
pour water in a recipient containing an acid solution, we only
* The frosting we see in T(0) results from a past action of the acids into dilute the acid; a huge dilution is necessary in order to lower
the skin. It can be compared to the fact that the starlight that we see has the resulting pH. Pouring water on the face after peeling, can-
been emitted millions years ago (the age of universe being supposed not therefore be considered as neutralization. Pouring a basic
to be at least 17,300,000,000 years). What we see in the night sky can
have been emitted in the past by a star that is now dead and maybe now
solution in a recipient containing acid will induce chemical
transformed into a black hole after a last fantastic explosion followed
by a contraction to infinite levels of energy. The frosting we see in T(0) † That fast, phenol coagulates sensitive nerve sensors, inducing local
results from a past action of the acids into the skin. anesthesia.
acid-base reactions; the acid will become a salt that has no structures that are supposed to regenerate the skin during
more protons to liberate in solution and therefore is no more the post-peel period. The actual scientific understanding of
acid. Neutralization changes the chemical structure of acids. the aging processes generally blames FR as one of the major
Simple sodium bicarbonate in a saturated solution can be used causes of cell degeneration. It is important to fight these FR
to neutralize AHAs. during the post-peel period. Phytic acid slowly penetrates the
Finally, the answers to the questions at the beginning of skin, after the three AHAs of the EPS solution have opened
this section are simple: we neutralize AHAs, but we cannot it, and can be present in the skin when FR are produced in
neutralize proteocoagulant molecules. A slightly basic solu- parallel to the inflammation. Scavenging FR cuts the vicious
tion, in good volume, will be poured on the skin until the cycle of inflammation-vasodilatation-FR and scavenges the
end of the chemical reaction (usually seen as little bubbles). FR produced post-peel.
Neutralization of AHAs should begin as soon as an erythema It is known that AHAs make a thicker epidermis and pro-
can be seen and before any frosting appears. duce more polymuccosaccharids in the dermis and a better
We touch here the big question: when to neutralize AHAs? quality elastin. The density of papillary dermis collagen is
Too-early neutralization does not allow enough time for acids better, and patients under EPS describe a tightening sensation
to interact with the skin, and the result will be very poor. A too- after peeling and a visible difference of the aspect of the skin.
late neutralization allows acids to burn the skin and induces How to use it? Cleanse the skin twice with SkinTech’s
many side effects. That is why the industry proposes partially cleanser foam, rinse and dry. Apply a maximum total vol-
neutralized AHAs (pH 2.5, 3, 3.5) which are less dangerous ume of 2.5 cc of EPS on the face, using a little cotton ball,
and can be washed with simple water since they are between poured once only into the peeling solution. Apply it in succes-
10 and 1000* times less aggressive (efficient) than pure AHA sive coats, massaging the face between every coat for uniform
solution, without partial pre-neutralization. coverage.
There is one exception, called Easy Phytic Solution (EPS). When the patient says he feels a tingling sensation, apply the
In spite of the solution’s very acid pH (0.5–1) and a total last coat, using the same cotton ball; no frosting at all should
concentration of acids of average 60%, this AHA medical occur. Two or three coats are usually sufficient. In the event of
device does not need to be neutralized. The time-controlled accidental frosting, neutralize immediately (sodium bicarbon-
technology permits slow release, complete progressive pen- ate solution). DO NOT NEUTRALIZE. For more information
etration, and full action of all acids. Absence of neutraliza- about details of the application technique, please refer to the
tion = absence of problems and greater efficacy. The best packaging insert or to www.skintech.info.
indications are acne and photoaging prevention and treat- Another way to manage the peeling neutralization is to do it
ment. EPS is made up of three AHAs: glycolic acid, lac- with a neutralizer that modifies its color, depending on the skin
tic acid, and mandelic acid. AHA is adsorbed on the polar pH. This is what has been recently done with Easy Droxy ver-
groups of keratin chains and inhibits the reactions between sicolor peel, a medical device patented by SkinTech Pharma
these groups. This improves elasticity of the skin, and alpha Group (Spain). A neutralizing blue cream is applied to the skin
hydroxy acids are better for that than beta hydroxyl acids at the end of the peeling procedure. This cream neutralizes the
because the alpha position of the hydroxyl group allows a skin and becomes yellow as long as the skin is acid. When the
better penetration between keratin chains than the beta posi- skin is at pH 7, the cream passes from blue to green. When the
tion. The three AHAs show different velocities of penetration skin pH is over 7, the cream simply stays blue. The endpoint of
through the skin. The smallest one, glycolic acid, penetrates the neutralization is achieved when the cream becomes green
first, followed by the lactic, followed by the mandelic. These or stays blue, and this allows control of the uniformity of the
acids begin their action at the level of the upper layers of the neutralization process.
epidermis. Because there is no neutralization, they continue
their action, going down inside the epidermis and reaching
the dermis, slowly and without ever passing the capacity of
natural neutralization by the skin itself, so, the acids of EPS
About TCA
progressively lose their aggressiveness into the skin, produc- Many books have been written about TCA-in-water application
ing their full activity. Phytic acid is not an AHA, but a big techniques so I will not go into great detail here. Nevertheless,
molecule of inositol hexaphosphoric acid considered as an I would like to point out a few important things.
excellent antioxidant and an antityrosinase. It binds out iron. The main questions of beginners are: What is the best TCA
In our point of view, phytic acid is unable to produce any concentration? How many coats? How often? How and when
peeling effect, so why do we find phytic acid in this solu- to neutralize? These are not the good questions since the
tion? Actually, every peel produces an inflammation; this answers would give an appearance of an easy cooking recipe
inflammation produces free radicals (FR) and vasodilatation. to be inflexibly respected.
Vasodilatation brings more oxygen in situ allowing the for- The easiest of these questions to answer is about when
mation of more FR. FR binds immediately with the closest to neutralize. TCA action cannot really be neutralized. See
structure, damaging it. So a peel always promotes the skin earlier.
regeneration but induces a lot of FR that can damage the The best TCA concentration is the one we selected, that
simple. The point is to know how to select a TCA concentra-
* Logarithmic relation between pH and aggressivity: pH 3 is 10 times less tion and how to calculate it. I largely explained in my Textbook
aggressive than pH 2, 100 times less than pH 1. of Chemical Peels (1) why I prefer to use a weight by weight
Chemical Peels 411
(w/w)† calculation and not a weight by volume (w/v) or a vol- tricky because there are so many variants that the problem of
ume by volume (v/v) one. In short, we are using chemical concentration is only a small part of the global decision.
products, and we should keep our calculations scientifically Globally, we can go two different ways. The first one con-
reproducible and totally correct. Only the w/w calculation sists of guessing what will be the right concentration for a
makes sense from this point of view, even if the w/v or the v/v single patient’s skin . . . and praying for days, hoping that there
is more common in the United States. was no mistake and that the acid will stop its action at the right
The second point is to select the right concentration for the depth. The second one, that I naturally prefer, is to use very
patient. Remember two points: first, a thick-skinned patient few different concentrations (three different concentrations)
will need more acid than a thin-skinned patient; second, the and progressively apply several coats until the desired kind of
most important is the total quantity of acid that is able to inter- frosting appears. This way always brings my peel exactly to
act with proteins. Too-concentrated acid applied on a thin skin the desired level, without possibility of mistake.
will burn it immediately but will do a great job on a thick, oily Let’s take an example: Patient with normal thickness and
skin. Looking at the thickness of the skinfold on the area of permeability skin, phototype 2, pre-peel classical condition-
the malar bone gives us a simple clinical appreciation of skin ing, and we would like to reach the Grenz zone: the very good
thickness: if the fold is one cm thick, the skin should be “nor- and easy case! I can decide to apply a 30% TCA (yes, but w/w?
mal”; less than 1 cm, the skin is thin, more than 1 cm, the skin w/v? etc.). What I cannot decide is about how deep this acid
is thick. Thin skin is more sensitive to acids than thick skin, so will penetrate by itself: I just can rub the product on the skin
this can help us to select the concentration. and see the result at the end, knowing that more than one coat
Transepidermal acid penetration does not only depend on of a 30% w/w TCA solution on such a skin can be dangerous,
skin thickness, it also depends on the type of acid itself (a little or conversely, it can be insufficient. We will see the action of
acid will penetrate faster than a big one—long fatty acids for the acid solution, but only when the eventual damage is done
example, penetrate more slowly through the skin than the little and irreversible. This is why there are so many reports of skin
lactic acid). Transepidermal penetration also depends on the damage after TCA peel, and this is why some authors errone-
skin permeability, on the pre-peel skin conditioning. A thick ously claim that TCA is not adapted to melasma treatment. It
oily skin,* after skin conditioning‡ and acetone§ degreasing is nevertheless only a question of application technique and
can become as permeable as a thin skin. A skin dermabra- pre-peel decisions. A 30% w/w TCA solution rubbed once on a
sion (preferably using 3M wet or dry sandpaper 200) easily normal thickness skin after pre-peel conditioning usually gives
removes the stratum corneum and greatly deepens the action a pink-white uniform frosting, showing a papillary dermis pen-
of the acids. I use this quite difficult technique that I call “ante- etration. We overpassed our target that was Grenz zone.
rior chemabrasion” together with Easy TCA peel in the treat- Another possibility for the same patient is to use a lower
ment of acne scars and old atrophic and deep stretch marks, concentration TCA solution, let’s say a 15% w/w solution.
with splendid results. A first coat induced only erythema: we understand from this
We can see that many events are able to modify the skin per- that the skin was less permeable than guessed and that we
meability: did the patient do a scrub to have clean skin before reached the epidermal level only. When the skin will be dried
seeing you? The skin will be more permeable. Did the patient by evaporation, we will apply another coat of the same acid
wax the face before peeling for depilation? More permeability! solution: the skin will show little “frosting points,” and we will
Did the patient apply an oily moisturizing, a sunscreen, a gel deduce that it has reached the basal layer depth. A next coat
containing hyaluronic acid before coming? These will reduce would induce a cloudy frosting, sign of the penetration of the
skin permeability. acids into the Grenz zone. When we see these frosting clouds,
How many coats to apply? Every peeler would like to have we stop the TCA solution application and we know that the
a clear and simple answer to this question. Unfortunately, the peel has reached exactly the desired depth. Easy, isn’t it?
number of coats depends on what is previously described about Usually, peelers focus their attention on good pre-peel
skin permeability. It also depends on the TCA concentration of conditioning for better and more even penetration and faster
the solution. Note also that considering concentration alone is regeneration. Nevertheless, closer attention should be paid to
the immediate post-peel events, to the inflammatory reaction
that began immediately after the first contact with the first
* Skinfold = more than 1 cm
† Indeed, a 40% TCA solution could be calculated in many ways: 40 gr drop of acid applied on the skin.
TCA + 60 gr water or 40 gr TCA + 100 mL water or 40 gr TCA + the This inflammatory reaction is necessary but dangerous.
necessary quantity of water for obtaining a final 100 mL solution or A peel that would induce no inflammatory reaction would also
even, 100 gr—or 100 mL—of any of the above described solutions, not be efficient since inflammation is the real skin rebuilding
diluted with water in w/w, w/v or w+v. This makes too many possi-
source. At the same time, if this inflammation is uncontrolled,
bilities, too many ways to create errors. For more reproducible peel-
ings, I definitively selected the w/w concentration. For me, 40% TCA if it is self-maintained, it enters into a vicious cycle in which
is always 40 gr of fresh TCA crystals mixed with 60 gr of water to do a the free radicals and the pro-inflammatory components liber-
final weight of 100 gr. This is a true 40%. ated from cell destruction induce more cell damage and more
‡ Glycolic acid to reduce stratum corneum thickness + tretinoine for inflammation. This inflammatory vicious cycle is responsible,
stimulating basal layer turnover and regeneration and for reducing i.e., for a long stimulation of melanocytes that will respond by
the stratum corneum permeability: this kind of pre-peel conditioning
makes the skin much more permeable.
synthesizing more melanin and inducing PIH.
§ Note that acetone not only degreases skin but also begins a protein It is easily understandable that a peel can be a booby trap:
denaturation that makes the skin more permeable. you think that your chemist prepared a 30% mass by volume,
but he did it w/w (which is stronger); or your patient had a vir- solution and post-peel mask do this), patient’s social life is
tual mesotherapy* or a depilation face wax the day before the possible (desquamation looks like a sunburn), no phototype
peel: the patient’s skin will be permeabilized, acids will pen- limitation (phototype allowed: from 1 to 6), and very little per-
etrate faster and deeper, and you will get (not surprisingly) an centage of side effects (average 1.7% transitory side effects,
overpeel and side effects. I have progressively solved this prob- duration less than 8 days§). This peel, applied according to
lem by using a safer and easier formula: Easy TCA peel.† This different protocols, allows for a wide spectrum of depths of
formula allows me to avoid the long and uncomfortable pre- action and therapeutic indications from active acne to pigmen-
peel conditioning phase in the great majority of cases‡ since tation and acne scars, photoaging and deep, old stretch marks.¶
it can be applied using the progressive technique explained It can be applied to both face and body. In addition, it can be
earlier; since it uses a specific post-peel mask, able to control used during the same session with laser, IPL, mesotherapy,
the post-peel inflammatory reaction; since it will be repeated radiofrequencies, depilation, botulinic toxin,** surgery, and
once a week for 4 weeks. Every peel, done up to frosting points telangiectasies treatment. Even hyaluronic acid injections for
or maximum local frosting clouds, treats an eventual pigment wrinkle treatment is allowed, immediately before Easy TCA
rebound induced by the preceding peel. Peel.††
The Easy TCA post-peel mask is a quite complex for- In the same time, I decided to stop trying to guess what
mula, containing vitamins, trace elements, a lot of strong would be the best concentration of TCA for a patient, but only
antioxidants, tretinoine precursors, selenio-methionin, anti- use the Easy TCA solution, which I progressively apply the
tyrosinases, etc. This cream is applied once by the practitio- necessary number of coats to get the desired frosting.
ner immediately after the desired frosting has been seen. It In the preceding paragraphs, I mentioned using only three
immediately scavenges FRs, stopping the excess of immediate different concentrations, and this will now be clarified. The
inflammatory reaction at the same time as the burning sensa- main peel I use, on about 80%–85% of my patients, is Easy
tion induced by the easy TCA peel solution. It brings into the TCA Solution, containing vitamins, antioxidants, AHAs, and
skin elements that can help it to regenerate faster and lowers saponines, together with 15% w/w TCA. This peel benefits
the tyrosinase activity. Post-peel penetration of ingredients is from the important post-peel mask protection against post-
dramatically modified by the previous application of the peel- peel inflammatory reactions and immediately stopping post-
ing solution. The post-peel rate of penetration is much higher peel burning. Depending on the number of coats I pass on the
than the normal skin rate. The skin is much more permeable skin, I drive my peel into epidermis, basal layer, Grenz zone,
during the close post-peel period: sebum and corneocytes no or even papillary dermis. Nevertheless, papillary dermis peel
longer act as a barrier and purely water soluble ingredients can needs many coats of Easy TCA, and this is uncomfortable for
rapidly pass through this modified epidermis. the patient. This is why I use a derivative of Easy TCA when
So high quantities of stimulating factors and antioxidants I want to reach the papillary dermis: Unideep‡‡§ has the same
can reach the dermis. It is clinically evident that the residual structure as Easy TCA. It is a peeling solution form which
inflammatory reaction is strong enough for stimulating the skin ingredients we can find 23% w/w TCA and an adapted post-
architectural rebuilding, but not strong and long enough for peel mask with the same aim as Easy TCA. Sometimes, I need
stimulating melanocytes or for slowing down the basal layer to go very deep into the skin for treating focal old lentigine or
regenerative event sequences. Colleagues often ask to me how solar keratoses: naturally, we often can do it using successive
and why this cream can immediately stop the burning sensa- focal coats of Easy TCA or Unideep, but the work is easier
tion, even if it is not a neutralizer (this cream is not a basic when using Only Touch Peel (OTP): it has same qualitative
one) and if the frosting signs continue to appear normally, even base solution than Unideep but contains 45% w/w TCA. OTP
after having applied the post-peel mask. I unfortunately can- has no post-peel mask and has to be used in combination with
not scientifically answer this question but have a theory: my Easy TCA for avoiding post-peel inflammation. Indeed, OTP
understanding is that the post-peel mask antioxidant proper- without Easy TCA induces PIH in more than 60% of the cases.
ties are such that they break the pro-inflammatory immediate
post-peel reaction. It is well known that inflammatory reaction § Unpublished statistic established on a total amount of 5000 peeling ses-
usually represents a big part of pain. sions in Clinica Hera, Empuriabrava, Spain: 28 transitory easy to treat
side effects. No definitive side effect.
So to summarize: After having used many different peel- ¶ See www.estetik.com, left column, treatment tips, peelings: you’ll find
ing formulas and spending post-peel nights of insomnia, there a complete description of active acne, stretch marks, melasma
I decided that it should be possible to use TCA without the treatments, together with the protocol for local phenol peel around eyes
post-therapeutic nightmare. This is what brought me this Easy and lips.
** Ten minutes after botulinic toxin injection, Easy TCA (as basal layer
TCA formula: it is easy to do (10 minutes as a maximum for
peel) can be performed. We never saw migration or shorter results after
face and neck), not expensive, not painful (never needs any
this association.
kind of anesthesia or painkiller), no skin conditioning (peeling †† As everybody did, I also read the HA notice for injection, which says
not to perform peelings after HA injections. Nevertheless, this recom-

* Virtual mesotherapy: slight abrasion using sandpaper, application of mendation is valid only because of the huge release of free radicals after
specific vitamins and other elements on the skin, use of Excellderm usual peelings. Free radicals rapidly damage the HA polymer, breaking
(non-thermogenic radiofrequencies for inducing an intracellular pen- it and making his life shorter. Easy TCA post-peel mask scavenges free
etration). Aestheticdermal.com. radicals at the same time they are produced, which can stop self-main-
† See Textbook of Chemical Peels or www.skintech.info. tained free radical reactions, able to damage HA polymer.
‡ I would use a pre-peel conditioning only in specific cases, as can be a ‡‡ § Easy TCA, Unideep, and Only Touch are peelings developed by Skin
phototype 4 or 5 patient with a long history of familial melasma. Tech, based on my own formulas.
Chemical Peels 413
When done immediately before Easy TCA, the percentage of are phenotypically modified fibroblasts having some character-
PIH is much less prevalent: a maximum of 10%, if the protocol istics of muscle cells and which are responsible of the retraction
is respected, even less if the patient does not scratch the scabs. processes during skin healing. Cytoplasms of myofibroblasts
OTP can be used on small surfaces only: it is always a focal contain myofilaments connected with cell membranes, respon-
peeling for treating lesions with diameter than 1 cm. OTP is sible for cell contraction and eventual scarring processes.
applied, avoiding excess product, with a fine cotton bud or a “Normal depth” peels will stimulate the full population of
wooden toothpick or skewer. Touch the lesion to be treated fibroblasts without overstimulating myofibroblasts. They give
quickly, precisely, and once only with the chosen applicator a better skin tension, without scarring (up to papillary dermis
and wait until the acid solution has dried completely. A sig- peels). Too-superficial peels (intraepidermal peels) are only
nificant frosting will appear quickly on the face, slowly on the able to slightly stimulate fibroblasts synthesis: the result on skin
body. If no such frosting occurs, however, repeat the appli- tension is weak. Deep peels will strongly stimulate fibroblasts
cation cautiously a few minutes after the solution has dried. and myofibroblasts, inducing a tridimensional tensing effect on
Immediately after the frosting occurs, apply the first of the facial tissues, giving a well-done phenol peel. Too-deep peel-
four basic protocols of Easy TCA on the entire treated area, ing, locally hypodermal peels, focal overpeels, leave the skin
including the one where OTP has just been applied, in order to without any other regeneration possibility than the strong myo-
obtain an even result and limit the risk of side effects. fibroblastic contraction, bringing about unaesthetic scarring
processes. We can therefore easily understand that scars only
occur when something wrong has happened to the skin: it can
be a problem induced by the physician having applied a too-
How Painful Is TCA Application? concentrated solution or a too-strong pre-peel conditioning, or
The burning sensation of TCA application is clearly linked to by a patient having scratched and infected newly peeled skin.*
its concentration and to the skin permeability. One coat of 30% Nevertheless, it is largely admitted that the papillary dermis
TCA will be very painful on thin skin but very tolerable when is the limit from which the scarring process can be switched
applied on thick and oily skin. On the same patient, a 30% peel on. This means that as long as a peeling does not enter into
will be more painful compared to a 20 or 15%. reticular dermis, there is no danger of scarring. The problem
An elegant solution has been recently launched by Skin here is how to strictly limit the penetration of acids until the
Tech Pharma Group: the medical device Easy TCA Peel Pain desired depth. One of the possible answers has been described
Control®. The peel is on average 25% more aggressive than the in the TCA paragraph.
classical Easy TCA® 15% but is 90% less painful. Frosting is
achieved more easily, and the patient only experiences a begin-
ning burning sensation during the first 10 seconds, or after the
About Phenol
third coat (when the peel is voluntarily done up to the papillary
dermis). This lack of burning sensation provides total comfort Many things have been said about this molecule, some true
to the patient. and others only urban legends. One example of truth: it is pos-
sible to iron completely the upper lip using phenol peel. One
example of legend: the patient can die right after the very first
contact with the first drop of phenol. I will not say much about
Peels and Fibroblasts
phenol peels since a little part of a short chapter is not the right
Dermal fibroblasts represent a major cell, not only in the place for learning about it. Nevertheless, let’s divide our phe-
understanding of peels: their correct stimulation by any means nol paragraph in two parts: local phenol and full-face phenol.
would lead to good skin rejuvenation. Fibroblasts have a den- Local phenol is a very simple procedure, the fastest of all
dritic appearance, like Langerhans cells, but have no immu- peels, and it gives amazing results. Chemical blepharoplasty
nological known function. Fibroblasts synthesize all the and/or cheiloplasty (lip procedures) are easy to perform with
intercellular matrix components and play a vital role during phenol. The quantities necessary are largely under the thresh-
the formation and the contraction of the granulation tissues old of toxicity and new formulas (see in the beginning of this
that appear during the wound healing processes and post-peel chapter) are considered as self-blocking at the level of the
regeneration events. Huge morphologic variations exist within upper part of reticular dermis. Moreover, new formulas no
this cellular population: papillary dermis shows little hori- longer induce “porcelain skin,” and skin tanning can still be
zontal fibroblasts (4–7 microns), their dendrites have contact possible in the future. Local phenol peels are therefore one of
with several collagen fibers. Stimulation of these fibroblasts is our frequent treatments for deep wrinkles of the upper lip, the
responsible for a dense deposit of horizontal neo collagen in eyelid area, and in some cases wrinkles between eyebrows,
the top of the papillary dermis. on the top of the nose pyramid. Lower lip and mental area are
Medium-depth dermis and deep dermis show larger fibro- much more difficult to treat with local phenol. Often, at this
blasts, with a variable orientation. Dendrites have contact with level, a deep mechanical abrasion has to be used after phenol
one big bundle of collagen only. The very deep dermis, at the peel in order to achieve good results.
limit of hypodermis, contains very large fibroblasts (16 microns)
with long dendrites (up to 180 microns), forming a continuous net. * Some genetic disorders make the skin prone for post-peel scarring, like
Inflammatory reactions and healing processes induce the Ehler Danlos syndrome. Insulin-dependent diabetes is also a risk factor
appearance of many hybrid cells, called myofibroblasts. These for deep peels. See Deprez 2016 (1) for more side effects.
FIGURE 40.12 Eight months after local phenol lower eyelid and Unideep.
you to detect infections, abnormal reactions, etc. For more prac-

FIGURE 40.10 Before local phenol (Lip and Eyelid Formula—Skin Tech). tical information, please refer to the website www.estetik.com,
left column: “Peelings” and “Treatment Tips.” There can be
found clear tables about how to do the peel and the post-peel.
Full-face peeling is another story since the phenol toxicity
has to be avoided or even treated in exceptional cases. Even if
some physicians still feel comfortable in doing it as an office
procedure, as in the past, I would strongly recommend per-
forming this kind of peel in a secure surgical environment,
with the help of a trained anaesthetist (nerve blocks associated
to a deep sedation or neuroleptanalgesy). Nothing usually hap-
pens but all the lights are red, and we have to be very careful
since an accident would never be forgiven. Strict application
rules have to be followed. The post-peel period after phenol
peel is quite uncomfortable for the patient; it looks like after a
deep ablative CO2 laser procedure. Procedure is specific, many
details have to be respected if we want to do it very safely,
and post-peel is difficult. I cannot describe here the full pro-
cess of a full-face phenol peel and how to avoid all the traps.
Nevertheless, Deprez 2016 (1) contains approximately 200
pages dedicated to all aspects of phenol and phenol-derivative
peel procedures.
FIGURE 40.11 Eight days after local phenol lower eyelid—Unideep on Regardless, full face phenol peeling is one of the most satis-
the rest of the face for uniformization.
fying treatments I perform: many patients look 15 or 20 years
younger after a phenol peel. Skin aging goes many years back
Special attention has to be paid to the patient selection: pho- and goes on from there: the patient never again has as old a
totypes 2 and 3 are the best patients, but patients showing yel- skin as they had before the peel. Full-face phenol peel can be
lowish sun-damaged skin should be avoided since post-phenol combined with surgery, but not at the same time. When neces-
skin regeneration will completely renew the treated skin, and sary, we perform a face lift as the first procedure and a phenol
it will appear like a baby skin surrounded by irregular-color peel as second treatment, 6 months later, in order to achieve
skin (Figures 40.10–40.12). The case of freckles is also a trap. complete face rejuvenation. At the same time, we treat neck,
These clear phototypes are good indications, but freckles will décolleté, and hands by other procedures.
completely disappear at the level of phenol peel and not on the
rest of the skin. In these cases, a local phenol peel can be tried,
together with a papillary dermis peel on the rest of the face,
Conclusion
calling attention of the patient that, even in this case, a demar-
cation line can be seen between the area treated by phenol and The world of peeling continues to be discovered; its trea-
the one treated by TCA. sures are able to make a large majority of our patients happy.
The post-peel period is dramatically important: see your Nevertheless, we cannot begin our exploration of these treat-
patient nearly every day during the first week; this will allow ments, groping our way along, following any light that can
Chemical Peels 415
appear in the sky as a shooting star: while we would look in Farnes S.W., Setness P.A. Retinoid therapy for aging skin and
this direction, we are at risk of falling into dangerous traps. acne. Postgrad Med 1992; 92(6):191–196, 199–200.
Exploration of the world of peeling has to be done carefully, Fischer T.C., Perosino E., Poli F., et al. For the cosmetic dermatol-
progressively, using good material, having at our disposal the ogy European expert group. Chemical peels in aesthetic der-
necessary experience for passing from one step to the other. matology: An update 2009. J Eur Acad Dermatol Venereol
In short: deep full-face phenol or chemoabrasive techniques 2009 Sept; 11(8).
for stretch marks should not be the first peel we ever do. The Gilchrest B.A. Retinoids and photodamage. Br J Dermatol 1992;
problem will not be the procedure itself but what we will have 127(Suppl 41):14–20.
to face and the problems we will have to solve later. The door Giroud J.P., Mathe G., Meyniel G. Pharmacologie clinique. In:
of the world of peeling should open on VHS or HS peels only, Schmitt H., ed. Elements de pharmacologie, 5th edition;
and beginners should use depth 1 to 3 peels first, trying deeper pp. 1590–1591.
treatments only when they are fully experienced. Griffiths C.E., Goldfarb M.T., Finkel L.J. Retinoic acid treatment
of hyperpigmented lesions associated with photoaging in
Chinese and Japanese persons. J Am Acad Dermatol 1994;
30(1):76–84.
REFERENCE
Hardman J.G., Limbird L.E., Gilman A.G., eds. Goodman &
1. Deprez P. Textbook of Chemical Peels, 2nd edition. Boca Gilman’s The Pharmacological Basis of Therapeutics, vol.
Raton, FL: CRC Press, 2016. 2, 8th edition. New York: McGraw Hill, 2001.
Khunger N., IADVL Task Force. Standard guidelines of care for
chemical peels. Indian J Dermatol Venereol Leprol 2008;
BIBLIOGRAPHY 74(Suppl):S5–S12.
Alberts B., Bray D., Lewis J., et al. Biologie Moleculaire De La Kligman A.M. Topical tretinoin can correct the structural abnor-
Cellule, 2nd edition. Medecine-Sciences, Flammarion. malities of human photoaged skin. In: Elson M.L., ed.
Berne M.B., Levy N.L. Physiology, 3rd edition. 1993. Evaluation and Treatment of the Aging Face. New York:
Briden M.E. Alpha-hydroxyacid chemical peeling agents: Case Springer, 1995; pp. 16–20.
studies and rationale for safe and effective use. Cutis 2004; Leterrier F., Gary-Bobo C.L. Biologie membranaire, structure et
73(2 suppl):18–24. dynamique des membranes biologiques. Hermann: Éditeurs
Brody H.J. Peeling Chimique de moyenne profondeur. J Med Esth des sciences et des arts, 1989.
et Chir Derm 1987; 14(56):313–318. Rapaport M.J., Kramer F. Exacerbation of facial herpes simplex after
Bulengo-Ransby S.M., Griffiths C.E., Kimbrough-Green C.K., phenolic face peels. J Dermatol Surg Oncol 1984; 10(1):57–58.
et al. Retinoic acid treatment for hyperpigmented lesions Schmitt D. Biologie de la peau (INSERM U. 346). Les Editions
caused by inflammation of the skin in black patients. N Engl INSERM, 1995.
J Med 1993; 328(20):1486–14867. Shalita A. Le vieillissement cutane et son traitement par la
El Samahy M.H., Ghoz M.M., Ramzy N. Morphological investi- tretinoıne. J Med Est et Chir Derm 1988; 15(60):313–316.
gation of chemical peel on photodamaged facial skin. Int J Stegman S.J. A comparative histologic study of the effects of three
Cosmet Sci 1998; 20(5):269–282. peeling agents and dermabrasion on normal and sun dam-
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41
Lasers and Light Sources for Vascular and
Pigmented Components of Photoaging
Shealinna Ge, Anne Marie Mahoney, and Robert A. Weiss
Spider telangiectasias of the face are most commonly seen in

Introduction patients with fair skin of Fitzpatrick Types I and II, indicative
of this group’s increased susceptibility to UV damage. Facial
Photoaging related changes most commonly occur on the face, telangiectasias are especially common on the nasal ala, dorsal
however, areas such as the chest and legs are also frequently nose, and mid-cheeks and may be related to UV induced col-
involved. Two clinical manifestations of photoaging for which lagen damage that leads to vascular wall fragility and persistent
patients present for treatment are vascular and pigmented arteriolar vasodilation and vessel ectasia. Additionally, there
lesions. Facial telangiectasias are the most common vascular is a relatively high incidence of rosacea in these Fitzpatrick
lesion related to photoaging in Caucasians. In contrast, Asians types, which may have a prominent telangiectatic component
with photodamage present more frequently with UV-induced (Figure 41.2). Rosacea consists of recurrent flushing episodes
pigmentary changes. The most common pigmentation con- that may be associated with telangiectasias, papules, or pustules.
cerns are lentigines, keratoses, and Hori’s macules (1). This These repeated flushing episodes may be induced by exercise,
chapter will review current treatment modalities of these com- alcohol, and spicy food, which lead to the development of tel-
mon problems. angiectasias. Genetic factors also play a large role as the rosy
cheek appearance can be seen in families susceptible to rosacea.
Photoaging and repeated trauma to the face, can also induce
Vascular Lesions
collagen breakdown, localized erythema, and ultimately vas-
The term telangiectasia refers to superficial cutaneous vessels cular dilatation (4).
visible to the human eye (2). These vessels measure 0.1 mm to Fortunately, the treatment of facial telangiectasias is rela-
1.0 mm in diameter and represent a dilated venule, capillary or tively safe and more predictable than treatment of telangiec-
arteriole (Figure 41.1). The vessel type determines the clinical tasias on other sites, particularly the legs. This is attributable
presentation of telangiectasias. Arteriolar telangiectasias are to several factors. Facial skin has the ability to heal quickly
small in diameter, bright red in color, and macular to touch. with fewer propensities toward scarring when injured to a
Venule-derived telangiectasias are wider, blue in color, and similar depth compared to other locations. Treatment results
often protrude above the skin surface. Telangiectasias arising can be observed more quickly with faster healing times. Facial
at the capillary loop initially present as fine, red lesions, but vessels are at better oxygenated, at a more consistent depth
can enlarge with time and become purple or blue in color (2). compared to those on the legs, the vascular walls are thinner
There are four classifications of telangiectasias based upon and more uniform, and there is no significant contribution of
clinical morphology: 1) simple or linear, 2) arborizing, 3) spi- hydrostatic pressure in its pathogenesis. Occasionally, arterial
der, and 4) papular. Linear and arborizing telangiectasias with pressure may play a role, as in the case of spider angiomata
red coloration are very common on the face, particularly the with a small central arteriole. This is important and can influ-
nose and midface regions. These lesions are also seen rela- ence therapeutic approach as the use of laser energy can shrink
tively frequently on the legs. In addition, patients can experi- the arteriolar component but sclerotherapy into a bright red
ence enlargement of slightly larger venulectases, which can arteriole on the cheek increases risks of necrosis.
appear as purplish vessels on the cheeks, periorbital region, Given that patients seek treatment for telangiectasia of vari-
and vermillion. Papular telangiectasias are less frequently ous types primarily due to cosmetic concerns, it is impera-
related to photoaging and more often manifestations of genetic tive that the therapy chosen minimizes the risk of scarring.
syndromes, such as Osler-Weber-Rendu Syndrome, or occur in Various modalities can be used to treat telangiectasia on the
the setting of collagen vascular diseases. Cherry hemangiomas face or other regions. Several of these modalities will be dis-
are small round red to purple dome shaped vascular ectasias cussed in more detail in this chapter, including electrodessica-
scattered anywhere on the face or body. All forms of telangi- tion, sclerotherapy, and a variety of lasers including the pulse
ectasias are thought to occur through the release or activation dye laser (PDL), long-pulse dye laser (LPDL), argon laser, fre-
of vasoactive substances under the influence of a variety of quency doubled neodymium:yttrium-aluminum-garnet laser
factors, such as anoxia, hormones, chemicals, infection, or UV (532Nd:YAG), intense pulsed light (IPL) in all its forms, and a
radiation, with resultant capillary or venular neogenesis (3). variety of 1064 nm long-pulsed Nd:YAG lasers (1064Nd:YAG).
416 DOI: 10.1201/b22897-41

Lasers and Light Sources for Vascular and Pigmented Components of Photoaging 417

FIGURE 41.1 (a) Telangiectasias on the cheek of a Caucasian female consistent with the early stages of photoaging. (b) The same patient following
treatment with IPL has fewer visible vessels and smoother skin. IPL with double-pulse 570 nm filter, 2.4 msec + 6 msec pulse with 10 msec delay, and
a fluence of 29 J/cm 2 was used.

