Biopolymers: Applications in wound healing and skin tissue ... · debridement, irrigation,...
Transcript of Biopolymers: Applications in wound healing and skin tissue ... · debridement, irrigation,...
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Molecular Biology Reports https://doi.org/10.1007/s11033-018-4296-3
REVIEW
Biopolymers: Applications in wound healing and skin tissue engineering
T. G. Sahana1 · P. D. Rekha1
Received: 29 May 2018 / Accepted: 1 August 2018 © Springer Nature B.V. 2018
AbstractWound is a growing healthcare challenge affecting several million worldwide. Lifestyle disorders such as diabetes increases the risk of wound complications. Effective management of wound is often difficult due to the complexity in the healing pro-cess. Addition to the conventional wound care practices, the bioactive polymers are gaining increased importance in wound care. Biopolymers are naturally occurring biomolecules synthesized by microbes, plants and animals with highest degree of biocompatibility. The bioactive properties such as antimicrobial, immune-modulatory, cell proliferative and angiogenic of the polymers create a microenvironment favorable for the healing process. The versatile properties of the biopolymers such as cellulose, alginate, hyaluronic acid, collagen, chitosan etc have been exploited in the current wound care market. With the technological advances in material science, regenerative medicine, nanotechnology, and bioengineering; the functional and structural characteristics of biopolymers can be improved to suit the current wound care demands such as tissue repair, restoration of lost tissue integrity and scarless healing. In this review we highlight on the sources, mechanism of action and bioengineering approaches adapted for commercial exploitation.
Keywords Biopolymers · Wound healing · Tissue regeneration · Collagen · Chitosan · Hyaluronan · Alginate · Cellulose
AbbreviationsECM Extracellular matrixPDGF Platelet derived growth factorVEGF Vascular endothelial growth factorTGF-β Transforming growth factor-βEGF Epidermal growth factorRGD Arginine glycine and aspartateMMP Matrix metalloproteinasesTIMP Tissue inhibitor of metalloproteinasesPCL PolycaprolactonePVA PolyvinylalcoholPLGA Poly(lactic-co-glycolic acid)
Introduction
Wound is one of the major health concerns due to the com-plications from co-morbidities such as diabetes or infec-tion. According to WHO [1] statistics, 58 million people are affected by fatal injuries among which 5 million people die each year. And the remaining several millions of people require proper treatment and care. Though, more than 3000 products are developed to treat wounds, it still remains a burden for the society and also at the individual level [2].
Wound healing process
Wound healing is a complex and dynamic process involv-ing a cascade of biological reactions initiated in response to an injury. The process mainly involves the interaction of immune cells (neutrophils, monocytes, macrophages, lymphocytes); non-immune cells (endothelial, fibroblasts, keratinocytes), soluble mediators (cytokines and growth factors), and extra cellular (ECM) components [3, 4]. The rate of healing of acute wounds differs from the chronic wounds and is also dependent on the immunological status of the patient [5]. Wounds under normal circumstances heal
* P. D. Rekha [email protected] T. G. Sahana [email protected] Yenepoya Research Centre, Yenepoya University, University
Road, Deralakatte, Mangalore 575018, India
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by themselves by the involvement of four major overlap-ping phases; haemostasis, inflammation, proliferation, and remodelling [6]. Depending on the depth and extent of tis-sue damage, wounds heal by primary intention or primary closure, secondary wound healing or spontaneous healing, third intention or delayed primary closure [7].
