Received: 7 November 2020 Revised: 6 December 2020 Accepted: 21 December 2020

DOI: 10.1111/dth.14716

ORIGINAL ARTICLE

Comparison of polycaprolactone and calcium hydroxylapatite

dermal fillers in a rat model

Irem Yanatma1 | Gulbahar Sarac2 | Mehmet Gul3 | Semir Gul3 |

4
Yelda Kapicioglu

1
Department of Dermatology, Seydisehir State
Hospital, Konya, Turkey Abstract
2
Department of Dermatology, Inonu Polycaprolactone (PCL) and calcium hydroxylapatite (CaHA) are semipermanent der-
University, Malatya, Turkey
mal fillers that are frequently preferred in the last decade. This study aims to compare
3
Department of Histology and Embryology,
Inonu University, Malatya, Turkey the effects of these two fillers in the rat skin. A total of 30 female rats were divided
4
Departmant of Dermatology, Liv Hospital, into; control, PCL, and CaHA group. Tissue samples taken at the second and fourth
Istanbul, Turkey
month were stained with hematoxylin-eosin, Masson trichrome, collagen type 1, and
Correspondence 3 immunohistochemical antibodies. Collagen density was quantitatively compared
Irem Yanatma, Department of Dermatology,
using the Image J computer program. At 2 and 4 months, the density of collagen
Seydisehir State Hospital, Alaylar 1 District
143 Street, Seydisehir, Konya, Turkey. increased in both filler groups compared to the control group. There was no signifi-
Email: [email protected]
cant difference between collagen density or type 1 and type 3 collagen H scores in
Funding information the filler groups. The number of fibroblast nuclei was significantly higher in the PCL
Inonu University Scientific Research Projects
group at 4 months compared to the other two groups. Dermis thickness was found
to be superior in both filler groups compared to the control group at the fourth
month, there was no significant difference between the filler groups. We compared
the effect of CaHA and PCL filler on collagenization histologically and
immunohistochemically. We found that PCL and CaHA fillers are effective in increas-
ing dermal collagen density, type 1 and type 3 collagen amount, and preventing der-
mis atrophy and showed that they have no advantage over each other in this respect.
We have shown that PCL filler provides more fibroblast increase compared to CaHA
filler and the effect of stimulating fibroblast proliferation takes longer.

KEYWORDS
calcium hydroxylapatite, dermal fillers, polycaprolactone

1 | I N T RO DU CT I O N imbalance that occurs with age. Filler procedures have been shown to
stimulate new collagen production in the skin and increase skin
Aging is an inevitable process that results in deterioration in skin qual- quality.4
1,2
ity due to intrinsic and extrinsic factors. It is thought that the imbal- The popularity of filler procedures has been increasing in the
ance between collagen production and destruction with age is one of last 20 years.5 In the studies, semipermanent fillers have been
the main causes of skin aging. Human skin contains 80% to 90% type compared with hyaluronic acid fillers. We did not find any study
1, 8% to 12% type 3 collagen.2 It has been shown that the collagen in comparing the two most popular semipermanent fillers in the lit-
3
the skin decreases by 1% each year. For this reason, many methods erature, polycaprolactone (PCL) and calcium hydroxylapa-
used for skin rejuvenation are aimed at reversing this collagen tite (CaHA).

Dermatologic Therapy. 2021;34:e14716. wileyonlinelibrary.com/journal/dth © 2020 Wiley Periodicals LLC. 1 of 7

https://doi.org/10.1111/dth.14716
2 of 7 YANATMA ET AL.

In this study, it was aimed to compare the effects of PCL and fourth month from the application point determined on the left side
CaHA fillers on dermis thickness, fibroblast number, type 1 and type to evaluate the late period findings (Figure 1).
3 collagen histologically and immunohistochemically.