FIGURE 41.2 Rosacea is thought to result in part from photoaging. IPL treatments reduce intensity and duration of flushing that worsens telangiectasias
in rosacea. Before (a) and after (b) three treatments with Vasculight IPL (Lumenis, Santa Clara, CA) using a 550 nm filter, double pulse of 2.4 and 7
msec, delay of 10 msec, and a fluence of 27–29 J/cm 2.
Using the lowest effective fluence and the finest electrodes

Electrosurgery produces the most optimal results. Electrodes that are coated
with Teflon to expose only the tip or one side of the electrode
Electrodessication is commonly used to treat facial telangiecta- tend to provide the safest treatment. In addition, use of a bipo-
sia because the device is readily available at relatively low cost, lar current (with the patient grounded to a plate at a distance
making it an accessible and affordable treatment worldwide. from the treated area) allows for effective treatment with
Electrodessication is a process in which heat is generated from a lower fluence. With bipolar treatment, the current passes
resistance of tissues to the passage of a highly damped current through the cannulated vessel for several millimeters with
from a single electrode. Dehydration occurs in tissues immedi- relative selectivity. When performed with care, electrodessica-
ately adjacent to the needle point, and tissue destruction results tion is effective, but is best reserved for the smallest of telan-
as cellular fluids are evaporated. The vessel must be cauterized giectasia. This technique has been popularized by Kobayashi
or electrocoagulated every 2 to 3 mm with very low amperage who reports excellent results (5).
current (1–2 amps). Some degree of epidermal necrosis may Serious adverse effects from electrosurgery such as distur-
occur due to the nonspecific nature of cauterization. Multiple bance of pacemakers and implantable cardio-defibrillators
treatments are typically necessary for successful treatment. are extremely rare. To prevent disruption to electric currents
Punctate white or pigmented scars may occur if excessive ther- in these devices, short bursts are recommended with minimal
mal damage occurs. Groove-type scars along the nasal ala are power settings. Rare instances of pacemaker interference with
the most common adverse effect of electrodessication. skipped beats and reprogramming have been reported in a
survey of dermatologic surgeons performing electrocoagula- and penetrate to the depth of mid-dermal vessels, over 1 mm
tion during cutaneous surgery. An incidence of 0.8 cases/100 into skin. Treatment parameters vary and laser powers of 0.8
years of surgical practice occurred, but may not be representa- w to 2.9 w, exposure times of 50 milliseconds (msec), 0.2
tive of all patients undergoing electrodessication of telangiec- seconds (sec), 0.3 sec, and continuous, and spot sizes of 0.1
tasia (6). mm and 1 mm have been used. Although the success rate in
treating facial telangiectasia is acceptable (10, 11), pitted and
depressed scars, hypopigmentation, hyperpigmentation, and
recurrence of veins have been noted. In addition, when com-
Lasers pared to the PDL, the latter is more efficacious.
There are multiple lasers available for treatment of facial telan- Adverse healing consequences with the argon laser arise
giectasia. These lasers cause vascular destruction by selectively from competition for absorption of its wavelength (411 nm and
heating the vessel through the absorption of laser energy by 514 nm) from epidermal melanin as well as radial diffusion
oxygenated and deoxygenated hemoglobin. The advantages and and dissipation of heat from the target blood vessels secondary
disadvantages of presently available lasers are described later. to long-pulse durations. Both of these factors result in rela-
Several factors must be considered when selecting an appro- tively nonspecific thermal destruction, making this laser a sub-
priate laser for telangiectasia treatment. In general, the choice of optimal choice for treatment of telangiectasias.
wavelength(s) and pulse duration are related to the type and size
of target vessel treated. Deeper vessels require a longer wave- KTP 532 nm Green Lasers
length to allow penetration to their depth. Pulse duration must
be matched to vessel size, longer pulse durations are required KTP crystals are highly reliable, convenient to work with, and
to effectively thermally damage vessels with larger diameters. easily available to laser manufacturers. While the mechanisms
The relative importance of hemoglobin absorption peaks in of these devices vary, each produce millisecond domain pulses
green (541 nm), yellow (585–595 nm), and red to infrared (800– at 532 nm. Pulsing in milliseconds allows vessel coagulation
1000 nm) shifts as the depth and size of blood vessel changes. to occur without producing purpura. The various KTP lasers
Absorption by hemoglobin in the long visible to near infrared available differ in the spot size, which ranges from 0.5 to 4
range appears to become more important for vessels larger than mm in diameter.
0.5 mm and at least 0.5 mm below the skin surface (7). Results of treatment of facial vessels with KTP lasers
It is important to note that while laser treatment of facial have been excellent (12). KTP is typically used with a 2 mm
telangiectasias has yielded excellent results, the use of lasers to spot, 10–20 msec pulse duration, and 10–15 J/cm2 of fluence.
treat leg telangiectasias has been far less successful than sclero- Cooling appears to be of significant benefit in protecting the
therapy. This is likely related to insufficient vessel destruction epidermis thus allowing use of higher, more effective fluen-
due to competition for laser absorption from overlying mela- cies. A randomized split face study comparing KTP to PDL
nin, and the failure of lasers to overcome the increased hydro- was done using a larger spot size (5 mm), pulse duration of
static pressure from the “feeding” venous system. 18–20 msec, and fluence of 8–11 J/cm2. At the 3 week follow-
up, there was a higher rate of facial telangiectasia clearance
in those treated with the KTP versus PDL (85% vs. 75%) (13).
In addition, a recent study of 647 patients demonstrated that
Continuous Wave Lasers 78% of patients experienced clearance or marked improve-
ment of vascular lesions after 6 weeks. In this same retrospec-
Carbon Dioxide Lasers
tive review, 6% of patients reported minor adverse effects, and
Carbon dioxide (CO2) lasers were used early on in an effort there was only a single report of bruising. No major adverse
to obliterate telangiectatic vessels by means of precise effects were reported (14).
vaporization without significant damage to adjacent tissue.
Unfortunately, because its wavelength is so well-absorbed by
Flashlamp Pumped-Pulsed Dye Lasers
water in the overlying epidermis and dermis surrounding the
vessels, non-specific thermal injury is unavoidable regardless The traditional pulsed dye laser (PDL) (585 nm, 450 sec pulse
of whether pulsed or continuous wave sources are used (8). All duration) is highly effective in treating a variety of cutaneous
reported studies have demonstrated unsatisfactory cosmetic vascular lesions, including port wine stains (PWS) and facial
results (9). Treated areas show multiple hypopigmented punc- telangiectasia. The original PDL was developed for the treat-
tate scars with either minimal resolution of the treated vessel ment of PWS in children, where the average vessel is superfi-
or neovascularization adjacent to the treatment site. Because cial with an average depth of 0.46 mm and a diameter of 100
of its non-selective action, the CO2 laser has no advantage um. Modern day PDL is delivered entirely differently, using
over the electrodessication needle and is associated with more 595 nm, 1.5–20 msec pulse durations, and synchronized skin
adverse effects. cooling with a spray or airstream.
In preliminary animal studies using the rabbit ear vein,
approximately 50% of vessels treated with an effective con-
Argon Lasers
centration of sclerosant demonstrated extravasated RBCs,
Argon (488 and 514 nm) and argon pumped continuous wave whereas extravasated RBCs were apparent in only 30% of ves-
dye lasers (515 to 590 nm) are well-absorbed by hemoglobin sels treated after PDL (15). Additionally, vessels treated with
the PDL demonstrated in a relative decrease in perivascular Newer FLPD lasers that extend the pulse duration to 1.5, 3,
inflammation compared to those treated with sclerotherapy 6, 10, 20, and 40 msec and use dynamic or continuous air cool-
alone. ing have eliminated most of the pain and minimized the pur-
The PDL treatment technique involves a series of pulses pura associated with the first generation FLPD lasers. Typical
with 10–50% overlap, tracing the vessels to be treated with a fluences of 10 J/cm2 with a 10 msec spot size can result in 90%
2, 3, 5, 7, 10 mm, or elliptical delivery spot. An area of inter- resolution of facial telangiectasias in one treatment with mini-
lacing telangiectasia can be treated with overlapping spots to mal pain and purpura (Figure 41.3). Improvement in rough tex-
cover the involved area. Delivery energies range from 5.0 to ture and pigmentation of photoaging is also seen.
14.0 J/cm2 depending on the spot size used and are adjusted Treatment of leg telangiectasias with this method has not pro-
according to vessel response. The end-point of treatment is duced satisfactory results, even with the use of longer pulsing.
purpura or vessel spasm. A study evaluating the long-pulse dye laser of 595 nm using two
Purpura is a common occurrence after treatment with tradi- different fluences of 20 J/cm2 and 24 J/cm2 demonstrated that
tional PDL with short pulse durations but is much less common after two treatments, there was a 50% improvement in leg telan-
with pulse durations longer than 6 msec. Initial studies using giectasias in 77% and 85% or patients, respectively, at 6 month
the 0.45 msec pulse duration FLPD laser demonstrated high follow up (19). After a single treatment of vessels less than
efficacy, but it was complicated by purpura that lasted for 1–2 0.4 mm on the leg using the available 595 nm, 1.5 msec PDL
weeks (16). In this study, 182 patients treated with the 0.45 msec (Cynosure) and an experimental 595 nm, 4 msec PDL, clear-
pulse durations at 6–7.75 J/cm2 with a 5 mm spot size were eval- ance rates were not clinically significant with either device, but
uated. Seventy-six to 100% clearance was obtained in 83.5% of the rates of both hypopigmentation and hyperpigmentation were
patients with the remainder having 51–75% clearance. significant (20). Despite advances in laser therapy, sclerotherapy
A technique that may increase efficacy and decrease pur- remains the gold standard for treatment of leg telangiectasias.
pura is to use double and triple pulses (pulse stacking) at sub-
purpuric fluences. Tanghetti used pulse stacking to increase
The Copper Vapor Laser
efficacy on photoaged skin with reduced side effects, but found
that with or without pulse stacking, multiple treatments may The copper-vapor laser operates at two specific wavelengths,
be needed for superior results for the signs and symptoms of 578 nm (yellow) and 511 nm (green), and delivers a “quasi-
photoaging including telangiectasias (17). continuous wave” composed of pulsed laser light energy in 20
nanosecond pulses at a frequency of 15,000 pulses per second.
This train of pulses interacts with tissue in the same manner as
Long-Pulse Dye Lasers
a continuous beam because of the accumulation of heat with
Based on the theory of selective photothermolysis, the predicted the large number of pulses delivered. Due to the resulting ther-
pulse duration ideally suited for thermal destruction of vessels mal diffusion, it is necessary to electronically gate the pulse to
the size of leg telangiectasia (0.1 to several mm in diameter) a 20–50 msec duration.
is in the 1–50 msec domain (18). Newer long-pulsed dye lasers These refinements should allow this laser to work within the
with variable pulse durations as long as 40 msec (V-Beam thermal relaxation time of telangiectatic vessels (21). When
Perfecta™, Syneron/Candela, Wayland, MA and Cynergy™, the laser is used without these refinements, it is somewhat safer
Cynosure, Chelmsford, MA) are now available. Each device and more effective than the argon laser for treatment of facial
uses a rhodamine dye to produce wavelengths of 585–595 nm. telangiectasia. It also has the advantage of leaving very minor
These longer pulse durations and longer wavelengths improve superficial crusts overlying treated vessels in contrast to the
our ability to treat deeper, larger caliber vessels. very visible dark purpuric impact spots of the FLPD laser.

FIGURE 41.3 Treatment with the long-pulsed dye laser (V-Star, Cynosure, Chelmsford, MA) improved this patient’s telengiectasias, skin texture, and
pigmentation (2 msec duration, 2.5 J, 10 mm spot, and three passes). (a) Pretreatment. (b) After treatment.
Long-Pulse Nd:YAG 1064 nm Lasers #6451007, Koop, Baumgardener and Weiss) of the heat released
from larger vessels following the laser heating. Topical lido-
Long-pulsed 1064 nm lasers have recently been developed caine has also proven efficacious in reducing pain (24).
in an effort to target deep, relatively large caliber cutaneous
vessels. This wavelength achieves deep penetration without
Intense Pulsed Light Source
absorption by melanin, thus allowing treatment of more darkly
pigmented individuals. However, high energies must be uti- The high-intensity pulsed light (IPL) source was developed
lized for adequate penetration, as the posterior wall of a large as a device to treat ectatic blood vessels using non-coherent
caliber (1–2 mm) vessel filled with deoxygenated hemoglobin light emanating from a filtered flashlamp (Lumenis One™,
can only be reached and heated with sufficient fluence and effi- Lumenis, Santa Clara, CA). Although Lumenis is the larg-
cient heat dissipation. est and most well-known of the IPL device manufactures,
The newer pulsed 1064 nm lasers have pulse durations other manufactures of pulsed light devices include Energis
between 1–200 msec (Vasculight™, Lumenis, Santa Clara, Technology (Swansea, UK), who markets an Energis Elite
CA, Cool Touch Varia™, CoolTouch Corp, Roseville, CA; IPL system for hair removal only and Danish Dermatologic
Lyra™, Laserscope Lyra, San Jose, CA, Coolglide™, Altus, Development (Hoersholm, Denmark), who markets the Elipse
Burlingame, CA). Large caliber vessels >0.5 mm in diameter system for both hair and vascular indications. The Energis sys-
respond best to these lasers, however, recent data suggests that tem is a low output device, with fluences of 5–19 J/cm2, spot
by using smaller spot sizes and higher fluences, even small size of 10 × 50 mm, pulse train length of 15–40 msec, and
vessels may respond. For a first generation 1064 nm device pulses per train of 4 to 5. There is a fixed delay between pulses
with a fixed 6 mm spot delivery hand piece, fluences settings of 1.5 msec. In comparison, the Lumenis device is a high out-
of 80–120 J/cm2 and single pulse durations of 10–30 msec put device with fluences up to 90 J/cm2, spot size of 8 × 35 mm,
were most optimal (22). Treatment of leg telangiectasias using variable pulse lengths of 2–40 msec, and infinitely variable
16 msec pulse durations at fluences of 130–140 J/cm2 showed delay between pulses of 1 to 1000 msec.
approximately 75% resolution at 3 months (22). Selectivity for IPL is achieved primarily by manipulating
Larger violaceous vessels of the face may also be treated pulse durations to match the thermal relaxation times of ves-
with these devices (Figure 41.4). The fluence must be lowered sels larger than 0.2 mm and by using filters to remove shorter
by 30–40% for facial vessels compared to the legs. A recent wavelengths of visible light. Fluences can be very high, up to 90
study of facial telangiectasias ranging in size from 0.2–0.3 J/cm2. Sequential pulses of 1–12 msec separated and synchro-
mm on the nasal alae and tip demonstrated a 92% decrease in nized with rest intervals of 1–100 msec deliver wavelengths of
vessel size (23). 515–1000 nm. It is most commonly used with the 550 and 570
It should be noted that treatment with a long-pulse 1064 nm nm filters to deliver the yellow and red wavelengths and some
laser is relatively painful, and both cooling and topical anes- infrared. The ability of IPL to produce a non-coherent light as
thesia should be utilized to minimize the discomfort. Stacked a continuous spectrum longer than 550 nm was thought to have
pulsing CANNOT be performed with 1064 nm due to a higher multiple advantages over a single wavelength laser system,
risk of heat buildup and skin breakdown. The pulse rate of 1064 including absorption by both oxygenated and deoxygenated
nm should never be faster than 1 Hz, and pulse positioning hemoglobin and absorption by larger blood vessels located
should never be closer than 1 mm apart. For patient comfort, deeper in the dermis. In reality, the primary advantage has
epidermal cooling can be accomplished via contact cool- been the allowance of larger spot sizes with relatively low inci-
ing or cryogen spray, which can be programmed before and dence of purpura on facial telangiectasia.
after the laser pulse. The concept behind applying the spray For facial telangiectasia, our experience has been that the
after the cooling pulse is for “thermal quenching” (US Patent 550 nm, 560 nm, or 570 nm produce optimal results. When

FIGURE 41.4 Larger facial veins can be treated with the 1064 nm Nd:YAG laser (Vasculight, Lumenis, Santa Clara, CA). (a) Pretreatment. (b) 50%
improvement 2 months after treatment.
treating darker skin types and larger blood vessels, we choose the vessels occurred in the 13–22 J/cm2 range. Pulse durations
a longer cut-off filter. For telangiectasia-predominant photoag- of 10 msec were used for vessels <0.4 mm in diameter and
ing, the typical pulse durations are 2.4 msec + 6.0 msec with pulse durations of 15 and 30 msec were used for larger vessels.
a 10 msec delay between pulses. The delay between pulses is Patients received 1–4 treatments with an average of 2.54 treat-
increased to 20–30 msec in darker skin types to reduce the risk ments. Seventy nine percent of patients had greater than 50%
of thermal injury. clearance with 38% having 75–100% clearance (27).
For pigmentation-predominant photoaging, the typical The development of the short pulse-long pulse protocol for
pulse durations are 2.4 msec + 4.0 msec (double pulse) with the IPL device at 2.4–3 msec and 7 msec pulses separated by
a 10 msec delay between pulses. Typical fluences range from a 10–20 msec delay using the 560 nm or 570 nm filter has
24–38 J/cm2 dependent on the sensitivity of the skin and the yielded the best results for leg veins (28). By combining a
degree of epidermal cooling. To minimize non-specific epi- shorter pulse (2.4–3 msec) with a longer pulse (7–10 msec),
dermal damage, the crystal is placed on a layer of cold clear it is theoretically possible to ablate smaller and larger vessels
gel 2–3 mm in thickness for non-cooled crystals (floating tech- overlying one another in the dermis. Smaller, more superficial
nique). When using the Quantum IPL with a thermoelectri- vessels absorb the shorter pulses more selectively, while the
cally cooled crystal, a thinner layer of gel is needed with the longer pulses are preferentially absorbed by the larger, deeper
crystal resting directly on the skin at maximal cooling (direct vessels. New contact epidermal cooling devices improve treat-
contact technique). ment results by allowing higher fluences while minimizing
Studies on the treatment of leg telangiectasia and poikilo- risk to the epidermis.
derma of Civatte have shown the efficacy and limitations of
IPL technology. Fewer have evaluated IPL efficacy purely on
facial telangiectasia. Those evaluating IPL’s efficacy for treat-
The Role of Cooling
ing telangiectasias have been consistently promising. Bitter
reported that IPL used in “FotoFacial settings” produced The concept of cooling the skin in an effort to protect the
>75% improvement in telangiectasia in 38% of patients and epidermis during laser treatment of dermal targets was first
>50% reduction in telangiectasia in 70% of patients (25). studied by Gilchrest, who incorporated the use of ice prior to
Tanghetti performed a split face randomized study comparing argon laser for treatment of PWS (29). Skin cooling during
the efficacy of PDL versus IPL for the treatment of facial telan- laser therapy offers multiple benefits, including cooling and
giectasias. Based on the Telangiectasia Grading Scale (TGS), protecting the epidermis, preventing collateral dermal dam-
the mean scores for both devices were 3.3 at 3 month follow age, and reducing associated treatment discomfort. Cooling
up, demonstrating that IPL may be as effective as PDL (26). is especially critical in the treatment of larger telangiectasia
Most studies on IPL mention its photorejuvenation effects in due to the higher fluencies required. Several cooling modali-
addition to treatment of telangiectasia, including elimination ties have been used including cooling coupling gels, refrig-
of lentigines, reduction of pore sizes, and minimization of fine erated spray cooling devices, and water-cooled chambers
wrinkles (Figure 41.5). applied directly to the skin through which the laser beam
Another IPL device (Ellipse Flex, Danish Dermatologic is directed. Preliminary results suggest that cooling reduces
Development, Hoersholm, Denmark) was used in 27 patients epidermal damage and allows the use of higher fluencies to
with facial telangiectasia. This IPL has a lower cut-off filter at create more damage of the targeted vessels, thereby achiev-
555 nm and an upper cut-off filter at 950 nm, with a median ing a greater degree of vessel clearance per treatment (30,
wavelength of 705 nm delivered through a 10 x 48 mm crystal 31). Cooling plays a lesser role in the treatment of pigmented
light guide. Fluences required to produce a slight bluing of lesions.

FIGURE 41.5 Poikilodermatous type of photoaging of the chest including telangiectasias and pigmentation. (a) Pretreatment of chest and neck areas.
(b) Following one IPL treatment. Note the disappearance of cherry hemangiomas on the right side of the chest.
Pigmented Lesions damage and subsequent leukotrichia when a higher fluence is

used. A study of 34 patients comparing a QS 532 nm Nd:YAG
Pigmented lesions are another common manifestation of laser and a long-pulse 532 nm Nd:YAG laser (36) showed that
photodamage for which patients present for treatment. the long-pulse laser (6.5 J/cm2, 2 mm spot size, 2 msec pulse
Actinic induced pigmentary changes occur in several man- duration) resulted in a lower risk of PIH when treating lentigi-
ners. Lentigos are the most common photoaging-associated nes in Asians.
pigmented lesions and arise from UV-induced melanocyte
proliferation. Ephilides (freckles) classically occur in a photo-
distributed pattern, favoring the face, shoulders, and extensor
arms. There is an altered pattern of melanin deposition and IPL
increased propensity to darken with increased sun exposure. Some investigators have suggested that the photomechanical
effect of QS lasers may be undesirable for treatment of lentigi-
Q-Switched Lasers nes (37). Photothermal effects, such as those produced by the
IPL, were initially considered efficacious when treating len-
QS lasers generate high-energy radiation with very short pulse tigines. For example, use of IPL for photoaging in Asians has
duration. This produces intense energy delivery that leads to been shown to increase collagen and decrease melanin without
rapid increases in temperature (1000 degrees Celsius) within significant adverse effects and relatively high patient satisfac-
the target subcellular chromophore. As the laser pulse duration rates (38). However, there have been few reports of IPL-
tion is shorter than the thermal relaxation time of the target, a induced long-term hyperpigmentation (39, 40) and although
temperature gradient develops between the target and its sur- temporary, hypopigmentation is also a well-recognized side
rounding tissue (32). When the temperature gradient collapses, effect of IPL. To minimize risks of scarring, it is important to
localized shockwaves are generated causing the fragmentation select a pulse duration that is shorter than the thermal relax-
of its targets. This photomechanical reaction leads to melano- ation time of the epidermis. The epidermal thermal relaxation
somal disruption that occurs after nanosecond pulse durations time is estimated to be approximately 10 msec when the epi-
of Q-switching (33). dermal thickness is 100 um. Therefore, pulse durations of less
Several laser systems have shown efficacy for the treat- than 10 msec with IPL are preferred for pigmented lesions (41).
ment of lentigines. These systems include the 510 nm PDL,
the frequency doubled Q-switched (QS) Neodynium:Yttrium-
Aluminum-Garnet 532 nm (QS 532 nm Nd:YAG), the QS
Selecting the Laser
Ruby laser, and the QS Alexandrite lasers (34) (Figure 41.6).
As with most aesthetic procedures, the risk of adverse effects When treating epidermal pigmented lesions such as lentigines,
is an important consideration. Patients with darker skin types patients should be informed about the advantages and disad-
have higher epidermal melanin contents and are at higher risk vantages of each treatment modality. IPL typically results in
of developing complications like proinflammatory hyperpig- little downtime and may also improve rhytids. Lasers, how-
mentation (PIH). Studies using Q-switched lasers in dark- ever, may be preferred for patients due to fewer number of
skinned patients have showed that the risk of PIH can be as treatments and lower cost. Test areas with different devices
high as 40% (35). may be performed, and the treatment modality reflecting a
QS ruby and QS Alexandrite wavelengths are well absorbed satisfactory clearance without development of PIH should be
by melanin. Greater depth of penetration can be disadvanta- chosen. Patients are advised that one to four sessions may be
geous due to the potential for permanent follicular melanocytic required for optimal results. If PIH develops at any time during

FIGURE 41.6 Solar lentigo. (a) Before treatment. (b) Following one treatment with Q-switched ruby laser at 4 J/cm 2.
the treatment phase, treatment is stopped, hydroquinone or an experienced by cutaneous surgeons. Dermatol Surg. 2001;
equivalent can be applied daily, and the patient is followed 27(4):385–90.
until resolution. Typically, we use IPL if multiple pigmented 7. Hare McCoppin HH, Goldberg DJ. Laser treatment of facial
lesions are scattered around the face, and QS Ruby if a few telangiectases: an update. Dermatol Surg. 2010;36(8):1221–30.
isolated lentigines are targeted. 8. Apfelberg DB. Side effects, sequelae, and complica-
tions of carbon dioxide laser resurfacing. Aesthet Surg J.
1997;17(6):365–72.
9. Apfelberg DB, Maser MR, Lash H, et al. Use of the argon
Pre- and Post-Treatment Considerations and carbon dioxide lasers for treatment of superficial
venous varicosities of the lower extremity. Lasers Surg
One cannot overemphasize the importance of pre-treatment
Med. 1984;4(3):221–31.
skin preparation in patients planning to undergo laser or light
10. Broska P, Martinho E, Goodman MM. Comparison of
treatment for pigmented and vascular components of photo- the argon tunable dye laser with the flashlamp pulsed dye
aging. The use of topical bleaching agents such as hydroqui- laser in treatment of facial telangiectasia. J Dermatol Surg
none, vitamins C and E, and UVA/UVB sunscreens of SPF Oncol. 1994;20(11):749–53.
30 or higher should be initiated 2 weeks prior to the laser/IPL 11. Ross M, Watcher MA, Goodman MM. Comparison of the
surgery and then resumed 5 to 7 days post-treatment or when flashlamp pulsed dye laser with the argon tunable dye laser
epidermal crusting resolves. Topical regimens should continue with robotized handpiece for facial telangiectasia. Lasers
for at least 6 months after a course of treatment and the use of Surg Med. 1993;13(3):374–8.
sunscreens should become a lifelong habit. 12. Clark C, Cameron H, Moseley H, et al. Treatment of super-
ficial cutaneous vascular lesions: experience with the KTP
532 nm laser. Lasers Med Sci. 2004;19(1):1–5.
13. Uebelhoer NS, Bogle MA, Stewart B, et al. A split-face
Summary comparison study of pulsed 532-nm KTP laser and 595-nm
Treatment of vascular and pigmented lesions in adults can be pulsed dye laser in the treatment of facial telangiectasias
very successful. Practically all laser devices available in the and diffuse telangiectatic facial erythema. Dermatol Surg.
visible light range, excluding red, can produce good results on 2007;33(4):441–8.
facial vascular lesions. Wavelengths of lasers may be fine-tuned 14. Becher GL, Cameron H, Moseley H. Treatment of superfi-
for size, color, or location of individual telangiectasias, and a cial vascular lesions with the KTP 532-nm laser: experience
knowledge of the lesion type and their varying responses can with 647 patients. Lasers Med Sci. 2014;29(1):267–71.
assist in selecting the procedure most likely to achieve optimal 15. Goldman MP, Fitzpatrick RE. Pulsed-dye laser treatment
results. Although electrocautery can be used, a more selective of leg telangiectasia: with and without simultaneous sclero-
therapy. J Dermatol Surg Oncol. 1990;16(4):338–44.
method such as laser or IPL is usually a better choice with sig-
16. Ruiz-Esparza J, Goldman MP, Fitzpatrick RE, et al. Flash
nificantly reduced risks of scarring. Larger cavernous lesions
lamp-pumped dye laser treatment of telangiectasia. J
may require deeper penetration with 1064 nm (infrared) wave-
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42
Nonablative Laser Rejuvenation
Shealinna Ge, Karen L. Beasley, Christian R. Halvorson, and Robert A. Weiss
aluminum garnet (Nd:YAG), 1450 nm diode and 1540 nm

Background erbium:glass lasers were developed. These lasers demonstrated
modest improvements in fine rhytides and acne scars (3–5),
The development of fractional photothermolysis is one of the and can produce results in patients with darker skin types (6).
most important discoveries in the field of laser medicine and But the results from these nonablative lasers often paled in
surgery. This concept has revolutionized laser skin resurfac- comparison to traditional ablative procedures, leading patients
ing. Previously patients could only significantly enhance their and physicians to seek more efficacious treatments leading to
skin through fully ablative lasers, like the 10,600 nm carbon the development of newer, more effective lasers and delivery
dioxide (CO2) or the 2940 nm erbium-doped yttrium alumi- systems. A comparison of types of ablative and nonablative
num garnet (Er:YAG) lasers. These laser treatments required lasers is shown diagrammatically in Figure 42.1.
at least 1 to 2 weeks of recovery depending on the depth of It is important to consider the risk-benefit ratio of any laser
resurfacing and the type of laser utilized. With deeper resur- procedure and the potential for post-procedure downtime.
facing procedures, patients could experience considerable Despite the more limited efficacy of nonablative treatments,
discomfort and side effects. Results could be exceptional, but many patients do not want the risk of serious adverse effects in
patients soon became aware of the potential disadvantages exchange for cosmetic improvements. Furthermore, demanding
of aggressive procedures. Besides the potential for infection work or social schedules in the current culture do not allow for
or permanent scarring, many patients who were treated with extended recovery times. Nonablative fractional laser (NAFL)
deep CO2 laser resurfacing experienced prolonged erythema resurfacing allows for visible results with fewer adverse effects
of the skin for 6 months to a year. Many also developed unex- and reduced downtime. This technology also allows for the
pected permanent hypopigmentation of the treated areas (1, 2). treatment of darker skin types and other body areas and can
In addition, patients also became aware of the stark contrast successfully treat a multitude of skin conditions. The disad-
between their beautiful resurfaced facial skin and the adja- vantages, compared with ablative resurfacing modalities, is the
cent severely sun-damaged neck and chest. Fully ablative laser need for multiple treatments due to a decrease in efficacy.
resurfacing was fraught with severe complications when used
off elsewhere on the body, and darker skin types were not can-
didates for the procedure. With these limitations, traditional
Fractional Photothermolysis
deep ablative resurfacing began to decrease in popularity.
Nonablative infrared lasers were developed in hopes of During fractional photothermolysis, the laser creates micro-
remodeling and rejuvenating the skin with fewer side effects. scopic noncontiguous columns of thermal injury in the dermis,
Infrared lasers, like the 1320 nm neodymium: yttrium referred to as microthermal zones (MTZ) (7) (Figure 42.2).
FIGURE 42.1 Schematic representation of laser impact from several lasers: (a) Ablative resurfacing (CO2 and 2.94 Erb:YAG) 10–200 microns;
(b) superficial ablative resurfacing (CO2 and 2.94 Erb:YAG) 10–200 microns; (c) nonablative fractional resurfacing (thermal only without vaporization)
600–1000 microns; (d) ablative fractional resurfacing, 600–1000 microns.
DOI: 10.1201/b22897-42 425

Each MTZ is surrounded by a limited zone of millisecond heat- MTZs by 3 months post treatment (9). In addition, histologic
shocked tissue as well as a larger zone of healthy unaffected evaluation reveals a localized, well-controlled melanin release
tissue. MTZs allow for transport and extrusion of necrotic der- and transport mechanism using microscopic exudative necrotic
mal content through the compromised dermal epidermal junc- debris (MEND) as the vehicle for pigmentary redistribution (9).
tion (8). The precise nature of tissue injury allows for quicker In other words, NAFL resurfacing improves pigmentation by
healing and recovery (7–9). Immunohistochemical studies shuttling melanin through the MENDs where it can be exfo-
have shown increased collagen III production around treated liated off the skin. The initial study by Manstein et al. also
MTZs by 7 days and replacement of damaged collagen within reported that there was little to no pigmentary alteration in
dark-skinned patients when utilizing laser treatments with low
to medium MTZ densities per treatment (7). This essential
combination of precise method of injury with the ability to
stimulate collagen regeneration and pigment redistribution is
the hallmark of fractional photothermolysis.
Nonablative Fractional Lasers (NAFL)

Two main NAFL families currently dominate the world
laser market; the Solta family of nonablative fractional lasers
(Solta Medical, Inc., Hayward, CA) and the Palomar fam-
ily of nonablative fractional lasers, which were acquired
by Cynosure in 2013 (Cynosure, Inc., Westford, MA). Both
families contain a variety of effective nonablative resurfac-
ing lasers. Laser wavelengths in the infrared range of light
are used in both families, which utilize water as their tissue
target, or chromophore. The families differ by using slightly
FIGURE 42.2 Microthermal zones of damage from a 1550 nm nonablative different wavelengths in their respective lasers. But the most
fractional laser. striking difference between the two families is the manner in
FIGURE 42.3 Treatment screen of a 1550 nm nonablative fractional laser.

