International Journal of Biological Macromolecules 138 (2019) 854–865

Contents lists available at ScienceDirect

International Journal of Biological Macromolecules

journal homepage: http://www.elsevier.com/locate/ijbiomac

Review

Natural composite dressings based on collagen, gelatin and plant

bioactive compounds for wound healing: A review
Alexandra Gaspar-Pintiliescu, Ana-Maria Stanciuc ⁎, Oana Craciunescu
National Institute of R&D for Biological Sciences, Bucharest, Romania

a r t i c l e i n f o a b s t r a c t

Article history: Skin wound dressings are commonly used to stimulate and enhance skin tissue repair. Even if wounds seem easy
Received 6 March 2019 to repair for clinicians and to replicate in an in vitro set-up for scientists, chronic wounds remain currently an
Received in revised form 24 July 2019 open challenge in skin tissue engineering for patients with complementary diseases. The seemingly simple pro-
Accepted 24 July 2019
cess of skin healing hides a heterogenous sequence of events, specific timing, and high level of organization and
Available online 25 July 2019
coordination among the involved cell types. Taken together, all these aspects make wound healing a unique pro-
Keywords:
cess, but we are not yet able to completely repair the chronic wounds or to reproduce them in vitro with high fi-
Skin repair and regeneration delity. This review highlights the main characteristics and properties of a natural polymer, which is widely used
Herbal molecules as biomaterial, namely collagen and of its denatured form, gelatin. Available wound dressings based on collagen/
Biopolymers gelatin and proposed variants loaded with bioactive compounds derived from plants are presented. Applications
of these composite biomaterials are discussed with emphasis on skin wound healing. A perspective on current
issues is given in the light of future research. The emerging technologies support the development of innovative
dressings based exclusively on natural constituents, either polymeric or bioactive compounds.
© 2019 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854
2. Wounds and the healing mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
2.1. Role of wound exudate and mechanical stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
2.2. Wounds classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3. Collagen-based wound dressings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.1. Collagen and its derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.2. Collagen and gelatin dressings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
4. Natural composite dressings of collagen/gelatin and plant compounds for wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
4.1. Porous scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
4.2. Electrospun matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
4.3. Film, membranes, sheets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
4.4. Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
4.5. Microspheres, microparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
5. Conclusions and future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862

1. Introduction

Wounds represent an increasing burden in the healthcare system.

⁎ Corresponding author at: 296, Splaiul Independentei, 060031 Bucharest, Romania. Statistics reported that there is a prevalence rate of approx. 2 million
E-mail address: [email protected] (A.-M. Stanciuc). wounded patients per 491 million EU inhabitants (~40%) and among

https://doi.org/10.1016/j.ijbiomac.2019.07.155
0141-8130/© 2019 Elsevier B.V. All rights reserved.
 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865 855

them 25–50% are hospitalized patients who have developed bed sores. antimicrobial activities to the wound dressings, helping in wound con-
It is estimated that 30 to 40 patients per 1000 operations presented sur- traction, vascularization and epithelization [13]. On the other hand,
gical site infections, including life-threatening ones, especially in elderly their controlled release can play an important role in inflammation sup-
or diseased persons [1,2]. On the other hand, chronic non-healing pression, angiogenic pathways promotion and collagen synthesis stim-
wounds have a prevalence rate of 2% in US population [3]. All these ulation, thus accelerating the wound healing process [14]. Not least,
data explain the great interest in improving the therapeutic potential polyphenols can cross-link natural polymers, in particular collagen
of commercial biomaterials by developing novel formulations with and gelatin, via hydrogen bonding, to increase their mechanical
high biocompatibility and regenerative capacity. strength and thermal stability [15,16].
In order to address all aspects of wound care treatment, wound However, such plant-polymeric wound dressings are not found on
dressings have been designed in different morphologies and properties the market due to lack of comprehensive evaluation of the characteris-
and used as films, foams, hydrogels, hydrocolloids or scaffolds, accord- tics for a suitable wound dressing, such as moisture vapors permeability,
ing to the complexity of the wound [4,5]. An ideal wound dressing exudate absorption, biodegradability and biocompatibility [4]. In addi-
should adhere to the injured tissue, maintain balanced moist conditions, tion, rigorous studies are needed to reach the standardization of
allow oxygen exchange and protect from bacterial infection, thus ensur- constituent's extraction, to establish the non-toxic dose of the bioactive
ing an optimal microenvironment to accelerate the healing process [4]. compound, in order to develop novel composite formulations for mod-
Currently, skin wound dressings are classified as temporary dressings ern management of skin wounds.
and permanent engineered skin substitutes [4]. The temporary ones This review will provide recent information regarding the mecha-
should provide wound exudate absorption and protection until nisms involved in the wound healing process and will discuss the ad-
wound closure, while skin substitutes are expected to integrate with vantages and disadvantages of collagen- and gelatin-based
the host skin and accelerate the regeneration process. Still, re- commercial wound dressings. Current advances in the technologies
epithelization is impaired by slow vascularization and optimization of for the fabrication of collagen and gelatin wound dressings incorporat-
several properties of the used biomaterials, such as porosity, density, ing plant bioactive compounds will be provided as main focus of the re-
fluid absorption, thickness and morphology is required [5]. As a result, view, to emphasize their improved properties and bioactivity. Future
temporary dressings included bioactive compounds, such as growth trends in the field of wound dressings fabricated from natural com-
factors or microbicidal agents for topic delivery [6,7]. Skin substitutes pounds of animal and vegetal origin are discussed.
were tailored in terms of porosity and biodegradability to act as better
scaffolds for cell migration, adhesion and proliferation, in order to pro- 2. Wounds and the healing mechanisms
vide novel epidermal regeneration approaches and reduce scarring [5].
Both synthetic and natural polymers were used for wound dressing The complex process of wound healing is based on dynamic and fas-
applications, but the synthetic ones were suitable only for superficial cinating mechanisms that differ on the evolutionary scale [9]. The four
wounds, presenting deficiencies of some important properties of highly integrated stages - hemostasis, inflammation, proliferation and
wound dressings, such as low adherence, absorption and permeability tissue remodelling must start in a definite order and continue for a cer-
[8]. Natural polymers, such as alginate, silk, fibrin, keratin, fucoidan tain duration (Fig. 1). Seconds after a skin lesion, blood clotting is pro-
were extensively used in skin tissue engineering due to their biocom- moted by released factors, preventing blood loss and pathogen agents
patibility, biodegradability, easy resorption and capacity to repair or re- entering the body. During the inflammatory phase, chemotactic signals
generate the damaged tissue [5], but are often prone to microbial recruit specialized cells to clean the injury from foreign particles, includ-
contamination. Collagen is the main component of the extracellular ma- ing microorganisms [17], and a fibrin eschar is formed. Then, a granula-
trix involved in scar formation, considered as a secondary process of tion tissue is formed by extracellular matrix (ECM) deposition,
healing, after wound contraction [9]. Although its ex vivo conditioning including collagen, which replaces fibrin. For wound re-
as topic wound dressing promotes epithelization and tissue regenera- epithelialization and closure, cells migrate from the epidermal edges
tion, due to its chemotactic properties, wound contraction issues are over the surface of the injured area.
still to be considered [10,11]. Mixtures of synthetic/natural polymers
were proposed to prolong the degradation time, up to that of the 2.1. Role of wound exudate and mechanical stress
healing process, to improve the mechanical properties, maintaining in
the same time the gas and water vapor permeability of the biomaterial A critical step during the healing process is the development of a
and the biocompatibility, even of the resulting degradation products wound exudate, acting like a natural balm that seals the wound from
[12]. bacteria and debris. The production of exudate is important during the
The combination of herbal constituents with natural polymers in inflammatory and proliferative stages of the healing process, but its ef-
new dressing materials represents the next step in wound care treat- fects are not fully understood. The plasma-derived exudate acts as a car-
ment. Incorporated plant-derived compounds confer antioxidant and rier system, whose volume vary depending on the healing stage and