The initial phase of wound healing is haemostasis where fibrin clot formed acts as a barrier from external factors and also helps in moisture retention [8–10]. Most of the tradi-tional wound care materials, particularly gauze-based dress-ings such as woven and non-woven sponges, conforming bandages, non-adherent bandages, and passive dressings target the first phase of healing by preventing excess bleed-ing and retaining moisture [11]. Hemostasis is followed by the inflammatory phase where pro-inflammatory cytokines released from the damaged tissues attract circulating leuco-cytes. De-granulated platelets and activated macrophages secrete growth factors such as, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), trans-forming growth factor-β (TGF-β), epidermal growth factor (EGF); cytokines such as interleukins: IL-1α, IL-1β, IL-8, tumor necrosis factor-α (TNF-α) and enzymes like matrix metalloproteinase (MMPs) [12]. The concentrations of growth factors and inflammatory cytokines vary among the individuals depending on the immunological status [13, 14]. The subsequent proliferation phase involves angiogenesis, granulation tissue formation, and synthesis of ECM com-ponents, epithelialization and wound contraction. Excess granulation tissue formation and abundant collagen lead to scar formation and hypertrophic scars like keloids [15]. Several developmental pathways like Wnt/β-catenin, TGF-β, MAPK, and PI3/Akt are involved in restoring the lost anat-omy, physiology and functions of the affected tissue [16, 17].
Complications involved in the healing process
As explained, the process of wound healing is highly com-plex and alterations in any of the key processes or the components involved in the healing can result in undesir-able outcomes. Hence, it remains a burden and a challenge [18–20]. The present clinical practices such as offloading, debridement, irrigation, suturing, negative pressure ther-apy, grafting and growth factor supplementation etc. [21] have their own limitations in addressing the challenges of comprehensive care. The treatment modality is generally based on the wound types, however inadequate manage-ment results in fibrosis, chronic wounds and loss of tissue functioning or amputation [22]. As the healing process is dynamic, effective management of wound at the early stages and prevention of wound progression to chronic conditions are the best possible prevention strategies
against undesirable. Researchers are focusing on devel-oping therapeutics for uneventful fetal-like healing pro-cess. Due to the advances in interdisciplinary approaches, bioactive materials have shown promising outcomes in this direction which can be potentially exploited as smart wound care materials [23, 24].
Bioactive materials can target inflammatory, prolifera-tive or re-modeling phases of healing by either by direct interaction with cells or mediated by ECM. They modulate cellular signaling pathways thereby triggering the growth, differentiation, and functioning of key players of healing process like fibroblasts, keratinocytes, macrophages and endothelial cells [13, 14].
Among the bioactive materials, widely exploited are biopolymers of different origin. Usage of biopolymers as wound care material has a wide scope due to their excel-lent properties of biocompatibility, ability to support cell growth, regenerative potential, biodegradability, and durability (Fig. 1). This review highlights the advances in the application of bioactive materials targeting the tissue repair process with special emphasis on biopolymers.
Biopolymer-based wound healing agents
Natural polymers or biopolymers are organic molecules synthesized by the living organisms. Structurally they are a sequence of repeating units/ monomers of amino acids, monosaccharides, nucleotides or esters held by covalent bonds to form peptides, polysaccharides, polyphenols or polyesters, etc. Biopolymers of diverse origin such as plant (starch, cellulose, and natural rubber), animal (collagen, hyaluronic acid, chitosan), fungi (chitin), bacteria (bacte-rial cellulose, exopolysaccharides) and algae (alginate) are used in based on their properties. These polymers offer advantage over the synthetic materials because of their biocompatibility, biodegradability, lower antigenicity and renewability [11, 25–28].
Collagen, cellulose, chitosan, alginate, hyaluronan, fucoidan, carrageen etc. are the most widely used biopoly-mers. They can possess either of antibacterial, anti-inflam-matory, proliferative or other targeted actions to specific cells, thus playing a key role in healing process (Table 1). Nanotechnology-based engineering strategies have driven the development of these biopolymers into a new genera-tion of wound care products [24]. Biopolymers have mate-rial properties that allow them to be easily moulded into hydrogel, scaffold and blend with other polymers which offer multiple benefits with increased mechanical strength, biomimetic properties and several other desired features for the development as skin substituent.