Nonablative Laser Rejuvenation 427
which the laser energy is delivered to the skin. Besides these by the laser treatment screen according to the set treatment
two main families, there is a multi-wavelength nonablative parameters.
fractional laser also by Cynosure, a fractional 910 nm laser by All Solta lasers have a continuous motion handpiece, which
Syneron Medical Ltd. (Irvine, CA), a fractional Q-Switched is equipped with rollers. The Fraxel laser treatment tip comes
1064 nm by Alma Lasers (Buffalo Grove, IL), and a new 1440 in two different sizes, 15 mm and 7 mm. Smaller cosmetic units
nm home-use device by Tria Beauty, Inc. (Dublin, CA). There like the eyelid, nose, or lip can be treated with the smaller tip
are also other NAFLs that are marketed outside the United (Figure 42.5). The Clear + Brilliant systemTM is a nonablative
States or that are currently in development. fractional 1440 nm laser. It is based on the technology of the
Fraxel lasers and has a similar, yet more simplified interface.
In all the NAFL devices by Solta Medical, the handpieces
should be positioned perpendicular to the skin and should not
The Solta Family of NAFL (Solta be lifted while the footswitch is depressed. Handpiece velocity
Medical, Inc., Hayward, CA) is also measured by the device during treatment. Passes should
The Solta family consists of the Fraxel division of laser devices be smooth and controlled and stay within the recommended
and the Clear + BrilliantTM laser system. The Fraxel division velocity levels. If treatment passes are delivered too fast, the
includes the Fraxel 1550 nm laser, the Fraxel DUAL 1550/1927 laser microdots become oval rather than round and therefore
nm laser, a stand-alone Fraxel 1927 nm laser and the Fraxel the energy delivered may be reduced by up to 50% causing
re:fine 1410 nm laser, which is mostly marketed outside of the under-treatment. As with the stamping technique of delivering
United States. The 1927 nm solid state laser is FDA cleared for fractional laser, the pulses delivered by the rolling technique
treatment of actinic keratoses. All of the Fraxel laser systems may not be uniformly distributed. Some pulses may overlap
have an interface that allows for a customized treatment by while others are adjacent, and some are farther apart while
controlling the pulse energy, treatment level, and number of others are closer together.
passes (Figure 42.3). The pulse energy is delivered in milli-
joules (mJ) and controls the depth of penetration, or the depth
of the MTZ. Different treatment depths can be used to treat Fractional 1550 nm Laser
different indications (Figure 42.4). The treatment level (TL) is
the percentage of skin treated or covered by MTZs during one The Fraxel 1550 nm laser, which is the most extensively stud-
treatment session, and it controls the aggressiveness of treat- ied nonablative resurfacing laser, was introduced in 2006.
ment. The number of passes is also set during the procedure. It is indicated for moderate skin resurfacing for periorbital
A pass is defined as a single unidirectional motion over the wrinkles, pigmented lesions, dyschromia, scars, melasma, and
skin that lays down one row of MTZs. On average, 6–8 passes actinic keratoses. It can deliver laser energy ranging from 4
are performed. Additional passes can be applied to individual to 70 mJ. Its treatment levels range from 5 to 48% coverage.
areas of scarring or deep lines. The total energy delivered Maximum absorption depth into the skin is estimated to be
per treatment session is constant regardless of the number of 1,400–1,500 µm deep. As discussed previously, different treat-
passes. For example, the quantity of energy per pass decreases ment depths can be used for different indications and treat-
as the number of passes increase. Alternately, the quantity of ment levels can be adjusted to determine the aggressiveness of
energy per pass increases as the number of passes decrease. treatment. For example, to target a deep scar with the Fraxel
A higher number of passes with less density of MTZ per each 1550 nm laser, a higher energy in the 50–70 mJ range would be
pass can be performed to increase patient comfort. Typically, selected. An example of an aggressive treatment level would
passes are delivered by alternating horizontal and perpendicu-
lar passes within one cosmetic unit at a time. Before a laser
treatment series begins, the skin surface can be measured and
an estimated energy total in kilojoules (kJ) can be computed
FIGURE 42.5 Tip for rolling nonablative fractional device. This must
FIGURE 42.4 Approximate depths of thermal impact by fluence. be replaced every 5–10 treatments.
be 12 and would cover 35% of facial skin in one treatment. 3–6 that corresponds to 30–45% coverage. See recommended
In patients with darker skin types (Fitzpatrick types IV–VI), treatment settings in Table 42.2. In 2011, the Fraxel 1927 nm
the density must be decreased by reducing the treatment level, laser became available in a stand-alone laser platform.
such as level 4–6 or 11–17% coverage, to reduce the chances The 1550 nm and the 1927 nm lasers can be combined for
of postinflammatory hyperpigmentation (PIH). See recom- a “DUAL” resurfacing treatment. When combining the wave-
mended treatment settings in Table 42.1. lengths, 2–4 passes of 1550 nm are performed over the treat-
ment area to target the dermis and then 2–4 passes of 1927
nm are performed to provide an epidermal treatment. Laser
energies and treatment levels are set lower than if you used
Fractional 1550 nm and 1927 nm Lasers the lasers separately. Our experience has taught us to use
Fraxel DUAL 1550/1927 was introduced in October 2009.
Both solid state lasers are housed in the same platform and
function independently of each other so that a fully 1550 nm
or 1927 nm treatment may be performed. Additionally, both
lasers can be layered on top of each other for a combination
treatment. The thulium 1927 nm wavelength has a higher
absorption coefficient for water than the 1550 nm wavelength
and has a greater ability to target the epidermis; Figure 42.6
illustrates the absorption of the two wavelengths. Energy flu-
ences for the 1927 nm laser range from 5 to 20 mJ and the TL
ranges from 20 to 70% coverage. It has a hypothetical maxi-
mum depth of penetration of 200 µm into the skin. Therefore,
this wavelength is more effective in treating epidermal pro-
cesses, like actinic keratoses for which it is FDA cleared.
An average energy and treatment level for a patient with a FIGURE 42.6 Comparison of thermal impact depths for 1550 nm vs.
Fitzpatrick skin type I–III would be 10–20 mJ and a TL of 1927 nm lasers.
TABLE 42.1
Fraxel 1550 nm Laser Treatment Settings
Mild-Moderate Parameters
Indication Pulse energy (Depth) Treatment level (Coverage)
Fitzpatrick Skin Phototype I–III
General Resurfacing (pigmented lesions, textural irregularities, fine lines)
Face 10–25 mJ 4–8 (11%–23%)
Eyelids (within orbital rim) 10–20 mJ 4–7 (11%–20%)
Off-face 10–25 mJ 4–7 (11%–20%)
Deep Wrinkles, Acne Scars
Face 25–70 mJ 5–9 (14%–26%)
Off-face 25–40 mJ 4–8 (11%–23%)
Melasma (evaluate patient after each treatment, 2–3 treatments)
Face 6–15 mJ 5–8 (14%–23%)
Surgical scars
40–70 mJ 5–8 (14%–23%)
Fitzpatrick Skin Phototype IV–VI
General Resurfacing (pigmented lesions, textural irregularities, fine lines)
10–25 mJ 3–7 (9%–20%)
Off-face 10–25 mJ 3–6 (9%–17%)
Deep Wrinkles, Acne Scars
Face 25–70 mJ 4–7 (11%–20%)
Off-face 25–40 mJ 4–6 (11%–17%)
Melasma (evaluate patient after each treatment, 2–3 treatments)
Face 6–15 mJ 3–7 (9%–20%)
Surgical scars
40–70 mJ 4–7 (11%–20%)
Source: From Beasley KL, Weiss RA, In: Goldman MP, Fitzpatrick RE, Ross VE, Kilmer SL, Weiss RA, eds. Laser and Energy Devices for the Skin.
Boca Raton, FL: CRC Press, 2013; pp. 178−91, with permission.
caution when treating with both wavelengths on the same types, we have experienced that the risk of post-inflammatory
day. Recovery times and discomfort may be greater than if hyperpigmentation is higher with 1440 nm devices than with
the lasers were used individually. See recommended treatment 1540–1550 nm devices. This system is marketed to medical
settings in Table 42.3. spas primarily as a preventative superficial laser treatment
with minimal downtime.
Fractional 1440 nm Laser

The Cynosure Icon (Formerly Palomar) Family
The Clear + Brilliant systemTM is a fractional diode 1440 nm
of NAFL (Cynosure, Inc., Westford, MA)
laser that was launched in May 2011. It is indicated for gen-
eral skin resurfacing. The laser has a fixed spot size of 140 With the acquisition of Palomar, the Cynosure family of
µm. Energy can be delivered on a low (4 mJ), medium (7 mJ) nonablative fractional lasers (NAFL) now includes primarily
or high level (9 mJ). The depth of penetration ranges from a 1540 nm erbium:glass laser that can be delivered through
280 to 390 µm depending on the energy level used. The low, a variety of microlenses, which can be used in three differ-
medium, and high level settings correspond to 4%, 7%, and ent laser/pulsed light platforms: These devices are based on
9% coverage, respectively. This system utilizes a disposable the stamping mode of administrating fractional energy with
treatment tip per treatment. While it can be used in all skin microdots of energy coming through the microlens arrays. The
TABLE 42.2
Fraxel 1927 nm Laser Treatment Settings
Moderate Parameters
Indication Pulse energy (Depth) Treatment level (Coverage)
Fitzpatrick Skin Phototype I–IV
General Resurfacing
Face 5–20 mJ 1–5 (20%–40%)
Off-face 5–15 mJ 1–4 (20%–35%)
Actinic Keratosis
Face 10–20 mJ 3–5 (30%–40%)
Off-face 10–20 mJ 2–4 (25%–35%)
Boca Raton, FL: CRC Press, 2013; pp. 178−91. With permission.
TABLE 42.3
Fraxel 1550 nm/1927 nm DUAL Laser Treatment Settings
1550 nm and 1927 nm Treatment Parameters
Moderate Parameters: 1550 nm Moderate Parameters: 1927 nm
Pulse energy Treatment level Pulse energy Treatment level
Indication (Depth) (Coverage) (Depth) (Coverage) Total coverage
General Resurfacing
Face 10–25 mJ 3–5 (9%–14%) 5–20 mJ 1–3 (20%–30%) (30%–40%)
Eyelids (within orbital 10–20 mJ 2–4 (7%–11%) 5–20 mJ 1–3 (20%–30%) (30%–35%)
rim)
Off-face 10–25 mJ 1–3 (5%–9%) 5–20 mJ 1–2 (20%–25%) (25%–35%)
Fitzpatrick Skin Phototype IV–VI
General Resurfacing
Face 10–25 mJ 1–4 (5%–11%) 5–20 mJ 1–3 (20%–30%) (25%–35%)
Eyelids (within orbital 10–20 mJ 1–3 (5%–9%) 5–20 mJ 1–3 (20%–30%) (25%–35%)
rim)
Off-face 10–25 mJ 1–3 (5%–9%) 5–20 mJ 1–2 (20%–25%) (20%–30%)
Boca Raton, FL: CRC Press, 2013; pp. 178–91, with permission.
latest generation of Cynosure’s NAFL is available through the more superficial conditions and higher energies, which pen-
Palomar IconTM Aesthetic System platform, which has four etrate deeper, are utilized for deeper indications such as acne
unique 1540 nm handpiece microlenses; the original 10 mm scars. The percentage of skin treated or covered by MTZs
and 15 mm microlenses, the 15 mm XF Microlens, and the during one treatment session is determined by the amount
XD Microlens; Figure 42.7 illustrates the IconTM 1540 nm of overlapping passes performed with the stamping tech-
interface. Furthermore, the new XD Microlens can be used nique of the microlens array. More overlapping and passes
on any of the previous generation 1440 nm and 1540 nm frac- increases the aggressiveness of treatment (total surface cover-
tional handpieces with the appropriate software and factory age). Additionally, use of manual compression with the XD
calibration. Microlens array hypothetically increases penetration of laser
The original fractional microlenses are composed of a energy into the skin.
microlens array that delivers a lattice of optical microbeams Regardless of tip or wavelength utilized, the laser proce-
that create micro columns of short duration heat in the skin. dure is delivered in a stamped method. Multiple stamps are
The microlens is responsible for taking a single beam of laser delivered onto the skin with varying amounts of overlap.
energy and separating it into smaller laser beams at a predeter- Rows of stamps are performed in a single cosmetic unit at a
mined pitch (Figure 42.8a, b). The XD Microlens has a chilled time. The rows may be overlapped from 0 to 50% depend-
12 × 12 mm square sapphire contact window that is composed ing on the wavelength, the microlens used, the desired total
of 49 micro-compression pins each co-aligned with a micro- coverage, and rate at which the coverage is administered. One
beam. Figure 42.9 depicts the XD Microlens tip, which allows pass is completed when the entire cosmetic unit is covered by
for much deeper (XD = extra deep) penetration of energy by stamps. Passes are then alternated between perpendicular and
compression of water from the upper layers of dermis. This horizontal directions. This is also known as the tile cascade
microlens is used with manual compression into the skin to method (Figure 42.11). One to five passes are typically per-
achieve deeper penetration of laser energy into the dermis. formed, depending on the total desired coverage. It is impor-
Figure 42.10 illustrates the effect on skin after compression tant to keep the treatment tip in full continuous contact with
with the XD tip. The act of compression displaces water into the skin during each laser pulse. As with the roller technique
interstitial spaces of the skin. Skin compression not only for delivering fractionated laser pulses, laser impact sites that
enhances beam penetration by reducing the scattering of laser are not evenly distributed on the skin surface can be created
light and enabling increased light absorption by deeper targets, when overlapping.
it also enhances skin cooling and prevents injury by decreased
heating of the epidermis. Clinically, this translates into fewer
side effects, less downtime, and a more comfortable treatment.
Compared to the original optics, the XF optic provides higher
Fractional 1540 nm Laser
coverage per pulse, thus reducing treatments times. It is simi- The 1540 nm original microlenses utilized in the Palomar
lar to 1440 nm with the added benefit of increased given the StarLuxTM and ArtisanTM and now the Icon™ laser platforms
increased penetration of the 1540 nm wavelength. are available in two sizes: a flat, circular 10 mm tip with a
These laser treatments are customized by controlling the microbeam density of 100 microbeams per/cm2 and a flat, cir-
microbeam energy, the amount of overlap between pulses and cular 15 mm tip with a microbeam density of 320 microbeams
the number of passes. The pulse energy is delivered in mil- per/cm2. The pulse durations are adjustable to 10 or 15 mil-
lijoules per microbeam (mJ/mb). Energies should be adjusted liseconds (ms). The 10 mm tip can deliver energies between
for the skin condition treated. Lower energies are utilized for 14–70 mJ/mb, with a smaller number of higher energy laser
beams that penetrate deeper with a wider coagulation col-
umn diameter compared to the 15 mm tip. The 15 mm tip can
deliver energies between 3–15 mJ/mb. The standard 10 mm tip
averages a 725 µm depth of penetration compared to 600 µm
for the 15 mm tip. See Table 42.4 for recommended treatment
settings.
The Palomar IconTM Aesthetic System can use a standard
10 mm or 15 mm handpiece, but additionally has the 12 × 12 mm
XD Microlens (25 microbeams/cm2) and the 15 mm XF
Microlens (115 microbeams/cm2). The XD mcrolens array
delivers laser energies from 20–70 mJ/mb with an average
penetration depth of approximately 1060 µm, while the emit-
ted energy range and average dept of penetration of the XF
Microlens are 6–60 mJ/mb and 750 µm, respectively. The XF
Microlens provides higher coverage per pulse compared to the
original optics, which allows faster treatment coverage com-
parable to the 1440 nm with the added benefit of increased
depth. Pulse stacking has been studied with the XD Microlens.
FIGURE 42.7 Treatment screen for a 1540 nm fractional laser. Here
each pulse is 15 ms, and each thermal zone is 50 mJ/cm2. Coverage is For example, 3 stacked pulses with the Lux 1540 XD tip can
determined by the percent overlap of each stamp. reach depths of 1900 µm into the dermis. Settings for the XD
FIGURE 42.8 (a) Microlens array for a stamped 1540 nm nonablative fractional laser; (b) 15 mm handpiece lens array.
FIGURE 42.10 XD optical prong pattern after 30 seconds of compression

on the skin.
FIGURE 42.9 XD optic showing optical prongs to displace water out
of tissue.
Microlens typically range from 40–70 mJ/mb. Three to six collagen remodeling and low-fluence regions to stimulate col-
passes with overlap of 10–50% are recommended depending lagen growth. A 14 mm spot size is used; usually two passes
on the desired total coverage and clinical condition treated. are suggested with 15–20% overlap. Four to six treatments
See Table 42.5 for recommended treatment settings. spaced 3–6 weeks apart are necessary for improvement in
superficial scars and photodamage. The 1440 nm laser has a
maximum energy of 8 J and the 1320 nm laser has a maximum
energy of 14 J. Typical recommended treatment parameters for
The Multi-Wavelength Fractional
skin rejuvenation was 2–3 J/cm2 for the 1440 nm component
1440/1320 nm Laser and 6–10 J/cm2 for the 1320 nm component (10).
No longer available is the AffirmTM Multiplex laser (Cynosure,
Inc.), a fractional laser that emits a combination of 1440 nm
and 1320 nm Nd:YAG wavelengths. The Multiplex technology
Other Fractional lasers
is defined as the sequential emission of two laser wavelengths
via laser fiber. It has a diffractive lens array that consists of A fractional Q-switched ruby laser (TattooStar FRx,
1,000 diffractive elements per cm2 to affect more surface area Asclepion Laser Technologies, Jena, Germany) was reported
per single pulse. The laser uses combined apex pulse technol- to improve melasma in Korean patients (11). A 1540 nm frac-
ogy (CAP) that delivers apex pulses of high-fluence regions for tional erbium:glass laser (Mosaic, Lutronic Co., Ltd., Seoul,
FIGURE 42.11 Tile cascade pattern for a stamping nonablative fractional laser showing 50% overlap pulse to pulse.
TABLE 42.4 Also, a medical history and physical examination must be