Fig. 1. Scheme of normal physiological wound healing process, consisting of four main stages – hemostasis, inflammation, proliferation and tissue remodelling.
856 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865

wound type, origin, location and size [18]. In acute wounds, the exudate [36]. In addition, chronicity is characterized by a series of common fea-
is rich in proteins and essential nutrients for the epithelial cells, but it tures: delayed and/or excessive inflammatory phase, nosocomial and
also contains endogenous proteolytic enzymes and their inhibitors, in persistant infections, development of drug-resistent microbial biofilms
a delicate balance, which degrade ECM components and contribute to and the dermal and epidermal cells failure to react to reparative stimuli
wound bed preparation before wound closure and remodelling [19]. [37]. Chronic wounds, such as venous leg ulcers, diabetic wounds and
The beneficial impact exhibited by acute wound fluid is contrasting pressure ulcers, present an increased risk of infection, which is the
with the chronic wound exudate, that containes numerous proteinases main cause of morbidity. According to the extent of the affected area,
that slow down or even block the proliferation of key cells involved in the wounds are classified as superficial, partial thickness or full-
the wound healing process [20]. A more complete understanding of thickness [33]. Superficial wounds present intact re-epithelialized tissue
the fluid production quantity, composition and effects will contribute after healing, while the large and deep wound sites can either not heal
to correct the wound management and proper healing. Use of wound due to additional complications, e.g. infections, or heal with scar forma-
dressings targets the removal of excessive exudate, debris and potential tion [21]. Full-thickness skin wounds (e.g., severe burn wounds) are
pathogens from the wound bed, while maintaining the optimal mois- often linked to a comprehensive loss of tissue and require a fast cover-
ture balance required for cell recruitment and wound healing in due age of the body with autologous or allogeneic grafts [38]. Due to previ-
time. ously reported limitations of these grafts (availability,
A significant aspect, often not exploited, is the mechanical stress at immunogenicity), natural and synthetic polymers were extensively
the wound site that greatly influences the rate and quality of healing. used to fabricate wound dressings and skin tissue substituents [39–41].
Skin mechanical properties play a fundamental role in both intact and
injured skin with implications in the wound healing process. Several 3. Collagen-based wound dressings
studies showed that skin wounds were more prone to develop a scar
under mechanical tension during the healing process [21–23]. These ob- Among natural macromolecules, collagen and its denaturated form,
servations have determined surgeons to reduce tension post-surgery, at gelatin represent the most appropriate building blocks for the develop-
the incision area [24,25]. The cells responsible for stress detection in the ment of wound dressings and biomaterials biomimetic to human skin.
connective tissue of the wound bed, i.e. fibroblasts and myofibroblasts
transduce it into a physiological response [26]. Several in vitro and 3.1. Collagen and its derivatives
in vivo studies have showed that increased tension promoted their pro-
liferation [27], inhibited fibroblasts apoptosis [28] and activated several Collagen is the main proteic component of the ECM. A variety of
signalling pathways that initiate an irregular deposition of ECM. sources from bovine, porcine, equine, avian to marine tissues are avail-
able for collagen extraction [42,43]. Although collagen is mainly ex-
2.2. Wounds classification tracted from cattle and porcine slaughterhouse wastes, fishery by-
products have recently become an important alternative source. From
The integrity of our biggest organ, the skin, plays a fundamental role all 29 types of collagens identified so far [44], collagen type I is the
in preserving the physiological homeostasis of the human body [29]. A most abundant and easy to extract from several types of mammalian
skin wound refers to a disruption in the continuity of the epithelial lin- connective tissues, such as skin, tendon, cornea, etc. [45]. Fish collagen
ing of the skin and/or mucosa caused by physical and/or thermal factors was extracted from recovered skin, fins, scales, bones or swim bladders
[30]. Wounds can be classified according to several criteria, such as ap- [46–48].
pearance, duration of the repair process and affected area, as presented Collagen extraction in its insoluble, acid-soluble or neutral salt-
in Table 1. soluble forms is based on a simple chemical or enzymatic hydrolysis,
Depending on the wounds appearance, they can be necrotic, as previously detailed [49,50]. Gelatin is a mixture of peptides derived
sloughy, granulating, epithelializing or infected [31]. There are several from collagen, extracted from tissues using the same methods as for col-
factors that can interfere along the process of wound healing, impairing lagen, but completed with thermal treatment or it is obtained by acid or
the mechanisms of proper tissue repair. The duration of the repair pro- alkaline treatment of collagen [51]. Currently used gelatins derive from
cess divides wounds in acute and chronic [30,32,34]. An acute wound bovine, porcine and poultry collagens, but also from fish and marine
occurs suddenly, due to accidental or surgical injury and normally organisms.
heals within 8–12 weeks depending on the size, depth and extent of Regardless of the animal source, i.e. terrestrial or marine, the ex-
skin layers (epidermis, dermis) damage [35]. Chronic wounds, on the tracted type I collagen exhibits the typical structure with two α1-
other hand, fail to follow the normal physiological stages of healing chains and one α2-chain, but it differs in terms of composition (primary