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Collagen
Collagen, the major component of the ECM is an abundant mammalian protein. Chemically, they are the triple helix of collagen fibrils where each fibril is a polymer of repeat-ing amino acids held by peptide linkages. Twenty-nine col-lagen types have been identified and type I, II and III are
the predominant in connective tissues [29]. Under normal circumstances, collagen and its proteolytic cleavage frag-ments (e.g. gelatin) help in tissue repair [30]. Type I col-lagen is the most important component involved in tissue repair. During inflammatory phase following injury, sev-eral proteolytic enzymes are released and cleave collagen into smaller fragments. Arg-Gly-Asp (RGD) sequences of these fragments are chemotactic for macrophages and
Fig. 1 Phases of wound healing and the role of biopolymers during each phase of wound healing
Table 1 Characteristics of biopolymers and their biological role in healing process
Bio-polymer Monomer units and linkage Sources Biological role References
Collagen Amino acids linked by amide linkage Bovine, porcine etc Induces fibroblast proliferation, induces secretion of ECM components by fibroblasts, chemotactic for mac-rophages
[29–51]
Cellulose β-D-Glucose linked by β-1,4-glycosidic linkage
Plant cell wall and bacteria Retention of moisture, absorption of exudates
[44, 52–77]
Alginic acid β-D-Mannuronic acid and α-L-guluronic acid linked by α-1, 4 glycosidic link-ages
Brown algae Stimulated monocytes, induces fibro-blast proliferation and migration
[78–92]
Hyaluronic acid D-glucuronic acid and N-acetyl-D-glu-cosamine linked by β-1,4 and β-1,3 glycosidic linkages
Animal origin Stimulates fibroblasts and keratinocytes proliferation and migration, anti-inflammatory
[93–108]
Chitosan N-acetyl glucosamine linked by β-1, 4 glycosidic linkages
Exoskeleton of crabs, molluscs, insects, fungal cell wall
Induces fibroblast and keratinocytes migration and proliferation
[109–125]
Fucoidan α-L-Fucose linked by α-1, 3 glycosidic linkages
Brown algae Angiogenic, mitogenic to fibroblasts and keratinocytes
[126–129]
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mitogenic for fibroblasts thus inducing formation of granu-lation tissue and proliferation [31]. Likewise, in the epithe-lium, keratinocytes interact with gelatin and undergo epi-thelial-mesenchymal transition thus promoting migration necessary for the tissue repair [32]. The balance between synthesis and degradation of collagen is a key factor in deciding the fate of healing [33]. In chronic wounds, the rate of collagen breakdown overcomes the synthesis rate due to impaired MMP/TIMP ratio because of which the newly formed collagens are cleaved into fragments pro-longing inflammatory phase [34] (Table 2).
The altered healing process due to the impairment of col-lagen synthesis has been overcome by supplementing exog-enous collagen to the wound site. Gelatin formed due to the cleavage of this collagen in addition to innate collagen deac-tivate the excess MMPs and trigger proliferation to take over inflammation phase [35]. Collagen-based materials involved in wound treatment act as sacrificing substrate. Main sources of collagen are bovine, porcine skin and tendons, bladder mucosa and intestine [36]. Collagens are used in two forms; either as decellularized collagen matrix that retains native ECM properties or collagen obtained by isolation, purifica-tion and depolymerization [37–39]. The rate of degradation of externally supplemented collagen can be maintained by the level of cross-linking by chemical, physical or enzymatic approaches [40–42].
The physiological action of collagen can be improved by surface modification, reduction in size to the nanoscale, depolymerization, tagging with anti-inflammatory and anti-microbial substances etc. Improvement of the physi-cal, mechanical and functional properties of biopoly-mers can be achieved by electrospinning, a formation of scaffolds and combinations with other drug molecules.