StarLux 1540 nm Laser Treatment Settings performed to identify contraindications or impediments to
treatment. An ideal candidate has mild to moderate skin dam-
Superficial/Moderate Deep age or discoloration. Those with severely damaged skin, deep
corrections corrections
acne scars/wrinkles, or extreme laxity will benefit more from
Handpiece (mm) 15 10 surgical procedures or emerging highly cross-linked fillers or
Millijoules per microbeam 6–15 25–50 newly designed PDO threads, which are placed just subder-
Pulse width (ms) 5–10 5–10 mal with cannulas pre-loaded with absorbable PDO threads.
Passes (20%–50% overlap) 2–5 2–4 Patients must also be counseled to have realistic expectation of
Number of treatments 3–5 3–5 treatment results. NAFL resurfacing yields slow and gradual
Treatment intervals (weeks) 3–4 3–4 improvement over a series of treatments. Reduction of fine
Source: From Beasley KL, Weiss RA, In: Goldman MP, Fitzpatrick RE, lines and scars can occur, but they cannot completely disap-
Ross VE, Kilmer SL, Weiss RA, eds. Laser and Energy Devices for the pear. Newer picosecond lasers have been shown to be superior
Skin. Boca Raton, FL: CRC Press, 2013; pp. 178–91. With permission. for these indications (16).
Definitive improvement in brown pigmentation and actinic
South Korea) was studied in the treatment of male and female keratoses can be seen but may recur with continued sun expo-
pattern hair loss and in skin rejuvenation (12–14). The 1540 nm sure and time. Daily sun protection is necessary for all patients
and 1340 nm fractional lasers were available through the post-treatment. It may take 3–6 months after the last treatment
DEKA Dot platform (DEKA laser, Firenze, Italy). In the to note the final results from treatment, which reflects the time
United States, there is also a fractional 910 nm laser by necessary to achieve collagen remodeling from NAFL. During
Syneron Medical Ltd. and a fractional Q-Switched 1064 nm by consultation, treatment experience is also discussed in detail.
Alma Lasers, which have been shown to improve superficial Patients are instructed that a series of treatments will be nec-
rhytides (15). An FDA-cleared home-use device (Tria Age- essary. Depending on the clinical indication, treatment can be
Defying Eye Wrinkle Correcting Laser, Tria Beauty, Inc., spaced over 2–5 sessions spaced 4–6 weeks apart. Topical anes-
Dublin, CA) for the treatment of multiple signs of facial aging thetic will be applied to the treatment area for approximately
remains on the market. 60 minutes before, and the treatment itself will take 20–40
minutes depending on surface area treated. Cool air and cold
ice rollers can be used to increase patient comfort during the
treatment. Depending on which NAFL system is used during
Clinical Considerations
the treatment, a prickly heat sensation or a zap of heat can be
Before initiating a NAFL treatment series, several clinical felt on the skin. Use of topical anesthetics and Zimmer air cool-
considerations need to be carefully examined. Specifically, the ing is highly recommended. Pain levels appear to be roughly
treating physician and support staff should carefully consult equivalent in treatment-naïve patients and those with a his-
with each patient about the indications for treatment, expected tory of past laser treatments (17). Post-treatment, patients may
results of treatment, and review the treatment process in detail. feel a sunburn-like sensation. Redness and swelling should be
TABLE 42.5
Icon 1540 nm Laser Treatment Settings
15-mm tip 10-mm tip XD Microlens XF Microlens
Millijoules per microbeam 10–15 40–70 40–70 30–50
Pulse width (ms) 10–15 10–15 15 10–15
Number of passes (20%–50% 3–4 3–6 3–6 1–2
overlap)
Number of treatments 2–5 2–5 2–5 1–2
Treatment intervals 3–4 weeks 3–4 weeks 3–4 weeks 1–3 months
Boca Raton, FL: CRC Press, 2013; pp. 178–91, with permission.
expected initially. Skin dryness with a flaky dot appearance can of eye protection for the patient, practitioner, and support staff
last a few days up to 2 weeks depending on treatment intensity is mandatory during the NAFL treatment. Intraocular metal
and body area treated. During consultation, side effects are also eye shields should be inserted if eyelid skin within the orbital
discussed, a medical history is reviewed, and physical exami- rim is to be treated. Handpieces are sanitized with Sani-Cloth®
nation of the treatment area is performed. Contraindications (Professional Disposables International, Inc., Orangeburg,
include oral retinoid use within the last 6 months, predisposi- NY) before each treatment. Laser system tests are performed
tion to keloid formation or excessive scarring, and lesions that to ensure a properly performing laser prior to treatment; for
appear to be suspicious for malignancy in the treatment area. example, a paper test strip is available with use with the Fraxel
Other considerations include recent sun exposure or tanned laser systems (Figure 42.12).
skin, pregnancy, an active infection in the treatment area, or When treating a patient with any NAFL, it is advisable to
a medical condition that compromises healing time or predis- divide each treatment area into smaller cosmetic subunits. For
poses to infection. Determining any history of herpes simplex example, the cosmetic units of the forehead, cheeks, nose, lip,
virus (HSV) infection is a mandatory portion when evaluating and chin are treated as separate areas. These subunits can be
medical history as reactivation of HSV can occur with NAFL individualized to the preferences of each practitioner, who
treatment. Pretreatment with an oral antiviral is recommended. should ensure complete treatment of one cosmetic subunit
For darker skin types or patients prone to hyperpigmentation, before proceeding further. Be careful not to overlap treatment
pre- and post-treatment with a hydroquinone cream is recom- between the individual cosmetic subunits that could cause over
mended and strict sun protection is discussed with all patients. treatment. In my practice, forced cold air is use during treat-
ments, which has been shown to reduce pain but can affect
thermal laser injury to tissues (20).
Treatment Preparation
To prepare for NAFL treatment, patients are asked to remove
Post-Care Routine
all jewelry and makeup and to cleanse their skin with a mild
cleanser. Consents are reviewed and signed. Premedication Each NAFL treatment is followed by a light-emitting diode
with an oral antiviral for patients with a history of HSV is doc- treatment (Gentlewaves, LLC., Virginia Beach, VA) to reduce
umented. Pretreatment standardized photographs are taken.
My practice primarily uses the VisiaTM and IntelliStudioTM
(Canfield Scientific, Inc., Fairfield, NJ) systems. The treatment
area is wiped with 70% isopropyl alcohol and allowed to dry.
A moderately thick (¼ inch) amount of a topical anesthetic is
applied. We use a compounded topical anesthetic with 15%
lidocaine and 5% prilocaine in an ointment base for treatment
of the face or localized body area. Application of such strong
compounded topical anesthetic agents should be limited to
two treatment areas as lidocaine toxicity is possible and has
been reported during NAFL treatment (18). The fractional
laser consensus panel recommends limiting treatment areas to
300–400 cm2 to minimize the potential for lidocaine toxic-
ity (19). If larger skin surfaces are to be treated, a standard
topical anesthetic cream, like lidocaine 5% cream (L.M.X.5,
Ferndale Healthcare Inc., Ferndale, MI), can be utilized.
Application of topical anesthetics should be extended beyond
the perimeter of the anticipated treatment area to ensure com-
fort. After 60 minutes, the topical anesthetic is removed. Use FIGURE 42.12 Test strip utilized with Fraxel laser systems.
the intensity and duration of post-treatment erythema (21). with a 1550 nm erbium-doped fractional nonablative laser
Patients are also treated with a thermal water spray (Avene (Fraxel Re:Store SR 1550; Solta Medical, Inc., Hayward, CA),
Thermal Water, Pierre Fabre Dermo Cosmétique USA, PIH occurred in 5 out of 115 total laser sessions (4%), with
Parsippany, NJ) to alleviate discomfort, and a physical sun- only one case lasting longer than a month (2 months total) (26).
block is applied prior to leaving the office. The next treatment The risk of PIH can be reduced with pre- and post-treatment
is scheduled in 3–6 weeks. using hydroquinone bleaching agents and strict sun protec-
Gentle post-care at home is paramount. In my practice, tion. Treatment densities and fluencies should also be lowered
patients are given skin care kits for their laser treatment to reduce this AE. Infection is rarely seen with nonablative
series. It consists of a gentle cleanser, non-occlusive mois- fractional resurfacing, but reactivation of HSV may occur.
turizer, thermal water spray, and a physical sunblock. Post- While rare, reactivation of herpes zoster along the trigemi-
care instructions are verbally reviewed with patients prior to nal nerve has also been reported after NAFL (27). Patients
them receiving written instructions. Patients are instructed to with history of herpes labialis should be pretreated with oral
cleanse the treated area twice a day with the gentle cleanser antivirals. Acneifrom eruptions may occur following NAFL
then immediately applying the gentle moisturizer. The broad- treatment. Patients who are prone to acne can be treated with
spectrum sun protection must be applied before sunlight expo- oral antibiotics, like minocycline or doxycycline and/or a topi-
sure and reapplied as necessary. Patients can also apply cool cal antibiotics, such as clindamycin. A retrospective study of
compresses to the treatment area or use the thermal water spray 961 nonablative 1550 nm laser treatments recorded a 7.6%
as needed to help reduce swelling and discomfort. Narcotic complication rate (24). The two most common complications
pain medication is rarely necessary, but over-the-counter acet- encountered were acneiform eruptions and HSV reactivation.
aminophen can be taken if needed. Patients should sleep with However, these occurred at rates of 1.87% and 1.77%, respec-
their head elevated for the first few nights to minimize swell- tively. Rarely, ulceration can occur, as reported recently in two
ing. They should also avoid vigorous exercise while swollen or cases of stable surgical scars that ulcerated following nonab-
red, smoking, and excessive alcohol consumption. Strict sun lative fractional resurfacing with a 1550 nm device (Fraxel
protection must be observed using a broad-spectrum SPF of Re:Store) (28). Interestingly, both of these cases involved the
30 or greater and direct sun exposure should be avoided for 3 use of intralesional lidocaine for pretreatment anesthesia.
months post-treatment. Topical products and medications can Overall, NAFL is a very safe treatment and has minimal AEs
be restarted 3–7 days post-treatment depending on the level of at the recommended settings.
treatment and sensitivity of the patient. Patients prone to PIH
or undergoing treatment for melasma should restart a topical
hydroquinone cream 1 to 4 days post-procedure.
Ablative and nonablative fractional lasers are increasingly
Clinical Applications
being utilized to enhance topical drug delivery. This concept Nonablative lasers have been used to treat an expansive range
can be applied to post-treatment care. In our practice, we of conditions with promising results (19, 29, 30). The main
frequently apply a topical serum containing L-ascorbic acid, areas of treatment include: photodamage and wrinkling, scars,
alpha tocopherol, and ferulic acid, as well as topical cortico- stretch marks, pigmentary disorders, and actinic keratoses.
steroids and bleaching agents to the skin post-treatment, to Evolving applications include the enhancement of topical drug
take advantage of this opportunity for enhanced epidermal and product delivery, which takes advantage of increased per-
absorption. meability of the epidermis and dermis after treatment. Case
reports have also shown NAFL treatment to be useful in other
miscellaneous applications that include improving residual
hemangiomas, minocycline induced pigmentation, nevus of
Complications
Ota, granuloma annulare, and male and female pattern hair
While the incidence of serious adverse effects (AE) of nonab- loss, among other applications described later (12, 13, 31–34).
lative fractional laser treatment are exponentially fewer than
with traditional ablative resurfacing, it remains possible.
Nonablative skin resurfacing has a low complication rate, and
most AEs are transient in nature (22–24). Possible AEs include
Photodamage
erythema, swelling, blistering, scarring, infection, pigmentary Many studies have examined nonablative fractional resurfac-
changes, herpes reactivation, and acne flare-up. Transient ery- ing of the face and non-facial skin for improvement in sun-
thema and swelling are normal and expected. In a review of induced discoloration and wrinkles. In 2007, Wanner et al.
short-term AEs from 1550 nm NAFL treatment by Fisher et examined 50 patients with mild to moderate photodamage,
al., post-treatment erythema and edema were present in 82% rhytides, and dyspigmentation who received 3 successive
of patients (25). Prolonged erythema, massive swelling, blis- treatments with a 1550 nm erbium-doped laser (Fraxel SR750,
tering, and subsequent scarring can occur if aggressive treat- Reliant Technologies, Inc.,* Mountain View, CA) (35). At least
ment parameters are utilized leading to overheating of the 51–75% improvement in photodamage was observed in 73%
skin. These AEs can be easily avoided with prudent selection and 55% of facial and non-facial (chest and neck) skin at
of treatment parameters. Hyperpigmentation can occur and is the 9-month follow-up. Fractional laser photothermolysis
more prevalent in patients with darker skin types (IV–V). In
a retrospective review of Fitzpatrick skin types IV–VI treated * Reliant Technologies, Inc. was acquired by Solta Medical, Inc. in 2008.
for photoaging of the hands was examined in a small cohort subjects with a 1440 nm diode-based nonablative fractional
of patients by Jih et al. (36). In this study, ten patients were laser (Clear + BrilliantTM Laser System, Solta Medical, Inc.,
randomized to receive five NAFL treatments with a 1550 nm Hayward, CA) (38). In this study, ten Chinese subjects with
laser (Fraxel SR) to either their left or right hand. Statistically Fitzpatrick skin types III–V received four treatments spaced
significant improvements in skin pigmentation and skin tex- 2 weeks apart. Most common AEs included transient ery-
ture without significant AEs were noted at the 1- and 3-month thema and edema, with one patient developing a discrete area
follow-up visits. Skin biopsies were also taken at baseline and of postinflammatory hyperpigmentation that resolved by the
each follow-up visit. Post-treatment biopsies showed thicken- end of the study. The authors suggest that a lower energy,
ing of the epidermis and notably increased collagen density in less intense treatment may be a good option for skin of color
the papillary and upper reticular dermis. In 2010, a 1550 nm patients with mild degrees of photodamage. This same laser
laser consensus panel published their recommended treatment has also been evaluated as a treatment for increased pore size.
settings for photoaging (19). The panel recommended settings In a 2013 study, Saedi et al. reported twenty patients who
of 10–20 mJ of energy with a treatment level (TL) of 7–11 received six treatments spaced 2 weeks apart at the highest
to improve dyschromia in patients with Fitzpatrick skin types tolerable energy (39). Utilizing pore scores calculated with
I–III. For rhytides, specifically in the periorbital region, the use of the Visia-CR imaging system (Canfield Scientific, Inc.,
consensus recommended settings of 30–70 mJ of energy using Fairfield, NJ), the investigators found a 17% average reduction
a TL of 7–11 with 8 passes. For dyschromia of the neck and in pore score, which was statistically significant. Subjects and
chest the panel recommended 10–40 mJ of energy using a TL investigators also scored their improvement, with both groups
of 7–11 with 8 passes for Fitzpatrick skin types I–III. Newer rating moderate to markedly improved appearance in pore
versions of the 1550 nm laser, as well as NAFLs of other size, skin texture, and overall appearance.
wavelengths, have been developed since the consensus meet- Photodamage can be addressed with an FDA-cleared
ing. Hopefully another consensus meeting will be planned that 1440 nm home-use device (Tria Age-Defying Eye Wrinkle
will include recommended treatment guidelines for all NAFL Correcting Laser, Tria Beauty, Inc., Dublin, CA). Rahman et
systems. Figure 42.13 shows results using a 1550 nm laser for al. reported significant improvements in periorbital wrinkles
the treatment of photodamage on the chest. using this device in 45 subjects after daily self-treatments for
In 2014, Brauer et al. examined a 1927 nm nonablative thu- 8 weeks (40). Treatments were 1 minute per eye and were well
lium laser for the treatment of photo-induced pigmentation tolerated with no serious AEs. The subjects were followed for
(Fraxel DUAL, 1550/1927 Laser System, Solta Medical, Inc., 12 weeks after the final treatment with 81% of participants not-
Hayward, CA) (37). Forty patients with photo-induced facial ing sustained improvement.
pigmentation received two treatments at an energy level of NAFL treatments can be combined with other modalities
10 mJ, coverage of 40%, and 4–6 passes. At 1 and 3 months on the same day for the treatment of photoaging. In 2012,
after the second treatment, overall improvement was graded Kearney et al. reported synergistic results when IPL was com-
as moderate to very significant in 82% and 69% of subjects, bined with a 1550 nm fractional device (Fraxel Re:Store) (41).
respectively. Lentigines and ephelides also showed moderate
to very significant improvement in 68% and 51% of subjects at
1- and 3-month follow-up, respectively. Treatments were well-
Scars
tolerated with a mean pain sensation of 4.3 on a 10-point scale,
with no serious AEs. Figure 42.14 shows a clinical example of Improvement in scars may significantly improve a patient’s
results with this device. self-esteem and quality of life. Commonly treated scars
In 2014, Marmon et al. reported mild improvement in skin include those caused by surgery, trauma, and acne. Scars are
texture, pigmentation, and wrinkling when treating Asian classified into two main categories, atrophic and hypertrophic.
FIGURE 42.13 Photodamage of the chest (a) before and (b) after two treatments with a 1550 nm device.
FIGURE 42.14 Improvement in pigmentation (a) before and (b) after one treatment with a 1927 nm device.
They can vary in color from white to red to brown. In 2007, a extremity scar following treatment with Fraxel DUAL (50).
pilot study by Vasily studied the treatment of 13 surgical scars The patient underwent six treatments spaced 4–8 weeks apart
and 18 traumatic scars in 31 participants with a 1540 nm 10 and received three treatments with the 1927 nm thulium laser
mm handpiece (42). Treatments utilized laser energies in the (10 mJ, 30% density, 8 passes) and three with the 1550 nm laser
range of 30–60 mJ, a 10 ms pulse duration, 3–5 passes, across (40 mJ, 17–26% density, 8 passes). Following the treatments,
a series of 1–8 treatments. A blinded observer noted 51–75% there was subjective and objective improvement in the range
improvement in scars at 1-month post-treatment in 59% of of motion of the right lower extremity, as well as a 50–75%
patients. The most improvement was seen after the first three improvement in scar texture and discoloration.
treatments. These results have further been confirmed in a Like surgical scars, acne scars can be cosmetically and psy-
more recent study utilizing NAFL for the treatment of surgical chologically disturbing to patients. NAFL therapy has been
scars and skin grafts following Mohs surgery (43). NAFL has proven successful in the treatment of acne scars. In 2008,
also been shown to outperform pulsed dye lasers (PDL) in the Weiss et al. presented a retrospective analysis of over 500
treatment of surgical scars (44). This was shown in a random- acne scar treatments with the Lux 1540 nm laser (51). A flu-
ized, blinded split-scar study in 12 patients using a 1550 nm ence rage of 50–70 mJ were used with a minimum of three
erbium-doped fiber laser (Fraxel SR) and the 595 nm V-Beam passes. Results assessed by blinded photographic evaluation
PDL (Candela Corporation, Inc., Wayland, MA). Settings of showed a median of 50–75% improvement in acne scars with
70 mJ, TL 8, and 16 passes were used on the NAFL side and 85% of patients rating their skin as improved. In 2012, Bencini
settings of 7.5 J/cm2, 0.45 ms pulse duration, and 10 × 3 mm et al. evaluated 87 acne scar patients with moderate to severe
spot size were performed on the PDL side. After a series of acne scarring who were treated with the same device (52).
four treatments, greater overall mean improvement was seen Four passes with 50% overlap at 15 ms pulse duration with
on the NAFL side (75.6%) compared to the PDL side (53.9%). energies ranging from 50–60 mJ were utilized. At 6-month
NAFL has also demonstrated efficacy for treatment of follow-up, 80/87 (92%) of patients had marked improvement
hypopigmented, hypertrophic, and thermal burn scars (45–49). and 7/87 (8%) showed a moderate improvement as graded by
In a study by Massaki et al., 14 patients with hypopigmented two blinded independent physicians. In a more recent study
scars were treated with an erbium-doped 1550 nm fraction- by Sardana et al., use of the Lux 1540 nm laser with a 10
ated laser in combination with either topical bimatoprost twice mm handpiece was found to markedly improve atrophic acne
daily plus topical tretinoin 0.05% or pimecrolimus 1% cream scars, particularly boxcar scars (53). In this study, 35 patients
daily for those who could not tolerate tretinoin (49). received six treatments with four passes per treatment and
Participants presented for an average of 4.5 treatment ses- energies ranging from 70–100 mJ. At 6-month follow-up, there
sions and 20.1 months follow up. At follow-up 4 weeks after was a reduction in the mean counts of ice-pick, rolling, and
the last treatment, there is significant improvement in scar boxcar scars, although only boxcar scars showed a statistically
pigmentation (greater than >50%) in 12 of 14 patients with significant reduction (52.9%). Additionally, 46.7% of patients
improved clinical scores that persisted throughout the follow reported moderate improvement of 25–50%, 26.7% reported
up period. The 1550 nm NAFL consensus panel recommended marked improvement of 51–75%, and 3.3% reported near total
settings of 50–70 mJ of energy with a TL of 7–11 for skin improvement. Acne scars have also been studied with the
types I–III in the treatment of surgical scars (19). Flattening Fraxel 1550 nm SR750 by Alster et al (54). Fifty-three patients
and improvement in hypopigmentation of a scar is shown in with acne scarring received three laser treatments. Ninety per-
Figure 42.15. cent of patients were found to have 51–75% improvement by an
Nonablative fractional resurfacing also has reported effi- independent observer.
cacy in the treatment of contracted scars. In a 2015 case report, Nonablative fractional laser treatments have also be used
Finney et al. reported improvements in a contracted right lower for the treatment of postinflammatory erythema secondary to
FIGURE 42.15 Flattening and improvement in hypopigmentation of a scar (a) before and (b) after several 1550 nm treatments.
acne. In a 2014 study by Park et al., 12 Korean patients with nm laser in 51 participants with striae of the abdomen, legs,
acne erythema received a total of three split-face treatments buttocks, arms, and flanks (57). Fluences of 35–55 mJ with a
with a 1550 nm erbium:glass nonablative fractional laser and 10 mm tip or 12–14 mJ with a 15 mm tip were utilized. Two
a PDL (55). Both treated sides had statistically significant to four treatments were performed. Patient and independent
improvement in erythema, with no significant difference observer evaluations noted improvements of 50% or greater
between them. 91.7% of patients reported good or excellent in all patients 6 months after the last treatment. More recently,
improvement on the fractional treated side, and 75% rated the Wang et al. compared the clinical efficacy of the Lux 1540
same for the PDL-treated side. nm with a low energy 1410 nm nonablative fractional laser
The 1550 nm laser consensus panel meeting recommended (EmergeTM, Cynosure, Inc., Westford, MA) (58). Ten partici-
treatment settings for acne scars that depended on skin type pants with abdominal striae were treated, half of their abdo-
(19). They recommended settings of 30–70 mJ at TL 7–11 for mens were treated with the 1540 nm device (XD: 50 mJ, 15
8–12 passes for skin types I–III and 30–70 mJ at TL 4–5 for ms pulse duration, 2 passes; XF: 50 mJ, 15 ms pulse duration,
eight passes for skin types IV–V. We presently employ the 2 passes, 25% total density), and the other half were treated
IconTM system with the 1540 nm XD handpiece for scars and with the 1410 nm device (30 J, 5 passes, 16% density). Six
anecdotally have seen responses in scars resistant to all other treatments were performed 2–6 weeks apart, with two blinded
NAFL devices. dermatologists scoring the photographs. Thirty-three percent
of participants demonstrated good or excellent improvement
on the side treated with the 1540 nm device and 28% on the
side treated with the 1410 nm device. Mild or fair improvement
Striae
was noted in 66% of participants treated with 1540 nm and
Striae are areas of disrupted collagen in the skin that can occur 72% of those treated with 1410 nm. However, these differences
during growth spurts, rapid weight changes, topical and oral were not statistically significant. All patients were either “very
steroid use, and conditions of hormonal change like preg- satisfied” or “moderately satisfied.” Of note, transient hyper-
nancy. It is estimated that 75–90% of women experience some pigmentation appeared to last longer in those treated with the
degree of striae formation during pregnancy. Previous treat- 1410 nm device.
ments have been ineffective, inconsistent, or not suitable for While not FDA cleared for this indication, Fraxel 1550 nm
all skin types (56). The Palomar* 1540 nm NAFL is currently NAFL has also been studied for the treatment of striae. Twenty
the only laser to gain FDA clearance for the treatment of striae. patients with striae were studied over six laser treatments.
One of the first studies in striae treatment used the Lux 1540 Randomly selected photos of eight patients were chosen from
the study, and an independent observer rated a 26–50% level
* Palomar Medical Technologies was purchased by Cynosure, Inc. in of overall improvement in five out of eight patients (59). In
2013. a separate study, Guimarães et al. treated ten cases of striae
on the breasts following breast augmentation with a 1550 nm area coverage, and total energies ranging between 1.72 kJ to
erbium:glass laser (Sellas, Dinona Inc., Seoul, South Korea) (60). 4.42 kJ. Notably, 7 of 15 patients demonstrated recurrence of
Each patient underwent four to eight treatments at 4 week their melasma with time. Although NAFL treatment has shown
intervals, with fluences of 80–100 mJ, a density of 100 points success in the treatment of melasma, its long-term efficacy is
per area, and one treatment pass. Responses were graded by still limited by the inherent recurrent nature of melasma. In
participants and by two plastic surgeons 4 weeks following the some patients with melasma, we have also noted increased
last treatment session. 50% of scores landed between 9 and hyperpigmentation and prolonged erythema after NAFL treat-
10 on a 0 (no improvement) to 10 (total improvement) scale. ment. Most NAFL and other laser treatments for melasma work
Nonablative 1550 nm treatments have also been compared to best when combined with topical depigmenting skin care and
ablative CO2 fractional laser resurfacing in Asian patients with aggressive sun protection.
striae on the abdomen, with significant clinical and histologic
improvement. There were no significant differences in clini-
cal efficacy between the modalities based on blinded physician
evaluations (61). The 1550 nm NAFL consensus panel recom-
Actinic Keratoses
mended settings of 40 mJ, TL 10 for eight passes in skin types An actinic keratosis (AK) is a precancerous, epidermal, scaly
I–III and reducing the TL to 4–7 in darker skin types (19). macule or papule that occurs on sun-damaged skin. Treatment
When treating striae, a laser test area is always suggested. Pre- of these lesions is indicated due to potential for progression to
and post-treatment with a hydroquinone bleaching cream is invasive squamous cell carcinoma. The 1550 nm and the 1927
suggested in patients with darker skin types and areas prone to nm wavelengths have been studied and have shown success
prolonged PIH, like the legs. in the treatment of these precancerous growths. Initially, the
1550 nm fractional laser (Fraxel Re:Store) was investigated in
a small group of men with Aks (69). These men underwent five
nonablative resurfacing laser treatments every 2 to 4 weeks.
Pigmentary Disorders
Energies ranged from 20–70 mJ, but the majority of treat-
Increased pigmentation of the skin, as seen in photodamage and ments were performed at 70 mJ. A treatment level of 11 was
melasma, has shown improvement through NAFL treatment. utilized and 8–10 passes were performed. A baseline biopsy
Melasma can be quite distressing to patients and is notoriously was performed and then repeated at the 3-month follow-up
difficult to treat. It is a chronic skin condition seen primarily visit, immediately adjacent to the initial biopsy site. Aks were
in female patients. It presents as a brown patchy discoloration counted at 1, 3, and 6 months. There was clinical improve-
over sun-exposed areas like the cheeks, forehead, upper lip, ment after each session, although histologically, precancerous
and sometimes arms. Contributing factors include sun expo- changes were still evident. At the 1-, 3-, and 6-month visits,
sure, hormones, pregnancy, and genetics (62). Many therapeutic actinic keratosis percent reduction from baseline was 73.1%,
modalities have been investigated over the years, but none have 66.2%, and 55.6%, respectively. With the introduction of the
been shown to be uniformly successful (63, 64). When the first 1927 nm thulium fractional laser, more AK treatment studies
1550 nm laser was released, several melasma studies were initi- began. This superficial wavelength selectively targets the epi-
ated. The first pilot study by Rokhsar et al. used a 1550 nm laser dermis and upper dermis and was postulated to have greater
on 10 patients (65). It showed some success with 60% of patients efficacy in the treatment of the mostly epidermal Aks. Weiss
demonstrating excellent clearing and 30% of patients demon- et al. studied 24 subjects with facial Aks receiving up to four
strating mild improvement. Another study compared 1550 nm treatments with a 1927 nm fractional laser (Fraxel DUAL)
laser resurfacing with a topical bleaching cream through a (70). One month after the final treatment, average AK clear-
split-face study (66). However, the patients in the study showed ance was 91.3% by an independent physician assessment. At
preference to the topical bleaching cream side over the 1550 nm 6 months after the final treatment, average AK clearance was
NAFL side. The 1927 nm laser is not approved for melasma, 86.6%. Histologic clearance of Aks was also documented in
but initial reports seem promising. A pilot study by Polder et 87.5% of those subjects who were biopsied. They found this
al. used the Fraxel 1927 nm thulium laser in the treatment of treatment to be well tolerated by patients, without incidents
18 patients with melasma (67). They performed 3–4 treatments of infection, scarring, or pigmentary changes. Friedman et al.
using 10–20 mJ of energy, a TL corresponding to 20–45% cov- performed split-face laser treatment of Aks using a 1550 nm
erage, and eight passes. Using the standard Melasma Area and laser in combination with the 1927 nm laser versus the 1927 nm
Severity Index (MASI) for blinded independent photographic laser alone (71). They found that the side treated with 1927
review of standardized photos, reviewers reported a 51% reduc- nm alone showed greater clinical reduction in Aks as well
tion in the MASI scores at 1-month follow-up. There was still as improvement in sun-induced pigmentation. The 1927 nm
a 33% and a 34% reduction of MASI score at 3- and 6-month laser has also been studied for the treatment of Aks of the
follow-up, respectively. More recently, a retrospective analy- lips, otherwise known as actinic cheilitis (72). This condition
sis of 20 patients treated with the same device found that 60% is notoriously hard to treat, prone to recurrence, and can be
of subjects had more than 50% clearance of their melasma at quite painful for patients. Anolik et al. performed a retrospec-
4 weeks after a single laser treatment (68). At 4 weeks after tive chart analysis of a small group of actinic cheilitis patients
the treatment, mean MASI scores improved by 35%, and by and found that after 1–2 treatments patients were improved
53.8% at the 6- to 12-month follow-up visit. Treatment settings by 50–75% or 75–100% as rated by blinded, non-treating
included fluences between 10–20 mJ, with 60–70% surface staff dermatologists (73). The procedure was well tolerated by
patients and had much fewer side effects when compared to seborrheic keratoses have been safely and effectively treated
ablation, surgery, or treatment with topical chemotherapeutic with a 1927 nm thulium fiber laser (82). Isolated steatocystoma
agents or immune modulators. multiplex has also substantially improved after two treatments
Nonablative fractional resurfacing can also be safely and of a 1450 nm diode laser and a 1550 nm fractionated erbium-
effectively combined with ablative fractional therapy for the doped fiber laser (83).
treatment of actinic keratoses. In 2015, Ortiz et al. reported a
91% clearance rate in 115 Aks located on the scalp, chest, fore-
arms, and dorsal hands when treated with a hybrid 1470/2940
nm fractional laser (74).
Picosecond Lasers
Picosecond lasers are a type of laser that emits light pulses with
a duration of trillionths of seconds. Typically, most commercial
Enhancement in Delivery of lasers for skin are within the 500–750 picosecond range. These
Topical Drugs and Products lasers are used for various dermatological treatments, including
photorejuvenation. Picosecond lasers have a high peak power
Research in this application of fractional lasers is still in its
density and can generate an array of concentrated microspots
infancy but there is expanding evidence supporting its role in
with high fluences when delivered through a fractional diffrac-
a variety of indication, particularly with ablative fractional
tive lens array (DLA). Fractional and flat optics picosecond
devices. One area of particular promise is the use of abla-
laser treatment are currently popular methods for photorejuve-
tive and nonablative fractional resurfacing for enhancement
nation. They produce laser-induced optical breakdown (LIOB)
of photodynamic therapy (PDT), as laser pretreatment offers
and laser-induced cavitation (LIC) in the epidermis and dermis,
the potential of increased ALA uptake with shortened incu-
respectively, depending on wavelength. This process encour-
bation and improved clinical outcomes. Compared to areas
ages skin regeneration and dermal remodeling. Fractional pico-
not exposed to the laser, a statistically significant increase in
second lasers have shown efficacy in skin rejuvenation with
porphyrin fluorescence of ALA has been demonstrated in an
improvement of not only dyspigmentation (84–87), PIH (88),
in vivo study after the skin was pretreated with a 1550 nm
and melasma (89), but also wrinkles (16, 90), enlarged pores
fractional erbium:glass laser (Mosaic) followed by topical
(91, 92), acne scars (93, 89, 94–96), and striae (97). Compare
5-aminolevulinic acid application (75). In my practice, we
with other fractional treatments, picosecond lasers showed
often pre-treat our PDT patients with 2–4 passes of NAFL,
decreased risk of PIH and increased tolerability (98). The
which allows for faster penetration of topical levulinic acid.
increased tolerability could be explained by the method of
This is especially helpful in areas like the arms and legs in
injury of picosecond lasers, which create focal areas of damage
which incubation time with levulinic acid would otherwise
with minimal non-specific thermal damage to surround tissues,
take hours. Enhancement of platelet-rich plasma (PRP) treat-
rather than full or partial thickness tissue injury (99).
ment of the skin has also been studied in NAFL (14). The
For treatment of rhytids, Weiss et al. found a significant
study showed that when PRP was combined with NAFL with
reduction in Fitzpatrick wrinkle score after four full face treat-
a 1550 nm laser (Mosaic), patient satisfaction and skin elas-
ments with the picosecond laser, with a concurrent improve-
ticity increased while erythema index of the skin decreased.
ment in fine lines, erythema, and dyschromia (16). They also
Histologically, patients who were treated with PRP plus NAFL
showed a significant increase in dermal collagen in the mid
demonstrated increases in length of the dermal epidermal
and lower dermis with thickened elastic fibers at 6 months fol-
junction, amount of collagen, and number of fibroblasts com-
low up. For treatment of atrophic acne scars, Huang et al. (100)
pared to patients treated with fractional laser alone.
found a positive correlation between the number of treatments
and improvement, with 50% improvement noted after six ses-
sions. For treatment of melasma, Feng et al. (101) found the
Other Clinical Indications
1064 nm wavelength to have more efficacy than the 755 nm
Nonablative lasers have also shown effectiveness in the treat- wavelength with reduced risk of PIH. The picosecond laser may
ment of a variety of other conditions. In 2014, Hsu et al. reported be noteworthy consideration for melasma due to its low adverse
favorable outcomes using a 1450 nm diode laser for the treat- event profile, with transient erythema or hyperpigmentation as
ment of xanthoma disseminatum (76). This same laser has also the only adverse events reported (102, 100). While the result
effectively treated xanthelasma palpebrarum (77). Beleznay et of picosecond laser treatment can last up to 1 year (84), up to
al. reported a case of lupus miliaris disseminates faciei treated 50% of patients can experience recurrence within 6 months of
with nonablative fractionated resurfacing utilizing a novel 1565 treatment (103, 104), therefore, pre-and post-treatment hydro-
nm device (78). Nonablative fractional resurfacing utilizing the quinone may reduce the risk for hyperpigmentation.
Lux 1540 nm laser with the XD handpiece has also been effec- Studies on the effects of the picosecond 755 nm laser on pore
tive in the treatment of iatrogenic hypopigmentation second- size, however, have been inconsistent, with some showing sig-
ary to intralesional steroid injections (79). In 2014, Emer et al. nificant improvement while others do not (105, 106). It is thought
reported improvement in a case of lupus pernio using combined that LIOB and LIC stimulate collagen remodeling and elastin
pulsed dye laser and nonablative fractional resurfacing (Fraxel production resulting in improvements in skin texture. An effec-
DUAL) (80). In 2013, Narinesingh et al. reported improvement tive reduction in pore size can be observed in as little as two
in the waffle pattern of a meshed skin graft following treatment treatments with the 755 nm picosecond laser when given 4 weeks
with a 1540 nm fractionated erbium:glass laser (81). Macular apart (107). However, more studies are needed in this area.
10. Peterson JD, Goldman MP. Rejuvenation of the aging

Conclusion chest: a review and our experience. Dermatol Surg.
2011;37(5):555–71.
Fractional photothermolysis, and its application of NAFL skin 11. Jang WS, Lee CK, Kim BJ, et al. Efficacy of 694-
resurfacing, is still considered a leading groundbreaking technol- nm Q-switched ruby fractional laser treatment of
ogy. Both the stamping modes and the continuous motion hand- melasma in female Korean patients. Dermatol Surg.
piece with rollers are effective methods of delivering the energy. 2011;37(8):1133–40.
New understanding and engineering have allowed the develop- 12. Lee GY, Lee SJ, Kim WS. The effect of a 1550 nm frac-
ment of optics that drive energy more deeply and safely to obtain tional erbium-glass laser in female pattern hair loss. J Eur
better results on scars and other clinical problems. NAFL’s Acad Dermatol Venereol. 2011;25(12):1450–4.
proven efficacy in a multitude of skin conditions prompts us to 13. Kim WS, Lee HI, Lee JW, et al. Fractional photothermoly-
utilize NAFL as an integral part of our daily practice of derma- sis laser treatment of male pattern hair loss. Dermatol Surg.
tology and medicine. Clinical applications include photodam- 2011;37(1):41–51.
age, wrinkling, scars, stretch marks, pigmentary disorders, and 14. Shin MK, Lee JH, Lee SJ, Kim NI. Platelet-rich plasma
actinic keratosis, among others. Study after study demonstrates combined with fractional laser therapy for skin rejuvena-
that fractional resurfacing is effective and safe, with minimal tion. Dermatol Surg. 2012;38(4):623–30.
AEs. NAFL and its applications related to enhancement of topi- 15. Luebberding S, Alexiades-Armenakas MR. Fractional,
cal therapies are still being investigated with early observations nonablative Q-switched 1,064-nm neodymium YAG laser
very encouraging. Picosecond lasers have emerged as another to rejuvenate photoaged skin: a pilot case series. J Drugs
revolutionary tool that is transforming the landscape for photore- Dermatol. 2012;11(11):1300–4.
juvenation, scar treatment, and tattoo removal. Their precision 16. Weiss RA, McDaniel DH, Weiss MA, et al. Safety and effi-
and versatility allow enhanced efficacy, improved tolerability, cacy of a novel diffractive lens array using a picosecond
and reduced adverse effects, leading to better outcomes and 755 nm alexandrite laser for treatment of wrinkles. Lasers
Surg Med. 2017;49(1):40–4.
greater patient satisfaction. The broader applications of picosec-
17. Kakar R, Ibrahim O, Disphanurat W, et al. Pain in I andI-
ond lasers and further refinement of their systems offer promis-
naive subjects undergoing nonablative skin tightening der-
ing opportunities for treatment and research.
matologic procedures: a nested randomized control trial.
Dermatol Surg. 2014;40(4):398–404.
18. Marra DE, Yip D, Fincher EF, Moy RL. Systemic tox-
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43
Cryolipolysis for Nonsurgical Fat Reduction
Alain Michon
colleagues reported on four adult females who regularly rode