Table 1
Classification of wounds according to their appearance, repair process and affected area.

Criterion Type of wound Characteristics Reference

Appearance Necrotic Accumulation of dead tissues [31]

Sloughy Wet and gristly rehydrated necrotic tissue
Granulating Abundant granulation tissue with production of excessive exudate
Epithelializing Associated with new epidermis formation
Infected and Contamination with microorganisms, inflammation and pus formation
malodorous
Repair Acute Tissue injuries that usually heal between 8 and 12 weeks; caused by mechanical or chemical factors, burns; include: (i) abrasions [30]
process (e.g., rope burns, skinned knees), (ii) avulsions (e.g., animal bites), (iii) contusions, (iv) crush wounds, (v) cuts, (vi) fish hook,
(vii) incised wounds, (viii) lacerations.
Chronic Delayed healing due to underlying physiological conditions, such as diabetes, infections; defined by the production of excessive [32]
exudate that leads to maceration of healthy skin tissue, reduction of lymphocytes mobility and, finally, disruption of the stages
sequence in tissue repair.
Affected Superficial Affects epidermal skin surface [33]
area Partial thickness Affects both epidermis and the inner dermal layers
Full-thickness Affects epidermis, dermis and the underlying subcutaneous tissue
 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865 857

Table 2
Several commercially available collagen- and gelatin-based wound dressings.

Type of Composition Collagen Product Advantages Disadvantages Type of wound Reference

dressing content
(wt%)

Temporary wound dressings

Pad Bovine collagen, 55 Promogran Haemostatic Not to be used in Partial and full thickness wounds including: abrasions, [71]
oxidized regenerated effect case of third-degree bleeding surfaces, diabetic or venous ulcers, pressure
cellulose burns, bovine source injuries, dehisced surgical incisions
Pad Type I native equine 100 Biopad Free from High cost, time Partial and full thickness wounds including: bleeding [72]
collagen collagen consuming, equine surfaces, diabetic or venous stasis ulcers, pressure
degradation source injuries, dehisced surgical incisions
products
Pad Bovine collagen, Manuka 88 Puracol No additional High cost, bovine Partial and full thickness wounds including: bleeding [73]
honey debridement source surfaces, abrasions, burns, pressure, venous or diabetic
needed ulcers, dehisced surgical incisions
Pad Collagen, calcium 90 Fibracol Maintain a Requires secondary Partial and full thickness wounds including: bleeding [74]
alginate Plus moist dressing surfaces, abrasions, 2nd degree burns, diabetic or
environment venous ulcers, pressure injuries, dehisced surgical
incisions
Pad Collagen, sodium Not ColActive Inhibits the Requires secondary Partial and full thickness wounds including: abrasions, [75]
alginate, available Plus Ag activity of dressing, bovine 1st and 2nd degree burns, pressure, diabetic or venous
carboxymethylcellulose, MMPs source ulcers, dehisced surgical incisions
EDTA, AgCl
Pad Collagen fleece, Not Septocoll E Activates Possible skin Partial and full thickness wounds including: bleeding [76]
gentamicin salts available platelets reactions, equine surfaces, infected wounds
source
Membrane Peptides derived from Not Biobrane Flexibility Requires secondary Partial thickness burn wounds [77]
porcine dermal collagen, available dressing, porcine
silicon, nylon source
Scaffold Acellular collagen matrix Not Permacol Flexibility Low elasticity, Full-thickness wounds including burns [78]
available porcine source
Powder Collagen 50 Catrix Reduce Requires secondary Partial and full thickness wounds including: cuts, [79]
bleeding dressing, bovine abrasions, irritations, post-surgical incisions 1st and
Biodegradable source 2nd, degree burns, radiation dermatitis, pressure, stasis
or diabetic ulcers
Gel Collagen 65 CellerateRX Maintain a Requires secondary Partial and full thickness wounds including: surgical [80]
moist dressing, bovine wounds, traumatic wounds, 1st and 2nd degree burns
environment source pressure, venous stasis, arterial or diabetic ulcers
Gel Short and long 52 Stimulen Maintain a Requires secondary Partial- and full-thickness wounds including: abrasions, [81]
polypeptides of collagen, moist dressing, bovine partial-thickness burns, pressure, venous, or diabetic
glycerin environment source ulcers
Compressed Porcine gelatin 100 Gelfoam Hemostatic, Nonelastic Bleeding wounds [82]
sponge resorbable
Sponge Porcine gelatin 100 Surgifoam Hemostatic Potential bacterial Bleeding wounds [83]
growth substrate