2.2 | Histological methods

2 | _ LS AND METHODS
M A T E R IA
Skin biopsy samples were fixed in 10% formaldehyde. For tissue
2.1 | Experimental animals and experimental plan processing, tissue samples were dehydrated by passing through eth-
anol series (70%-99%), cleared in xylene series, and immersed in par-
The study was approved by the Inonu University Faculty of Medicine affin wax. After tissue processing tissue samples were embedded
Experimental Animals Ethics Committee. Adult female Winstar albino into paraffin blocks and vertical sections at 5 μm thickness were cut.
rats with an average age of 1 year and weight of 280 to 300 g were Sections were stained with hematoxylin and eosin (H&E) and
used in the study. A total of 30 female rats were divided into three Gomoris' trichrome stain. Analysis of all slides was carried out by
groups with 10 animals in each group; control group (n = 10), PCL Eclipse Ni-U light microscope, DS-Fi2 camera, and a NIS-Elements
(n = 10), and CaHA group (n = 10). The animals were housed in cages Documentation Image Analysis System (Nikon Corporation, Tokyo,
of five subjects, in a suitable environment where a temperature of Japan). First, the full thickness of the dermis was determined by cal-
20 C to 22 C and a 12 hour light cycle were maintained. Throughout culating the average thickness of at least three different points in
the experiment, animals were fed standard animal feed and a suffi- the cross-sections. Second, the mean numbers of fibroblasts were
cient amount of water. Animals were cared for in accordance with the found by counting 10 different areas at ×40 objective in each sec-
principles set forth in the relevant articles of the Helsinki Final Act. tion. Finally, percent of collagen areas in all images of all groups were
Ketamine-hydrochloride (Ketalar 5% solution, Parke-Davis license calculated by using the ImageJ program (National Institutes of
_
with Eczacıbaşı Ilaç Sanayii, _Istanbul) - 60 mg/kg- and Rompun Health, Bethesda, Maryland).
(Xylazine 2% solution, Bayer, _Istanbul) - 10 mg/kg intraperitoneally,
anesthesia was applied. While under anesthesia, an area of 4 × 4 cm2
was shaved in the back of the subjects. Two points at a distance of 2.3 | Immunohistochemical staining
12 cm from the tip of the nose and 1.5 cm bilaterally from the spinal
midline were marked for application. In the marked points, 0.2 mL cal- Tissue sections were cut at 5 μm thickness and were taken on posi-
cium hydroxyapatite filler in group B and 0.2 mL PCL filler in group C tively charged slides. Sections were rehydrated through 100%, 95%,
were injected intradermally using a 25-gauge needle. No injection was and 70% alcohol. Slides were put into a pressure cooker (Retriever
given to the subjects in the control group. In the second month, a 2100, Aptum, Southampton, UK) for antigen retrieval and heat-
4 mm punch biopsy was taken from the application point determined treated in citrate buffer with a pH 7.6 (Thermo Scientific, Fremont,
on the right side in order to evaluate the early findings, and in the California) at 121 C for 15 minutes. After cooling of slides to room

FIGURE 1 (A) Marking for application, (B) Injection of the filler, (C) Obtaining biopsy samples
YANATMA ET AL. 3 of 7

temperature (RT), slides were washed with phosphate-buffered saline collagen immunreactivity levels of fibroblasts were determined by cal-
(PBS). A 3% of hydrogen peroxide was dropped onto sections for culating the H-score (H-score = staining intensity × percentage of sta-
10 minutes and washed with PBS. Protein-V blocking solution ined cells) based on the staining intensity (no staining = 0, weak
(Thermo Scientific) was dropped onto sections for 5 minutes. After staining = 1, medium intensity staining = 2, strong intense staining = 3)
removal of protein blocking, sections were incubated with primer anti- and percentage of stained cells.
_
body type 1 collagen (BIOSS Antibodies, bs-10423R), dilution rate;
1:300, and type 3 collagen (B_IOSS Antibodies, bs-0549R), dilution
rate; 1:300) for 1 hour at RT and washed with PBS. Then, the tissue 2.4 | Statistical analysis
sections were incubated with a seconder antibody (biotinylated goat
antipolyvalent) for 15 minutes at RT and washed with PBS. Numerical data were summarized with median, minimum, and maxi-
Streptavidin peroxidase was dropped onto sections for 15 minutes at mum values. Kruskal-Wallis test and then Conover pairwise compari-
RT and washed with PBS. Staining was completed with the application son method were used for independent group comparisons. The
of AEC chromogen onto sections (Thermo Scientific) for 10 minutes time-variance of the groups was examined using the Wilcoxon test.
at RT. After washing with PBS, sections were counterstained with Two-sided significance level was accepted as 0.05 in all tests. IBM
Mayer's hematoxylin for 2 minutes. Slides were covered with an aque- SPSS Statistics for Windows version 22.0 (New York) was used for
ous mounting medium (Thermo Scientific). Type-I collagen and type-III analysis.