Introduction horses in cold winter weather and went on to develop pannicu-
litis in the thighs, starting with small pruritic papules and pro-
Nonsurgical approaches to fat reduction are increasingly popular gressing to tender indurated plaques and nodules (10).
worldwide. Indeed, a recent global survey from the International This knowledge provided the rationale for two key ‘proof of
Society of Aesthetic Plastic Surgery estimated that over 730,000 concept’ studies of cryolipolysis conducted in porcine models—
such procedures were performed in 2021, an increase of 30% assessing whether selective damage to subcutaneous fat could be
compared with 2020 (1). As a result, fat reduction is now the achieved through controlled application of a cold temperature to
fifth most frequently undertaken nonsurgical aesthetic proce- the surface of the skin (11, 12). In these animals, exposure of test
dure—behind only mainstays like botulinum toxin, hyaluronic areas to a prototype cryolipolysis device for up to 45 minutes
acid fillers, hair removal, and skin tightening (1). led to significant reductions in subcutaneous fat, with decreases
Nonsurgical approaches to fat reduction cannot entirely in the thickness of the upper fat layer of up to 80% in selected
replace surgery. Nonetheless, in appropriately selected patients, bodily areas over a 3.5-month period (11). Moreover, there
they can mitigate against some of the key disadvantages asso- was no clinical or histological evidence of damage to the skin.
ciated with liposuction—such as infection risk, pain, bleeding, Inflammation was confined to the superficial fat and declined
scarring, prolonged recovery, and the requirement for general over the course of 3 months following treatment (11, 12).
anaesthesia (2, 3). Relative safety, steadily improving levels of Early studies in human patients confirmed that the appli-
efficacy, and reduced cost are also important factors in driving cation of a cryolipolysis device to the flanks—specifically to
some patients toward nonsurgical procedures. so-called ‘love handles’—could produce clinically meaning-
Various devices can be used for nonsurgical fat reduction. ful fat reductions without causing lasting skin damage or other
Body contouring modalities that have been approved by the US significant complications (13, 14). For example, in an analysis
Food and Drug Administration (FDA) include cryolipolysis, of ten treated individuals, mean ultrasound-assessed fat layer
radiofrequency energy, high-intensity focused electromagnetic reductions were 20.4% at 2 months and 25.5% at 6 months
field, laser, high-intensity focused ultrasound, and mechanical (13). Some patients experienced transient decreases in sensa-
methods (massage or vibration) (4, 5). The most recent sur- tion in the treatment area, but this was restored within a few
vey of dermatologic procedures conducted by the American weeks, and biopsies demonstrated no long-term changes in
Society for Dermatologic Surgery, published in 2021, found epidermal nerve fibre structure (13).
that the most popular nonsurgical body contouring procedure As a result, in 2010, the CoolSculpting® cryolipolysis sys-
is cryolipolysis (Figure 43.1) (6). The cryolipolysis technique tem (Allergan Aesthetics, Pleasanton, CA) received clearance
is based on the external application of intense controlled cool- from the US FDA for fat reduction in the flanks. Since then,
ing (3, 7) and is the focus of the current chapter. this device has been approved for use in dozens more countries
and for the treatment of many other parts of the body. In addi-
tion, various other cryolipolysis systems have been developed
Origins of Cryolipolysis and approved for use.
There has long been a suggestion that adipose tissue might
have a preferential sensitivity to cold injury. As far back as
1902, Hochsinger reported induration of the submental sub-
Mechanisms of Action
cutaneous tissue in young children following particularly cold
weather, primarily among individuals with abundant subcuta- Two alternative mechanisms have been proposed to explain the
neous fat (8). Then, in 1970, the term ‘popsicle panniculitis’ effect of controlled cooling on subcutaneous adipose tissue. The
was used for the first time to describe an infant who developed first and most longstanding hypothesis is that it causes crystal-
a deeply situated, indurated nodule in her cheek after suck- lization of lipids in the cytoplasm of adipocytes as a result of
ing on a popsicle, which then diminished over a week to leave their higher phase transition temperature compared with water,
unblemished skin; brief application of ice to the same girl’s thus making adipocytes more vulnerable than water-based
buttock reproduced a similar lesion (9). This phenomenon is cells (11, 12, 15). This effect was described in the initial proof-
not limited to children. For example, in 1980, Beacham and of-concept porcine studies, with needle-like crystals observed
444 DOI: 10.1201/b22897-43

Cryolipolysis for Nonsurgical Fat Reduction 445
FIGURE 43.1 Body sculpting procedures in 2019 (American Society for Dermatologic Surgery). Cryolipolysis currently accounts for around a
quarter of all such procedures.
Source: Reproduced with permission from the American Society for Dermatologic Surgery 2019 Survey on Dermatologic Procedures (6).
in the pigs’ fatty tissue at around 10°C (11). Lipid crystalliza- do not induce systemic inflammatory responses (19).
tion then leads to loss of cellular integrity and hence to pro- Nonetheless, further work is required before definitive
grammed cell death—apoptosis—and a local inflammatory judgments can be made. A recently developed mouse
response. As a result, subcutaneous adipose tissue is selectively model of selective cryolipolysis could play an important
reduced over a period of several weeks or months. role in elucidating the underlying mechanisms at cellular
A second hypothesis is based on the notion that exposure and molecular levels (20).
to cold temperatures could increase energy expenditure via
fat metabolism and thermogenesis—thus causing selective fat
reduction without cellular disruption (16).
An important difference between these two hypotheses is that Technological Overview
the first is predicated on a local inflammatory response, and the The CoolSculpting device remains the most widely used and
second is not. This can be assessed histologically. A microscopy well-studied cryolipolysis system. A recent expert consensus
study of tissue biopsies from six women undergoing cryolipoly- described five key parameters that differentiate it from the
sis found that adipocytes appeared to be fragmented, anisomet- other available devices (3):
ric, and dysmorphic at days 15 and 45, with areas of cellular
dissolution that appeared to preface their death (Figure 43.2) • Established safety profile
(17). Macrophages and other inflammatory cells were also evi-
• Well supported by data from clinical trials and other
dent, suggesting a need to repair the effects of adipocyte apopto-
studies
sis (17). Similar findings were observed in a study of abdominal
tissue from a single patient following cryolipolysis (18). • Reproducibility of results
These results tend to support the apoptotic/inflamma- • Greater overall treatment efficacy
tory hypothesis—possibly via localized mechanisms that • A wide variety of applicators
The CoolSculpting system consists of a control unit and a vari-

ety of applicators that can be used to treat different areas of
the body (Figure 43.3). Practical methods for operating the
device will be described in more detail later in this chapter.
In brief, most of the applicators use a technology based on a
contoured vacuum application system that gently draws the
underlying tissue into a cooled cup, thereby maximizing over-
all contact (21, 22). In addition, there are non-vacuum-based
surface applicators for use in body areas with non-pinchable
fat (e.g. lateral thigh and upper abdomen) (22). Temperatures
below 0°C (down to –15°C) are then applied for durations of
up to 120 minutes per treatment cycle, depending on the spe-
cific applicator used and the indication for treatment (22). To
optimize the degree of fat reduction, patients may sometimes
receive multiple cycles (i.e. separate runs of the applicator) in
a single session to cover the targeted area and a second treat-
ment session a few weeks after the first one.
The US FDA has cleared the CoolSculpting system for use
on nine areas of the body, including fat under the jawline, under
the chin, the upper arms, back fat, bra fat, the flank area, abdo-
men, thighs, and under the buttocks (also known as banana
rolls) (Figure 43.4) (7). Regulators in many other countries
have approved the system for use in some or all of these areas.
Efficacy of Cryolipolysis
A wide variety of techniques have been used in clinical studies
to assess objectively the results of cryolipolysis. These include
circumference measurements, caliper-based assessments of
skinfold thickness, ultrasound, magnetic resonance imaging
(MRI), and three-dimensional (3D) photography.
Based on these assessment methods, systematic reviews
of data from multiple studies have established the efficacy
of cryolipolysis in localized fat reduction (Table 43.1) (23–25).
The most recent systematic review analyzed five studies that
employed a randomized controlled design and noted signifi-
cant reductions in subcutaneous adipose tissue layer thick-
ness—as assessed by ultrasound, abdominal circumference
and skinfolds, MRI, and 3D photography (25).
An older systematic review from 2015 incorporated a
broader range of studies, including those with nonrandomized
designs (23). Among 19 studies assessed, that analysis found
average cryolipolysis-induced reductions in fat thickness of
14.7–28.5% based on caliper measurement and 10.3–25.5%
using ultrasound assessment.
However, some more recent studies have observed greater fat
reductions than those previously described—possibly owing
to improvements in cryolipolysis technologies and greater use
FIGURE 43.2 Histopathological analysis of alterations to human of more intensive regimens (based on multiple cycles or ses-
adipose tissue induced by cryolipolysis. Part A shows untreated adipose sions of treatment). For example, in an analysis of 30 women
tissue (hematoxylin-eosin stain, 40×), demonstrating lobular architecture,
homogeneity of adipocyte size, and a lack of inflammatory cells. Part B receiving 4–6 cycles of abdominal cryolipolysis in a single
shows the effects of cryolipolysis at 15 days post-treatment (hematoxylin- session, the mean reduction in fat layer thickness (assessed by
eosin stain, 40×); in scattered areas, the adipocytes appear fragmented,
anisometric, and dysmorphic, with areas of dissolution in which cellular ultrasound) was 46.6% (95% confidence interval: 41.2–51.9)
adipose tissue organization can no longer be distinguished. Part C shows (26). Similarly, in a study of 28 patients treated with a mean
the impact at 45 days (hematoxylin-eosin stain, 20×), with some areas
still appearing fragmented, anisometric, and dysmorphic, with areas of 2.8 cycles of cryolipolysis (range 1–8) across various parts
of dissolution; there are also effects on the connective tissue, including of the body over one or two separate sessions, mean skinfold
fusion, fragmentation, and hyalinization of collagen.
Source: Reproduced with permission from: Pugliese D et al. Aesthet Surg thickness was decreased by 40% (p<0.001) (27). Reductions
J. 2020;40:761–6 (17). were significantly greater among individuals undergoing ≥
FIGURE 43.3 The CoolSculpting system.

Source: Image courtesy of Project Skin MD.
FIGURE 43.4 Body areas in which CoolSculpting is approved for use in the United States. Approved areas are shown in white.
Source: Image courtesy of Allergan Aesthetics.
TABLE 43.1
Efficacy Summary: Cryolipolysis Treatment
Efficacy measure Description
Localized fat reduction • Significant reductions in the thickness of the subcutaneous adipose
tissue layera (23–25)
• Potential for greater effects with more intensive regimens, based on
multiple cycles and/or sessions of treatment (26, 27)
Skin improvements • Visible skin tightening and improvements in skin texture in treated
areas (28–31)
Patient satisfaction and psychosocial benefits • High rates of patient satisfaction (23, 32, 33)
• Significant psychosocial effects (reduced self-consciousness, anxiety,
bother, and situation avoidance; increased happiness) (33)
a Assessed by ultrasound, abdominal circumference and skinfolds, magnetic resonance imaging, and three-dimensional photography.
TABLE 43.2
Novel Patient-Reported Outcome Instruments
Questionnaire What it assesses Scales used Items
Cryolipolysis Satisfaction Patient satisfaction and treatment 5-point Likert scale • Satisfaction with overall results
Questionnairea effectiveness • Noticeability of fat reduction
• Improvement in the fit of
clothing
• Overall effect of the procedure
Cryolipolysis Psychosocial Impact Psychosocial impact of treatment 4- and 5-point Likert scales • Self-consciousness
Questionnaire—Midsection specifically relating to midsection • Happiness
appearance • Anxiety
• Bothersomeness
• Avoidance of social situations
Cryolipolysis General Procedure General procedure-related items 4-point Likert scale or yes/no • Comfort levels during the
Questionnaire procedure
• Likeliness of considering
additional treatments on a
different body part
• Willingness to recommend the
procedure to a friend
aThree treatment plan-specific versions (abdomen, flanks, abdomen and flanks).
Source: Modified from Ref. 33.
3 cycles compared to those receiving 1–2 cycles (p = 0.01). lipoprotein), as well as reductions in liver enzyme levels (34).
In addition, there was a signal that the effect may have been A subsequently published analysis of 30 patients receiving five
increased in those undergoing two separate treatment sessions treatment cycles over 2–3 days also demonstrated significant
per body area compared with one single session. However, this decreases in weight, BMI, and total fat mass but no effects on
did not reach statistical significance (p = 0.06) (27). blood lipids (35). However, other studies have typically found
Cryolipolysis has also been linked with visible skin tighten- no meaningful effects of cryolipolysis—either favorable or
ing and improvements in skin texture in treated areas (28–31). unfavorable—on body composition or lipid profiles (19, 25,
Molecular and histological analyses have suggested that der- 36). For the moment, cryolipolysis should not be considered as
mal remodeling may underlie this effect based on the induc- a weight-loss treatment (7), but it remains an interesting area
tion of type I collagen (31). Further assessment is warranted in of study.
clinical studies. Irrespective of this, cryolipolysis treatment is associated
With regard to the anthropometric and metabolic impact of with high patient satisfaction rates (23, 32). However, efforts
cryolipolysis, a systematic review of randomized controlled to better understand the psychosocial impacts have been ham-
trials (25) found only one study that observed a significant pered by a lack of patient-report outcome (PRO) measures
positive impact: in an analysis of 60 centrally obese women specifically designed for use with this technique (33). In an
randomized to a low-calorie diet regimen with or without the attempt to rectify this, three separate PRO questionnaires
addition of three sessions of cryolipolysis, the patients who have recently been developed (Table 43.2). In a prospective,
received cryolipolysis showed significantly greater decreases multinational study using these instruments, 89.6% of patients
in waist-to-hip ratio and body mass index (BMI), improve- said they were ‘satisfied’ or ‘very satisfied’ with the results
ments in lipid profiles (reduced total cholesterol, low-density of cryolipolysis (regardless of the number of cycles admin-
lipoprotein, and triglycerides, and increased high-density istered), 90.6% reported ‘noticeable’ or ‘very noticeable’ fat
reductions, 89.6% said they were ‘likely’ or ‘very likely’ to may have been a factor in preventing PAH, as discussed later
treat additional areas, and 93.4% would recommend cryolipol- in the current chapter.
ysis to a friend (33). Furthermore, at 12 weeks post-treatment, A recent multicenter Canadian study estima©ed a PAH inci-
patients reported significant psychosocial impacts, based on dence (by cycles) of 0.39% with the older cryolipolysis units
reduced feelings of self-consciousness, anxiety, bother, and that they employed between 2015 and 2016, but a much lower
situation avoidance, and increased happiness (p <0.0001). This rate of 0.05% with the next-generation technology used in sub-
is particularly relevant given that psychosocial benefits are a sequent years (46). This paper suggests that mechanical issues
key patient goal. For example, in a recent survey, the main with older devices, which were based on parallel cooling
motivation for undergoing cryolipolysis (apart from correcting plates and longer treatment durations, may have been a con-
the specific defect) was “to feel more self-confident” (37). tributory factor as compared with the newer technology based
on a contoured cup surface with reduced tissue suction and
shorter treatment times (46, 47). Other possible risk factors for
PAH may include male sex, Hispanic ethnicity, use of large
Treatment Safety applicators, treatment of the abdomen, and genetic aspects (39,
In a systematic review of 53 clinical studies and case reports 41, 46). However, further studies will be required to confirm
assessing the safety of cryolipolysis among 3312 patients, and better understand these associations.
the most commonly reported adverse events (AEs) included
treatment-site erythema, numbness/paresthesia, bruising, and
oedema (38). These typically developed within a week of
treatment and resolved spontaneously and usually swiftly—
although a small number of patients (< 1%) experienced local-
ized numbness that lasted for more than 4 weeks (38).
Other commonly observed but mostly rapidly resolving
events include localized sensations of pulling, pinching, tin-
gling, stinging, aching, or cramping during the treatment itself
(which often subside as the area becomes numb); localized
redness, firmness or transient blanching immediately after
cryolipolysis; and swelling, tenderness, itching or tingling
developing 1–2 weeks post-treatment (22).
Importantly, small studies using more intensive cryolipoly-
sis regimens—based on multiple cycles and sessions across
different parts of the body—have suggested that these are safe
and well-tolerated (26, 27, 36), although confirmation may be
required in larger patient cohorts.
Irrespective of treatment intensity, the most clinically sig-
nificant types of AEs associated with cryolipolysis are rare.
When these do occur, they may include cases of paradoxical
adipose hyperplasia (PAH), delayed-onset pain, cold burn
and frostbite, vasovagal symptoms, subcutaneous induration,
hyperpigmentation, and hernia (22, 38, 39).
The most widely debated complication is PAH, typically
characterized by visibly enlarged tissue volume within the
treatment area, developing around 2–5 months after the pro-
cedure (22). The underlying adipocyte growth is benign, but
it does not resolve spontaneously and can be particularly
distressing for patients given that they undergo cryolipolysis
in the first place specifically to reduce adiposity. The patho-
aetiology of PAH is not yet fully understood. However, it has
been suggested that it could relate to the ‘natural selection’ of
adipocytes with altered activity associated with greater toler-
ance to cryolipolysis (40).
Estimates of the incidence of PAH vary significantly. Some
groups have asserted that rates could be as high as 0.5–1% (41–
43). Conversely, a large, multicenter Japanese analysis of over
4000 individuals treated with cryolipolysis found no cases of
PAH (44). Similarly, a review of the present author’s practice
identified no cases of documented or suspected PAH among
patients receiving a total of 3100 treatment cycles (45); in this FIGURE 43.5 Zimmer shockwave therapy system.
cohort, the use of shockwave therapy (SWT) in combination Source: Image courtesy of Dr Michon and Project Skin MD.
(77%) described the treatment-associated discomfort as mini-

Combination Approaches with Cryolipolysis mal or tolerable, and around 70% were satisfied with the
overall results (49). Sample images demonstrating patient
Combining cryolipolysis with other non-invasive techniques outcomes with this combination approach are provided in
could optimize outcomes further and reduce the risk of com- Figures 43.6–43.8.
plications. For example, the use of SWT (Figure 43.5) at the Furthermore, SWT has been linked with a reduced risk
cryolipolysis treatment area (in place of manual massage) may of cryolipolysis-associated PAH—through antifibrosclerotic
increase blood circulation and stimulate collagen regeneration, effects, reduced oxidative stress, and improved microcircula-
thereby possibly improving the firmness and elasticity of the tion (45, 47). In the present author’s practice, there have been
skin (48, 49). This approach can also improve patient com- no cases of PAH among patients receiving more than 3000
fort. Indeed, in a prospective study of 30 individuals undergo- treatment cycles based on this approach (45).
ing cryolipolysis followed by SWT, more than three-quarters
FIGURE 43.6 Cryolipolysis combined with shockwave therapy. A 41-year-old female who received two cycles of cryolipolysis on her lower abdomen
in a single session, followed by shockwave therapy. She is shown in frontal view (A), left oblique view (B), and left lateral view (C). Images demonstrate
subcutaneous fat reduction between baseline (left) and 3 months post-treatment (right).
Source: Reproduced with permission from: Michon A. Aesthetic Plast Surg 2021;45:2317–25 (Springer Nature) (49).
FIGURE 43.7 Cryolipolysis combined with shockwave therapy. A 47-year-old female who received two cycles of cryolipolysis on her upper abdomen,
one cycle on her lower abdomen, two cycles on the bra fat area, and two cycles on her flanks in a single session, followed by shockwave therapy. She
is shown in frontal view (A), left oblique view (B), and posterior view (C). Images demonstrate subcutaneous fat reduction between baseline (left) and
3 months post-treatment (right).
Source: Reproduced with permission from: Michon A. Aesthetic Plast Surg 2021;45:2317–25 (Springer Nature) (49).
Another possible combination strategy involves pairing but were not statistically significant. The safety profile
cryolipolysis for localized fat reduction with electromag- appeared to be consistent with the individual treatment
netic muscle stimulation for improving underlying muscle modalities (50).
tone in the abdominal area (50). In a recent feasibility study, A third possible combination method uses radiofre-
this approach was associated with increased scores on the quency immediately before and after cryolipolysis to create
Global Aesthetic Improvement Scale (GAIS) compared the conditions for what has been described as ‘heat shock
with cryolipolysis alone, although the magnitude of the lipolysis’ (51). In a retrospective analysis of this strategy,
effect did not reach statistical significance. Improvements around 75% of patients showed cosmetic improvements
in abdominal circumference and patient-assessed body based on physician-assessed GAIS, and there were no major
satisfaction were also greater with the combination safety concerns (51).
cryoglobulinemia, cold agglutinin disease, or paroxysmal cold

hemoglobinuria—and the system has not been studied in chil-
dren, pregnant or lactating women, or individuals with known
sensitivity to cold (e.g. cold urticaria, Raynaud’s disease, or
chilblains) (22).
At least two expert groups have attempted to define the char-
acteristics of good candidates for cryolipolysis as compared
with surgical options (Table 43.3) (3, 52). In general, it is well
suited to the treatment of non-obese individuals wanting local-
ized reduction of well-defined fat pockets, particularly among
those who would prefer not to undergo surgery (e.g. wishing to
avoid downtime or scarring).
Patient Consultation and Assessment

Comprehensive patient consultation is essential to achieving
good outcomes. Before proceeding, it is important to evaluate
the patient’s medical history, understand their motivations for
treatment, and confirm with them the body areas that are of
particular concern. Potential treatment sites must be checked
to ensure there is sufficient fat to fit the applicator; cryolipoly-
FIGURE 43.8 Cryolipolysis combined with shockwave therapy. sis should not typically be undertaken in areas with a subcuta-
A 35-year-old female who received two cycles of cryolipolysis on each neous fat layer that is < 1 cm thick (22).
upper arm in a single session, followed by shockwave therapy. Posterior-
view images show subcutaneous fat reduction between baseline (top) and 3 Patients should also be thoroughly briefed on how cryo-
months post-treatment (bottom). lipolysis works, how much fat reduction can realistically be
Source: Reproduced with permission from: Michon A. Aesthetic Plast Surg
2021;45:2317–25 (Springer Nature) (49). expected, and the likelihood that results could take several
months to fully develop (52). In addition, they must be edu-
cated on potential AEs—including common but typically tran-
sient events like erythema and bruising, as well as rarer but
TABLE 43.3
more clinically significant complications like PAH.
Possible Criteria for Defining Good Candidates for Cryolipolysis
• Non-obese individuals seeking contouring or localized fat reduction
rather than significant debulking or weight-loss treatment (3, 7, 52) Treatment Methods
• Fat pockets that are well-defined rather than diffuse (3)
• Patient preference for cryolipolysis over surgery (e.g. wishing to The CoolSculpting system comprises a control unit and appli-
avoid anaesthesia, downtime or scarring) (3, 52) cators, as well as additional supplies, such as (22)
• Skin laxity of no more than mild–moderate severity (52)
• Wanting treatment of body areas associated with a risk of contour • Treatment cards, providing cycles and system profiles
irregularities with liposuctiona (52)
• Foam borders, to minimize the movement of surface
a For example, banana rolls, thigh, back, or bra fat. applicators
• Gel pads, to facilitate thermal contact between the
applicator and the skin
Practical Methods • Liners, for providing a clean surface between the
patient and the applicator, and minimizing gel spread
Patient Selection from the gel pad
In the United States, the CoolSculpting cryolipolysis system is • Pretreatment skin wipes, for preparing the treatment
indicated for the following (7, 22): site
• Securement systems, to minimize the movement of
• Treatment of visible fat bulges in the upper arm, bra surface applicators
fat, back fat, banana roll, thigh, abdomen, and flank
in individuals with a BMI of ≤ 30 kg/m2 A protective gel pad should always be placed on the treat-
• Treatment of visible fat bulges in the submental and ment area to provide thermal coupling at the interface
submandibular areas, and the appearance of lax tis- between the skin and the applicator’s cooling surfaces. The
sue in the submental area, in individuals with a BMI applicator can then be positioned over this site, and if using
≤ 46.2 kg/m2 a vacuum applicator, suction should be initiated to draw
in the targeted subcutaneous fat (Figure 43.9). With non-
Cryolipolysis should not be considered as a weight-loss treat- vacuum surface applicators, the securement system pro-
ment (7). In addition, it is contraindicated in patients who have vided can be used to keep them in place. Sensors within the
FIGURE 43.9 Use of the CoolSculpting system. Treatment of the abdomen and flank with different applicators, individualized for each patient.
Source: Images courtesy of Project Skin MD and Dermapure.
TABLE 43.4
Expert Consensus on the Recommended Number of Treatments
Body area Recommended treatment cycles
Outer thighsa 2–4
Mid-abdomen 2–4
Submental/submandibular 2–4
Mons pubis 1–3
Banana rolls 2–4
Upper bra fata 2–4
Lower bra fata 2–4
Upper abdomen 3–5
Lower abdomen 3–5
Backa 3–5
Inner thighsa 2–4
Distal thighs/kneesa 2–4
Male chesta 3–5
Upper armsa 3–5
Flanks 4–6
aI nclusive of left and right. Green indicates a ‘complete’ or ‘strong’ consensus (≥ 9 of the 11 expert panelists); orange indicates a ‘moderate’ consensus
(7–8 of the 11 panelists); red indicates that no consensus was reached.
Source: Modified from Ref. 3
cooling surfaces provide real-time feedback that controls complications, including PAH. The latter usually presents
the heat flux rate (22). late (several months after treatment), and although it does not
Recommended applicators and cycle durations for specific appear to be a health risk per se, it can be particularly distress-
areas of the body are provided by the manufacturer of the ing for patients. Furthermore, it does not resolve spontaneously
CoolSculpting system (22). If the clinician can access suffi- and is likely to be permanent without surgical intervention. In
cient applicators and more than one device, it is feasible to most cases, this can be accomplished with liposuction (43, 52).
treat several areas simultaneously. The number of cycles and Instances of frostbite and cold burn are also very uncom-
sessions given should be tailored to the individual patient’s mon. They may require an aggressive treatment approach, and
specific needs. However, a recent expert consensus offers in some instances have been known to necessitate excision and
guidance on the preferred number of cycles per treatment area split-thickness skin graft (3, 55). Clinicians should consider
(Table 43.4) (3), and their recommendations provide a good referral to a specialist burns center in these particularly rare
framework, particularly for less-experienced practitioners. but troubling cases (55).
The use of multiple treatment sessions in the same area may For patients with suspected hyperpigmentation, confirming
yield greater overall fat reductions, although physicians should the diagnosis before considering treatment is important, as it
allow around 4–8 weeks between sessions (3). Once a treat- can appear similar to bruising (3). Once confirmed, manage-
ment plan has been completed, it is advisable to wait at least 8 ment strategies may include bleaching creams, laser, or topical
weeks before evaluating the final outcome (3). acids such as tranexamic acid (TXA) (3); some clinicians also
advocate the use of prophylactic TXA in high-risk individuals,
such as those with previous hyperpigmentation (56).
Aftercare
Infrequently, patients may experience subcutaneous indu-
Massage is recommended after completion of a cryolipolysis ration following cryolipolysis, presenting as generalized
treatment session to increase blood circulation and aid the hardness or discrete nodules in the treatment area that are
removal of apoptotic fat cells (3, 49). A split-side study of ten sometimes painful (22). In most instances, no clinical inter-
patients confirmed that 1 minute of massage using a vigor- vention is required, but massage may be helpful (3).
ous kneading motion, followed by 1 minute of circular manual Finally, cases of late-onset pain are not usually severe in
massage, improved the clinical outcomes of cryolipolysis— nature, and self-management with oral pain medications such
resulting in a 44% greater mean reduction in the fat layer at 4 as acetaminophen is often sufficient—but stronger options
months (53). However, as already described, the present author should be considered if necessary (3, 22).
favors the use of SWT instead of massage—applied with an
electromagnetic generator as a projectile accelerator (120 MJ,
15 Hz, 2500 pulses).
Conclusion
It has been suggested that active heating of the treatment
area with a mud pack after cryolipolysis could improve out- Cryolipolysis is a popular nonsurgical body contouring treat-
comes. This approach was the subject of a recent split-body ment for localized fat reduction. Compared with surgical
study (54). However, although it was associated with a reduc- alternatives, it offers important advantages regarding safety
tion in minor post-procedural side effects, it also significantly considerations, decreased downtime, and removal of the need
decreased the overall efficacy of localized fat reduction—and for anaesthesia (2, 3). Moreover, technological improvements
should therefore be avoided (54). in the application systems—allied to greater use of more
Typically, once a patient leaves the clinic, they can imme- intensive regimens based on multiple cycles and treatment ses-
diately resume their normal daily activities. However, it is sions—can increase the fat reductions possible with cryolipol-
worthwhile to advise them that the treated area could remain ysis (26, 27). The benefits for patients include not only physical
red, swollen, or tender for some time and that they may wish improvements in body contouring but also high rates of overall
to refrain from wearing tight-fitting clothes. satisfaction (23, 32) and significant psychosocial effects within
their daily lives (33). Combination approaches with other non-
surgical techniques offer the potential to optimize outcomes
Adverse Event Management
further. From a practical standpoint, cryolipolysis is straight-
The vast majority of AEs associated with cryolipolysis are forward to administer. Nonetheless, practitioners should take
minor cases of erythema, numbness, bruising, and oedema. the necessary time to educate themselves and their patients
These typically resolve rapidly without any intervention (38), on the underlying mechanisms, the benefits and limitations of
but patients should nonetheless be warned to expect them. this method, and proper risk management strategies. Lastly,
Some individuals experience itchiness as a result of the pro- appropriate patient selection is essential for optimal outcomes.
cedure; these patients do not usually require active manage-
ment, but diphenhydramine may be considered if needed (3).
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44
Radiofrequency for Minimally Invasive Body Contouring
Yu-Ching Weng
Definition of Radiofrequency
The definition of radiofrequency is the utilization of high-fre-
quency alternating current output, with the current following
Ohm’s law. As the current passes through the tissue, it induces
vibration in the tissue molecules, resulting in the generation
of varying amounts of heat energy due to the differences in
impedance between different parts. In general, higher fre-
quencies result in shallower treatment depths. Instruments
employing this technology are commonly used in the field of
cosmetology, utilizing the thermal effect generated by radio-
frequency to elevate the temperature of the skin tissue [1,2].
The Mechanisms of Monopolar Radiofrequency FIGURE 44.1 The ligament or fibrous septum shrinks and tightens
immediately after being heated, which will bring about the phenomenon
Monopolar radiofrequency has gained widespread recognition of face lifting.
as an effective nonsurgical method for facial skin tightening.
It is indicated for the treatment of fine lines and wrinkles on These changes enhance skin elasticity and create a firming
various areas of the body, aiming to achieve skin tightening effect [6,7].
effects. This technique utilizes energy within the radiofre- According to the principle, radiofrequency energy transfer
quency range of the electromagnetic spectrum to generate heat typically follows the path of least resistance. In other words, the
within the skin [3,4]. fibrous septa of the subcutaneous fat lobules are preferentially
The heating method employed by monopolar radiofre- heated. This phenomenon has been observed and explains the
quency is known as volumetric heating. One prominent exam- laws that devices such as radiofrequency waves follow when
ple is Thermage®, which holds the highest market share among delivering heating energy to deeper layers of the skin. When
monopolar radiofrequency devices. Thermage® has received the treatment area has more vertical fibrous septa, the energy is
approval from the U.S. Food and Drug Administration (FDA) expected to penetrate deeper than an area with more horizontal
for improving fine lines and wrinkles across the entire body. fibrous septa. This is believed to be important in subsequent
It can be applied to different skin layers throughout the body, subcutaneous tissue remodeling and skin tightening [7].
with a penetration depth reaching subcutaneous levels of There are currently literatures analyzing the quantity and
4.3 mm or even deeper [5]. distribution of new collagen and new elastic fibers after 2
The rejuvenation effect of any thermogenic device involves months of treatment with monopolar radiofrequency and high-
heating the dermis to a temperature range of 50–60°C. This intensity focused ultrasound. The new collagen produced by
temperature range triggers an inflammatory response, lead- monopolar radiofrequency therapy mainly gathers in the pap-
ing to local collagen remodeling within 72 hours. When using illary dermis and the middle and upper reticular layers of the
monopolar radiofrequency, the thermal energy generated dermis, while the new collagen produced by high-intensity
induces molecular vibration at a rate of 6 million times per focused ultrasound therapy mainly gathers in the upper, mid-
second. This vibration generates heat and stimulates fibro- dle, and lower reticular layers of the dermis [8].
blasts, which then utilize proline and lysine to produce colla-
gen, resulting in neocollagenesis and neoelastinogenesis. This
controlled wound healing process leads to the deposition of
newly developed collagen and elastic fibers in the papillary New Concept of Energy Setting in
dermis, as well as the upper, middle, and deep reticular der-
Monopolar Radiofrequency
mis. The thermal effects also cause the fibrous septum of the
subcutaneous tissue to contract and tighten, contributing to an In the past, many experts and scholars recommended using
immediate lifting effect (Figure 44.1). high energy and a low number of shots to maximize the
DOI: 10.1201/b22897-44 457
effectiveness of radiofrequency therapy for skin tightening and from the periosteum to the dermis, providing coverage over
lifting. This approach often involved using a handheld device the bones in specific facial regions. They also play a crucial
with a high energy setting (around 7–8 watts μW/cm2) and a role in maintaining the major soft tissue structures of the face.
small number of passes. However, it has been reported that this False retaining ligaments, on the other hand, connect the inter-
method can cause discomfort during treatment and may lead vening layers of facial tissue to each other [5,6].
to skin blistering or atrophy [9,10]. The 「True ligament heating method」 targets the “real liga-
Currently, the trend in monopolar radiofrequency treatment ments” using a portion of monopolar RF therapy. This approach
is to use a low-fluence with a multiple-pass technique, which involves using low energy settings (Watt μW/cm2) with higher
induces more collagen denaturation [11,12]. The approach pass counts, focusing on the seven true ligaments present in
involves performing a higher number of monopolar radiofre- the face. These seven true ligaments include the mandibular
quency treatments at lower energy settings, which provides a ligament, buccal-maxillary ligament, zygomatic ligament, tear
safer option for face and neck rejuvenation compared to fewer trough ligament, orbital ligaments, and the superior and infe-
passes with higher energy settings. Additionally, using lower rior temporal septum (Figure 44.3) [17].
energy settings improves patient tolerance and reduces the risk The「Neck circular tightning method」 focuses on improv-
of side effects [13]. ing laxity in the lower face and neck. In this method, mono-
polar radiofrequency therapy is primarily applied to heat and
tighten the investing layer of the face and neck (Figure 44.4)
[17]. The investing layer has multiple attachment points in the
The History and Introduction lower face, front of the neck, and lower area of the neck. It
of Heating Methods is the superficial layer of the deep cervical fascia, which is a
thin subcutaneous connective tissue sheet situated between the
There are several published methods for the application of skin’s dermis and the deep cervical fascia. The investing layer
monopolar radiofrequency. The first proprietary technique surrounds all structures of the neck and contains the platysma,
introduced was the single-pass radiofrequency treatment, nerves of the skin, blood vessels, and lymph vessels. It splits
which aimed to improve laxity in areas such as the eyelids, into two when it reaches the trapezius and sternocleidomastoid
lower face, and neck. It was reported that about one-third of muscles [17].
the subjects expressed high satisfaction with the results after The「Neck circular tightning method」 employs multiple
a single-pass treatment, with greater improvement observed passes but lower energy level settings to provide patients with
over time in patients who underwent multiple sessions [14]. It a more comfortable, safer, yet effective treatment approach.
has been noted in the literature that younger patients treated The treatment area is divided into four treatment endpoints:
with higher energy levels tend to exhibit greater clinical upper, front, lower, and rear (Figure 44.5). The upper part is
improvement, while older patients may not experience signifi- attached to the posterior hairline and paraspinal junction (A),
cant clinical changes [15]. the front side is the xternal occipital prominence (B), the lower
Subsequently, the suggestion of multiple radiofrequency part (C) is attached to the spine and acromion of the scapula,
passes during a single treatment session with lower fluences and the rear part (D) corresponds to the attachment of the
emerged. Additionally, it has been mentioned that lower flu- nuchal ligament along the spine [17].
ences may be as effective as higher fluences [14]. The devel-
opment and widespread use of multi-pass vector technology
followed. This treatment approach allows for addressing
sagging in the upper, middle, and lower face and neck using Comparison of Different Monopolar
slightly lower energy levels and multiple directed deliver-
Radiofrequency Instruments
ies (approximately four to five), leading to notable clinical
improvement. Theoretically, stacking pulses without time The method of heating in monopolar radiofrequency is volu-
delay may impede heat dissipation in deep tissue. It is com- metric heating. There are several monopolar radiofrequency
monly believed that deeper heat penetration can damage fatty devices available in the market, and while they all employ the
tissue, which may be utilized to reduce unwanted facial fat same heating method, their relative output power may vary. The
pads or submental fat. The multi-vector operation method difference in power output can impact the depth of penetration.
also helps minimize fat damage and employs the contrac- Moreover, the amount of collagen production under the same
tion of fiber septa between fat to achieve lifting and firming number of passes can also be influenced by the power output.
effects [16]. Each type of collagen has its optimal heating temperature
With a better understanding of anatomy, more specific and remodeling threshold. As a result, different instruments
application methods have been developed and published. have different indications. Some instruments can be expected
True ligaments refer to anatomical fibrous structures that to provide lifting and firming effects, while others primarily
directly connect bones and layers of skin (Figure 44.2). The focus on improving skin texture. The figure (Figure 44.6) pres-
retaining ligaments of the face can be categorized as true or ents a comparison of three commonly used monopolar radio-
false. frequency devices currently available in the market.
According to current anatomical definitions, true retaining Furthermore, the variation in power output can also affect
ligaments are a series of fibrous bundles that extend directly the occurrence of side effects and the overall safety of the
Radiofrequency for Minimally Invasive Body Contouring 459
FIGURE 44.2 Anatomy of the true ligaments in the face.
FIGURE 44.3 The seven true ligaments targeted during treatment.
procedure, such as nerve damage or lipolysis. However, it is Some instruments may have a built-in skin cooling system,
important to note that the occurrence of side effects is primar- while others may not. This factor should also be taken into
ily related to the correct use and technique of the operator. consideration when selecting and operating the instrument.
are the key principles for body sculpting using radiofrequency