Skin substitutes
Scaffold Collagen, 92 Integra Strength and Not to be used in Partial and full thickness wounds including: abrasions, [84]
glycosaminoglycan, flexibility case of infected lacerations, surgical wounds incisions, 2nd degree
silicon layer wounds, bovine burns, pressure, venous, diabetic or vascular ulcers
source
Scaffold Collagen, elastin Not Matriderm Flexibility High cost, bovine Full thickness wounds including burns [85]
available source
Cellular Collagen type I Not Orcel Total Not to be used in Full thickness wounds including burns [86]
matrix cultivated with allogenic available resorbable case of infected
skin cells wounds, high cost,
bovine source
Cellular Collagen cultivated with Not Apligraf Resorbable Not to be used in Partial and full thickness wounds including: diabetic [87]
matrix skin cells, polycarbonate available case of infected foot ulcers, venous leg ulcers
membrane wounds, high cost
bovine source

structure) and conformation (secondary and tertiary structure) [52]. variability of the enzymatic degradation rate and susceptibility to bacte-
Significant differences were reported in the amino acid content of rial infection [54]. Regarding gelatin, it is soluble in water at tempera-
type I collagen extracted from cattle, pork and poultry, on the one tures above 35 °C, forming a transparent gel and it solidifies when
side, and frog and shark, on the other side [53]. However, both collagen cooled [55].
and gelatin contain the same characteristic and repeating amino acids When used as an implant, exogenous collagen is exposed to in vivo
sequence of Gly-X-Y, where X and Y are mainly proline and degradation by endopeptidases, leading to products that exhibit a che-
hydroxyproline. motactic effect for several cell types, essential in the wound healing pro-
In direct correlation with their proline and hydroxyproline content, cess [56]. Its biodegradability can be controlled by cross-linking, which
collagens extracted from mammalian tissues presented higher denatur- results in formation of additional covalent bonds between amino and
ation temperature and stability, compared to marine collagens [53]. carboxyl groups. Collagen cross-linking was usually achieved using glu-
Nevertheless, acid and enzymatic preparations of collagen had de- taraldehyde, carbodiimides or other chemical products, but increased
creased mechanical strength, when compared to in vivo behaviour, cytotoxicity of the final product was often reported [57,58]. Physical or
858 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865

Table 3
Composite wound dressings based on two components, collagen/gelatin and a plant extract/compound with synergistic activity.

Type of Natural Plant extract/source Cross-linking Manufacturing Advantages Type of wound Reference
dressing polymer/source agent technique

Sponge Collagen from Herbal formulation of – Freeze-drying Antibacterial activity against S. aureus and P. Full-thickness [105]
bovine tendon Terminalia chebula, aeruginosa. Stimulated the in vivo wound infected wound
Phyllanthus emblica and healing process by increasing hydroxyproline
Terminalia bellerica content in granulation tissue and decreasing
extracts MMPs levels
Herbal formulation of – Freeze-drying Good biocompatibility in L929 fibroblast cells – [106]
Arnica montana,
Artemisia absinthium and
Urtica dioica extracts
Total polyphenolic – Freeze-drying Induced proliferation and attachment of human – [107]
extract of Artemisia dermal fibroblasts and HaCaT cells; stimulated
absinthium the synthesis of extracellular matrix proteins
Collagen Phenolic extract of Genipin Lyophilization Inhibited myeloperoxidase and collagenase – [108]
Hamamelis virginiana activity. Good biocompatibility in NIH3T3 cells.
Collagen from Extract of Coccinia – Freeze-drying Antimicrobial properties against S. aureus and Full-thickness [109,110]
fish skin grandis E. coli. Good biocompatibility in NIH3T3 and excision wound
HaCaT cells. Stimulated the in vivo wound
healing process by enhancing the collagen
synthesis
Collagen Polysaccharides from Carbodiimide Lyophilization Good biocompatibility in HUVEC cells. Chorioallantoic [111]
Astragalus root Promoted the in vitro and in vivo angiogenesis membrane
process assay
Collagen from Polysaccharides from Cinnamon bark Lyophilization Antimicrobial activity against B. subtilis, S. – [112]
cow hide Delonix regia seeds extract aureus and E. coli
Nanofiber Gelatin from Crude extract of Centella Glutaraldehyde Electrospinning Release of asiaticoside, a compound with – [113,114]
membrane porcine skin asiatica wound healing properties
Gelatin from Carvacrol – Blow-spinning Antimicrobial activity against E. coli, S. enterica, – [115]
fish skin L. monocytogenes
Gelatin Curcumin Glutaraldehyde Electrospinning Induced migration and proliferation of Hs-27 Full-thickness [116]
cells. Decreased MCP-1 inflammatory marker. punch biopsy
Enhanced the in vivo healing process by wound
increasing collagen deposition
Aerogel Collagen from Extract of Triticum – UV light Antimicrobial activity against B. subtilis and E. Chorioallantoic [117]
goat tendon aestivum reinforcement, coli. Good biocompatibility in EAHy926 cells. membrane
followed by salt Promoted the in vitro angiogenesis process. assay and
leaching and Stimulated the in vivo wound healing process excision wound
freeze drying
Collagen from Curcumin – UV light Increased adhesion and proliferation of EA. Chorioallantoic [118]
rat tail cross-linking, hy926 cells. Promoted the in vivo angiogenesis membrane
followed by salt process. Induced faster in vivo wound healing assay and
leaching and process excision wound
freeze drying
Film Collagen from Thymol – Casting method Antioxidant activity and antibacterial – [119]
rat tendon properties against S. aureus, B. subtilis, E. coli
and P. aeruginosa
Solvent Inhibited the growth of S. aureus, E. coli, B. – [120]
evaporation subtilis, E. aerogenes and C. albicans
method
Fucoidan from Laminaria – Air-drying Stimulated NIH3T3 cells proliferation and – [121]
japonica migration
Gelatin from Extract of Lawsonia – Air-drying Antioxidant activity. Accelerated the in vivo Excision [122]
cuttlefish skin inermis wound healing process by increasing the wound
antioxidant profile and the hydroxyproline
content
Gelatin from Thymol Glutaraldehyde Air-drying Antioxidant activity and antibacterial – [123]
bovine source properties against S. aureus, B. subtilis, E. coli
and P. aeruginosa