F I G U R E 2 Results at 2 months: Control, PCL, and CaHA groups. I (×10), II (×40), (H&E), III (×10), IV (×40), Masson's trichrome, V (×20), (type
1 collagen), and VI (×20), (type 3 collagen). CaHA, calcium hydroxylapatite; PCL, polycaprolactone

F I G U R E 3 Results at 4 months: Control, PCL, and CaHA groups. I (×10), II (×40), (H&E), III (×10), IV (×40), Masson's trichrome, V (×20), (type
1 collagen), and VI (×20), (type 3 collagen). CaHA, calcium hydroxylapatite; PCL, polycaprolactone
4 of 7 YANATMA ET AL.

3 | RESULTS was a significant increase in collagen in the filler groups compared to

the control group (P: .024). When compared within each group, there
3.1 | Hematoxylin and eosin and trichrome was no difference in collagen density between 2 and 4 months
staining (Table 1).

Epidermis and dermoepidermal junction were observed in normal

histological structure in skin sections stained with hematoxylin- 3.2 | Dermis thickness and cell count
eosin in the second and fourth month in all groups. In the dermis
layer, collagen fiber bundles of different thicknesses stained with When we evaluated in terms of dermis thickness, no significant differ-
eosin in pink/red color (eosinophilic) and fibroblast/fibrocyte nuclei ence was found between any groups in the second month (P: .325). At
stained with hematoxylin in blue-purple color (basophilic) were 4 months, there was a significant difference in both the PCL and
observed in normal histological appearance. Besides, hair follicles, CaHA groups compared to the control group (P < .001). However,
sebaceous glands, vascular structures, and hypodermis layer were there was no difference between PCL and CaHA groups. Dermis
assessed in normal histological structures. It was noticed the colla- thickness decreased from 526.08 to 411.77 μm in the control group
gen fiber network was looser and the transparent areas between during the 4-months follow-up and this difference was statistically
the fibers were wider in the skin sections taken in the second and significant (P: .017). It was observed that there was no difference in
fourth month in the control group compared to the filler groups dermis thickness between the second and fourth month in PCL and
(Figure 2, Figure 3). CaHA groups (P: .066, P: .674) (Table 2).
In trichrome stained sections, dermis collagen was stained green, When we compared the number of fibroblast nuclei, there was no
cell nuclei were stained purple-black and were seen in the usual significant difference between the groups in the second month, while
structure (Figure 2, Figure 3). As a result of Image J analysis of there was a difference between the three groups in the fourth month
trichrome stained sections, a significant increase in total collagen (P < .001). An average of 39 nuclei was counted per field in the PCL
density is observed in PCL and CaHA group at the end of the second group, 32 in the CaHA group, and 28 in the control group. In the sec-
month compared to the control group (P: .002). However, no statisti- ond and fourth-month results, we see that CaHA (P: .866) and the
cally significant difference was found between the two filler groups. control group (P: .553) did not make a significant difference on fibro-
At the end of the fourth month, similar to the second month, there blast proliferation, but increased significantly in the PCL group
(P: .007) (Table 2).

T A B L E 1 Collagen density according to Image J analysis of

trichrome stained sections 3.3 | Tip 1 and tip 3 collagen staining

Collagen density
Type 1 and type 3 collagen H scores increased significantly in both
2 mo 4 mo the PCL and CAHA groups in the second and fourth month compared
Group Median (min-max) Median(min-max) P value to the control group (p2.months < 0.001, p4.months < 0.001). However,
there was no difference between the two filler groups. During the
Control 67.73 (59.61-77.14) 68.79 (57.01-76.04) .515
4-months follow-up, no difference was observed within the groups
PCL 72.25 (70.73-93.97) 76.34 (66.68-90.08) .594
(Table 3, Figures 1 and 2).
CaHA 76.63 (69.59-80.26) 76.85 (71.78-87.42) .779
There was no difference between the groups in the comparison
P value .002 .024
of the ratio of type 1/type 3 H scores (p2.months: 0.355, p4.months:
Abbreviations: CaHA, calcium hydroxylapatite; PCL, polycaprolactone. 0.691) (Table 4).

TABLE 2 Dermis thickness and cell count results of the study

Dermis thickness(μm) Fibroblast nucleus number

Median (min-max) Median (min-max)

Group 2 mo 4 mo P 2 mo 4 mo P
Control 526.08 (454.49-590.51) 411.77 (368.92-505.41) .017 29 (21-41) 28 (23-34) .553
PCL 490.23 (428.35-623.01) 590.51 (405.54-736.38) .066 33 (27-40) 39 (32-64) .007
CaHA 600.45 (398.47-55 658) 579.37 (458.68-623.19) .674 33 (26-42) 32 (27-43) .866
P .325 <.001 .494 <.001

Abbreviations: CaHA, calcium hydroxylapatite; PCL, polycaprolactone.