therapy [18]. Studies conducted on buttock skin biopsies
exposed to radiofrequency treatment have shown destruc-
tion of the integrity of fat cell membranes and thickening
of the membranes [19]. Post-treatment, there is an enhance-
ment of cell function, increased expression of heat shock
proteins, increased expression of growth factors like TGFb1
(Transforming Growth Factor Beta 1), local changes in lym-
phatic drainage, and alterations in vascular flow, all of which
play important roles in the tissue repair process [20].
Research has demonstrated that radiofrequency energy, with
its deeper penetration compared to laser radiation, is an effec-
tive method not only for treating facial wrinkles and sagging but
also for body contouring [21,22]. In the case of striae distensae
(stretch marks), some experts and scholars have used a combi-
nation of monopolar radiofrequency and dye laser treatments.
Regardless of clinical or histological changes, varying degrees
of improvement have been observed after 3 months of combined
treatment [23]. Figure 44.7 shows a case photo taken before the
FIGURE 44.4 Treatment area and direction of passes.
operation and after one month of follow-up (i.e., 2 months later).
In this particular case, monopolar radiofrequency treatment was
administered alone without any other combined treatments.
The 「Ring heating method」 was employed, applying multiple
passes in a circular pattern from the prominence of the humeral
head to the midline of the upper arm.
The Differences of Monopolar Radiofrequency

and Bipolar Radiofrequency
The principle of monopolar radiofrequency is to generate a
heating effect on deep skin tissue using electromagnetic waves
of a specific frequency. It has stronger penetration power and
provides a good skin firming effect with a single treatment
course. The lifting effect on the skin can last for about one and
a half to two years. Its advantages include long-lasting effects,
significant results after a single treatment, and the ability to
penetrate deep into the dermis and subcutaneous tissue.
Bipolar radiofrequency, on the other hand, differs from
monopolar radiofrequency in that it utilizes two electrodes in
contact with the skin simultaneously at a treatment point, and
the area between the electrodes becomes the treatment area
FIGURE 44.5 The treatment area of the neck circular tightening method. (Figure 44.8). The energy penetration range of bipolar radio-
frequency is in the superficial layer of the skin, and it provides
an immediate effect upon application. However, the degree
of maintenance of the results is relatively poorer compared to
Body Contouring in Monopolar Radiofrequency monopolar radiofrequency.
Body contouring can be achieved through minimally invasive
radiofrequency therapy. In the subcutaneous space, various
types of collagen tissues, such as papillary dermis, reticular The Mechanisms of Microneedle
dermis, reticular fibers, septal connective tissues, and fascia,
Bipolar Radiofrequency
can be targeted. Reticular fibers surround subcutaneous fat
cells, while septal connective tissues connect the dermis with With microneedle radiofrequency therapy at a constant volt-
the fascia and separate fat lobules [18]. age, coagulation efficiency is limited as electrode impedance
Each type of collagen has an optimal temperature at which increases in the tissue over time. As the impedance increases,
shrinkage occurs without causing thermal damage to the con- the current flowing through the tissue decreases [24]. For
nective tissue. This leads to the reorganization of collagen example, impedance begins at about 80 Watts at the beginning
fibers, resulting in soft tissue contraction and modeling, which of treatment, starts to rise after approximately 90 seconds, and
FIGURE 44.6 Comparison of three common unipolar radiofrequency radios currently on the market.
then reaches a plateau of around 100 Watts after 120 seconds coagulation range of microneedle radiofrequency forms a
as tissue blood flow is interrupted. The increase in impedance spherical coagulation area. The interruption of tissue blood
inevitably reduces coagulation and thermal coagulation effi- flow allows the heating process to produce a larger coagula-
ciency. This means that microneedle radiofrequency delivers tion area compared to without blood flow interruption [24].
current in a bipolar radiofrequency manner, resulting in size After microneedle bipolar radiofrequency treatment, it
limitations in the coagulated area of the tissue. The local tis- is necessary to apply ice to the skin immediately, as it will
sue temperature of the needle-tip electrode also increases with affect the occurrence of subsequent unexpected side effects.
heating time and tissue conditions. Therefore, the thermal The heated local tissue then creates a transition zone whose
FIGURE 44.7 A case study: body contouring with monopolar radiofrequency (A, before; B, 1 month after; C, 2 months after).
FIGURE 44.8 Different types of radiofrequency (for example, monopolar radiofrequency and micro needle radiofrequency) have different treatment
effects.
size is influenced by the presence or absence of postoperative remodeling, activating the collagen regeneration process.
cooling. The literature showed that the transition zone was Collagen regeneration at different local depths is the mecha-
significantly larger in the group without postoperative cool- nism used to treat various skin problems. Currently, most
ing than in the group with postoperative cooling. After the microneedle bipolar radiofrequency methods are applied in a
microneedle electric wave heats the local tissue, the residual stacked manner within the treatment area. The healing effect
heat energy causes secondary indirect damage, and a transi- of each position is related to the energy setting and stacking
tion zone is formed outside the direct coagulation zone. The method. Possible side effects of microneedling bipolar waves
tissue in this transition zone also gets injured [25]. When bipo- include erythema, pain, edema, scabbing, bleeding, blisters,
lar radiofrequency treatment produces thermal coagulation post-inflammatory hyperpigmentation, and temporary skin
points in the tissue, the subcutaneous tissue enters collagen irritation [26,27].
distensae. Treatment with bipolar radiofrequency alone or in

The Clinical Applications of Microneedle combination with infrared light has shown promising results,
Bipolar Radiofrequency with a noticeable reduction in the depth of stretch marks
observed in clinical images and a more uniform distribution of
Microneedling bipolar radiofrequency can be used alone or collagen fibers seen in histological analysis [35]. Additionally,
in combination with topical products, other types of lasers, or some experts have suggested that multi-polar radiofrequency
monopolar radiofrequency, providing various clinical options can also be utilized for the treatment of striae distensae, result-
[28]. Based on current research literature, microneedle radio- ing in high patient satisfaction [36]. Currently, it is widely
frequency has shown effectiveness in treating atrophic acne accepted among experts and scholars that striae rubra can
scars [28], skin rejuvenation [29], melasma [30], wrinkles [31], be effectively treated with infrared rays or dye lasers, while
striae distensae [32,33], hair loss [34], and axillary hyperhi- striae alba may benefit from a combination approach involving
drosis [35]. The recent advancements in microneedle radiofre- carbon dioxide destructive lasers to achieve improved clinical
quency technology have resulted in smaller contact points and therapeutic effects. It is important to note that patients with
shorter treatment durations, leading to fewer side effects and darker skin are more prone to post-inflammatory hyperpig-
making it more favorable among both operators and patients. mentation, thus treatment parameters, frequency, and intervals
should be carefully selected based on the patient’s skin color,
depth of skin texture, clinical response, and tolerance.
Body Contouring in Microneeding
Bipolar Radiofrequency
Comparison of Monopolar Radiofrequency
Striae distensae exhibit the phenomena of collagen fiber loss,
and Microneedling Bipolar Radiofrequency
random distribution of collagen fibers, and the presence of
elastic fibromas in tissue sections. Clinical prospective ran- Figure 44.9 illustrates the differences between monopo-
domized controlled studies have been conducted to investigate lar radiofrequency and microneedle bipolar radiofrequency.
the use of bipolar radiofrequency in the treatment of striae Apart from variances in their mechanisms of action, these two
FIGURE 44.9 Comparison of monopolar radiofrequency and microneedling bipolar radiofrequency.

methods differ in heating methods, maximum output power, 4. Ruiz-Esparza J, Gomez JB. The medical face lift: a nonin-
treatment depth, clinical application range, and postoperative vasive, nonsurgical approach to tissue tightening in facial
wound status. Microneedle bipolar radiofrequency employs skin using nonablative radiofrequency. Dermatol Surg.
pin-point volumetric heating as its heating method, whereas 2003 Apr;29(4):325–32; discussion 332.
monopolar radiofrequency utilizes simple volumetric heat- 5. Polder KD, Bruce S. Radiofrequency: thermage. Facial
ing, resulting in a larger heating range with a single pass. Plast Surg Clin North Am. 2011 May;19(2):347–59.
Currently available instruments in the market still offer higher 6. Yokoyama Y, Akita H, Hasegawa S, et al. Histologic study
maximum output power with monopolar radiofrequency. The of collagen and stem cells after radiofrequency treatment
treatment penetration depth also varies between the two meth- for aging skin. Dermatol Surg. 2014 Apr;40(4):390–7.
ods. Monopolar radiofrequency treatment can reach a depth of 7. González-Suárez A, Gutierrez-Herrera E, Berjano E, et al.
4.3 mm, whereas microneedle bipolar radiofrequency allows Thermal and elastic response of subcutaneous tissue with
adjustable treatment depths ranging from 0.1 mm to 3.5 mm. different fibrous septa architectures to RF heating: numeri-
cal study. Lasers Surg Med. 2015 Feb;47(2):183–95.
The clinical application scope of monopolar radiofrequency
8. Suh DH, Choi JH, Lee SJ, et al. Comparative histomet-
primarily focuses on skin firming throughout the entire body,
ric analysis of the effects of high-intensity focused ultra-
while microneedle bipolar radiofrequency is used for pore
sound and radiofrequency on skin. J Cosmet Laser Ther.
tightening, addressing fine lines, wrinkles, and scars at the skin
2015;17(5):230–6.
layer. In terms of postoperative wounds, monopolar radiofre-
9. de Felipe I, Del Cueto SR, Pérez E, et al. Adverse reactions
quency does not cause any wounds, whereas microneedle bipo- after nonablative radiofrequency: follow-up of 290 patients.
lar radiofrequency surgery may result in tiny punctate scabs. J Cosmet Dermatol. 2007 Sep;6(3):163–6.
10. Narins RS, Tope WD, Pope K, et al. Overtreatment effects
associated with a radiofrequency tissue-tightening device:
Summary rare, preventable, and correctable with subcision and autol-
ogous fat transfer. Dermatol Surg. 2006 Jan;32(1):115–24.
In conclusion, radiofrequency therapy utilizes a controlled 11. Zelickson BD, Kist D, Bernstein E, et al. Histological and
wound healing process in the dermis to achieve skin reju- ultrastructural evaluation of the effects of a radiofrequency-
venation. Through thermal effects, collagen is remodeled based nonablative dermal remodeling device: a pilot study.
and regenerated, resulting in skin firming, rejuvenation, and Arch Dermatol. 2004 Feb;140(2):204–9.
potential fat cell destruction. Monopolar radiofrequency, in 12. Kist D, Burns AJ, Sanner R, et al. Ultrastructural evalu-
particular, has deeper penetration capabilities when passing ation of multiple pass low energy versus single pass high
through vertical fiber septa, and it can stimulate fibroblast energy radio-frequency treatment. Lasers Surg Med. 2006
activation, leading to lifting effects. The availability of mono- Feb;38(2):150–4.
polar, bipolar, and multipolar radiofrequency devices in the 13. Suh DH, Hong ES, Kim HJ, et al. A survey on monopolar
market allows for tailored and combined treatments based on radiofrequency treatment: the latest update. Dermatol Ther.
individual patient needs, aiming to minimize side effects and 2020 Nov;33(6):e14284.
maximize clinical efficacy. With the wide utilization of vari- 14. Ruiz-Esparza J, Gomez JB. The medical face lift: a nonin-
ous instruments for body sculpting and rejuvenation, operators vasive, nonsurgical approach to tissue tightening in facial
must carefully consider how to effectively reduce side effects skin using nonablative radiofrequency. Dermatol Surg.
and enhance clinical satisfaction. This chapter aims to provide 2003 Apr;29(4):325–32; discussion 332.
therapists with insights to make appropriate and flexible use 15. Hsu TS, Kaminer MS. The use of nonablative radiofre-
of different treatment effects for optimal clinical outcomes. quency technology to tighten the lower face and neck.
In the future, further research and evidence are expected to Semin Cutan Med Surg. 2003 Jun;22(2):115–23.
16. Finzi E, Spangler A. Multipass vector (mpave) technique
explore the expanding applications of radiofrequency therapy
with nonablative radiofrequency to treat facial and neck
in the field of dermatology and aesthetics.
laxity. Dermatol Surg. 2005 Aug;31(8 Pt 1):916–22.
17. https://issuu.com/im-aesthetics/docs/prime_ journal_
nov_dec_2022/38
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45
Minimally Invasive Upper Arm Contouring in Esthetic Medicine*
Uwe Wollina, Alberto Goldman, and Ömer Kutlu
Introduction Combined Liposuction Techniques

The contour of upper arms is defined by humerus bone, mus- Laser-assisted liposuction. In an open trial 28 women (mean
cles (M. biceps brachii, M. triceps brachii, M. brachioradialis, age 42.3 years) with a smooth to moderate skin laxity of the
deltoid muscle) and soft tissue. The esthetics of upper arms are upper arms were included. Standardized circumferential
characterized by sexual dimorphism. measurements and photographs were used before and after
The female arms are ideally characterized by a cylindric follow-up of 3 months to assess the effect. A pulsed 1,064 nm
shape with smooth transitions to the posterior plane, the del- neodym-YAG-laser connected to the tip of the liposuction can-
toid plane, and the lateral arm groove. The male arms have a nula was combined with microcannular liposuction in tumes-
stronger musculature with enhancement of triceps, biceps, and cent anesthesia. The control group was treated by liposuction
deltoid muscles. only. Laser-assisted liposuction resulted in an improved skin
Cutaneous elastosis, aging and weight changes can result in tightening (11.4% compared to 8.7% in the liposuction only
disfigurement of upper arm shape. While most techniques are group). No adverse events were observed (7). Dermal remodel-
surgical, minimal invasive procedures like liposculpture have ing, collagen shrinkage and neocollagenesis are the underlying
gained increasing interest (1,2). mechanisms of the laser effect (8).
In another open trial 45 patients with upper arm ptosis
Teimourian grades I and II got a single session of laser-assisted
liposuction using a 1470 nm diode laser. Skin tightening was
Targets of Upper Arm Contouring assessed by skin caliper measurements. After treatment arm
Upper arm contouring consists of three major targets: circumferences became reduced between 4.7 cm—5.5 cm but
prolonged arm edema was noted in 11 patients (9). The same
(a) skin redundancy schedule was used in 22 patients with Teimourian grades III
(b) lipodystrophy or and IV. Here the mean decrease of circumferences was 4.9 to
(c) a combination of both 5.5 cm (10).
An open trial compared laser-assisted liposuction with
The classification of El Khatib (3) for severity of upper arm open suction-assisted brachioplasty (the Pascal & Leouarn
ptosis is shown in Table 45.1. technique). In each study arm 30 patients with grade 2b El
Khatib arm ptosis classification were included. Patient satis-
faction was statistically significant better in the laser-assisted
liposuction group with less pain and earlier return to work
Classical Liposuction Techniques (11). Figures 45.2 and 45.3 show the clinical outcome of this
procedure.
Liposuction is an established method in body contouring per-
Radiofrequency-assisted liposuction (RAFL). Thirty-
formed in tumescent anesthesia (4; Figure 45.1). When lipo-
nine women and a male were included in an open trial (mean
suction of upper arms is focused on the postero-lateral region
age 40 years) for upper arm contouring. BMI was < 35. The
only, this may result in a disharmonic contour (5). The multi-
bipolar BodyTie® platform (Invasix, Yokneam, Israel) had
positional circumferential arm liposuction (MCAL) has over-
been used with a power of 35 W followed by microcannu-
come this disadvantage. The arm is positioned in 90-degree
lar liposuction in tumescent anesthesia. Target temperature
abduction, 180-degree lifting and 45-degree abduction. In one
was 38 to 40 degrees Celsius during the procedure. Patients
study, 34 young female patients (BMI < 28) were treated by
were re-evaluated for up to 52 weeks. More discomfort had
this method. The upper arm deformity was classified in three
classes (I–III). Objective analysis was performed using an
EVA 3D® scanner (Artec, Santa Clara/CA, USA) before and
2 to 3 months after the procedure. The volume reduction was * Portions of the text and figures are reprinted from Wollina U, Goldman
10.8% for class I, 17.3% for class II, and 22.8% for class III. A. Upper arm contouring—a narrative review. Georgian Med News.
Transient limb edema was noted (6). 2022;332:29–35, with permission.
466 DOI: 10.1201/b22897-45

Minimally Invasive Upper Arm Contouring in Esthetic Medicine 467
TABLE 45.1 Another trial compared three different techniques to tar-

Classification of Upper Arm Ptosis According to El Khatib (3) get upper arm skin laxity: Power-assisted VASER liposuction
followed by BodyTite® RF (InMode Corporation, Toronto,
Stage Remarks Canada) therapy (n = 53) or Renuvion® (Apyx Medical,
Stage 1 Minimal fat deposit and no ptosis Clearwater/FL, USA) helium plasma subdermal coagulation
Stage 2a Moderate fat deposit and grade 1 (n = 66) or VASER® (Solta Medical, Bothell/WA, USA) lipo-
ptosis suction alone (n = 57). The mean age of patients was 32 years
Stage 2b Severe fat deposit and grade 2 ptosis (153 females and 23 males). Patients were followed for another
Stage 3 Severe fat deposit and grade 3 ptosis 6 months before re-evaluation by third party plastic surgeons.
Stage 4 Minimal or no fat deposit and grade After 6 months 80.6% of all patients reported satisfaction with
3 ptosis the techniques. Third party surgeons considered the outcome
good to excellent in 81.5% of patients (13). It is important to
spare the bicipital groove where the vessels and nerves lie (14).
Radiofrequency Techniques
Monopolar radiofrequency (RF). Monopolar RF with
a TECAR (Transferencia Eléctrica CApacitva Resistiva)
device (Capenergy C 200®, Capenergy, Barcelona, Spain)
was used in young women to improve body contour in a half
side trial. The average decrease in upper arm circumference
was 2.9 cm (15).
Thermistor-controlled monopolar subsurface radiofre-
quency has been studied in a prospective, open trial. A single
treatment of 24 arms was performed combined with a follow-
up of 90 days. Significant improvement of skin laxity was
noted on days 30 and 90. Firmness and skin texture were also
improved. Adverse events on day 7 after treatment included
erythema, irregularities of the contour and bruising. These
adverse events completely disappeared until day 30 (16).
Microfocused Ultrasound
Microfocused ultrasound (MFU) can be used in either single-
plane or dual-plane mode. Both modes have been compared
in a randomized, single-blinded, controlled trial for upper
arm skin laxity in 30 patients in a side-by-side study. Single-
plane MFU (4 MHz/4.5 mm transducer) and dual-plane MFU
(4 MHz/4.5 mm transducer and 7 MHZ/3.0 mm transducer)
resulted in a comparable improvement after 1, 3 and 6 months.
Median pain-scores were slightly higher for single-plane
MFU, but no other adverse events were observed (17).
Cryolipolysis
FIGURE 45.1 Lipedema grade I in a 27-year-old woman. Mild to
moderate upper arm ptosis (stage 2b): (a) and (b), before treatment; In a retrospective study 4,122 patients (average age 34.7
(c) to (f), after classical liposuction. Despite reduction of upper arm years) underwent a treatment with CoolSculpting® (Allergan
circumference by 5 cm, ptosis was only mildly improved.
Aethetics, Irvine/CA, USA). There was a female predomi-
nance of 96.3%. Twenty-seven patients received treatments
been reported during radiofrequency compared to liposuc- for upper arms what resulted in reduction of upper arm cir-
tion alone. Six months after treatment 95% of patients were cumference by 1.3 cm on average. Possible adverse events of
satisfied to extremely satisfied with the outcome. Third party cryolipolysis include paradoxical lipohypertrophy, frostbites,
plastic surgeons reported that 80% of patients achieved a good post-inflammatory hyperpigmentation, skin necrosis and per-
to excellent improvement of the upper arm shape after 1 year sistent erythema (18).
follow-up. Adverse events included a full thickness burn and In a second study 15 patients (mean age 51 years; mean BMI
a seroma (12). of 26.8) underwent two treatment cycles of cryolipolysis for
FIGURE 45.2 A 37-year-old woman with localized adiposity (stage 2a): (a) and (c), before treatment; (b) and (d), 8 months after laser-assisted
liposuction with improved contour and skin tightening.
FIGURE 45.3 57-year-old woman with skin flaccidity (stage 1). (a) before treatment. (b) 3 months after laser-assisted liposuction Improved contour
and skin tightening.
upper arms. Re-evaluation clinically and by diagnostic ultra- viscosity and elastic modulus G’ (26). It exerts no cytotoxicity
sound was performed after 12 weeks. The mean adipose tissue to keratinocytes and fibroblasts (27). Clinical trials have dem-
layer reduction was 2.5 mm. Eighty-seven percent of patients onstrated long-lasting effects of contouring (12–18 months)
were satisfied with the procedure. Mild edema, erythema and and volumizing with an excellent safety profile for the face
transient numbness were the major adverse events that fully and hands (28, 29).
resolved within the 12-week follow-up (19). Radiesse® has been used in an open trial with 30 women
A third trial used a CoolCup applicator (Zeltiq Aesthetics; (mean age 55.6 years) for upper arm contouring. Skin flaccid-
Pleasanton/CA, USA) for bilateral treatment of upper arms. ity and arm volume have been classified using a visual ana-
Thirty female patients completed the study (mean age 46 years; logue scale (VAS), where “0” was very bad and “10” was very
mean BMI 28.2). Follow-up was 12 weeks. By using diagnostic good. Most participants had a type III or IV VAS upper arm.
ultrasound, a mean reduction of subcutaneous adipose tissue Radiesse® 1.5 mL was mixed with 0.5 mL 2% lidocaine and
layer of 3.2 mm was found. The pain score during treatment injected per arm twice—injections 1 month apart. Injections
was “1” (very mild pain). Prolonged numbness and bilateral were performed using a 27 Gauge needle 1 to 2 cm apart in
erythema were reported as possible adverse events (20). the deep dermis. Follow-up was 4 months after the second
Other rare adverse events are prolonged neuropathy, either injection. Improvement of flaccidity and volume reached sig-
sensory or motoric, and paradoxical adipose tissue growth nificance at visit 2 and 3 compared with the pre-treatment
(21–23). findings. While all participants achieved some improve-
ment, 43.3% assessed the effect as a “great improvement”. No
adverse events were recorded (30).
In another case series, ten women were included. CaHA was
Injection Lipolysis diluted 1:2 with 2% lidocaine solution and injected in the sub-
Phosphatidylcholine (RC) and deoxycholic acid (DA) are used dermis with a linear-threading technique. Skin elasticity was
for injection lipolysis. In a retrospective study 169 patients measured with a Cutometer before, 1 and 3 months after injec-
were evaluated with upper arm contouring. The authors used tion. The skin elasticity increased from 72 U at baseline to 85
a cocktail of PC and DA on average four times every month. U at month 3 after a single filler treatment. The procedure was
Outcome was assessed 2 months after the last injection. All well tolerated (31).
female patients were satisfied, not the two male patients A consensus conference on the use of hyperdiluted CaHA
included. The injection causes a temporary panniculitis with (Radiesse®) suggested the use of retroinjection with a fanning
lipolysis and skin tightening (24). technique. The preferred dilution ranges from 1:2 to 1:4 mL
Commonly encountered adverse events are injection pain, (32). The skin tightening effect is possibly achieved by dermal
edema, and erythema. A pinch technique has been recom- remodeling and production of precollagen type I and collagen
mended to avoid accidental intramuscular injection (25). type III (33, 34). Furthermore, induction of pre-adipocytes by
dermal fillers has been suggested (35).
Dermal Fillers
Liposculpture
Calcium hydroxyl apatite (CaHA) filler Radiesse® (Merz,
Frankfurt/Main, Germany) composed of CaHA microspheres Cell-assisted lipotransfer (CAL) is a novel technique for adi-
embedded in a hyaluronic acid matrix is used or facial and pocyte grafting which seems to be an alternative to classical
hand rejuvenation. This filler is characterized by a high adipose tissue grafts. A recent meta-analysis investigated the
TABLE 45.2
Techniques and Targets for Minimal Invasive Upper Arm Contouring (Arm Ptosis Stages According to El Khatib [3, 39]).
Technique Flaccidity Targets adipose tissue Skin texture Arm ptosis stages
Brachioplasty + ++ — 2a—4
Liposuction (+) ++ — 2a—3
Laser-assisted liposuction ++ ++ + 1, 2a
Radiofrequency-assisted ++ ++ + 2a—3
liposuction
Monopolar radiofrequency + (+) + 1, 2a
Microfocused ultrasound + (+) (+) 1. 2a
Cryolipolysis + + — 1, 2a
Injection lipolysis + + — 1, 2a
Calcium hydroxyl apatite filler + — + 2a, 4
clinical efficacy of CAL technology compared with conven- 3. El Khatib HA, Classification of brachial ptosis: strategy for
tional fat grafting. CAL was associated with a significantly treatment. Plast Reconstr Surg. 2007;119:1337–1342.
higher patient satisfaction rate for liposculpture of the arms 4. Katz BE, Sadick NS. Body Contouring. Philadelphia, PA:
than fat graft (OR = 64.60, 95% CI 58.79, 70.41; P < 0.001) (36). Saunders, 2009.
In a prospective trial 95 patients (mean age 39 years, mean 5. Lillis PJ. Liposuction of the arms. Dermatol Clin.
BMI 28) were treated by power-assisted liposuction in combi- 1999;17(4):783–797.
nation with lipotransfer and lipofilling in the bicipital triangle 6. Gu Y, Kang N, Lv Q, et al. Application of a proposed multi-
of the medial upper arm. All patients had mild to moderate positional circumferential arm liposuction method and
brachial ptosis. Average follow-up was 24 months. Mean lipo- quantification of its clinical efficacy evaluation. Aesthetic
suction volume was 240 mL and mean lipofilling volume was Plast Surg. 2021;45(3):1115–1124.
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8. Goldman A, Wollina U, de Mundstock EC. Evaluation of
jection into the muscle bulge for biceps, triceps and deltoid
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9. Palm MD, Goldman MP. Laser lipolysis: current practices.
underwent previously bariatric surgery, BMI of ≥ 30kg/m2, Semin Cutan Med Surg. 2009;28(4):212–219.
and severe clotting disorders. In a study with 275 males and 10. Leclère FM, Alcolea JM, Vogt P, Moreno-Moraga J,
14 females, no major complications had been registered. Mordon S, Casoli V, Trelles MA. Laser-assisted lipolysis for
Prolonged bruising and numbness have been reported in 16 arm contouring in Teimourian grades I and II: a prospective
patients (38). study of 45 patients. Lasers Med Sci. 2015;30(3):1053–1059.
11. Leclère FM, Alcolea JM, Vogt PM, Moreno-Moraga J,
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A variety of different techniques are available including mini- 12. Fayek M, Rizk IN, Hashem AM, El Sharkawy OA.
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in combination with bariatric surgery. Table 45.2 summarizes ptosis. Plast Reconstr Surg. 2022;149(5):881e–892e.
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upper arm skin laxity: a randomized, single-blinded, con- 31. Lapatina NG, Pavlenko T. Diluted calcium hydroxylapatite
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Med. 2018; 50. doi: 10.1002/lsm.22811. Epub ahead of print. and body biostimulatory agent. Plast Reconstr Surg Glob
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Index
Note: Page numbers in italics indicate figures, and page numbers in bold indicate tables on the corresponding pages.
A diagnosis of, 188 phytotherapy, 140 – 141