enzymatic treatments were non-cytotoxic, but the degree of collagen considered an optimal solution for immunogenicity elimination [65].
cross-linking was reduced [59,60]. Recently, riboflavin and plant- However, acid treatment of collagen molecules had a low yield, while
derived molecules, such as tannic acid, genipin, were used as natural their enzymatic cleavage took place at different sites with a reaction ki-
cross-linking agents that interact with proline-rich proteins, such as col- netics variation depending on the working parameters [66]. As a result,
lagen and gelatin by hydrogen and covalent bonds, or hydrophobic link- one could obtain heterogenous collagen extracts, containing both
ages [51,61,62]. Proanthocyanidins were reported as cross-linkers of atelocollagen and intact molecules of collagen, with increased solubility,
collagen, improving its thermal stability [63] and inducing a stronger in- but decreased mechanical strength, compared to collagen in vivo [65].
teraction between collagen fibrils, compared to chemical agents [64]. However, these extracts were able to form collagen fibrils with the char-
In regard to collagen biocompatibility, there are some concerns on acteristic band pattern at 67 nm, similar to in vivo biosynthesis [67]. It
possible antigenic/immunogenic response due to the presence of N- was reported that the higher structural integrity of collagen was pre-
and C-terminal telopeptides. Their amino acid sequences vary with served after extraction, the better its interaction with fibroblasts and
the species and their removal by acid or enzymatic treatment is suitability for skin tissue engineering applications [68]. Cross-linking
 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865 859