YANATMA ET AL. 5 of 7

T A B L E 3 Type 1 and type 3 collagen

Type 1 collagen H score Type 3 collagen H score
H score results of the study
Group 2 mo 4 mo P 2 mo 4 mo P
Control 120 (50-160) 140 (60-160) .671 140 (70-160) 120 (70–160) .944
PCL 210 (160-270) 240 (160-270) .478 240 (160-270) 240 (140-270) .786
CaHA 210 (160-270) 210 (160-270) 1000 180 (160-270) 180 (160-240) .248
P <.001 <.001 <.001 <.001

Abbreviations: CaHA, calcium hydroxylapatite; PCL, polycaprolactone.

TABLE 4 Ratio of type 1/type 3 H scores results of the study early period and the fillers preserved this effectiveness in the follow-

Type 1/type 3 collagen H score

ing months in both PCL and CaHA fillers.
In their study, Zerbinati et al examined the effect of CaHA filler
2 mo 4 mo
on collagen under a polarized microscope using picrosirius red dye.
Group Median (min-max) P Median (min-max) P They realized the amount of type 3 collagen was significantly higher
Control 0.86 (0.36-1.75) .355 1.0 (0.50-1.17) .691 in the CaHA group in the second month. In our study, it was observed
PCL 1.0 (0.67-1.69) 1.0 (0.88-1.50) that both type 1 and type 3 collagen was significantly higher in the

CaHA 1.0 (0.89-1.33) 1.0 (0.67-1.69) CaHA group. The picrosirius red dye examination distinguishes the
collagen due to different reflections under polarized light. Studies are
Abbreviations: CaHA, calcium hydroxylapatite; PCL, polycaprolactone.
arguing that polarized light is not as useful as the immunohistochemi-
cal antibody dyes we use in the differentiation of type 1 and type
4 | DISCUSSION 3 collagen.12
Yutskovzkaya et al performed a histopathological examination on
With the widespread use of fillers in recent years, many studies have humans in the fourth and ninth month after the CaHA application.
been conducted on filler materials and new active ingredients have They showed that the amount of type 3 collagen was higher in the
been introduced to cosmetic dermatology. Studies are continuing to fourth month, and that type 1 collagen was more in the ninth
produce the ideal filler that is nonimmunogenic, nontoxic, and nonca- month.13
rcinogenic, with sufficient efficiency and long-term permanence in It is known the amount of type 3 collagen increases in wound
terms of histopathological and patient satisfaction in the correction of healing and growing tissues, and the newly formed thin and disorga-
aging effects.6 Comparative studies on fillers will contribute to the nized collagen is replaced by thicker, tightly packed organized type
field of cosmetology in finding out the ideal filler. 1 collagen.14 In our study, we compared the results of PCL and CaHA
CaHA contains microspheres of 25 to 45 μm size containing 2 to fillers at 2 and 4 month. We saw that there was no significant change
5 μm micropores. It is argued these microspheres serve as a tissue in type 1 and type 3 collagen H scores. According to these results,
scaffold in the neocollagenization process.7 both fillers increase the amount of both type 1 mature collagen, and
PCL filler consists of 25 to 50 μm, spherical and flat-shaped PCL newly formed type 3 collagen. Although enough time has passed to
microspheres without crosslinking.8,9 The size and flat structure of the resorb the microspheres, the high amount of type 3 collagen indicates
microspheres in its composition allow it to stimulate neo- that both fillers continue to rebuild the active matrix in the long term.
collagenization by protecting the filler from phagocytosis. Thus, new In Paliwal's study, they found that collagen type 1 and type 3 pro-
8
collagen fibrils form around the microspheres. tein gene expression was significantly higher for 12 weeks in the
Coleman et al observed that the percentage of new collagen for- group treated with HA than the control group. But there was no sig-
mation in the fourth week was higher than the 16th week in their nificant difference in type 1/type 3. Relative changes which may
study on the effect of CaHA on neo-collagenization on the canine occur in the ratio of collagen type 1 and type 3 can cause both deteri-
10
model. Paliwal et al examined the effects of hyaluronic acid on the orations of skin quality and skin dysfunction. Maintaining this ratio is
ECM by using ELISA and reverse transcriptase-polymerase chain reac- important in maintaining collagen homeostasis.11 In our study, we
tion method. They showed that procollagen type 1 (COL1A1) and immunohistochemically demonstrated that the amount of type 1 and
procollagen type 3 (COL3A1) gene expressions increased in the first type 3 collagen in both filler groups were significantly higher than the
4 weeks after HA injection, and this increase remained close to the control group. The fact that being no difference between the groups
control group after the fourth week.11 in the comparison of the ratio of type 1/type 3 H scores shows fillers
In our study, the total collagen density was higher than the con- do not disturb collagen homeostasis. We compared the increase in H
trol group after the second month. But there was no significant differ- score rates between the groups and could not find a significant
ence between the second and fourth month in the within-group difference.
comparison in both filler groups. Our findings support the data of Pal- The deterioration of the balance among ECM components with
iwal and Coleman. In other words, collagen increase is higher in the aging causes a decrease in type 1 collagen and thinning of the
6 of 7 YANATMA ET AL.

dermis.2 It is known fillers increase skin thickness and quality by stim- We think that it will be a pioneering work for further studies on this
ulating collagen production.15 However, we did not detect an increase subject.
in skin thickness. We did not measure the dermis thickness at the
beginning of our study. Yet, the fact that there was no significant dif- ACKNOWLEDG MENTS
ference in dermis thickness between the control group, which was This study was supported by Inonu University Scientific Research
expected to have slightly thinned with aging, and the filler groups in Projects.
the biopsies taken at the second month, supports this.
In our study, there was a significant difference in the thickness of CONFLIC T OF INT ER E ST
the dermis in the filler groups compared to the control group at the The authors declare no potential conflict of interest.
end of the fourth month. We realized that this difference is due to the
thinning of the dermis in the control group rather than the thickening AUTHOR CONTRIBU TIONS
in the filler groups. In other words, PCL and CaHA did not cause der- Conception and design of study: Yelda Kapıcıoglu, Gulbahar Sarac, Irem
mal thickening in our study but prevented age-related atrophy. Yanatma, Mehmet Gul. Acquisition of data: Mehmet Gul, Semir Gul. Analy-
Although fillers are known to stimulate fibroblast proliferation sis and/or interpretation of data: Irem Yanatma, Mehmet Gul, Semir Gul.
and function, there is no study in the literature comparing the effect Drafting the manuscript: Irem Yanatma, Gulbahar Sarac. Revising the man-
of fillers on fibroblast count. In our study, the average of fibroblast/ uscript critically for important intellectual content: Yelda Kapıcıoglu,
fibrocyte nuclei was counted in three different dermis areas randomly Gulbahar Sarac, Irem Yanatma, Mehmet Gul, Semir Gul.
selected at ×40 objective magnification on sections stained with
Hematoxylin-eosin. Although the number of fibroblasts was higher in ET HICS S TAT E MENT
both filler groups in the second month, there was no statistically sig- The study was approved by the Inonu University Faculty of Medicine
nificant relationship. A significant difference was observed between Experimental Animals Ethics Committee.
the groups in terms of the number of fibroblasts in the fourth month.
Accordingly, the number of fibroblasts in both filler groups was signifi- DATA AVAILABILITY STAT EMEN T
cantly higher than the control group. The PCL filler caused a signifi- Data available on request from the authors. Author elects to not
cantly higher increase in fibroblasts than the CaHA filler. In addition, share data.
when the results of the second and fourth month are compared, PCL
filler significantly increased the number of fibroblasts in the fourth OR CID
month. This shows that the positive effect of PCL filler on fibroblast Irem Yanatma https://orcid.org/0000-0002-4772-5397
proliferation is more pronounced and long-lasting compared to CaHA. Gulbahar Sarac https://orcid.org/0000-0002-7246-6382
An interesting finding we observed during the experiment is the
mobility and agitation that occur after the application of the PCL filler. RE FE RE NCE S
As far as we know, no psychiatric symptoms such as anxiety, depres- 1. Kapicio itcan B, Gözükara H. Comparison of
glu Y, Gül M, Saraç G, Yig
sion, or psychosis have been reported after PCL filler injection in the antiaging effects on rat skin of cog thread and poly-L-lactic acid
thread. Dermatol Surg. 2019;45(3):438-445. https://doi.org/10.1097/
studies conducted so far. In an animal experiment conducted by
dss.0000000000001717.
Stander et al using Balb/c mice, perforated PCL particles were 2. Shin J-W, Kwon S-H, Choi J-Y, et al. Molecular mechanisms of dermal
injected into the subjects. They reported scratching in the injection aging and antiaging approaches. Int J Mol Sci. 2019;20(9):2126.
site in more than 50% of the animals. However, since similar symp- 3. Zouboulis CC, Ganceviciene R, Liakou AI, Theodoridis A, Elewa R,
Makrantonaki E. Aesthetic aspects of skin aging, prevention, and local
toms were seen in the control group injected with PBS, it was not
treatment. Clin Dermatol. 2019;37(4):365-372.
considered significant by the authors.16 4. Carruthers J, Carruthers A, Humphrey S. Fillers and neocollagenesis.
Dermatol Surg. 2014;40:134-136. https://doi.org/10.1097/DSS.
0000000000000227.
5. Van Loghem J, Yutskovskaya YA, Werschler WP. Calcium hydroxylap-
5 | C O N CL U S I O N
atite: over a decade of clinical experience. J Clin Aesthet Dermatol.
2015;8(1):38-49.
In this animal experiment, we aimed to compare two filler materials, 6. Alijotas-Reig J, Fernández-Figueras MT, Puig L. Inflammatory,
which are frequently preferred in recent years and have close struc- immune-mediated adverse reactions related to soft tissue dermal
ture. To the best of our knowledge, there is no other study comparing fillers. Semin Arthritis Rheum. 2013;2:241-258.
7. Berlin AL, Hussain M, Goldberg DJ. Calcium hydroxylapatite filler for
CaHA and PCL fillers histologically and immunohistochemically. We
facial rejuvenation: a histologic and immunohistochemical analysis.
used the most specific immunohistochemical methods to show type Dermatol Surg. 2008;34:64-67.
1 and type 3 collagen. Also, investigating the number of fibroblasts 8. Morhenn VB, Lemperle G, Gallo RL. Phagocytosis of different particu-
and dermal thickness can be shown as another strength of our study. late dermal filler substances by human macrophages and skin cells.
Dermatol Surg. 2002;28(6):484-490.
The weakest aspect of our study is that the lifting effect of these two
9. Laeschke K. Biocompatibility of microparticles into soft tissue fillers.
fillers could not be compared, since it was performed on the rat back. Semin Cutan Med Surg. 2004;23(4):214-217.
YANATMA ET AL. 7 of 7

10. Coleman KM, Voigts R, DeVore DP, Termin P, Coleman WP. 15. Kim JS. Changes in dermal thickness in biopsy study of histologic
Neocollagenesis after injection of calcium hydroxylapatite composi- findings after a single injection of polycaprolactone-based filler into
tion in a canine model. Dermatol Surg. 2008;34:53-55. the dermis. Aesthet Surg J. 2019;39(12):484-494.
11. Paliwal S, Fagien S, Sun X, et al. Skin extracellular matrix stimulation 16. Stander BA, Van Vollenstee FA, Kallmeyer K, et al. An in vitro and
following injection of a hyaluronic acid–based dermal filler in a rat in vivo study on the properties of hollow polycaprolactone cell-
model. Plast Reconstr Surg. 2014;134(6):1224-1233. delivery particles. PLoS One. 2018;13(7):198248.
12. Lattouf R, Younes R, Lutomski D, et al. Picrosirius red staining: a use-
ful tool to appraise collagen networks in normal and pathological tis-
sues. J Histochem Cytochem. 2014;62(10):751-758.
13. Yutskovskaya Y, Kogan E, Leshunov E. A randomized, split-face,
histomorphologic study comparing a volumetric calcium hydroxylapa- How to cite this article: Yanatma I, Sarac G, Gul M, Gul S,
tite and a hyaluronic acid-based dermal filler. J Drugs Dermatol. 2014; Kapicioglu Y. Comparison of polycaprolactone and calcium
13(9):1047-1052. hydroxylapatite dermal fillers in a rat model. Dermatologic
14. Nicolau P, Marijnissen-Hofsté J. Neocollagenesis after injection of a
Therapy. 2021;34:e14716. https://doi.org/10.1111/dth.
polycaprolactone based dermal filler in a rabbit. Eur J Aesth Med
Dermatol. 2013;3(1):19-26. 14716