diclofenac, 191 Primula obconica, 140
AA, see alopecia areata DNA repair enzymes, 192 – 193 α-hydroxyacids (AHAs), 70, 70
ablative laser therapy, 192 field of cancerization, 189, 189 α-tocopherol, 93 – 95
Acacia nilotica, 127 5-fluorouracil, 191 alternative and natural treatments, 125 – 141
ACD, see allergic contact dermatitis hyperkeratotic actinic keratosis, 189, 190 acne, 137 – 139, 140
acid neutralization, 409 – 410, see also specific imiquimod, 191 alopecia areata, 139 – 141, 141
types immunocompromised patients, treatment atopic dermatitis, 131 – 136, 138
acid strength, 72 in, 193 hyperpigmentation, 125 – 127, 128
acne, 77, 137 – 139, 140, 334 – 336, 371, see also ingenol mebutate, 191 onychomycosis, 127 – 131, 132
keratolytics management of, 190 pruritus, 138
alternative and natural treatments, multiple, non-hyperkeratotic AK, 191 psoriasis, 136 – 137, 138
137 – 139, 140 multiple hyperkeratotic actinic ambulatory phlebectomy, 271, 271
botanicals, 138 – 139 keratoses, 192 amino acids, 72, 73
cosmetic cryotherapy, 371 nonablative laser rejuvenation, 438 – 439 5-aminolevulinic acid (ALA), 362
ethnic cosmetics, 334 – 336 photodynamic therapy, 192 AN 2690, 41
microdosing for, 387 secondary prevention, 189 anagen effluvium (AE), 277
niacinamide, 137 sequential combination treatments, 192 analgesics, 82, 83
pomade-acne, 335 spinocellular carcinoma, 188 – 189 anatomic site, sensitive skin, 61
vitamin C (ascorbic acid), 137 therapeutic perspectives, 192 androgenetic alopecia (AGA), 274 – 275,
zinc, 137 – 138 treatment, 190, 190 – 193 275, 278
acne keloidalis, 281 ultra pulse ablative laser therapy, 192 androgens, 342
acne management, 326 – 330 acupuncture, 139, 141 anesthesia, 395
cleansers, 328 – 329 adapalene, keratolytics, 320 – 321 animal hooves, 33
comedogenicity, 326 – 327 adhesive disc squametry, 242 anisometry, younger and older skin, 49
comedogenic raw material, 327 adjunctive treatments, 386 antagonistic acetoxyacids, 80
cosmetic camouflages, 329 advanced glycation end products (AGEs), 115 anti-aging, 113, see also ageing; skin aging
cosmetics, 326 – 327 adverse event management, 454 anticellulite, 259 – 262, see also cellulite
emulgators, 326 – 327 adverse nail reactions, 218 – 219 classification of, 260
fungal compounds, 327 – 328 adverse skin reactions, perfumes, 119 endermologie, 261 – 262
herbal compounds, 327 – 328, 328 aesthetic procedure, geriatric patients, etiopathogenesis, 259 – 260
keratolytics, 329 355 – 356 food supplements, 262
moisturizers, 326 – 327 aesthetic surgery, 353 laser Doppler flowmetry (LDF), 260 – 261
postbiotics, 327 AffirmTM Multiplex laser, 431 magnetic resonance imaging (MRI), 261
probiotics, 327 age, sensitive skin, 59 massage treatment, 261
sebum absorbants, 328 – 329 ageing mesotherapy, 262
sunscreens, 329 – 330 anatomical changes in, 353 noninvasive techniques for evaluation,
unmet needs, 330 defined, 113 260 – 261
acne scarring, 336 skin, 79, 353 – 354 optical devices, 262
acne scars, 364 age spot keratoses, 79, 79 pharmacological agents, 261
after three sessions using Dermaroller, 361 AK, see actinic keratosis plicometry, 261
before treatment, 361 aldobionic acids (ABAs), 69, 71, 72 surgical subcision, 262
acne vulgaris, 139, 364 aldonic acid, 71, 71 therapies, 261 – 262
acoustic spectrometer, 247 alduronic acid, 71 thermography, 261
acquired dermal hypermelanocytosis, 295 alkyl AHAs, 70 thigh circumference measurement, 260
acquired Ota nevus (Hori nevus), 295 allergic contact dermatitis (ACD), 119 – 121, ultrasonography, 260
acrylate monomers, 208 195 – 198, 196, 232 – 233 antifungal efficacy coefficient, comparison
acrylic nails allergic patient, perfumes, 121 – 122 of, 40
with decorative art, 229 allergic reactions, 208, 213 – 214 antioxidants, 79 – 80, 92 – 98, 97
onychoschizia due to improper removal of, 232 all-trans retinoic acid (ATRA), 101, see also combinations, 97
acrylic prosthesis, 228 tretinoin constitutive skin antioxidant network, 93,
acrylonitrile butadiene styrene (ABS), 208 Aloe barbadensis, 328 93 – 94
actinic keratosis (AK), 79, 79, 188 – 193 aloe vera, 136 environmental stressors on, 94 – 95
ablative laser therapy, 192 alopecia areata (AA), 139 – 141, 275 – 277, enzymes, 93
chronicity, 189 277, 278 evaluating, 98
comprehensive approaches for acupuncture, 139, 141 photoprotection of human skin by topical
treatment, 192 cryotherapy, 139, 141 antioxidants, 95 – 97
cutaneous squamous cell carcinoma essential oils, 140 polyphenols, 96
(cSCC), 188 – 189 garlic extract, 140 property, 72
472
Index 473
reactive oxygen species (ROS), 92 – 93 bis-ethylhexyloxyphenol methoxyphenyl Canfield EpiLume®, 345

vitamin C, 95 – 96 triazine, 155 Cannabis sativa, 328
vitamin E, 95 Bisoctrizole, 155 capacitance, 248
Aquaflux, 46, 252 blackcurrant seed oil (BCSO), 132 capsaicin, 65
aralkyl AHAs, 70, 70 bleaching products, 288 carbohydrate metabolism, 72 – 73
argon laser, 418 blood flow, 352 carbon dioxide (CO2) lasers, 313 – 314,
arterial injection, 269 – 270 BM, see basement membrane 313 – 315, 418
artificial nails, 207 – 209, 212 – 216, see also body sculpting procedures, 445 carnosine (β-alanyl-l-histidine), 97
nails botanicals, 138 – 139 carotenoids, 93
acrylic resin technique, 207 botulinum toxins (BT), 378 – 388 carrier oil, 133 – 134
composition for polymerizable gels, 207 adjunctive treatments, 386 Cassia fistula, 127
indication, advantages, 207 asymmetric smile, 385 cell/tissue injury, 370
preformed, 230, 231 bunny lines, 382, 383 cellular retinoic acid proteins, 319
sculptured, 213 – 215, 214 – 216 cellulitic chin, 384 cellular retinol-binding protein (CRBP), 101
side effects of, 208 – 209 commercial preparations of, 379 cellulite, 259 – 262, see also anticellulite
technique for photopolymerizable gel, complications and side effects, 387 classification of, 260
207 – 208 contraindications, 380 etiopathogenesis, 259 – 260
ascorbic acid, 125 – 126 crow’s feet lines, 382, 383 noninvasive techniques for evaluation,
asymmetric smile, 385 décolleté wrinkles, 385 – 386 260 – 261
atopic dermatitis, 131 – 136, 138 depressor angulis oris, 384 therapies, 261 – 262
balneotherapy, 135 dilution, 378 – 379, 379 – 380 cellulitic chin, 384
gentian violet (GV), 133 dose equivalence, 378 – 379 Centipeda minima, 140
Mahonia aquifolium, 135 facial asymmetry, 385 central centrifugal cicatricial alopecia
oatmeal, 131 forehead lines, 381 – 382 (CCCA), 280 – 281
plant oils, 131 – 134 gingival smile, 384 – 385 chemical peels, 288 – 289, 336, 362, 403 – 415
stress, 136 glabellar lines, 380 – 381, 381 acid neutralization, 409 – 410
Traditional Chinese Herbal Medicine handling, 378 – 379 depth of, 403 – 409, 404
(TCHM), 135 – 136 hyperhidrosis (HH), 386 – 387, 388 fibroblasts and, 413
vitamin B12, 131 indications, 388 phenol, 413 – 414, 414
atrophic scars, grading of, 360 lip augmentation with hyaluronic acid, 386 side effects, 409
automated phototrichograms, 343 – 344 lower face, 383 – 385 trichloracetic acid (TCA), 410 – 413
autonomic function, 9 masseteric hypertrophy, 385 chemical structure, hydroxyacids, 76
Avobenzone, 155 mechanism of action, 378 chromhidrosis, 298
axillary hidradenitis suppurativa, 309 mentalis, 384 chronic eczema, 84
Azadirachta indica, 328 microdosing for oily skin, acne, and chronicity, actinic keratosis (AK), 189
azelaic acid, 321 – 322 rosacea, 387 chronic telogen effluvium, 340 – 341
middle face, 382 cicatricial hair loss, 279, 279 – 281
B nasal tip droop, 382 ciclopirox, 41, 127 – 128
perioral area, 383 – 384 14C-ciclopirox penetration, 39
Bacillus subtilis, 327 periorbital feet lines, 382 citrate cycle, 72 – 73

ballistometry, 245 pharmacology, 378 classic inorganics, 154
ball-shaped insertion, 230 platysmal bands, 385 – 386 classic pseudopelade, 281
balneotherapy, 135 precautions, 380 classic UV filters, 154
basal layer peel, 404 – 405, 405 – 406 recommendations, 380 cleansers, 328 – 329
basement membrane (BM) reconstitution, 378 – 379 Clear + Brilliant systemTM, 429
disassembly of, 111 repeated nasal flare, 382 closed-chamber instruments, 27 – 28, 46
in photoaged skin, 108 – 109 total doses of, 381 Clostridium botulinum, 378
transmission electron microscopic images upper face, 380 coefficient-of-friction devices, 246
of human skin, 110 Bouea macrophylla Griffth, 328 cohesography, 247
urokinase and plasmin in disruption breast augmentation, 355 collagen, 262, 352
of, 109 BT, see botulinum toxins collagen 1 alpha 1 (COL1A1) gene, 114
Becker nevus, 295 – 296, 296 buffered formulation, 73 colored UV gels, 217
behind-the-knee (BTK) test, 62 – 63 bunny lines, 382, 383 colorimetric assay, 117
Bemotrizinol (BEMT), 155, 160 burn scars, 360 combination measures, 345 – 346
bend of elbow, washing test on, 20 ButylMethoxydibenzoyl-methane, 155 combination therapies, 288
benzoyl peroxide (BPO), 317 – 318 Butyrospermum parkii, 328 comedogenicity, 326 – 327
β-hydroxyacids, 69, 70 – 71 comedogenic raw material, 327
Bier spots, 286 C computer-aided diagnosis (CAD), 44 – 45
bioavailability, 153, 157 – 158 condenser-chamber method, 28
bioavailable concentration, 73 café-au-lait macules, 295 conductance, 248
biochemical action, 76 – 77 calcium hydroxylapatite (CaHA), 51, confocal laser scanning microscopy
biochemistry, hydroxyacids, 72 – 73, 73 397 – 398, 398 (CLSM), 34
bioengineering techniques, 235 – 239, 239 – 254 Calendula officinalis, 134, 328 confocal Raman microspectroscopy (RCM),
biological action, hydroxyacids, 76 calibrated electrical stimulation of skin, 64 103, 254
biotin (vitamin H), 226 – 227 Camellia sinensis, 139 confocal scanning laser microscopy
bipolar radiofrequency, 460 camouflaging, 291 (CSLM), 253
bis-(diethylaminohydroxybenzoyl benzoyl) cancerization, actinic keratosis (AK), confounding lifestyle factors, 60
piperazine, 155 189, 189 congenital hypermelanocytosis, 295
474 Index
constitutive skin antioxidant network, 93, mechanisms of, 444 – 445 dilution of BT, 378 – 379, 379 – 380, see also
93 – 94 novel patient-reported outcome botulinum toxins
contact dermoscopy, 44 instruments, 448 Dimethicodiethylbenzal-malonate, 155
contact immunotherapy, 275 origin of, 444 diphenylcyclopropenone and squaric acid
contact urticaria, 215 patient consultation and assessment, 452 dibutyl ester (SADBE), 275
continuous wave lasers, 418 – 421 patient selection, 452 DIP nail coatings, 220
cooling of skin, 421 – 422 shockwave therapy, 450 – 452, 450 – 452 dip powder manicure, 228, 229, see also
CoolSculpting®, 444, 445, 448, 467 technology, 445 – 446 manicure
copper-vapor laser, 419 treatment, 448, 449, 452 – 454, 453, 453 direct manual hair count, 343
corneometer, 18 – 19, 24 – 25 upper arm contouring, 467 – 469 discoid lupus erythematosus (DLE), 280
cosmetic cryotherapy, 368 – 376 Zimmer shockwave therapy system, 449 dissecting cellulitis (DC), 279 – 280
acne, 371 cryotherapy, 139, 141, see also cosmetic DNA repair enzymes, actinic keratosis (AK),
cell/tissue injury, 370 cryotherapy 192 – 193
complications, 374 – 375, 375 – 376 cultural factors, sensitive skin, 60 dose equivalence, BT, 378 – 379
cysts, 372 cutaneous appendages, 334 dosing procedures, nail plate, 35, 37 – 38
facial edema, 376 cutaneous microcirculation, 7 drug delivery, 153 – 156, 361 – 362, 364
facial peeling, 371 – 373 cutaneous microvasculature, 5 – 6 drug-induced pigmentation, 296
filiform wart of upper lip, 374 cutaneous necrosis/ulceration, 269 drug-induced sensitivity, 61
heat transfer, 370 cutaneous squamous cell carcinoma (cSCC), drug penetration, into human nail, 39
inflammation, 370 188 – 189 dry skin, 77
keloids, 374 Cutibacterium acnes, 322, 326 – 329 intra-epidermal secondary factors,
lesion selection, 371 cyanoacrylate, 216 – 219 106 – 107
mechanism of action, 370 cyanoacrylate adhesive, 230 plasmin in, 106, 107, 107
melanocytic lesions, 371 Cymbopogon citratus, 328 t-AMCHA methylamide, 108, 108 – 110
nevi, 372 cystamine, 287 urokinase activity in stratum corneum of,
periorbital edema, 376 cysteamine, 287 107 – 108
pigmentation, 371 cystine, 227 urokinase in, 106, 107
pyogenic granuloma, 373 cysts, 372 D-Squame®, 241
rhinophyma, 373 cytoplasmic retinol-binding protein durometer, 246
seborrheic keratosis, 374 (CRBP), 87 dyschromia, 286 – 298
sun-damaged skin, 371 – 373 acquired dermal hypermelanocytosis, 295
tattoos, 373 – 374, 375 D acquired Ota nevus (Hori nevus), 295
technique and terminology, 368 – 370 Becker nevus, 295 – 296, 296
tumors, 372 dark rings, 296 bleaching products, 288
vascular lesions, 371, 372 Dea Sea salts, 136 café-au-lait macules, 295
vascular stasis and occlusion, 370 décolleté wrinkles, 385 – 386 camouflaging, 291
viral warts, 373 dehydroretinol (vitamin A2), 93 chemical peels, 288 – 289
cosmetic skin parameters, 15 – 26 demodex, 51 chromhidrosis, 298
of analysis, 17 – 18 depigmenting agents, 287 combination therapies, 288
bend of elbow, washing test on, 20 dermabrasion, 289 congenital hypermelanocytosis, 295
corneometer, 18 – 19, 24 – 25 dermagraph, 245 cosmetic products, 288
correlating climate data with, 15 dermajet injector, 312 cystamine, 287
fast optical in vivo topometry of human Derma Lab®, 252 cysteamine, 287
skin (FOITS), 16 – 20, 17 – 18, 25 dermal components, 74 dark rings, 296
indoor climate, 22 – 24 dermal fillers, 469 depigmenting agents, 287
laser profilometry, 15 – 16 dermal testing, 159 dermabrasion, 289
outcomes, 20 – 24 dermoscopy, 44, 48 drug-induced pigmentation, 296
outdoor climate, 20 – 22 detergent agents, 267 – 268 dyskeratosis, 297
positive and negative standards, 15, 16 Deutsche Industrie Norm (DIN), 16 freckles, 295
Ra parameter, 15, 21 – 22 developmental toxicity, 163 halo nevi, 293
regeneration, 19 – 20 Dexpanthenol, 275 hemosiderosis, 296
Rz parameter, 15, 19, 21 – 22 D-gluconolactone, 72 hydroquinone (HQ), 287, 288
cosmetic surgery, age-related pathological DHA, see dihydroxyacetone idiopathic guttate hypomelanosis,
condition, 353 Dia-Stron device, 345 296 – 297, 297
creatine derivatives (CREs), 69, 82, 83 diclofenac, actinic keratosis (AK), 191 isobutylamido thiazolyl resorcinol
critical surface tension (CST), 254 dietary supplements, 226 – 227 (Thiamidol®), 288
cross-polarized light, 65 Diethylamino hydroxybenzoyl hexyl Kligman’s formula, 288, 291
cross-sectional trichometer, 345 benzoat, 155 lasers and phototherapy, 289 – 290
crow’s feet area, 103 dihydroxyacetone (DHA), 19 – 20, 146, 291 lentigines, 295
crow’s feet lines, 382, 383 application, 147, 148 linear hypermelanosis, 296
cryolipolysis, 444 – 454 chemical structure of, 146, 146 – 147 liquid nitrogen cryotherapy, 289
adverse event management, 454 exponential decay curves of, 23 melasma, 291, 291 – 292
aftercare, 454 indications, 148 Neotone®, 288
body sculpting procedures, 445 mechanism of action, 147 nevus depigmentosus, 295
combination approaches with, 450 – 452, safety, 148 nevus spilus, 295
450 – 452 skin darkening with concentrations ochronosis, 297
CoolSculpting, 445, 448 of, 147 pathophysiology of, 286 – 287
efficacy of, 446 – 449 sunscreen activity, 147 – 148 phenolic compounds, 287
Index 475
piebaldism, 295 skin aging, 337 follicular unit extraction (FUE), 275
pigmentary lesions, treatment of, 291 – 298 skin color, 333 folliculitis decalvans, 280
pigmentary mosaicism, 296, 296 skin disease, 334 – 336 forehead lines, 381 – 382
pigmented seborrheic dermatosis, 295 solar lentigines, 336 Fourier-transformed infrared spectroscopy
poikiloderma of Civatte, 295 stratum corneum, 333 – 334 (ATR-FTIR) (attenuated total
postinflammatory pigmentation, 296 sun protection, 336 reflectance), 249
progressive macular hypomelanosis water content, 333 – 334 Fractional 1540 nm Laser, 430 – 431, 430 – 431
(PMH), 297, 297 ethnicity, sensitive skin, 59 – 60 Fractional 1550 nm Laser, 427 – 429, 428
pseudochromhidrosis, 298 ethylcyanoacrylate gels, 207 Fractional 1927 nm Laser, 428 – 429
siderosis, 296 Ethylhexyl methoxy-cinnamate, 155 fractional photothermolysis, 425 – 426
solar lentigines, 295 Ethylhexyl salicylate, 155 fractionated microneedle, 364
surgical approaches, 290 – 291 Ethylhexyl triazone, 155, 160 fragrance-allergic patients, 122
tattoos, 298, 298 etiopathogenesis, 259 – 260 fragrance ingredients, 120 – 121, 121
tranexamic acid, 287 Euphorbia supina, 328 adverse skin reactions to, 119
tretinoin, 287 – 288 Europe, 159 Fraxel 1550 nm Laser, 428, 428 – 429
vitiligo, 292, 293 – 294 keratolytics used in, 318 freckles, 295
whorled hypermelanosis, 296 regulation for cosmetics, 162 frequency distribution of depth (FDD), 17 – 18
dyskeratosis, 297 evaporimeter, 252 functional magnetic resonance imaging, 64
evening primrose oil (EPO), 134 functional skin properties, racial
E exfoliation, 403 differences, 59
exogenous ochronosis, 287, 335 – 336 fungal compounds, 327 – 328
econazole, 34, 37, 39 expert assessment, 347 fungus identification methods, 34
14C-econzaole, profile of, 38, 38 extensometry, 242
eczema, 78 extracellular matrix (ECM), 113 G
chronic, 84 extrinsic skin aging, 78 – 79, 78 – 80
positive patch tests in patient, 122 garlic extract, 140
efficacy potential, 73 F gas-bearing electrodynamo-meter (GBE), 243
efinaconazole, 129 gel matrix, 72
elasticity, 352 facelift surgery, 354 gel nail polish (GNP), 195 – 200
elastosis, 78 facial ageing, 353 application procedure, 195
electrodermal responses, 9 facial asymmetry, 385 patient information on safe use of, 200
electrodessication, 417 facial edema, 376 removal of, 195
electron spin resonance (ESR) facial fat transfers, 354 side effects, 195 – 199
spectroscopy, 98 facial fillers, 354 gel nails light curing, 216
electrosurgery, 417 – 418 facial hair removal, 354 gender, sensitive skin, 58, 58 – 59
ellipsometry, 254 facial peels, 354, 371 – 373 general side effects (phenol), chemical
emulgators, 326 – 327 facial resurfacing, 354 peels, 409
endermologie, 261 – 262 facial scar, 365 genistein, photodamage, 176 – 179, 178
endothelin-B receptors, 6 fast optical in vivo topometry of human skin gentian violet (GV), 133
endovenous closure techniques, 270 (FOITS), 16 – 20, 17 – 18, 25 geographies, perception of sensitive skin,
enhancer effects, 38 female hair with aging, changes in, 340 – 348 57 – 58
Ensulizole, 155 androgens, 342 geriatric patients, aesthetic procedure,
environmental factors, sensitive skin, 60 – 61 chronic telogen effluvium, 340 – 341 355 – 356
environmental stressors, antioxidants, 94 – 95 female pattern hair loss (FPHL), 340 gingival smile, 384 – 385
epidermis, 362 hair greying, 342 ginkgo biloba, 262
ergothioneine, 97 hair regrowth in humans, efficacy glabellar lines, 380 – 381, 381
erosive pustular dermatosis of scalp, 281, 282 measures of, 343 – 347 Global Aesthetic Improvement Scale (GAIS),
erythema, 56, 58, 59, 61 – 63 hair shaft, 341 – 342 360, 451
Escherichia coli, 134 mechanisms, 342 – 343 global macro photos, 346 – 347
essential oils, 133 – 134, 140 menopause/estrogens, 342 – 343 glycolic acid, 70, 209, 322 – 323
e-Stamp, 358, 358 – 359 patterns, 341 glycosaminoglycans (GAGs), 73, 79 – 80, 82
estrogens, 342 – 343 pigmentation, 343 GNP, see gel nail polish
effects on structural component of senescent alopecia (SA), 340 gotu kola, 262
skin, 352 senescent signals, 343 GPSkin Barrier®, 252
ethnic cosmetics, 333 – 337 telogen effluvium, 340 – 341 green tea (Camellia sinensis), 96
acne, 334 – 336 female pattern hair loss (FPHL), 340 green tea extract, 262
chemical peeling, 336 feminine-care products, 61 Grenz zone peels, 405 – 406, 406
cosmetic problems, 334 – 336 ferulic acid, photodamage with vitamin C and
cutaneous appendages, 334 E, 173 H
exogenous ochronosis, 335 – 336 fiberoptic fluorescence laser scanning
irritation and stinging, 334 microscopy, 253 hair, see also female hair with aging, changes in
melasma, 336 fibroblasts, 413 density, 343
mottled pigmentation, 336 fibrous septum, 457 diameter, 345, 346
nonablative photorejuvenation, 337 field of cancerization, 189, 189 greying, 342
pH, 333 – 334 filiform wart of upper lip, 374 sebaceous glands and, 352 – 353
PIH, 336 finasteride, 275 shaft, 341 – 342
post-inflammatory hyperpigmentation, 335 5-fluorouracil, actinic keratosis (AK), 191 transplantation, 355
pseudofolliculitis barbae, 336 foam sclerotherapy, 268, 268 weight, 345 – 346
476 Index
hair loss, management of, 274 – 282, 361 human nail plate, 37 injection technique, soft tissue augmentation,
acne keloidalis, 281 flux of panthenol into/through, 40 393 – 395
alopecia areata (AA), 275 – 277, 277, 278 hyaluronic acid (HA), 51, 191, 226 insoluble “classic” UV filters, 161
anagen effluvium (AE), 277 lip augmentation with, 386 insoluble “modern” UV filters, 161
androgenetic alopecia (AGA), 274 – 275, microneedling, 362 intense pulsed light (IPL), 292, 420 – 423
275, 278 soft tissue augmentation, 395 – 397, 396 intercellular lipids, 27, 157, 327
central centrifugal cicatricial alopecia hydration intraepidermic peel, 403 – 404
(CCCA), 280 – 281 mapping by electrical methods, 45 – 46 intrinsic skin aging, 78 – 79, 78 – 80
cicatricial hair loss, 279, 279 – 281 measurements of, 45 – 46 Inverse 500-Da Rule, 156
classic pseudopelade, 281 hydration-controlled method, 33 iron deficiency, 227
discoid lupus erythematosus (DLE), 280 “hydration touch,” 403 irritant agents, 268
dissecting cellulitis (DC), 279 – 280 hydroquinone (HQ), 287, 288, 335 irritant dermatitis, 5, 6
erosive pustular dermatosis of scalp, hydroxyacids, 69 – 84 irritant test, 56, 58, 62
281, 282 aldobionic acids, 71 irritation and stinging, ethnic cosmetics, 334
folliculitis decalvans, 280 alpha, 70, 70 isobutylamido thiazolyl resorcinol
lichen planopilaris, 280 beta, 70 – 71 (Thiamidol®), 288
non-cicatrical hair loss, 274 – 275 bioavailable concentration, 73 isolated actinic keratosis, 188
telogen effluvium (TE), 277 – 278, 278 biochemistry, 72 – 73, 73 isotretinoin, keratolytics, 320
traction alopecia (TA), 279 cosmetic and dermatological indications, Ivermectine, 51
trichotillomania (TTM), 278 – 279, 279 77 – 78
hair regrowth in humans, efficacy measures of, intrinsic and extrinsic skin aging, 78 – 79, K
343 – 347 78 – 80
automated phototrichograms, 343 – 344 mechanisms of action, 76 – 77 Kaempferia parviflora, 328
Canfield EpiLume®, 345 nomenclature and occurrence, 69 – 70 keloids, 306 – 315, 374
combination measures, 345 – 346 optimal release formulation, 73 – 74 axillary hidradenitis suppurativa, 309
cross-sectional trichometer, 345 physicochemical properties, 71 – 72 on the chest, 307
Dia-Stron device, 345 polyhydroxy acids (PHAs), 71 clinical aspects of, 306 – 307
direct manual hair count, 343 similarities and differences of, 80, 80 – 83 CO2 laser, 313 – 314, 313 – 315
expert assessment, 347 topical actions, 74 – 76 Dermajet injector, 312
global macro photos, 346 – 347 2-Hydroxyethyl methacrylate (HEMA), 198, etiology, 306
hair density, 343 209, 215 histology, 309 – 310, 310
hair diameter, 345, 346 2-Hydroxypropyl methacrylate (HPMA), 198 hypertrophic scars, 306, 307
hair weight, 345 – 346 hyperhidrosis (HH), 386 – 387, 388 N-tralig mechanical injector, 311 – 312
linear density, 345 hyperkeratotic actinic keratosis, 189, 190 pathogenesis of, 310, 310 – 311
macro-photographic manual hair count, hypermelanosis, 286 piercing of the ear, 308
343, 344 hyperosmotic agents, 266 – 267, 267 surgical excision, 314
optical fiber diameter assessment hyperpigmentation, 125 – 127, 128, see also transmural excision, 309
(OFDA), 345 pigmentation treatment of, 311, 311 – 315, 312
phototrichogram, 345 ascorbic acid, 125 – 126 keratinization
semi-automated phototrichograms, niacinamide, 125 – 126 hydroxyacids effects on, 74
343 – 344, 344 plant extracts, 126 – 127 in vitamin A, 101
subject self-perception, 347 serine protease inhibitors, 127 keratolytics, 317 – 323, 329, see also acne
TrichoScan®, 344 hypertonic saline (HS), 266 – 267, 267 azelaic acid, 321 – 322
halo nevi, 293 hypertonic saline and dextrose (HSD), benzoyl peroxide (BPO), 317 – 318
Hamamelis virginlana, 328 267, 267 glycolic acid, 322 – 323
handling, BT, 378 – 379 hypertrophic scars, 306, 307, 364 resorcinol, 323
hard keratin, 32 retinoids, 318 – 321
heat transfer, 370 I salicylic acid (SA), 322
Helianthus annuus, 134 sulfur, 322
hemosiderosis, 296 idiopathic guttate hypomelanosis, superficial peelings, 322 – 323
herbal compounds, 327 – 328, 328 296 – 297, 297 used in United States and Europe, 318
HEXINOL™, 115, 116, 117 imaging and analysis, skin, 44 – 45 KeryFlex nail restoration system, 228 – 229, 229
4-hexyl-1,3-phenylenediol, 115 – 117, 116, 116 imiquimod, actinic keratosis (AK), 191 Kligman’s formula, 288, 291
high-frequency, 252 – 253 immunocompromised patients, AK treatment KTP 532 nm green lasers, 418
high-frequency impedance, 248 in, 193
high-frequency microwave, 249 immunology, 63 L
high-frequency ultrasound (HFUS), 50, 51 impedance (capacitance calculated), 248
high-resolution magnetic resonance imaging impedance (surface characterizing), 248 lactic acid, 65
(MRI), 253 impedance microscopy (IS), 33 – 34 Lactiplantibacillus plantarum, 327
Hippophae rhamnoides, 127 indentometry, 246 lactone form, 72
homogentisic acid (HGA), 335 indigo naturalis, 136 – 137 lamellar ichthyosis, 75 – 76
homomenthyl salicylate, 155 indoor climate, 22 – 24 laminin 308, 109
Homosalate, 155 inflammation, 132, 370 lanced sheet technology, 230
hormones inflammatory skin diseases, diagnosis lasers, 418
influence on skin physiology and gender, of, 45 argon, 418
10, 11 infrared (IR) microscopy, 33 – 34 CO2, 313 – 314, 313 – 315
influence on skin thickness, 1 ingenol mebutate, actinic keratosis (AK), 191 continuous wave, 418 – 421
human fingernail plates, 35 injection lipolysis, 469 phototherapy and, 289 – 290
Index 477
picosecond lasers, 439 physiological changes during, 352 – 353 monobenzylether of hydroquinone (MBEH),
profilometry, 15 – 16, 64 symptoms, 353 – 356 292 – 293
Q-switched, 422 vulvovaginal problems, 353 monopolar radiofrequency, 457 – 460, 467
selection of, 422 – 423 mentalis, 384 body contouring, 460
Solta family laser devices, 427 mesotherapy, 262, 275, 276 – 277 energy setting in, 457 – 458
StarLux 1540 nm Laser, 432 metalized nail forms, 213, 213 mottled pigmentation, 336
therapy, 130 – 131 microfocused ultrasound (MFU), 467 multiphoton laser tomography, 251
laser-assisted liposuction, 466 microindentometer, 247 multiple, non-hyperkeratotic AK, 191
laser Doppler flowmetry (LDF), 260 – 261 microlens, 431 multiple hyperkeratotic actinic keratoses, 192
lax skin, 360 microneedle bipolar radiofrequency, 460 – 464, multispectral dermoscopy, 44
leg veins, sclerotherapy of, 355 see also radiofrequency Multi-Wavelength Fractional 1440/1320 nm
lentigines, 295 body contouring in, 463 Laser, 431
lesion selection, 371 clinical applications of, 463
levarometry, 245 mechanism of, 460 – 462 N
lichen planopilaris, 280 monopolar radiofrequency compared
light-curing acrylic gels, 207 with, 463 N-acetylamino acids (NAAs), 69, 80 – 82,
Lilium plant, 328 microneedles/microneedling, 357 – 365 81, 83
limited stripping, 270 – 271 acne scars, 364 N-acylpeptides (NAPs), 69, 82 – 83
linear density, 345 acne vulgaris, 364 nail(s), see also artificial nails
linear hypermelanosis, 296 with ALA for photodynamic therapy, 362 clippings, 33
linear skin rheometer (LSR), 243 with chemical peels, 362 coating, 218
line field confocal optical coherence combinations, 364 distribution, 38
tomography (LC-OCT), 52 – 53, 53 complications, 365 drilling tip, 35
lip augmentation, 386 drug delivery, 364 fungal elements in, 34
liposculpture, 469 – 470 for drug delivery, 361 – 362 hardeners and treatments, 220 – 223
liposuction, 355, 466 e-Stamp, 358, 358 – 359 incubation, 35, 36
liquid nitrogen cryotherapy, 289, see also fractionated microneedle, 364 infections, 233
cryotherapy with hyaluronic acid, 362 lacquer formulations, 38, 40
liquid sclerotherapy, 266 hypertrophic scars, 364 mending, 219 – 220, 221
local anesthetics block response, 62 indications, 357 – 361, 364 permeation barrier, 33
localized adiposity, 468 practical and safety aspects, 365 permeation testing and sampling, 33 – 34
locoregional side effects, chemical peels, 409 with PRP, 362 physical and chemical properties of, 32 – 33
long-pulse dye lasers, 419, 419 radiofrequency, 363, 363 – 364 plate, hydration of, 36
long-pulse Nd:YAG laser, 420, 420 – 421 rollers and stamps, 357, 357 – 359 transungual delivery, 38
lower face, 383 – 385 rosacea and melasma, 364 wrapping, 219 – 220, 222
soft tissue augmentation, 394 – 395 safety considerations, 362 – 363 nail cosmetics, 202 – 210, 212 – 223
low-frequency impedance (frequency scientific rationale and terminology, 357 adverse nail reactions, 218 – 219
domain), 248 skin rejuvenation, 364 allergic reactions, 213 – 214
low-power surface magnification, 239 skin tightening of lower face, jawline and artificial nails, 207 – 209, 212 – 216
neck region, 364 colored UV gels, 217
M striae, 364 contact urticaria, 215
with subcision, 361 DIP nail coatings, 220
macro-photographic manual hair count, techniques, 357 – 358 gel nails light curing, 216
343, 344 teleangiectasia and vessels, 364 manicure, 202 – 203
magnetic resonance imaging (MRI), 253, 261 without damage to stratum corneum or medical environment and, 209
magnetic resonance spectroscopy (MRS), 250 epidermis, 362 nail hardeners and treatments, 220 – 223
Mahonia aquifolium, 135, 137 microscopic exudative necrotic debris nail mending, 219 – 220
manicure, 202 – 203, 217 (MEND), 426 nail polish, 204 – 206
side effects of, 202 – 203 microthermal zones (MTZ), nail wrapping, 219 – 220
stages of, 202 425 – 427 non-allergic reactions, 215
massage treatment, 261 middle face, 382 patch testing, 214 – 215
mass balance, of radioactivity recovery, 37, 37 midface, soft tissue augmentation, 394 preformed artificial nails, 219, 219
masseteric hypertrophy, 385 milk thistle extract, 96 removable UV gels, 217 – 218
Matricaria recutita, 328 millimeter wave reflectivity, 249 removing UV gel nail coatings, 217
matrix metalloproteinases (MMPs), 109 minimally invasive surgical approaches, 270 risk of, 223
mechanical damage, 232 minimum inhibitory concentration (MIC), 33, salon safety measures, 209 – 210
mechanical impedance, 244 41 – 42 UV-curing gels, 216
mechanical nail lesions, 197, 198, 199 minoxidil, 275 UV gel polish/manicure, 217
medical environment and, 209 mitochondrial DNA (mtDNA), 92 – 93 nail fragility, 225 – 227
Melaleuca alternifolia, 328 modern UV filters, 154 associated with hand dermatitis, 225
melanocyte-stimulating hormone (MSH), 11 Mohs surgery, 45 cure of, 226
melanocytic lesions, 371 moisture map, 45 – 46 dietary supplements, 226 – 227
melasma, 291, 291 – 292, 361 moisturemeter, 45 due to onychophagia (nail biting), 226
ethnic cosmetics, 336 moisturizers, 234 – 255, 326 – 327 lamellar onychoschizia and fissures, 225
rosacea and, 364 bioengineering techniques, 235 – 239, measures, 225 – 226
melatonin (N-acetyl-5-methoxytryptamine), 97 239 – 254 topical product application, 226
menopause, 342 – 343 efficacy studies of, 234 – 236, 239 – 254 nail penetration, 32 – 42
general dermatological problems, 353 molecular complex, 73 – 74 14C-econzaole, profile of, 38, 38
478 Index
antifungal efficacy coefficient, comparison noninvasive diagnostic tools for applications of, 119
of, 40 onychomycosis, 34 – 36 causative ingredients and diagnosis, 120
nail lacquer formulations, 38, 40 methodology, 34 – 36 cosmetic products, 120 – 121
nail permeation barrier, 33 optical coherence tomography (OCT), 34 defined, 119
nail permeation testing and sampling, results, 36 ingredients, 120 – 121, 121
33 – 34 noninvasive techniques, anticellulite, 260 – 261 interventions and regulations, 122
nail plate and bed, hydration of, 36 nonkeratinized vulvar skin, 61 positive patch tests in eczema patient, 122
noninvasive diagnostic tools for novel patient-reported outcome perioral area, 383 – 384
onychomycosis, 34 – 36 instruments, 448 periorbital edema, 376
physical and chemical properties of, 32 – 33 N-tralig mechanical injector, 311 – 312 periorbital feet lines, 382
ungual drug permeability studies, 33 nuclear magnetic resonance spectroscopy permeability, 59
nail polish, 204 – 206, 215 – 216 (NMR-S), 250 pH, 333 – 334
composition of, 204 – 205 pharmacology, 378
types of, 206 O phenol, chemical peels, 413 – 414, 414
nail prosthesis, 215, 228 – 233 phenolic compounds, 287
attachment and fitting techniques, 230 – 232 oatmeal, 131 phenylbenzimidazole sulfonic acid, 155
complications of, 232 – 233 occlusion, 370 phenylene bis-diphenyltriazine, 155
methods of, 228 – 230 ochronosis, 297 photo-acoustic spectroscopy (PAS), 251
nail sampling, 35 – 36 Octinoxate, 155 photoaged skin, basement membrane (BM) in,
accuracy of, 36 Octisalate, 155 108 – 109
system, 36 Octocrylene, 155 photoaging, 60, 79 – 80, 416 – 423
“Nano means Big,” 161, 162 oily skin, microdosing for, 387 continuous wave lasers, 418 – 421
nasal tip droop, 382 omega-3 fatty acids, 262 cooling, 421 – 422
near-infrared spectroscopy (NIR), 250 onycholysis electrosurgery, 417 – 418
needling + injection, 362 due to formaldehyde, 222 intense pulsed light (IPL), 422 – 423
Neotone®, 288 traumatic, 215, 232 lasers, 418
neurogenic causality, 63 – 64 onychomycosis, 78, 127 – 131, 132 poikilodermatous type of, 421
neurogenic inflammation, 64 ciclopirox, 127 – 128 pre- and post-treatment, 423
neurologic events, 270 efinaconazole, 129 with topical estrogens, 180
nevi, 372 laser therapy, 130 – 131 vascular lesions, 416
nevus depigmentosus, 295 noninvasive diagnostic tools for, 34 – 36 photodamage, 167 – 180, 434 – 435, 435
nevus spilus, 295 photodynamic therapy (PDT), 129 – 130 genistein, 176 – 179, 178
Newtone Systems, 44 – 45 tavaborole, 129 selenium, 174 – 175
NF-κB (nuclear factor kappa B), 113 – 114, 116 tea tree oil, 128 – 129 selenium and vitamin E, 175 – 176
niacinamide, 125 – 126, 137 topical therapy for, 32 by topical antioxidants, 177
nomenclature and occurrence, hydroxyacids, Vicks® VapoRub, 129 vitamin C (L-ascorbic acid), 167 – 169, 170
69 – 70 onychophagia (nail biting), 225, 226 vitamin C with ferulic acid and
nonablative fractional laser (NAFL), 426, onychopharmacokinetics, 33 phloretin, 173
426 – 427, 429 – 430 onychoschizia, 232 vitamin C with vitamin E, 171 – 173
nonablative laser rejuvenation, 425 – 440, open-chamber instruments, 27 – 28 vitamin C with vitamin E and ferulic
431 – 432 optical coherence tomography (OCT), 34, 45, acid, 173
actinic keratosis (AK), 438 – 439 51 – 52, 52, 254, 337 vitamin E, 169 – 171
clinical applications, 434 optical fiber diameter assessment (OFDA), 345 photodynamic therapy (PDT), 129 – 130, 191,
clinical considerations, 432 – 433 optimal release formulation, 73 – 74 362, 439
clinical indications, 439 optothermal infrared spectrometry (OTIS), 251 actinic keratosis (AK), 192
complications, 434 osseointegration, 232 photopolymerizable gel, 207 – 208
delivery of topical drugs and products, 439 outdoor climate, 16, 20 – 22 photoprotection
Fractional 1540 nm Laser, 430 – 431, oxidation, 72 of epidermis, 59
430 – 431 oxybenzone, 152, 155 of human skin by topical antioxidants,
Fractional 1550 nm Laser, 427 – 429, 428 oxygen radical absorbance capacity 95 – 97
Fractional 1927 nm Laser, 428 – 429 (ORAC), 98 phototrichogram, 345
fractional photothermolysis, 425 – 426 physical response, increasing sensitivity of
Multi-Wavelength Fractional 1440/1320 nm P assessment, 63
Laser, 431 phytotherapy, 140 – 141
nonablative fractional laser (NAFL), 426, pain sensation for skin, 9 picosecond lasers, 439
426 – 427, 429 – 430 Panax ginseng, 328 piebaldism, 295
photodamage, 434 – 435, 435 panthenol concentration, 41 piercing of ear, 308
picosecond lasers, 439 papillary dermis peel, 406 – 407, 406 – 407 pigmentary disorders, 361, 438
pigmentary disorders, 438 partial neutralization, 73 pigmentary lesions, treatment of, 291 – 298
post-care routine, 433 – 434 patch testing, 214 – 215 pigmentary mosaicism, 296, 296
scars, 435 – 437, 437 pathological nails, 212 – 223 pigmentation, 343, 371, see also dyschromia;
Solta family laser devices, 427 PDT, see photodynamic therapy hyperpigmentation
striae, 437 – 438 peel solutions, 74 – 76 pigmented lesions, 422
treatment preparation, 433 percutaneous absorption, 156 – 157 pigmented seborrheic dermatosis, 295
nonablative photorejuvenation, 337 perfumes, 119 – 122 pilocarpine iontophoresis, sweat test, 3
non-allergic reactions, 215 adverse skin reactions, 119 pilosebaceous unit, 10 – 12, 11
non-cicatrical hair loss, 274 – 275 allergic contact dermatitis, 119 – 121 pKa, 72
non-contact dermoscopy, 44 allergic patient, 121 – 122 plant extracts, 126 – 127
Index 479
plant oils, 131 – 134 Q Sapindus mukorossi Gaertn, 328

plasmin scanning microdensitometry of
in disruption of basement membrane Q-switched lasers, 422 macrophotographs, 241
(BM), 109 quantitative structure activity relationship scars, 359 – 360, 435 – 437, 437
in dry skin, 106 (QSPR) model, 33 acne, 361, 364
laminin 308, 109 burn, 360
localization of, 107 R cicatricial, 290, 298
in skin aging, 108 – 109 hyper- or hypopigmented, 190
in skin diseases, 107, 107 Radiesse®, 397 – 398, 398 hypertrophic, 306, 307, 309 – 313, 310,
in skin pigmentation, 109 radiofrequency (RF), 355, 363, 363 – 364, 311, 364
platysmal bands, 385 – 386 457 – 464, see also microneedle bipolar sclerosing solutions, 266 – 269, 267
plicometry, 261 radiofrequency sclerotherapy (endovenous chemo-ablation),
poikiloderma of Civatte, 295 fibrous septum, 457 265 – 266, 266
polarized dermoscopy, 44 heating methods, 458 of leg veins, 355
polidocanol (POL), 267, 267 microneedle bipolar radiofrequency, side effects and complications of, 268 – 269
polycarboxyl AHAs, 70, 70 460 – 464 SCORAD, 131, 133, 135
Polycephalomyces phaothaiensis, 328 monopolar radiofrequency, 457 – 460 scratch-resistance test, 246
polyhydroxy acids (PHAs), 69, 71, radiofrequency-assisted liposuction (RAFL), Sculptra®, 398 – 399, 400
77, 78 466 – 467 sebaceous glands, 10 – 11
poly-L-lactic acid (PLLA), 51, 398 – 399, 400 Ra parameter, 15, 21 – 22 hair and, 352 – 353
polymethylmethacrylate (PMMA), 399 RCM, see reflectance confocal microscopy seborrheic keratosis, 374
polyphenols, 96 reactive oxygen species (ROS), 79, 92 – 93, 114 sebum absorbants, 328 – 329
polypropylene prosthesis, 230 reflectance confocal microscopy (RCM), 45, sebum production, 62, 137, 317, 387, 405
pomade-acne, 335 50 – 51 Sebutape®, 63, 65
post-acne facial scars, 360 regeneration, 19 – 20 secondary prevention, actinic keratosis
postbiotics, 327 regional side effects, chemical peels, 409 (AK), 189
post-care routine, 433 – 434 removable UV gels, 217 – 218 selenium
post-inflammatory hyperpigmentation (PIH), removing UV gel nail coatings, 217 photodamage, 174 – 175
296, 334, 335, 336, 403 repeated nasal flare, 382 photodamage with vitamin E, 175 – 176
post-sclerotherapy hyperpigmentation, reproductive toxicity, 163 self-adhesive varnishes, 209
268 – 269 resorcinol, 323 semi-automated phototrichograms,
preformed artificial nails, 219, 219, 230, 231, response to insult, 60 343 – 344, 344
see also artificial nails reticulary dermis peel, 407, 407 – 409 senescent alopecia (SA), 340
preformed plastic nails retinoic acid-binding protein (CRABP), 87 senescent signals, 343
dystrophic nails due to, 221 retinoic acid receptors (RARs), 87 – 88 sensitive skin, 56 – 65
tips, 219, 219 retinoids, 87 – 90, 318 – 321 factors in, 58 – 61
pressure sensitivity, 9 efficacy, 88 – 90 immunology and, 63
Primula obconica, 140 first generation of, 319 – 320 methodologies used for, 65
probiotics, 327 fourth generation of, 321 perception in various geographies, 57 – 58
profilometry (interference), 240 metabolic pathways in skin, 88 sensory effects and objective signs, 61 – 62
profilometry (mechanical), 239 structure of, 102 zeroing in on biological origin, 62 – 64
profilometry (optical), 240 third generation of, 320 – 321 sensitive skin syndrome (SSS), 56
progressive macular hypomelanosis (PMH), treatment, 89 sensory effects and objective signs, sensitive
297, 297 retinol (vitamin A1), 87 – 88, 88, 93, 101 – 104 skin, 61 – 62
Propionibacterium acnes, 297 biological effects on skin cells, 101 – 102 sensory functions, 6 – 9, 8
prosthetic nail, 213, 215, 219, 230 clinical aspects of, 102 – 103 autonomic function, 9
PRP, 275, 277 clinical efficacy of, 103, 103 – 104 thermal response to stimulation, 9
pruritus, 78, 138 metabolism of, 101 thermoregulatory response, 6 – 9
pseudochromhidrosis, 298 retinyl esters, 87 – 90, 88 sensory responses, quantifying, 62
pseudofolliculitis barbae, 336 retinyl propionate, 87 – 90 sequential combination treatments, actinic
Pseudomonas aeruginosa, 133 retronychia of great toenail, 229 keratosis (AK), 192
psoriasis, 136 – 137, 138 Reviscometer®, 247 serine protease inhibitors, 127
aloe vera, 136 RF, see radiofrequency Shellac©, 207
Dea Sea salts, 136 rhinophyma, 373 shockwave therapy, 450 – 452, 450 – 452
indigo naturalis, 136 – 137 rollers and stamps, 357, 357 – 359 siderosis, 296
Mahonia aquifolium, 137 rosacea, 77 silicone prosthesis, 230
Pterygium inversum, 222 and melasma, 364 skin aging, 113 – 117, 337
ptosis microdosing for, 387 4-Hexyl-1,3-phenylenediol, 115 – 117,
of breast, 355 Rosa davurica Pall, 328 116, 116
brow, 394 rule of five (Ro5), 153 – 154 NF-κB (nuclear factor kappa B),
classification of, 467, 467 Rz parameter, 15, 19, 21 – 22, 102 113 – 114, 116
nasal tip, 382 plasmin in, 108 – 109
upper lip, 382 S urokinase in, 108 – 109
pulmonary embolism, 269 skin antioxidants, 94 – 95
pulsed dye laser (PDL), 418 – 419 safe product, 162 skin bioengineering, 44 – 46
punch grafting, 290 salicylic acid (SA), 322 imaging and analysis, 44 – 45
pyogenic granuloma, 373 Salix alba, 328, 329 measurements of hydration, 45 – 46
pyruvic acid, 74 salon safety measures, 209 – 210 transepidermal water loss (TEWL), 46
480 Index
skin cancer diagnosis, 45 indications, 393 – 395 superficial peelings, 322 – 323
skin color, 9 – 10, 10, 333 injection technique, 393 – 395 superficial thrombophlebitis, 269
skin disease, 334 – 336 poly-L-lactic acid (PLLA), 398 – 399, 400 surface washing procedures, nail plate, 35, 38
skin flaccidity, 469 polymethylmethacrylate (PMMA), 399 surgical approaches, 290 – 291
skin homeostasis, 113 – 114 pre-injection preparation, 395 surgical excision, 314
skin imaging, 48 – 54 safety and complications, 399 – 401 surgical ligation, 270 – 271
anisometry, younger and older skin, 49 solar lentigines, 295, 336 sweat secretion rates, 3
dermoscopy, 48 solar lentigo, 422 synergistic compositions, 76
high-frequency ultrasound (HFUS), 50, 51 Solta family laser devices, 427
line field confocal optical coherence solubility, 72 T
tomography (LC-OCT), 52 – 53, 53 soluble “classic” UV filters, 160
optical coherence tomography (OCT), soluble “modern” UV filters, 160 tactile sensor (Venustrom®), 247
51 – 52, 52 somatosensory function, 60 t-AMCHA methylamide, 106 – 108, 108 – 110
reflectance confocal microscopy (RCM), spider veins, see telangiectatic webs tanning product types, 146
50 – 51 spinocellular carcinoma, actinic keratosis tantalizing clues, 62
spots and lesions, measurement of, 49 (AK), 188 – 189 tattoos, 298, 298, 373 – 374, 375
trichoscopy, 48 – 49, 49 split-thickness grafting, 290 tavaborole, 129
visioscan camera, 49 spots and lesions, measurement of, 49 tazarotene, keratolytics, 320
skin irritant reactivity, 59 squametry of tape strippings, 241 tea tree oil (TTO), 128 – 129, 138 – 139
skin layers, 3D thickness of, 53 standard L, 15, 16, 20 – 21, 21 telangiectatic matting, 269
skin lightening (whitening), 286 Staphylococcus aureus, 133, 280, 322 telangiectatic webs, 264 – 271
skin peeling, 74 – 76 Staphylococcus epidermidis, 322 ambulatory phlebectomy, 271
skin permeation theory, 153 – 159 StarLux 1540 nm Laser, 432 arterial injection, 269 – 270
bioavailability, 157 – 158 stereoisomers, 71 contraindications to treatment of, 265
dermal testing, 159 sticky slide, 241 cutaneous necrosis/ulceration, 269
drug delivery, 153 – 156 stinging response, 59 endovenous closure techniques, 270
percutaneous absorption, 156 – 157 stratum corneum (SC), 3, 15, 27, 362 epidemiology, 264
skin physiology and gender, 1 – 12 barrier, 73 history of, 264 – 265
autonomic function, 9 colored with DHA, 22 lasers and light sources, 271
biochemical composition of, 2 – 3, 3 compared with human nail, 32 liquid sclerotherapy, 266
cutaneous microvasculature, 5 – 6 measure of, 53 minimally invasive surgical approaches
functional differences of, 3 – 5, 5 permeability barrier in, 56 for, 270
hormonal influence, 10, 11 sphingolipid, 2 neurologic events, 270
irritants, differences in response to, 5, 6 structure, water content, and pH, 333 – 334 pulmonary embolism, 269
mechanical properties of, 3, 4 two-dimensional model of, 28 sclerosing solutions, 266 – 269, 267
pain sensation, 9 urokinase activity in dry skin, 107 – 108 sclerotherapy (endovenous chemo-ablation)
pilosebaceous unit, 10 – 12, 11 water content of, 106 techniques, 265 – 266, 266
pressure sensitivity, 9 Streptococcus pyogenes, 133 superficial thrombophlebitis, 269
sebaceous glands, 10 – 11 Streptococcus salivarium, 327 surgical ligation and limited stripping,
sensory functions, 6 – 9, 8 Streptococcus thermophilus, 327 270 – 271
skin color, 9 – 10, 10 stress, 136 telangiectatic matting, 269
structural and anatomical characteristics, stretch marks, 360 treatment techniques, 265
1, 2 striae, 364, 437 – 438 venous anatomy and physiology, 265
tests, 20 subcision, 361 teleangiectasia, 364
thermal response to stimulation, 9 subepidermal nonechogenic band telogen effluvium (TE), 277 – 278, 278,
thermal sensation, 9 (SENEB), 337 340 – 341
thermoregulatory response, 6 – 9 subject self-perception, 347 terbinafine HCl flux rate, 41
skin pigmentation, urokinase and plasmin in, suction chamber (disproportional superficial tewameter, 252
109, 111 strain), 244 TEWL, see transepidermal water loss
skin rejuvenation, 364 suction chamber (proportional full-thickness therapeutic perspectives, actinic keratosis
skin smoothing, 77 strain), 245 (AK), 192
skin surface biopsy with microscopy, 241 sulfur, 322 thermal quenching, 420
skin thickness, 74, 76 sunburn cells, 78 thermal response to stimulation, 9
skin tightening, 364 sun-damaged skin, 371 – 373 thermal sensation for skin, 9
skin transparency, 59 sunless tanning products, 146 – 148 thermal sensing with skin hydration sensor
Smart Stickers™, 242 application, 147, 148 (SHS), 250
Smilax china L, 328 chemistry of, 146, 146 – 147 thermography, 261
snap-fit design, 230, 232 indications, 148 thermoregulatory response, 6 – 9
sodium lauryl sulfate, 65 mechanism of action, 147 thermoscan, 65
sodium morrhuate, 267, 268 safety, 148 thickness of skin, 352
sodium tetradecyl sulfate (STS), 267, 267 – 268 sunscreen activity, 147 – 148 thimble-type prosthesis, 232
soft keratin, 32 sun protection, 336 tissue dielectric constant (TDC), 45
soft tissue augmentation, 393 – 401 sunscreens, 151 – 164, 329 – 330 tissue-type plasminogen activator (tPA), 107
anesthesia, 395 activity, 147 – 148 tonometry, 245
calcium hydroxylapatite (CaHA), management of risk, 161 – 163 topical actions, 74 – 76
397 – 398, 398 safety assessment, 161 – 163 torque meters (disproportional strain
history, 393 skin permeation theory, 153 – 159 measurements), 243
hyaluronic acid (HA) fillers, 395 – 397, 396 UV filters used in, 152, 152, 159 – 161 traction alopecia (TA), 279
Index 481
Traditional Chinese Herbal Medicine unmet needs, acne management, 330 verrucae vulgares (warts), 77
(TCHM), 135 – 136 upper arm contouring, 466 – 470 very low dermal absorption, 159
tranexamic acid, 287 classification of ptosis, 467 vessels, 364
TranScreen-N TM, 33 cryolipolysis, 467 – 469 Vicks® VapoRub, 129
transcutaneous oxygen pressure, 6 dermal fillers, 469 viral warts, 373
transepidermal water loss (TEWL), 27–29, 46, 58 injection lipolysis, 469 virtual mesotherapy, 412
atopic dermatitis, 135 laser-assisted liposuction, 466 viscoelasticity skin analyzer
biological background, 27 liposculpture, 469 – 470 (VESA), 247
borage oil (BO), 134 liposuction, 466 VISIA, 44
ethnic cosmetics, 333 – 334 localized adiposity, 468 visioface (non-invasive imaging
measurement of, 27 – 28 microfocused ultrasound system), 44
moisturizers for acne, 327 (MFU), 467 visioscan camera, 49
parameter in skin research, 29 monopolar radiofrequency (RF), 467 vitamin A1, see retinol (vitamin A1)
racial differences in functional skin radiofrequency-assisted liposuction vitamin B12, 131
properties, 59 (RAFL), 466 – 467 vitamin C (ascorbic acid), 95 – 97, 137
skin, 28 – 29 skin flaccidity, 469 photodamage, 167 – 169, 170
transient thermal transfer (TTT), 251 targets of, 466 photodamage with ferulic acid and
transmural excision, 309 techniques and targets for, 470 phloretin, 173
transparency (transmission) upper face, 380 photodamage with vitamin E, 171 – 173
proliferometry, 240 soft tissue augmentation, 393 – 394 photodamage with vitamin E and ferulic
trans-retinoic acid (tRA), 87 treatment areas, 397, 398, 400 acid, 173
trauma-induced nail lesions, 197, 198 urokinase vitamin E, 95, 97
traumatic onycholysis, 232 activity in stratum corneum of dry skin, photodamage, 169 – 171
treatment response, monitoring of, 45 107 – 108 photodamage with vitamin C, 171 – 173
tretinoin, 287 – 288 defined, 106 photodamage with vitamin C and ferulic
keratolytics, 319 – 320 in disruption of basement membrane acid, 173
trichloracetic acid (TCA), 410 – 413 (BM), 109 vitiligo, 292, 293 – 294, 361
TrichoScan®, 344 in dry skin, 106, 107 vulva, 61
trichoscopy, 48 – 49, 49 in skin aging, 108 – 109
trichotillomania (TTM), 278 – 279, 279 in skin pigmentation, 109 W
trifarotene, keratolytics, 321 US Food and Drug Administration (FDA),
tris biphenyl triazine, 155 129, 159 – 160, 274, 290, 318, 378, 393, warts (verrucae vulgares), 77
true ligament heating method, 458, 459 444, 457 water content, 333 – 334, 352
tumors, 372 UV-curing gels, 216 water vapor, 28
UV filters, 152, 152, 159 – 161 whorled hypermelanosis, 296
U insoluble, 161 wound healing, 353
molecular structures of, 155 wrinkles
ultra-pulse ablative laser therapy, actinic soluble, 160 aging skin and, 79
keratosis (AK), 192 UV gel polish/manicure, 217 lax skin and, 360
ultrasonography, 260 periorbital, 170 – 171
ultraviolet (UV) induced lesions, 197, 198 – 199 V photoaging, 170
uncoated needles, 363
ungual drug permeability, limitations of, 33 vapometer, 46 Z
United States, 159 – 160 VapoMeter, 252
consumer exposure to sunscreen active vascular lesions, 371, 372, 416 zeroing in on biological origin, 62 – 64
ingredients, 162 – 163 vascular stasis, 370 Zimmer shockwave therapy system, 449
keratolytics used in, 318 vasoactive response, 60 zinc, 137 – 138

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Textbook of Cosmetic Dermatology, Fifth Edition

Disorders of Fat and Cellulite: Advances in Diagnosis and Treatment

Botulinum Toxins in Clinical Aesthetic Practice 3E: Two Volume Set

Aesthetic Rejuvenation Challenges and Solutions: A World Perspective

Illustrated Manual of Injectable Fillers, Second Edition

Adapting Dermal Fillers in Clinical Practice

Cosmeceutical Science in Clinical Practice, Second Edition

Textbook of Cosmetic Dermatology, Sixth Edition

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6. Advances in Skin Imaging in Cosmetology and Aesthetic Dermatology������������������������������������������������������������������������ 48

13. 4-Hexyl-1,3-Phenylenediol, a NF-κB Inhibitor, Improves Clinical Signs of Aging������������������������������������������������������113

Josette André Frank Dreher

Philippe Deprez Doris Hexsel

Nilton Gioia Di Chiacchio Xiaoying Hui

Yuji Katsuta Preethi B. Nayak

Simarna Kaur John E. Oblong

Douglas Schoon Poorna Weerasinghe

Georgios N. Stamatas Yu-Ching Weng

significant increase in ceramide 1 and 2 accompanied by

(b) No significant differences

Cutaneous Microvasculature (Table 1.6)

(b) No significant differences

(a2) Significant differences: Transcutaneous oxygen pressure

(b) No significant differences

Mathias Rohr and Andreas Schrader

measured continuously at a station by a computer (CAN sys-

FIGURE 2.1 Climatic outdoor conditions at Holzminden, Germany,

FOITS 1995 1998 2003 2006

FIGURE 2.3 Synopsis of the technical side parameters of FOITS.

is calculated in the range from −600 mm to 600 mm (after Corneometer

investigation. In a second series of measurements, five differ-

TABLE 2.2 Further statistical treatment is described in detail in Refs. 3

Methods” section. Figure 2.9 shows clearly how important

In theory, water molecules may take two routes through

Without effective protection of the “moist inside” of the human

Xiaoying Hui and Howard I. Maibach

to transport a therapeutically sufficient quantity of antifungal 4 Correlation of in vitro onychopharmacokinetics assays

diseases. The authors used IR and IS to characterize the effects Methodology

Emerging Noninvasive Diagnostic Formulations

Dosing and Surface Washing Procedures Nail Sampling

collected was measured by the difference in weight of the

enhancer. In each case the test formulation enhanced drug

Topical Formulation Comparison

supersaturated antifungal drug. This film provides a chemical

Enzo Berardesca and Norma Cameli

Optical Coherence Tomography

Transepidermal Water Loss

FIGURE 6.3 Trichoscopy of the scalp, normal aspect.

A few years ago, the only available machines were the

2. Follow-up the pigmentary lesions such as melasma,

imaging technique that uses near infrared light (1300 nm)

15. Gniadecka M, Gniadecki R, Serup J, et al. Ultrasound

Miranda A. Farage and Howard I. Maibach

have hindered a better understanding of this condition. It is typi-

TABLE 7.1 (Continued)

TABLE 7.3 (Continued)

Ruey J. Yu and Eugene J. Van Scott

ring. It is not chemically a true BHA, but it is erroneously

6. Advances in Skin Imaging in Cosmetology and Aesthetic Dermatology�� 48

13. 4-Hexyl-1,3-Phenylenediol, a NF-κB Inhibitor, Improves Clinical Signs of Aging��113