with glutaraldehyde or 1,4-butanediol diglycidyl ether was another ap- composite dressings is improved by the interactions between collagen,
proach to block side groups that render collagen antigenicity [51,69]. On gelatin or other natural polymers and plant compounds [104]. They
other hand, gelatin processing used high thermal operations that de- can be classified as natural wound dressings consisting of two compo-
grade the proteic molecule to smaller peptides of various molecular nents, i.e. a polymer (collagen or gelatin) and a plant extract or com-
weights and no aromatic radicals, thus limiting significantly its immu- pound (Table 3) and multicomponent wound dressings consisting of a
nogenic potential [55]. mixture of natural polymers and plant extracts or compounds
(Table 4). These wound dressings can be cross-linked or not with chem-
3.2. Collagen and gelatin dressings ical agents (glutaraldehyde, carbodiimide) or plant compounds
(genipin, cinnamon). Depending on the manufacturing technique,
Both collagen and gelatin were widely used as wound dressings and wound dressings based on collagen containing other natural polymers
tissue engineering products for human use, due to their haemostatic and plant bioactive compounds can be classified in different types of po-
properties, excellent biocompatibility, reduced cytotoxicity, low antige- rous scaffolds: sponges, electrospun nanofiber matrices, films,
nicity, controlled biodegradability and ability to stimulate cellular at- hydrogels. In addition, microspheres and microparticles of collagen or
tachment and growth [70]. From more than 3000 types of wound gelatin are developed as new drug delivery systems. All these natural
dressings available on the market, addressing all aspects of wound wound dressings were proposed to overcome the disadvantages of
care, this review will focus on collagen- and gelatin-based dressings. existing products, widening their applications, as further discussed.
The advantages and disadvantages of the products available on the mar-
ket are presented in Table 2. 4.1. Porous scaffolds
In several studies, both collagen and gelatin polymers were condi-
tioned as powders, gels, films or scaffolds to provide haemorrhage con- The porosity of a wound dressing is essential for promoting cellular
trol in various surgical procedures [88]. Porous matrices of collagen and infiltration and proliferation and to provide a suitable template for ECM
gelatin absorbed wound exudates, maintaining in the same time a moist synthesis and deposition [39,56,124]. Porous structure is a desirable
environment, thus stimulating the wound healing process [51]. There property for allowing the transport of oxygen, drugs, nutrients and met-
are several reports that have proved the biocompatibility of collagen abolic wastes to and from the cells. Several studies reported the associ-
dressings not only in vitro [45,89], but also in vivo [90,91], especially ation of collagen with polyphenols for manufacturing new materials
for bovine- and porcine-derived collagen. Recently, marine collagen with synergistic activity for skin tissue engineering (Table 3). Our
gained attention and several new biocompatible collagen dressings group showed that the stability of collagen porous scaffolds was im-
were developed as films, nanofibers, sponges, sheets and hydrogels for proved after mixing with herbal formulations of Arnica montana, Arte-
wound treatment [92,93]. In a comparative study, fish skin collagen- misia absinthium and Urtica dioica extracts [106]. The porosity of
based dressings accelerated the wound healing process in vivo, in a sim- composite dressings consisting of collagen-plant extract decreased
ilar extent to collagen from bovine source [90]. However, regardless of compared to that of collagen dressing, but maintained values over
the conditioning form, wound dressings were generally manufactured 70%, recommended for biomedical applications in order to allow cell in-
for temporary use, only to protect against pathogens, to reduce pain filtration and attachment (Fig. 2a). TEM observations on composite
and, in some cases, to release beneficial compounds at the wound site dressing structure revealed the presence of collagen fibrils with the typ-
[4,89]. ical banding pattern (Fig. 2b). Moreover, collagen dressings loaded with
In addition, collagen and gelatin matrices acting as porous scaffolds total polyphenolic extract from Artemisia absinthium induced prolifera-
for cell migration provided both structural and mechanical support tion and attachment of human dermal fibroblasts and keratinocytes,
and stimulated the growth of new tissue [56,88]. It is important to high- also stimulating the synthesis of skin ECM components [107].
light that, in this case, a special attention was paid to the physico- Other studies have showed that the herbal formulation of Terminalia
chemical parameters of the collagen scaffold, such as porosity and bio- chebula, Phyllanthus emblica and Terminalia bellerica mixed with colla-
degradability in physiological or inflammatory conditions, and to its ul- gen resulted in a porous dressing with wound healing properties in in-
trastructure [89,94]. fected full-thickness rat wounds [105]. Collagen dressings incorporating
In order to accelerate the wound healing process in animal skin de- Hamamelis virginiana polyphenols had inhibitory properties against
fects, biomaterials that combined collagen and gelatin were also devel- chronic wound enzymes, such as myeloperoxidase and collagenase
oped and used as carrier matrices [56,95,96]. Fish gelatin films were also [108]. Extracts of Coccinia grandis were loaded on 3D collagen scaffolds
used as drug delivery systems for therapeutic molecules, such as the obtained from fish skin and presented synergistic activity, such as good
epidermal growth factor, known to exert significant effect in wound biocompatibility in vitro, anti-microbial properties against Escherichia
healing [97]. They presented lower permeability for water and oxygen, coli and Staphylococcus aureus and increased healing effects in vivo
compared to mammalian gelatin films [98]. [109,110]. Collagen matrices incorporating polysaccharides extracted
from Astragalus root were developed as promising wound dressings
4. Natural composite dressings of collagen/gelatin and plant com- with angiogenic properties [111], while collagen scaffolds loaded with
pounds for wound healing Delonix regia seed polysaccharides exhibited antimicrobial activity
against wound pathogens [112].
There is a need to develop a new generation of multicomponent Combinations of collagen and gelatin with other natural polymers
products with synergistic and complementary effects that are expected were recently proposed for wound dressings manufacturing. Thus, col-
to better address the interdependent aspects within all stages of wound lagen was mixed with polysaccharides from animal (chitosan,
care treatment. These composite dressings are intended to treat super- hyaluronic acid) or vegetal sources (starch, cellulose), proteins of ani-
ficial, partial and full-thickness wounds, as well as acute or chronic mal and vegetal origin (silk, zein), or microorganisms-derived polyes-
wounds. Thus, collagen or gelatin dressings were functionalized with ters, such as poly (3-hydroxybutyric acid) (Table 4). These polymeric
plant-derived compounds [99] to manufacture new biomaterials that composites were combined with plant bioactive compounds for the im-
can accelerate the wound healing process of skin wounds [100–102]. provement of the physicochemical and biological properties of wound
Loading the natural polymers with bioactive agents, such as polysaccha- dressings. Sponge-like materials of collagen and hyaluronic acid, loaded
rides, terpenoids, alkaloids, saponins, essential oils, fatty acids and poly- with epigallocatechin gallate were obtained for the treatment of chronic
phenols can stimulate the healing process due to the anti-inflammatory, wounds and, besides good biocompatibility they demonstrated inhibi-
antioxidant, antimicrobial and other regenerative properties exhibited tory effects against major wound enzymes, myeloperoxidase and colla-
by these natural molecules [99,103]. In addition, the stability of these genase [125]. In addition, it was reported that collagen-chitosan
860 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865

Table 4
Multicomponent wound dressings of polymeric mixtures and plant extract/compound for improved wound healing.

Type of Natural polymer/source Herbal Cross-linking Manufacturing Advantages Type of wound Reference
dressing compound/source agent technique

Sponge Collagen from bovine Epigallocatechin Carbodiimide Lyophilization Inhibited myeloperoxidase and – [125]
skin - hyaluronic acid gallate, catechin, collagenase activity
gallic acid
Collagen from cat fish Gel of Aloe vera – Lyophilization Stimulated the proliferation of 3T3L1 cells – [126]
-chitosan
Nanofiber Collagen from bovine Berberine – Electrospinning Antibacterial activity against E. coli and S. Full-thickness [128]
membrane tendon - zein aureus. Good attachment and spreading of wound
L929 cells. Fast tissue regeneration in vivo
Commercial gelatin - Astragaloside IV – Electrospinning Promoted cell adhesion and proliferation Partial-thickness [129]
silk fibroin of keratinocytes. Accelerated the wound burn wound
healing process in vivo by increasing blood
vessel density and VEGF level
Gelatin from porcine Extract of – Electrospinning Induced L929 fibroblasts attachment, A second-degree [130]
skin - starch Lawsonia inermis proliferation, and collagen secretion. burn
Antibacterial activity against E. coli and S.
aureus. Accelerated the wound closure
in vivo by decreasing the inflammatory
response
Nanofiber Gelatin – poly Extract of Coccinia – Electrospinning Antibacterial activity against E. coli and S. Excision wound [110]
coating of (3-hydroxybutyric grandis and air-drying aureus. Good biocompatibility in NIH 3T3
scaffold acid) with coating of and HaCat cells. Stimulated the wound
collagen from fish skin healing process in vivo by enhancing the
collagen synthesis and decreasing the
inflammation response.
Double-layered Gelatin -poly Curcumin – Electrospinning Good biocompatibility in NIH 3T3 and Full-thickness [132]
nanofibrous (3-hydroxybutyric and HaCat cells. Stimulated the wound healing excision wound
scaffold acid) overlaid on lyophilization process in vivo by enhancing the collagen
keratin/fibrin/gelatin synthesis and growth factors expression
sponge containing
antibiotic
Hydrogel Commercial gelatin Polyphenols of Laccase Air-drying Inhibited myeloperoxidase and – [133]
-chitosan Hamamelis collagenase activity. Antibacterial activity
virginiana against S. aureus and P. aeruginosa
Film Collagen from fish Extract of – Air-drying Antibacterial activity against B. subtilis, S. Full-thickness [134]
scales - fibrin Macrotyloma aureus, P. vulgaris and E. coli. Good excision wound
uniflorum biocompatibility in NIH 3T3 fibroblasts and
HaCaT cells. Accelerated the wound
healing process in vivo by increasing
hydroxyproline content and decreasing
MMPs and inflammatory markers level
Collagen from tendon Pequi oil – Casting method Improved stability of the dressing – [135]
bovine - commercial and drying at 25
gelatin °C
Commercial gelatin - Lupeol Glutaraldehyde Casting method Antioxidant activity. Antibacterial activity – [136]
chitosan and drying at 35 against P. aeruginosa. Good
°C biocompatibility in NIH/3T3 cells
Microspheres Gelatin microspheres Curcumin Glutaraldehyde Emulsion Antibacterial activity against E. coli, P. Full- thickness [137]
incorporated loaded in collagen - solvent aeruginosa and S. aureus. Accelerated the burn infected
in composite cellulose composite evaporation wound healing process in vivo by wound
porous scaffold method and decreasing the inflammatory response
scaffold freeze-drying
Gelatin microspheres Ginsenoside Rg1 Glutaraldehyde Emulsion Induced HUVEC cells proliferation and – [138]
loaded in collagen condensation promoted the angiogenesis process in vitro
-chitosan composite method and
scaffold freeze-drying
Microparticles Microparticles of Flower extract of Glutaraldehyde Water-oil Inhibited collagenase activity – [139]
incorporated collagen (from bovine Calendula emulsion
in porous source) and gelatin officinalis method and
scaffold loaded in collagen Powder extract of freeze-drying Good biocompatibility in L929 fibroblasts Full -thickness [140]
scaffold Aloe vera and inhibited collagenase activity excision wound

scaffolds supplemented with Aloe vera gel enhanced fibroblasts recruit- a highly interconnected porous microstructure, resembling natural
ment, and efficiently promoted cell attachment and proliferation in a ECM [127]. The manufactured electrospun matrices exhibit high poten-
higher rate than scaffolds without plant extract [126]. tial as functional wound dressings due to their physicochemical proper-
ties, such as oxygen permeability, protection against infections,
4.2. Electrospun matrices maintaining of moist environment. Two component electrospun mem-
branes of gelatin and Centella asiatica extract were successfully pre-
Electrospinning technique has a series of advantages in the prepara- pared in different ratios and analysed for asiaticoside release capacity
tion of wound dressings, allowing the production of mixtures of fibres [113]. In vitro and in vivo tests recommended the use of these new ma-
with diameters ranging from microns to nanometers that assemble in terials for the treatment of skin wounds due to high recovery of skin,
 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865 861

Fig. 2. Micrographs of collagen-nettle porous composite showing its porous structure by scanning electron microscopy (a) and collagen-wormwood porous composite showing
reconstituted collagen fibrils (arrows) by transmission electron microscopy (b).

compared to commercial wound dressings [114]. Recently, blow- The same compound incorporated into collagen films decreased the in-
spinning technique was used to obtain gelatin nanofibers encapsulating flammatory response in carrageenan induced oedema in rodent models
carvacrol with great potential for wound dressing applications regard- and exhibited antimicrobial efficiency against Escherichia coli, Pseudo-
ing antimicrobial activity [115]. In another study, curcumin was loaded monas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Enterobacter
into electrospun gelatin nanofiber mats in order to improve its bioavail- aerogenes and Candida albicans [119,120]. An extract of Lawsonia inermis
ability during the wound healing process [116]. incorporated in fish gelatin films improved the wound healing activity
Still, electrospinning of collagen and gelatin is poor and there is a in a rat model [122]. The antioxidant activity analysed by catalase, su-
need of special treatments, such as cross-linking or mixing with other peroxide dismutase and glutathione peroxidase content determinations
natural or synthetic materials. Lin et al. [128] improved the were up-regulated by L. inermis released from the gelatin films. Collagen
electrospinnability of collagen by mixing it with zeins, a group of pro- was mixed with different concentrations of fucoidan, a polysaccharide
teins derived from corn. After berberine incorporation into these from Laminaria japonica seaweed and the obtained solutions were left
nanofibrous membranes, the multicomponent wound dressings exhib- to dry at room temperature [121]. These films presented improved en-
ited antibacterial properties and stimulated tissue regeneration in mice. zymatic stability compared to native collagen films and stimulated the
Silk fibroin/gelatin electrospun dressings were loaded with proliferation and migration of fibroblast cells, showing potential in
astragaloside IV, a compound isolated from Astragalus membranaceus skin tissue engineering. A multicomponent biosheet based on fish
extract and stimulated the wound healing process by increasing angio- scale collagen, fibrin and Macrotyloma uniflorum plant extract signifi-
genesis and collagen synthesis [129]. Hadisi et al. [130] obtained a new cantly up-regulated the wound healing rate by reducing the inflamma-
wound dressing based on gelatin-oxidized starch nanofibers loaded tory stage at the wound site [134]. Lupeol was loaded on chitosan-
with Lawsonia inermis extract. Several biological activities were demon- gelatin films cross-linked with glutaraldehyde by casting method and
strated for the fabricated scaffold, such as antibacterial activity, stimula- drying at 35 °C [136]. These membranes exhibited antioxidant, antibac-
tion of fibroblasts proliferation and collagen synthesis, promotion of the terial activities and good biocompatibility in vitro, acting also as delivery
healing process in a second-degree burn wound model. wound dressings for a sustained release of lupeol, a pentacyclic
Collagen nanofibers obtained by electrospinning were also used for triterpene with wound healing properties. Composite films of collagen
coating a scaffold based on gelatin, poly (3-hydroxybutyric acid) and and its denatured form, gelatin were recently developed to be loaded
Coccinia grandis extract [131]. This scaffold demonstrated good with pequi oil, a natural compound that improved the physico-
cytocompatibility when tested on skin cells from NIH 3 T3 and HaCaT chemical properties of the final product, suggesting potential applica-
cell lines and wound healing properties in a rat anti-inflammatory tion in wound care treatment [135].
model. Singaralevu et al. [132] reported a double-layered 3D
nanofibrous scaffold, as a promising dressing material for the treatment
of full-thickness excision wounds in rats. The fabricated biomaterial was 4.4. Hydrogels
constructed from a multicomponent nanofibrous scaffold, consisting of
gelatin, poly (3-hydroxybutyric acid) and curcumin overlaid on a Hydrogels are widely used for damaged tissue repair and regenera-
keratin-fibrin-gelatin sponge loaded with an antibiotic, Mupirocin. tion, mainly due to their properties, such as porosity, permeability, vis-
This complex material exhibited good biocompatibility, antimicrobial coelastic properties, biodegradability and biocompatibility [141]. For
activity and enhanced wound healing process through increased colla- skin tissue engineering applications, an original sponge-like scaffold
gen deposition, granulation tissue formation and growth factors was obtained from collagen aerogel reinforced with different concen-
regulation. tration of Triticum aestivum and presented good biocompatibility
in vitro, antimicrobial activity and pro-angiogenic properties [117]. Sim-
ilar, aerogels from collagen cross-linked with curcumin were
4.3. Film, membranes, sheets manufactured as 3D scaffolds for biomedical applications due to their
controlled anti-proteolytic activity cumulated with increased restora-
An elastic, thin wound dressing can be obtained by drying collagen tion of damaged tissue [119]. Rocasalbas et al. [133] reported the devel-
or gelatin solutions in a special oven with controllable temperature or opment of multicomponent dressings based on chitosan/gelatin
at room temperature [56]. More complex structures were obtained in hydrogels loaded with phenolic compounds from Hamamelis virginiana
the form of bioactive coatings or double-/triple-layered scaffolds by sin- and enzymatically cross-linked with laccase. The developed hydrogels
gle or multi-approaches processing technologies (Table 3, Table 4). A were stable and resistant to collagenase action due to enzyme adsorp-
natural monoterpene, thymol was added to gelatin films, in order to ob- tion and additionally exhibited antimicrobial activity against Pseudomo-
tain wound dressings with antioxidant and antimicrobial effects [123]. nas aeruginosa and Staphylococcus aureus due to bioactive polyphenols.
862 A. Gaspar-Pintiliescu et al. / International Journal of Biological Macromolecules 138 (2019) 854–865

4.5. Microspheres, microparticles inflammatory, antimicrobial and biostimulatory properties, helping

both researchers and clinicians to achieve improved healing of
Collagen and gelatin have been extensively investigated as carriers acute and chronic wounds.
for controlled drug release [51,142]. Gelatin microspheres containing
curcumin were incorporated in collagen-cellulose nanocrystal scaffolds
Declaration of Competing Interest
and applied on infected full-thickness burns in rat models [137]. Wound
healing studies showed that these multifunctional biomaterials exhib-
All authors declare that they have no conflict of interest.
ited anti-inflammatory properties and induced dermal regeneration.
Gelatin microspheres incorporating ginsenoside Rg1, a natural com-
Acknowledgments
pound isolated from Panax notoginseng were loaded in collagen/chito-
san scaffolds. Due to the angiogenic effect of the plant bioactive
The authors thank Prof. Dr. Otilia Zarnescu from the Faculty of Biol-
compound, the dressing was used to regenerate the damaged skin tis-
ogy, University of Bucharest for TEM image acquisition and interpreta-
sue [139]. Microparticles of collagen and gelatin were produced by
tion and also Dr. Larisa Ionita from the National Institute of R&D for
water-oil emulsion method and were loaded in collagen scaffolds
Biological Sciences for SEM images acquisition. This work has been sup-
[139]. They were further associated with Calendula officinalis extract to
ported by a grant of the Romanian National Authority for Scientific Re-
obtain novel delivery systems of the bioactive compounds with applica-
search and Innovation within Programme Nucleu, project no 25N/
tions in skin wound treatments. A similar delivery system, based on col-
2019 (19270102).
lagen microparticles, loaded with Aloe vera extract and cross-linked
with glutaraldehyde showed good resistance against collagenase diges-
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