Electrospun collagen nanofibres coated with laminin closely resembles the native collagen of the ECM and shows improved cell adhesion and migration of keratino-cytes [43]. Kim et al. developed an injectable methylcel-lulose hydrogel with silver oxide nanoparticles for burn wound treatments that can improve the response [44]. Quercitin and curcumin incorporated separately in differ-ent experimental set-ups into the collagen matrix showed healing of the diabetic wound by effective scavenging of reactive oxygen species and re-epithelialization respec-tively [45, 46]. PEGylated graphene oxide and quercetin incorporated to acellular dermal collagen matrix showed differentiation of mesenchymal stem cells into adipogenic and osteoblasts, promoting cell adhesion, collagen depo-sition, angiogenesis in diabetic wound model [47]. Col-lagen and sulphated xylorhamnoglycuronan conjugate by electrospinning showed collagen alignment closely mimicked natural skin with increased tensile strength promoting fibroblast proliferation [48]. Alignment of col-lagen by can play a major role in determining the tissue repair process. A nanofibrous scaffold of collagen laid in the basket-weave pattern similar to anatomical features of normal skin enhanced the healing process by reducing inflammation, accelerating fibroblasts and keratinocytes migration and promoting angiogenesis [49, 50]. Patterned electrospinning of collagen and PCL showed accelerated directional migration and proliferation of fibroblasts [51].
Collagen-based wound healing materials in the form of sponges, hydrogels, films, membrane, powder, and freeze-dried sheets are commercially available under different trade names. Most commonly used are; Biopad, Helix bioactive collagen, Stimulen, Biostep, Citrix, Cellerate, Cutimed, Derma Col, Fibracol, etc. The active component of these
Table 2 Biopolymers and their suitability for specific wound types with merits and demerits
Biopolymer Wound types Merits Demerits References
Collagen Bed sores, minor burns, foot ulcers, large open cuts, chronic wounds, low to heavy exudation wounds, surgical wounds
Cost effective, high water holding capacity, high tensile strength, flexible
Cannot be used for patients allergic to birds, cattle or swine products
Cannot be used for third degree burns, dry wounds
Does not possess antimicrobial activities
[29–42]
Cellulose Burns, chronic wounds, plastic/recon-structive surgeries
Antibacterial Cannot be used for second and third-degree burns
[52–56]
Alginate Moderate to heavily draining wounds, partial- and full-thickness wounds, pressure ulcers (Stages III and IV), dermal wounds, surgical incisions or dehisced wounds, sinus tracts, tunnels, cavity wounds, and infected wounds, postoperative wounds
Haemostatic Cannot be used for eschar and dry wounds and for third degree burns
[78–82]
Hyaluronate Chronic wounds, partial and full thickness wounds
Flexible, highly biocompatible, bacteriostatic
– [93–97]
Chitosan Acute wounds, pressure ulcers Antimicrobial – [109–114]
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products varies and the use of appropriate products for spe-cific wound types influences the therapeutic outcome.
Cellulose
Cellulose is the most abundant biopolymer present in plant cell walls. It is made up of repeating units of β-D-glucose held by β-1, 4-glycosidic linkages. However, bacterial cel-lulose is relatively pure in nature and porous compared to plant-derived cellulose. It is also produced by certain bacte-ria belonging to genera Acetobacter, Sarcina ventriculi and Agrobacterium [52, 53].
Application of cellulose in wound care is mainly due to its moisture retaining properties and moist wounds are known to heal faster due to the adequate supply of growth factors and other molecules to the healing tissues [54, 55]. It aids in the absorption of exudates resulting in the intake of cell debris (such as necrotic tissue and fibrinous coating) and the porous cellulose structure mimics ECM of skin thus helping in tissue regeneration [56].
Bioengineering of cellulose by surface immobilization with drugs or therapeutic molecules, blending with other polymers and electrospinning have shown improved func-tional properties. Cellulose can also be readily blended with other materials particularly the antimicrobials to prevent the infection of the wound site. Myostatin, silver nanoparticles and chloramphenicol impregnated cellulose have shown bac-tericidal activities against E. coli and Staphylococcus aureus [57–62]. Cellulose loaded with therapeutic drugs like vacca-rin, povidone iodide and minocycline have been studied for efficient drug release and wound healing abilities [63–65]. Lin et al. reported that bacteria derived cellulose membrane coated with chitosan enhanced epithelialization and faster regeneration compared to the commercially available Tega-derm [62]. The hydrogel formed by UV cross-linking of cellulose with acylic acid improved neovascularization and re-epithelialization in burn wounds [66]. Some of the engi-neered forms like nano-fibrillar cellulose show promising activities due to its nanostructure [44, 67]. Functionaliza-tion of cellulose by methylation and oxidation has shown improved modulation of cellular responses [68]. Studies have also reported the hemostatic activity of oxidized cellu-lose [69]. Oxidized cellulose is the insoluble cellulose where the primary component of the material is polyuronic acid formed as a result of oxidation of cellulose. Oxidized regen-erated cellulose (ORC) differs from oxidized non-regener-ated cellulose due to its organized fibrils. ORC alone and in blend with collagen show improved fibroblast proliferation in vitro [70, 71]. Garrett and co-workers reported acceler-ated corneal epithelial healing in rabbits by carboxymethyl cellulose mediated by ZO-1 expression resulting in corneal epithelial barrier regeneration [72]. Bacterial cellulose and
acrylic acid hydrogel formed by freeze drying with human epidermal keratinocytes and fibroblasts showed accelerated healing in partial thickness burn wounds [66]. 3D scaffold made using bacterial cellulose and gelatin by showed com-plete regeneration of epithelium in wounded mice [73]. The ability of cellulose at varying pH were assessed for healing abilities. Acidic cellulose showed improved healing proper-ties in cutaneous wound model [74]. Cellulose conjugated with tungsten oxide, polydopamine, soy protein hydrolysate separately showed increased integrin β1 expression, acceler-ated re-epithelialization with antibacterial and anti-inflam-matory properties [75–77].
Some of the commercially available cellulose-based dressings are; Dermafill, Suprasorb, Exu-Dry Cellulose, Curity etc. They provide mechanical cellular barrier by protecting fragile granulation tissue in addition to moisture retention. There is huge scope for cellulose-based active materials in tissue repair applications and with current bio-technological developments the material properties can be easily improved to meet the demands.
Alginic acid
Alginic acid is a linear polymer made up of repeating units of β-D-mannuronic acid and α-L-guluronic acid linked by α-1, 4 glycosidic linkages. Alginic acid is mainly marine derived from the brown algae such as Laminaria, Macro-cystis, and Ascophyllum sp.
Alginates provide a moist environment at the wound bed and absorb exudates. They reduce wound pain, lower the infection burden of the wound, reduce odor and also, help in hemostasis [78]. An alginate containing dressing in contact with wound exudate initiates the ion exchange between the calcium ions in the alginate and the sodium ions in blood or exudate. When sufficient calcium ions are replaced by sodium ions, the alginate fibres swell, partially dissolve and form a gel [79]. Alginates are known to stimulate monocytes for IL-6 and TNF-α production that have the direct role in the healing process [80, 81].
Alginate by itself has low cell adhesion properties how-ever cell interacting alginates are produced by attaching peptide sequences. Most common peptide sequence used for attachment is RGD sequences which are recognized by integrin receptors [82]. Cell interactive alginates are reported to show enhanced cellular responses by mimicking the structure of ECM. The physical and mechanical proper-ties of sodium alginate when blended with other polymers like PVA and PCL have shown higher stability. Studies on alginate and PVA electrospun dressings exhibit superior qualities compared to some of the commercial products [83, 84]. Hydrogel developed by blending sodium alginate with Aloe vera extract followed by UV cross-linking reduced UV
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transmittance and protected wound by light extremities [85]. Murakami et al. reported re-epithelialization of mitomycin treated impaired wound by the blend of chitosan, alginate, and fucoidan [86]. Several similar studies highlight the feasi-bility of alginate for modifications. Curcumin or silver nano-particle embedded alginate; silk fibroin and alginate com-posite and chitosan–alginate dressings have been reported to possess better healing outcomes [87–89]. Composite made up of cellulose, chitosan and alginate by freeze dry-ing showed facilitated fibroblast and endothelial cell migra-tion, anti-seawater immersion and increased expression of EGF, bFGF, CD31 in full thickness wounds [90]. Hydrogel containing N-carboxymethyl chitosan and alginate loaded with EGF showed accelerated healing in rats [91]. Among hydrogel variants formed by different divalent crosslinkers like calcium, zinc, copper; zinc cross linked alginate showed improved epithelialisation in rats [92].
Alginate is used as the main ingredient in several com-mercially available wound care products such as, 3M Tega-derm, Algicell, Algisite, Calcicare, Cutimed alginate, Der-malginate, Kaltostat, Nu-derm etc. Each of them differs in composition of active ingredient and the additional modifi-cations which are developed for meeting the requirements of the specific wound types.
Hyaluronic acid
Hyaluronic acid is a glycosaminoglycan present in the skin. It is an evolutionarily preserved mammalian biopoly-mer made up of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine linked by alternating β-1,4 and β-1,3 glycosidic linkages. Hyaluronic acid is found as high molecular weight compound (5 × 106 Da). High molecular weight hyaluronan has anti-inflammatory properties whereas the fragments/low molecular weight hyaluronan has pro-inflammatory activities [93]. It plays a vital role in wound healing by stimulating fibroblast proliferation, remodeling of ECM and keratinocyte migration. The degradation prod-uct of hyaluronic acid is found to have the pro-angiogenic effect [94]. It activates a series of cascades by binding to CD44 receptors present on the keratinocytes facilitating dif-ferentiation [95].
Hyaluronic acid though is an indigenous biopolymer, supplementation of exogenous hyaluronic acid post injury has shown to alter the healing pattern with reduced scar and decreased collagen synthesis [96, 97]. This benefi-cial aspect has made hyaluronan an important therapeutic for tissue repair. A study conducted by Li et al. showed improved anti-enzymatic degradation by hyaluronic acid grafted with pullulan. It also showed accelerated healing with the hemostatic ability [98]. Likewise, chitosan/hyalu-ronate hydrogels with vancomycin containing PLGA micro-spheres showed reduced microbial load at the wound site
along with the enhanced proliferation of endothelial cells [99]. Similar effects were seen by a hybrid nano-hydrogel containing aminoethyl methacrylate hyaluronic acid and methacrylated methoxy polyethylene glycol as well using electrospun bilayered chitosan/polycaprolactone and hya-luronic acid scaffold [100]. Hyaluronan cross-linked with epoxy and other layers showed vigorous angiogenesis and restoration of the dermis in diabetic ulcers [101]. A skin sub-stitute prepared by combining hyaluronic acid-gelatin-chon-droitin sulfate base with seeded keratinocytes and fibroblasts enhanced cell migration, reduced oxidative damage and had bactericidal activities on infected wounds [102]. Glycidyl methacrylate hyaluronic acid conjugate formed by photopo-lymerization has shown improved hydrogel properties [103]. Three-dimensional hyaluronic acid scaffold developed by Hu et al. showed fetal-like environment for wound healing by reducing the expression of TGF-β1 [104]. In a randomized controlled clinical trial, topical application of hyaluronate in gingival surgery patients showed accelerated palatal wound healing [105, 106]. Mouldable hydrogel formed by coupling hyaluronic acid, bisphosphonate and silver showed antimi-crobial, self-healing in rats [107]. Conjugate of chitosan/hyaluronate and edaravone showed higher blood compat-ibility [108].
A few of the most widely used wound care commercial products derived from hyaluronic acid are; Dermaplex, Regenecare, Hyalomatrix, Hyalofill etc. Most of them are used to treat chronic wounds in diabetic patients. Hyaluronic acid is also a component of skin care protective products with cosmetic outcomes.
Chitosan
Chitin is a natural biopolymer present in crustaceans, mol-luscs, insects and also synthesized by some of the fungi. It is made up of N-acetyl glucosamine held by β-1, 4 linkages. Chitin is inert and its deacetylated product, chitosan, is the active form. Chitosan has been proved to stimulate haemo-stasis and accelerate tissue regeneration [109, 110]. Chi-tosan is widely studied as an antimicrobial agent to prevent bacterial and fungal infection of the wound site [111, 112]. Apart from antibacterial and antifungal activities, chitosan has shown cell proliferative activities essential for efficient healing. It is known to activate polymorphonuclear leuco-cytes and macrophages for phagocytosis and production of IL-1, TGF-β, and PDGF. Chitosan also stimulates fibroblast proliferation [113] and the degree of de-acetylation is posi-tively correlated with fibroblast activation [114].
Chitosan along with other polymers are used to prepare hydrogels, foams and scaffolds. The blending of chitosan with other biopolymers along with surface modification has shown promising results in wound healing. Biagini et al.
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used freeze dried sheets of N-carboxybutyl chitosan for donor sites in the patients who underwent plastic surgery. It helped in the formation of better organized cutaneous tissue with reduced anomalous healing [115]. Chitosan–polyethyl-ene glycol blending show increased protein adsorption, cell adhesion, growth, and proliferation [116]. Several studies have reported the surface attachment of growth factors to chitosan and attachment of EGF, bFGF to chitosan show improved healing of diabetic and burn wound in non-dia-betic mice. This is achieved by the increased rate of wound contraction and increased re-epithelialization respectively [117, 118].
Chitosan is used as drug carrier molecules due to its cationic nature. Wound dressing developed by combining chitosan with polyphosphate and silver had hemostatic and anti-microbial properties against S. aureus and Psuedmonas aeruginosa [119]. Curcumin impregnated chitosan compos-ite increased collagen synthesis in vitro and in vivo [120]. Moura et al. studied the effect of chitosan dressing contain-ing a neurotensin, a neuropeptide and an immunomodulator in wound healing, on early diabetic healing. It decreased inflammatory infiltrate on the 3rd day, increased fibroblast migration and deposition of collagen [121]. Immobilization of chitosan with such as taurine and rutin increased healing of wounds [122, 123]. Chitosan with cerium oxide nano-cubes showed anti-inflammatory activities with down regu-lated TNF-α, IL-10 expression in rats [124]. Ready to use aerogel formed by chitosan and chondroitin sulfate without the use of cross-linkers showed accelerated healing process in rats [125].
Several chitosan-based dressings are also available in the market. Dextatic, dextrosan have hemostatic and anti-micro-bial activities. Opticell is used for partial- and full-thickness wounds, first- and second-degree burns, diabetic foot ulcers, venous ulcers, pressure ulcers, surgical wounds, donor sites and arterial and leg ulcers.
Other biopolymers
In addition to these widely studied and reported biopoly-mers, there are several similar biomolecules of therapeutic interest such as; fucoidan, carrageenan, and glucans that are less explored. Research is being carried out to explore the potential capabilities of these molecules in facilitat-ing healing process. Fucoidan is fucose rich, uronic acid containing, sulphated polysaccharide isolated from brown algae. Heparin-binding cytokines like FGF-1 and FGF-2 in the wound exudates are activated by fucoidan inducing angiogenesis and wound repair [126]. Fucoidan can alter the effect of TGF-β1 in wound repair [127]. Park et al. reported wound healing activities of low molecular weight fucoidan in rats mediated by improved collagen distribution
and angiogenesis [128]. Over sulphated fucoidan scaffold formed with chitosan/alginate and bFGF showed controlled release and prevented digestion by trypsin [129]. Carra-geenan is a polysaccharide produced by red algae. Structur-ally, it consists of alternating galactopyranose units linked by α 1,-3 and β-1,4-glycosidic bonds. Cyclic β-(1,3)-(1,6) glucan/carrageenan/hydrogel showed improved wound heal-ing in vitro and in vivo [130].
Another notable biopolymer with therapeutic applica-tions is pullulan. It is derived from fungi and made up of repeating units of maltotriose. