1 s2.0 S0141813024010997 Main

International Journal of Biological Macromolecules 263 (2024) 130296
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules

journal homepage: www.elsevier.com/locate/ijbiomac
Review
A review on natural biopolymers in external drug delivery systems for

wound healing and atopic dermatitis
Patrícia C. Pires a, b, c, Fouad Damiri d, n, Ehsan Nazarzadeh Zare e, f, Anwarul Hasan g, h, *, Rasoul
Esmaeely Neisiany i, j, Francisco Veiga a, b, Pooyan Makvandi k, l, m, Ana Cláudia Paiva-Santos a, b, **
a
Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Coimbra, Portugal
b
REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Coimbra, Portugal
c
Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
d
Laboratory of Biomolecules and Organic Synthesis (BIOSYNTHO), Department of Chemistry, Faculty of Sciences Ben M’Sick, University Hassan II of Casablanca,
Casablanca, Morocco
e
School of Chemistry, Damghan University, Damghan 36716-45667, Iran
f
Centre of Research Impact and Outcome, Chitkara University, Rajpura-140401, Punjab, India
g
Department of Mechanical and Industrial Engineering, Qatar University, Doha 2713, Qatar
h
Biomedical Research Center, Qatar University, Doha 2713, Qatar
i
Biotechnology Centre, Silesian University of Technology, Krzywoustego 8, 44-100 Gliwice, Poland
j
Department of Polymer Engineering, Hakim Sabzevari University, Sabzevar 9617976487, Iran
k
Institute for Bioengineering, School of Engineering, The University of Edinburgh, Edinburgh, UK
l
Chitkara Centre for Research and Development, Chitkara University, Himachal Pradesh 174103, India
m
Department of Biomaterials, Saveetha Dental College and Hospitals, SIMATS, Saveetha University, Chennai 600077, India
n
Chemical Science and Engineering Research Team (ERSIC), Department of Chemistry, Polydisciplinary Faculty of Beni Mellal (FPBM), University Sultan Moulay
Slimane (USMS), Beni Mellal 23000, Morocco
A R T I C L E I N F O A B S T R A C T
Keywords: Despite the advantages of topical administration in the treatment of skin diseases, current marketed preparations
Biopolymer face the challenge of the skin’s barrier effect, leading to low therapeutic effectiveness and undesirable side ef
External drug delivery fects. Hence, in recent years the management of skin wounds, the main morbidity-causing complication in
Nanocarrier
hospital environments, and atopic dermatitis, the most common inflammatory skin disease, has become a great
concern. Fortunately, new, more effective, and safer treatments are already under development, with chitosan,
starch, silk fibroin, agarose, hyaluronic acid, alginate, collagen, and gelatin having been used for the develop
ment of nanoparticles, liposomes, niosomes and/or hydrogels to improve the delivery of several molecules for the
treatment of these diseases. Biocompatibility, biodegradability, increased viscosity, controlled drug delivery,
increased drug retention in the epidermis, and overall mitigation of adverse effects, contribute to an effective
treatment, additionally providing intrinsic antimicrobial and wound healing properties. In this review, some of
the most recent success cases of biopolymer-based drug delivery systems as part of nanocarriers, semi-solid
hydrogel matrices, or both (hybrid systems), for the management of skin wounds and atopic dermatitis, are
critically discussed, including composition and in vitro, ex vivo and in vivo characterization, showing the promise
of these external drug delivery systems.
1. Introduction
1.1. Overview: Background and significance
The treatment of skin diseases through topical drug administration
* Correspondence to: A. Hasan, Department of Mechanical and Industrial Engineering, Qatar University, Doha 2713, Qatar.
** Correspondence to: A.C. Paiva-Santos, Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra,
Coimbra, Portugal.
E-mail addresses: [email protected] (A. Hasan), [email protected] (A.C. Paiva-Santos).
https://doi.org/10.1016/j.ijbiomac.2024.130296
Received 17 November 2023; Received in revised form 14 February 2024; Accepted 17 February 2024
Available online 19 February 2024
0141-8130/© 2024 Published by Elsevier B.V.
P.C. Pires et al. International Journal of Biological Macromolecules 263 (2024) 130296
offers significant advantages compared to systemic routes. These ad antibiotic resistance, which delays the healing process, increases
vantages include targeted drug delivery, minimized systemic drug morbidity, and also makes health costs rise [21,22]. Several antibacte
exposure (and, consequently, fewer systemic side-effects), and avoid rial agents have been used to manage wounds, mainly antiseptics, an
ance of hepatic first-pass effect [1–3]. Topical formulations are also easy tibiotics, and metallic nanoparticles (NP). Traditionally, antiseptics and
antibiotics are administered topically in the form of creams, ointments,
and gels. In these conventional formulations, there is a higher chance of
these drugs not reaching the adequate concentration at the site of
Abbreviations
infection, due to their degradation in the wound environment, difficulty
in penetrating biofilms, short application period and rapid clearance.
AD Atopic dermatitis
The resulting inadequate dosing accuracy can potentiate antiseptics
AgNPs Silver nanoparticles
toxic effects on human cells, and lead to the development of contact
BMV betamethasone 17-valerate
dermatitis and bacterial resistance caused by antibiotics [20]. Further
CHX Chlorhexidine
more, conventional semi-solid bases are poorly suited for wound
CMA carboxymethyl agarose
exudate absorption, and metallic NPs have also shown cytotoxic effects
DDS Drug delivery system
[23]. On the other hand, traditional dry dressings such as gauze, cotton
DFV diflucortolone valerate
wool, and synthetic bandages do not provide the moist environment
HA Hyaluronic Acid
necessary for wound healing. Also, polyurethane film dressings do not
HC Hydrocortisone
absorb exudates enough, silicone or polyurethane foam requires a sec
HNTs Halloysite clay nanotubes
ondary dressing to adhere to the skin, and hydrocolloids are cytotoxic,
HT Hydroxytyrosol
not providing the ideal environment for accelerated wound healing
NP Nanoparticle
[20]. To tackle these issues, a large panoply of new drug delivery sys
TEWL Transepidermal water loss
tems (DDS) has emerged, in which hydrogels based on natural polymers
ZnO NPs zinc oxide nanoparticles
have had a relevant role, attending to their favorable features, namely
provision of a moist environment, absorption of wound exudates,
controlled release of active agents and nanocarriers, among others
and painless to administer (non-invasiveness), ensuring good patient [24–28].
compliance. They can be tailored to have controlled drug release, Additionally, natural polymers have several other relevant features
leading to therapeutic effects that last for a longer period of time [3–5]. that make them suitable for drug delivery in general, such as their
Nevertheless, marketed preparations face considerable challenges, since biocompatibility and biodegradability, low cost and easy access, and
the skin’s barrier effect makes it difficult for drugs to permeate it, with intrinsic bioactivity, with antibacterial and wound healing effects being
existing therapies having lack of effectiveness, need of repeated dosing, quite useful when meant for topical application in the treatment of AD
and local as well as systemic side effects [6–8]. Hence, the development and wound healing [29–32]. These polymers can be part of the
of new, more effective, and safer treatments is greatly needed. composition of the nanocarriers themselves, form semi-solid hydrogel
Among the various diseases and injuries that can affect the skin, matrices, or both, making the so called hybrid systems, with several
atopic dermatitis (AD) and wounds have become a growing concern, not hybrid systems for the management of AD having already emerged in the
only for patients but also for healthcare professionals [9,10]. AD is the scientific literature, namely chitosan NPs, starch NPs and liposomes
most common inflammatory cutaneous disease, being characterized by a incorporated into creams, Carbopol® gels or chitosan gels, to improve
disruption of the skin barrier that leads to increased transepidermal the delivery of corticosteroids, hydroxytyrosol (HT) or phytoceramides
water loss (TEWL) and inflammation [11,12]. In addition, the impair [9,15–18,33–36]. In parallel, hybrid systems for the management of skin
ment of the skin barrier may trigger secondary infections, namely in wounds have also emerged, namely liposomes, silver nanoparticles
fections by Staphylococcus aureus [13]. Therefore, the treatment of AD (AgNPs), zinc oxide nanoparticles (ZnO NPs), silica NPs, halloysite clay
focuses on repairing the skin barrier, reducing inflammation processes, nanotubes (HNTs) and niosomes, which have been incorporated into
and bacterial infections. Additionally, skin hydration plays an important chitosan, silk fibroin, agarose, hyaluronic acid (HA), alginate, collagen
role in AD, as it improves dryness, pruritus and helps with the restora or gelatin hydrogels, to improve the delivery of chlorhexidine (CHX),
tion of the compromised stratum corneum [14]. Corticosteroids are the Ag+, Aloe vera, mupirocin, gentamicin, rifamycin, vancomycin, cipro
mainstay of AD treatment, traditionally applied through creams and floxacin and polymyxin B sulfate [10,21,22,24,37–44].
ointments. However, in these conventional formulations, corticosteroids In this review, some of the most recent success cases of natural
have several topical and systemic side effects that limit their applica polymer DDSs development for the management of AD and skin wounds
bility in chronic treatment regimens, namely allergic contact dermatitis, will be critically discussed (summary in Fig. 1), including their
TEWL increase, telangiectasia, reduction of keratinocytes after 3 to 4 composition and in vitro, ex vivo and in vivo characterization, showing
weeks, adrenal suppression, among others [15–19]. Fortunately, the promise of these types of systems for the future of topical treatments.
corticosteroid-loaded nanocarriers have been developed and incorpo
rated into creams, ointments, and chitosan gels, which have shown 2. Natural polymers-based hybrid systems for topical
increased viscosity for suitable topical administration, controlled drug application.
delivery, increased drug retention in the epidermis (site of the inflam
mation process), and mitigation of the adverse effects of corticosteroids 2.1. Natural polymers as nanocarrier components
[9,17,18].
Conversely, the incidence of skin wound infections and chronic skin 2.1.1. Chitosan-based polymeric nanoparticles
wounds has steadily increased in the past few years. While acute wounds Chitosan is a deacetylated derivative of chitin, a natural poly
usually heal spontaneously, chronic wounds exhibit a high pH value, saccharide that can be obtained from several mollusks, crustaceans,
necrotic tissue, and a high number of metalloproteases, impeding the insects, or fungi [45,46]. High pH values will lead to the neutralization
physiological process of wound healing [20]. The most common bacteria of its amine groups, leading to the arrangement of a polymeric solution
associated with wound infection are Staphylococcus aureus and Pseudo into a 3D crosslinked polymeric network, resulting in gel consistency
monas aeruginosa. Fighting wound bacterial infection is a great challenge [47,48], which will be relevant for chitosan-based hydrogels, and
because they have the ability to form biofilms and present increasing leading to an easier assembly for vesicle formation, relevant for
chitosan-based nanoparticles’ preparation [49,50]. For topical
2
Fig. 1. Natural polymers used for development of drug delivery systems for the management of atopic dermatitis and skin wounds, as answer to current conventional
therapies’ limitations, including drug delivery system types.
application, chitosan has the additional advantage of being a mucoad has been proven that chitosan has the ability of transiently opening tight
hesive polymer, which will lead to an increased retention time of the junctions, leading to increased drug permeation through the skin
formulation at the application site, resulting in increased drug absorp [53,54], and many studies have proven it to have intrinsic antibacterial
tion and, consequently, increased bioavailability [51,52]. Moreover, it and wound healing properties, adding to its benefits for the treatment of
3
several skin diseases [55,56]. release, and also as a part of polymeric NPs composition [63,64].
In this context, chitosan-based polymeric NPs incorporated into a A common feature of skin with AD is the depletion of stratum corneum
semi-solid base have been extensively studied to treat inflammatory skin lipids, especially ceramides. Hence, it would be beneficial to develop
diseases [17,18,33–35,57]. The study by Hussain et al. [17] is an novel DDSs that can bring to the skin exogenous lipids capable of
example applied to the management of AD, in which the authors pre nourishing it. In this context, Tessema et al. [36] developed oat-derived
pared hydrocortisone (HC) loaded chitosan-based polymeric NPs into a phytoceramides-loaded starch-based NPs into a Carbopol® gel. Ex vivo
QV® cream [58]. Ex vivo permeation studies demonstrated that the permeation studies in human skin showed that the developed NP gel
formulation with NPs had a significantly lower drug permeation flux allowed a higher retention of oat-derived phytoceramides in the stratum
compared to the commercial cream without NPs after 24 h, but a higher corneum, when compared to the same NPs in an aqueous suspension,
retention of HC in both epidermis and dermis, which indicated both a with a controlled release profile. The existence of Carbopol® in the
more sustained and controlled drug permeation across the skin and a formulation’s composition led to an increased viscosity, which
higher retention at the intended therapeutic site of action, thus leading decreased the depth of oat-derived phytoceramides penetration into the
to a potentially higher therapeutic efficacy and safety, due to the skin layers and sustained drug delivery, while the use of NPs provided a
minimization of systemic absorption. Furthermore, in vivo studies high specific area that facilitated the contact of phytoceramides with the
showed a better control of TEWL and a more significant reduction in stratum corneum itself. Hence, the developed formulation was consid
erythema intensity for the developed NP cream (compared to all other ered to be a potentially promising hybrid system for the delivery and
formulations), which further supported the potential of the developed maintenance phytoceramides in the topmost skin layers, as it functions
preparation containing NPs. as a reservoir for the release of phytoceramides in a controlled manner
Hussain et al. [18] also prepared chitosan-based polymeric NPs into the stratum corneum, being valuable for regenerating the aged,
containing HC co-encapsulated with HT, a potent antioxidant, to both diseased, and/or affected skin barrier.
minimize systemic side effects and provide benefits to the treatment of
AD. The co-loaded NPs were incorporated in an occlusive cream 2.2. Natural polymers applied as formulation semi-solid bases
formulation, in order to increase skin contact time and improve stratum
corneum hydration, to facilitate the drug diffusion through the skin. An 2.2.1. Chitosan-based nanoparticle containing-gels and hydrogels
ex vivo study was conducted comparing the developed formulation to a On the topic of drug delivery for AD management using hybrid sys
commercial cream formulation with free HC or with free HC/HT co- tems, chitosan-based semi-solid bases have been used. In this context,
solution. Here, compared to the other formulations, again the devel two studies, by Özcan et al. [15,16], loaded two anti-inflammatory
oped formulation showed a significant decrease in drug permeation flux drugs, betamethasone 17-valerate (BMV, moderate potency corticoste
across mouse skin, but an increase in drug retention in the epidermis and roid) and diflucortolone valerate (DFV, high potency corticosteroid),
dermis. Such results are in line with the initial objective of decreasing into a lecithin/chitosan NPs chitosan gel, and compared them with a
the systemic effects of HC by transcutaneous permeation and increasing previously developed liposomes chitosan gel [9]. In vivo studies (AD rat
its site-specific clinical response in the AD lesion. The local controlled model) showed a more significantly reduced erythema intensity for the
drug release was a result of chitosan’s high viscosity and mucoadhesive liposomes-loaded chitosan gel, compared to the lecithin/chitosan NPs-
properties. Then, an in vivo study involving an AD mice model was loaded chitosan gel. In addition, both formulations had superior effi
performed, with the developed NPs into a cream base showing lower cacy compared to commercial drug formulations with a 10-fold higher
TEWL and erythema intensity values in comparison with all other concentration of corticosteroid, due to their high drug retention times in
groups after 6 weeks. This was likely because the synergy between HC the epidermis, thus concluding on the increased the safety of the novel
and HT promoted an increased regeneration of the stratum corneum, as formulations. Additionally, the developed formulation showed adequate
well as a decrease in inflammatory cascades’ activation. These results viscosity for topical application, which led to an increased drug reten
allowed to infer that HC/HT-loaded chitosan-based polymeric NPs into a tion time in the epidermis, also improving its anti-inflammatory activity.
cream base, contributing to collagen regeneration and increased wound Furthermore, loading the drugs into liposomes reduced the skin irrita
healing, and lower erythema intensity, may be a promising therapy for tion commonly caused by corticosteroids, by providing hydration of the
AD, leading to a reduction in this disease’s signals and symptoms. stratum corneum and a sustained drug release.
In line with the previous studies, more recently HC/HT-loaded chi Liposomes have also been applied in wounds, particularly in infected
tosan-based polymeric NPs were incorporated into an aqueous cream wounds. A recent study, conducted by Hemmingsen et al. [22], devel
formulation, to test their tolerability and safety in healthy human vol oped CHX-loaded liposomes incorporated into a chitosan hydrogel for
unteers [19]. TEWL and erythema intensity was measured after formu chronic wound treatment (Fig. 2A). CHX is an antiseptic molecule with a
lation application onto the arms of the subjects for 28 days, and results broad and rapid bactericidal effect, commonly used in local treatment of
showed that neither parameter underwent significant changes. In gen infected wounds. The developed formulation revealed a more sustained
eral, no irritation, signs of skin atrophy, redness, systemic absorption, or drug release than CHX-loaded liposomes (no hydrogel base), and these,
toxicity were detected after the application of the NP formulation. in turn, a more sustained release profile than free CHX in a chitosan-
Therefore, the prolonged use of HC/HT-loaded chitosan-based poly based hydrogel. Furthermore, the formulations showed substantial
meric NPs into an aqueous cream was found to be safe and well toler anti-inflammatory effects, as they significantly reduced macrophages’
ated, as no signs of skin irritation or atrophy were observed, being a produced nitric oxide levels (Fig. 2B), and improved CHX antibacterial
potentially promising innovative formulation for the treatment of AD effect against Staphylococcus aureus and P. aeruginosa, by showing a
with good acceptability. lower minimal lethal concentration than controls. Furthermore, the
chitosan hydrogel exhibited antimicrobial activity by itself against both
2.1.2. Starch-based polymeric nanoparticles bacteria, and the antibiofilm activity was higher for CHX-loaded lipo
Starch is a natural polysaccharide that is part of the constitution of somes in a chitosan-based hydrogel, as compared to the other formu
many plants, several of which are part of human diet, such as potatoes, lations (Fig. 2C). Hence, the incorporation of CHX into positively
rice, corn, maize, wheat, and oat [59,60]. The ratio between the two charged liposomes favored their penetration into the extracellular ma
macromolecules that are part of its composition, amylose, and amylo trix of the biofilm. Consequently, it was concluded that the designed
pectin, has a substantial influence on its viscosity and gel formation formulation is an innovative and promising strategy for topical appli
ability and stability [61,62]. Due to its easy availability and low cost, cation in chronic wounds, as it could mitigate antimicrobial resistance
starch has been used for a high variety of applications, including drug and the inhibition and eradication of biofilms.
delivery, in which it has had an important role in controlled drug The same group of researchers [21] designed chitosan-infused
4
Fig. 2. A – Schematic representation of the developed chlorohexidine (CHX) liposomes chitosan hydrogel, and its potential antibacterial and antibiofilm effects; B -
Anti-inflammatory activity evaluation in murine macrophages, with measurement of NO production, for liposomes, CHX-loaded liposomes, chitosan hydrogel, and
CHX-liposomes-in-hydrogel; C - Antibiofilm activity evaluation against Pseudomonas aeruginosa, with biofilm development and eradication of pre-formed biofilm
inhibition percentage, for free CHX, liposomes, chitosan hydrogel, CHX-loaded liposomes, CHX chitosan hydrogel, and CHX-liposomes-in-hydrogel; adapted from
Hemmingsen et al. [22].
liposomes (chitosomes) loaded with CHX in their lipid bilayer, liposomes, which may be due to competition between chitosan and CHX
embedded in a chitosan-based hydrogel for the treatment of burns in the lipid bilayer, expelling CHX more rapidly, and vesicles within a
(Fig. 3A, B and C), cuts, and other acute skin injuries, with special focus hydrogel matrix led to more sustained release profiles, as expected due
on infection prevention and control. Drug release studies (Fig. 3D) to increased viscosity. Additionally, the antimicrobial activity against
showed a higher CHX release from chitosomes compared with Staphylococcus aureus and Staphylococcus epidermidis was superior for the
5
Fig. 3. A - Schematic representation of the developed chlorohexidine (CHX) chitosomes chitosan hydrogel, and its potential antibacterial effects; B – Transmission
electron microscopy image of non-loaded chitosomes; C - Transmission electron microscopy image of CHX-loaded chitosomes; D – In vitro drug release results from
the developed formulations; adapted from Hemmingsen et al. [21].
CHX-loaded chitosomes, comparing with empty chitosomes and CHX- properties, gelation capability, and drug stabilization and controlled
loaded liposomes, hence indicating a synergistic effect between chito release ability, it has proven to be quite advantageous in the field of drug
san and CHX. Chitosan available on the vesicles’ surface most likely delivery [65,66]. It is also biocompatible and can form hydrogels with a
enabled its close and immediate interaction with the bacterial mem sponge-like three-dimensional network, which can be of great use in
brane, by electrostatic interaction between chitosan’s positive charge topical drug delivery, particularly in the field of wound healing [67,68].
and the negative charge of the bacteria, leading to bacterial membrane AgNPs have been one of the most used metallic NPs for antimicrobial
destruction. Furthermore, hydrogel formulations showed greater anti effects [69]. Silver is a noble metal with recognized antimicrobial
microbial effects compared to suspension formulations. Particularly, properties, including multiresistant bacteria [70]. AgNPs combine these
CHX-loaded chitosomes in a chitosan-based hydrogel showed the most broad-spectrum antimicrobial properties with advantageous physico
potent antibacterial action, thus highlighting the potential of this chemical properties, making them ideal for incorporation into wound
formulation for infected wound treatment. dressings [24]. It has also been reported that AgNPs play an important
role in wound healing, improving the biological properties of some
2.2.2. Silk fibroin-based composites polymers, such as silk fibroin, since silk fibroin has tyrosine amino acid
Silk fibroin is a natural occurring protein extracted from Bombyx residues that provide a strong electron donation capable of reducing Ag+
mori, the commonly known silkworm, and due to its good mechanical to Ag [71]. Based on this reaction, Fei et al. [37] developed a AgNPs-
6
loaded silk fibroin-based composite, a hybrid system that showed As previously mentioned, AgNPs exhibit antibacterial activity,
effective antibacterial and antibiofilm activity against methicillin- through oxidation of Ag to Ag+. Nevertheless, this is a slow process, and
resistant Staphylococcus aureus. Additionally, the composite was pro results in low effective Ag+ concentrations, leading to short antibacterial
duced by an easy and environment-friendly method, also proving to be activity. Thus, interest in the investigation of wound dressings that can
economical, which added to its potential as an effective antimicrobial incorporate appreciable amounts of Ag+ and prolong its release has
material for clinical application. grown over the years [24,76,77]. A recent example was presented by
Huang et al. [24] who prepared a macroporous hydrogel dressing
2.2.3. Agarose-based hydrogels composed of carboxymethyl agarose (CMA) loaded with Ag+, with the
Agarose is another natural-derived polysaccharide, usually extracted purpose of having antibacterial, anti-inflammatory, and pH-responsive
from red algae, and composed of a disaccharide, made of D-galactose properties to accelerate wound healing. The hydrogel was formed by
and 3,6-anhydro-L-galactose, having the ability to form thermosensitive physical cross-linking of CMA chains by hydrogen bonding and ionic
gels through physical crosslinking via ionic and hydrogen bonds [72,73]. interaction between the deprotonated carboxylic groups and Ag+. Sur
It is known to have good gelling capability, good mechanical properties, face morphology analysis showed a compact structure and small pore
and biocompatibility, which added to its low cost and easy availability size, and the swelling assay showed that acidic conditions disrupted the
have made this polymer widely applied in drug delivery, especially in complexation between Ag+ and carboxymethyl groups, lowering the
wound dressings [74,75]. strength of intermolecular ionic connections, which ultimately led to an
Fig. 4. A – Schematic representation of the developed HA hydrogels (left) and ZnO nanobelt-like structures-loaded HA-based hydrogels (right); B – Scanning electron
microscopy image of the developed HA hydrogel; C – Scanning electron microscopy image of the developed HA-ZnO hydrogel, at lower concentration; D – Scanning
electron microscopy image of the developed HA-ZnO hydrogel, at higher concentration; E – Photographic images of blood clot formation after treatment with the
developed HA hydrogel, HA-ZnO hydrogel at lower concentration, and HA-ZnO hydrogel at higher concentration (pig whole blood); F – Hemolysis percentage after
treatment with the developed HA hydrogel, HA-ZnO hydrogel at lower concentration, and HA-ZnO hydrogel at higher concentration (pig whole blood); G – Anti
bacterial activity against Escherichia coli and Staphylococcus aureus after treatment with the developed HA hydrogel, HA-ZnO hydrogel at lower concentration, and
HA-ZnO hydrogel at higher concentration; adapted from Rao et al. [38].
7
increased hydrogel swelling. This explains the higher release of Ag+ as animal model (Staphylococcus aureus infection) showed a marked ac
the pH decreased. Temperature-responsive properties were also tested, celeration in wound closure for the developed CMA-Ag hydrogel. Hence,
showing that the release of Ag+ increases with increasing temperature, the authors concluded that the prolonged Ag+ release, exudate absorp
due to the decrease in ionic interactions strength as a consequence of tion ability and dressing surface properties provided by the agarose
higher temperatures. In vivo studies with an infected cutaneous wound hydrogel may have greatly contributed to the positive results in wound
Fig. 5. A – Particle size distribution of the developed ZnO NPs; B - X-ray powder diffraction results of the developed alginate-Aloe vera NPs (grey graph) and alginate-
Aloe vera/ZnO NPs (blue graph); C - Fourier-transform infrared spectroscopy spectra of alginate, alginate-Aloe vera, and alginate-Aloe vera/ZnO NPs hydrogel; D and E
- Scanning electron microscopy images of the developed alginate-Aloe vera/ZnO NPs hydrogel film surface, before (D) and after (E) degradation; F – Weight loss
percentage during hydrolytic degradation of the developed alginate-Aloe vera/ZnO NPs hydrogel; G – REEDA (redness, edema, ecchymosis, discharge and cesarean
section approximation) score before, 12 days after and 24 days after treatment with the developed alginate-Aloe vera/ZnO NPs hydrogel containing mupirocin, and
common ointments containing mupirocin; adapted from Hou et al. [10].
8
healing. based wound gel dressing, with vancomycin (antibiotic effective

against Gram-positive bacteria) loaded within the tubular structures
2.2.4. Hyaluronic acid-based hydrogels (Fig. 6A). HNTs loaded into the alginate-based gel showed a more sus
Hyaluronic acid is yet another natural occurring polysaccharide, tained release of vancomycin compared to a previous study using silica
made of N-acetyl-β-D-glucosamine and β-D-glucuronic acid di (Fig. 6C), and the incorporation of gelatin in the gel dressing had a
saccharides [78,79]. It can be found in several biological components, favorable impact on slowing drug release. Nevertheless, this change had
such as the eye’s vitreous humor, articular cartilage, and the skin’s a negative impact on the antimicrobial activity of the tested system
layers [80,81]. Given its ubiquitous nature, it is seen as a highly (Fig. 6B). Hence, vancomycin-loaded HNTs in an alginate-based gel was
biocompatible polymer, with particular interest for skin drug delivery selected as the most promising approach for wound treatment, being an
due to additional gelling capacity, viscoelasticity and mucoadhesive effective antimicrobial platform for topical application, without
ness, with complementary intrinsic bioactivities, such as anti- compromise on drug release rates.
inflammatory and wound healing effects [82–86].
Although ZnO NPs have shown significant bacterial properties for a 2.2.6. Collagen-based hydrogels
wide variety of bacteria, the use of these nanocarriers embedded in Collagen is an abundant animal structural protein, being the most
wound dressings promotes the enhancement of their stability and pro prevalent component of the extracellular matrix, and being composed of
longs their action at the infection site. Rao et al. [38] prepared ZnO repetitive units of glycine, proline and hydroxyproline amino acids
nanobelt-like structures-loaded HA-based hydrogels (Fig. 4A) for wound [94,95]. Due to being an important part of the skin’s composition, and
dressing application. The incorporation of the ZnO nanostructures into on account of its role in tissue regeneration, it has been widely exploited
the hydrogel improved the rheology properties of the formulation, and for topical application, more specifically for wound treatment, being
increased its porosity (Fig. 4B, C and D) and swelling capacity. Addi incorporated in hydrogels, films, and wound dressing materials, with the
tionally, through in vitro blood clotting experiments (Fig. 4E and F) it additional advantages of being biocompatible and contributing to
was verified that ZnO nanostructures in a hydrogel base had better blood controlled drug release [96–98].
clotting capability than a simple hydrogel. Lastly, antibacterial experi Although silica NPs are inorganic nanocarriers with a high drug
ments against Staphylococcus aureus and Escherichia coli (Fig. 4G) loading capacity, it was found that they do not allow antibiotics’ skin
showed higher antibacterial activity for larger amounts of ZnO nanobelt- retention beyond 24 h, hence benefiting from an approach aimed at
like structures in the hydrogel, whereas the simple hydrogel did not controlled drug release [39,99]. In this context, Alvarez et al. [39]
show any activity at all. Hence, this newly designed system proved to encapsulated two antibiotics, rifamycin and gentamicin, in plain silica
having potential application in wound dressings. NPs, which in turn were incorporated into a collagen hydrogel, for
infected wound healing treatment. In accelerated enzymatic degrada
2.2.5. Alginate-based hydrogels tion experiments using collagenase, the researchers verified that a
Alginate is a brown algae-derived polysaccharide, made of an simple collagen hydrogel was completely disrupted, while the incorpo
alternation between β-D-mannuronic acid and 1–4 α-L-guluronic acid ration of silica NPs into the collagen hydrogel preserved 40 % of its
residues [87,88]. Through ionic crosslinking with divalent cations, it is weight. This more limited and slower degradation was explained as
known to form a gel matrix, thus having gelling ability, with the added being due to the lower availability of the collagen molecules due to
advantages of being easy to obtain, inexpensive and biocompatible, all interaction with the silica NPs. This increase in proteolytic stability is of
beneficial properties for controlled drug delivery through topical great importance, since the breakdown of the dressing by metal
administration, with especial interest in wound management [89–92]. loproteases can considerably affect their lifetime when in contact with
Recently, in vivo studies in humans using ZnO NPs-loaded hybrid the wounded skin tissues, consequently compromising the therapeutic
systems for wound management have been described in the scientific effect. Moreover, although the attractive electrostatic interactions be
literature. Hou et al. [10] designed an alginate-based hydrogel incor tween rifamycin and collagen caused this drug to remain trapped inside
porated with Aloe vera (plant with antibacterial, antifungal, and wound the collagen network, hindering its diffusion to inhibit Staphylococcus
healing properties), mupirocin (antibiotic commonly present in oint aureus growth, on the contrary gentamicin had an overall higher and
ments for topical application in wounds), and ZnO NPs, a combinational sustained release, that lasted up to 7 days, without changing the struc
approach to accelerate the healing process of cesarean section cuts. The ture and mechanical properties of the hydrogel. These findings are in
developed nanoparticles showed very small particle size, around 4 nm line with the ideal characteristics of a wound healing preparation, as
(Fig. 5A), and all formulation components showed great compatibility controlled and sustained delivery of antibiotics into the skin can protect
(Fig. 5B and C), allowing for the production of a stable preparation. In the wound from infections, while at the same time avoiding systemic
vitro hydrolytic degradation studies showed that as the hydrogel weight side effects due to high drug concentrations, leading to a decrease in
decreased its loaded elements were easily released (Fig. 5D, E and F). As daily wound dressing change as well.
for human studies, two groups were formed, one treated with the In another study, Mebert et al. [39] designed a collagen hydrogel
developed formulation, and another treated with regular ointment loaded with core–shell silica NPs (Fig. 7A, B and C), which in turn car
incorporated with mupirocin (control). After 24 days, the group treated ried two topical antibiotics, rifamycin in the shell, and gentamicin in the
with the developed formulation presented lower values of ecchymosis, core, for wound infection prevention. In vitro therapeutic performance
redness, discharge, edema, and cesarean section approximation (REEDA tests of the developed dual-drug formulation against Staphylococcus
score) (Fig. 5G). Furthermore, almost no patients had an allergic reac aureus showed a sustained antibacterial activity for 10 days, while the
tion, and all had a faster recovery compared to the control. Hence, the NP hydrogel loaded with only gentamicin showed weaker antibacterial
developed technology could be considered as a possible new treatment activity, but it was also sustained for a 10-day period. In vivo antibac
for the reduction of complications associated with cesarean section, by terial efficiency against Staphylococcus aureus in a rat model with
accelerating the wound healing process, and consequently reducing infected wound showed a significant reduction of bacteria population
nursing care and associated costs. for the rifamycin and gentamicin NP hydrogel, in comparison with the
HNTs are natural occurring tubular structures containing a lumen of unloaded nanocomposite (Fig. 7D, E and F). Furthermore, at the end of
positively charged alumina and an outer surface of negatively charged the treatment, macrophages with M1 phenotype (pro-inflammatory)
silica, making it possible to selectively load and release various drugs, were not detected in the animal’s skin, which indicates an acceleration
and hence having an advantage as a nanocarrier when compared to of the healing process. Hence, the developed formulation showed po
other clay derived materials [93]. Kurczewska et al. [41] studied the tential application for controlled antibiotics’ dual release to prevent
influence of HNTs incorporation into an alginate or alginate/gelatin- infection and aid wound repair.
9
Fig. 6. A – Schematic representation of the developed vancomycin HNTs; B – Bacterial growth inhibition zones after treatment with the developed vancomycin HNTs
hydrogels, for Streptococcus pneumoniae (left), Streptococcus pyogenes (middle), and Enterococcus faecalis (right); C – In vitro drug release profiles of the developed
vancomycin HNTs hydrogels, and related controls; adapted from Kurczewska et al. [41].
2.2.7. Gelatin-based elastomers Additionally, a plasticizer was added to increase gelatin flexibility, and a
Gelatin is obtained from the same sources as collagen since it derives crosslinking agent was added to extend gelatin’s degradation time. Tests
from its partial hydrolysis [100,101]. It is a water-soluble protein with to evaluate the developed formulation’s mechanical properties showed
the capacity to form hydrogels through crosslinking, giving formulations that the incorporation of HNTs in the gelatin elastomer increased the
a controlled drug release ability, also having proven biocompatibility tensile strength of the whole system, due to the formation of hydrogen
and intrinsic hemostatic and wound healing effects, promoting cellular bonds between the HNTs and gelatin which allowed for a firmer struc
growth and attachment [102–105]. Given these characteristics, it has ture, necessary to protect the wound from external interference and
been used for both tissue engineering and topical drug delivery, being prevent the bacterial breeding. In vitro degradation tests showed an
part of wound dressings and other topically applied semisolid prepara accentuated initial weight loss due to the release of part of the drug
tions [106,107]. within glycerol (which leaved the system more quickly due to its high
Shi et al. [42] prepared a gelatin elastomer incorporated with free hydrophilicity), and after 3 days a slow and linear degradation of the
ciprofloxacin and polymyxin B sulfate-loaded HNTs (Fig. 8A, B and C). dressing was observed, due to the degradation of gelatin, with
10
Fig. 7. A – Scanning electron microscopy image of the collagen hydrogel; B – Scanning electron microscopy image of the unloaded core-shell-collagen composite; C –
Scanning electron microscopy image of the double loaded core-shell-collagen composite; D – Number of bacteria per animal skin square centimeter, after exposure to
the developed core-shell nanocomposites, either unloaded (blue bar, “Comp. cs”) or double-loaded (orange bar, “Comp. GcsR”); E and F – Rat skin, with Staphy
lococcus aureus infection, after giemsa staining, treated with the developed core-shell nanocomposites, either unloaded (E) or double-loaded (F), showing inoculated
bacteria (blue arrow, Fig. E); adapted from Mebert et al. [39].
consequent additional drug release. Furthermore, the increase in HNTs drug administration in general, and for wound healing in particular.
content led to lower degradation rates, explained by HNTs and gelatin
interactions. Water absorption tests showed an 8-fold increase in dres
sing weight, and the incorporation of HNTs in the elastomer had a 2.3. Hybrids of natural polymers-based blends
substantial influence in water absorption. Therefore, based on its
degradation rate and high swelling ability, the tested dressing could 2.3.1. Alginate/gelatin-based hydrogels
maintain its function and structure for at least 3 days and absorb the Among the multiple nanoscale DDSs that have been recently devel
surrounding tissue fluid of the wound, thus allowing drug delivery and oped, niosomes, which are vesicular nanocarriers composed of nonionic
efficient wound healing. In vitro drug release studies (Fig. 8D and E) surfactants, have been trending for drug delivery applications, due to
showed an initial burst release of the two drugs in the first 5 h, and a their capability for high drug loading and biocompatibility [43]. Addi
sustained release in the following hours for 3 days. These results allowed tionally, although alginate-based hydrogels are largely applied in wound
the authors to infer that an initial rapid release of the two antibiotics dressings, alginate is biologically inactive, and hence the preparation of
with synergistic action can lead to the elimination of the majority of blends with other bioactive polymers, such as gelatin, could allow for
initial bacteria present in a wound, with the subsequent sustained drug better adhesion and elongation of the cells, making it a desirable ma
release eliminating the remaining bacteria. In vitro antibacterial studies terial for application in tissue engineering [43]. Furthermore, several
proved that there was a substantial antibacterial activity against studies have already reported satisfactory results from the application of
Staphylococcus aureus and P. aeruginosa lasting more than 7 days, due to alginate/gelatin blends in wound dressings and drug release [108–110].
the prolonged release of the drugs. Hence, the developed hybrid system On the other hand, the incorporation of herbal agents in these dressings,
showed great potential for application in pathologies requiring chronic such as Aloe vera, has proven to improve their bioactivity, due to having
antioxidative, antibacterial, antiviral, and also healing properties,
11
Fig. 8. A, B and C – Transmission electron microscopy images of the developed gelatin-based bio-elastomer nanocomposites, at higher (A) and lower (B) magni
fication, with the respective schematic representation (C); D and E – Cumulative drug release percentage of polymyxin B sulfate (D) and ciprofloxacin (E) from the
developed gelatin-based bio-elastomer nanocomposites, with varying HNTs content; F and G – Bacterial inhibition zone diameter (F) and images (G) after exposure of
the agar plates containing Staphylococcus aureus (a to f) or Pseudomonas aeruginosa (g to l) to the developed formulations; adapted from Shi et al. [42].
mainly because of containing glucomannan in its composition release, while the niosomes presented a burst release on the first day.
[111–113]. In this context, Dadashzadeh et al. [43] prepared Aloe vera Swelling experiments were also performed, to assess the ability of the
gel-loaded niosomes incorporated into an alginate/gelatin-based developed formulations to absorb excessive fluid from the wound, and
hydrogel. For in vitro Aloe vera release tests, three formulations were results showed that an alginate hydrogel had a lower swelling ratio than
prepared: niosomes, an alginate/gelatin-based hydrogel, and niosomes the niosomes alginate/gelatine hydrogel, and with this last formulation
incorporated into the hydrogel. Both hydrogels exhibited a sustained having a lower ratio than the alginate/gelatin hydrogel. Thus, the
12
presence of gelatin increased the hydrogel’s ability to absorb water, and only due to safety and regulatory issues, but also due to the complexity
the lower water absorption of the niosomes alginate/gelatin hydrogel and costs associated with nanotechnology formulation production [11].
compared to the alginate/gelatin hydrogel could be explained by the Nevertheless, despite this being the reality for most nanoscale technol
interactions between the polar heads of the niosomes and the carboxyl ogies, some recent studies in humans with promising results have begun
groups present in gelatin, making the free hydrophilic groups available to appear in the scientific literature, both for AD treatment and wound
to bind to the water molecules exist in smaller amounts. Given all these healing. A particular study for AD showed safety and good tolerability
results, Aloe vera-loaded niosomes incorporated into an alginate/gelatin- for the application of hybrid systems in humans, which could be a lever
based hydrogel could be a promising candidate for application as wound for further clinical studies, as the way to determine the treatment
dressing. regimen and for the developed formulation to finally become commer
cially available [19]. In the case of wound healing, it was observed that a
2.3.2. Chitosan/gelatin-based xerogels hybrid system applied to post-cesarean wounds in humans resulted in a
Uncontrolled bleeding can cause up to 40 % of deaths in traumatic faster healing process and the absence of allergic effects, which offers
accidents. Conventional topical hemostatic agents, such as gauze, are hope for the arrival of these new treatment approaches to patients and a
inadequate to halt large blood loss. Other traditional hemostatic phys contribution to lower health costs and nursing care in the near future
ical agents such as gelatin foam, synthetic agents such as glutaraldehyde [10].
and cyanoacrylates, and biological agents such as fibrin sealants also Furthermore, specifically regarding AD, there is only 30 % similarity
have important drawbacks, since they can cause inflammation, tissue between murine and human skin associated genes, and although mouse
toxicity, and transmission of viral infections. Additionally, although models are still the gold standard for early research, they do not allow
chitosan is also known for its hemostatic potential, with commercial for a spontaneous development of AD. Although several studies included
formulations such as Celox™ already having reached the market, these in this review used induction by chemical stimulus to obtain AD-like
wound dressings lack porosity and mechanical strength, and tend to lesions, in order to test the efficacy of the developed formulations, it is
adhere to the wound surface, which can disrupt the already formed clot only a model, and hence has its limitations, which could lead to un
or lead to repeated bleeding. Given these limitations, it becomes clear successful results in clinical trials, even if favorable results were
that it is very important to create new effective and safe hemorrhage observed in mice. Therefore, in the near future it would be opportune to
control dressings. In this context, chitosan xerogels, which are porous select experimental models that use human cells to mimic both healthy
structures obtained from the dehydration of wet polymeric gels (with or and diseased human skin as much as possible, for the obtained results to
without crosslinkers), have emerged, having been reported to be good be as close as possible to the human-related situation. Furthermore,
hemostatic agents, with good porosity and absorption capacity. Addi more clinical trials must be carried out in order to obtain more robust
tionally, gelatin can be incorporated into chitosan xerogels not only to promising results, so that these types of formulations can be closer to
strengthen their porous structure, but also because it has intrinsic he reaching the pharmaceutical market [11].
mostatic potential, by activating platelet aggregation, and silica and Furthermore, in what concerns pre-clinical studies, and similarly to
calcium have also shown to improve blood clotting themselves. In line what happens for AD, the study of wound healing also has its own
with this, Patil et al. [44] incorporated silica NPs and calcium into a limitations, since the immune response significantly differs between
chitosan/gelatin-based xerogel, ionically crosslinked with sodium tri animal models (for example between mice and rats). Additionally, the
polyphosphate, with the purpose of improving hemostasis. The newly animals that have the most similarities with humans, such as pigs, have
developed wound dressing showed high absorption, good swelling ca higher associated costs, as well as regulatory aspects in some countries,
pacity, high porosity, and high robustness (good mechanical strength). It hindering their use. Likewise, the fact that animal models differ sub
also showed high in vitro efficacy, with a 16-fold higher blood clotting stantially between studies reduces result comparability, and hence the
capacity than gauze and commercial Celox™, also being superior to correlation between these models should be assessed. Therefore, in
these marketed options in in vivo studies (rat artery bleeding model), future experiments there should be a preferential choice for in vitro and
leading to a significantly faster hemostasis, in addition to having the ex vivo wound models using human cells, capable of minimizing result
added advantage of being easily removed from the wound injury site. bias, reducing the gap that may exist between studies carried out in
Furthermore, the incorporation of silica NPs and calcium separately in animals and those carried out in humans [20].
the chitosan/gelatin xerogel already improved the blood clotting ca
pacity, with the incorporation of both of them together further 4. Conclusion
enhancing the clotting capacity. All these results showed the great po
tential of the developed hybrid preparation for wound healing purposes. Although topical administration has several advantages when
compared to other routes of administration, especially for diseases with
3. Current limitations and what’s next for natural polymers- a skin etiology, the barrier properties of the skin severely hinder drug
based systems for topical management of wound healing and molecule penetration. In addition, concerns regarding the side effects of
atopic dermatitis topically administered drugs, such as corticosteroids, for the treatment
of atopic dermatitis, and antibiotic resistance and biofilm formation, in
When it comes to including natural polymers in DDSs for the man the case of wounds, are major concerns that make the management of
agement of wounds and AD, there are still a few challenges to overcome. these skin lesions a great challenge. Therefore, nanotechnology can be of
For both conditions, there is still a poor toxicological characterization in great help, since drug encapsulation can reduce systemic and local side
the early stages of the development of technologies that make use of effects, and lead to controlled and targeted drug release. Furthermore,
natural polymers [11,20]. A clear example are cytotoxicity tests in natural polymers-based nanocarriers and hydrogels have proven to be
wound studies, in which researchers usually only use one single cell line, advantageous for the topical management of AD, leading to increased
often derived from animals, not humans, which could increase the drug retention in the epidermis, improved visible appearance of skin
likelihood of failure in clinical trials, if made [21,22,42,44]. Thus, it is lesions, and decreased inflammation, erythema and TEWL. Not only
necessary to develop new protocols that can address all toxicological have in vitro and in vivo results proved to be promising, but also clinical
concerns, in order to create truly biocompatible macro- and nano trials have made evident that the developed formulations are not only
materials. On the other hand, although many studies report successful effective, but also safe and well tolerated.
results for formulations based on nanotechnology, the existence of these Specifically in the topical treatment of skin wounds, nowadays we
technologies in the market is not proportional, since the scale-up are concerned not only about bacterial resistance to antibiotics, but also
translation for clinical application is one of the biggest challenges, not about the potential toxicity of antiseptics and metallic NPs to human
13
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The authors declare that they have no known competing financial (2021) 1545–1567, https://doi.org/10.1007/s13346-021-00932-7.
interests or personal relationships that could have appeared to influence [21] L.M. Hemmingsen, K. Julin, L. Ahsan, P. Basnet, M. Johannessen, N. Škalko-
the work reported in this paper. Basnet, Chitosomes-in-chitosan hydrogel for acute skin injuries: prevention and
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International Journal of Biological Macromolecules 263 (2024) 130296

Contents lists available at ScienceDirect

International Journal of Biological Macromolecules

A review on natural biopolymers in external drug delivery systems for

1.1. Overview: Background and significance

The treatment of skin diseases through topical drug administration

healing. based wound gel dressing, with vancomycin (antibiotic effective

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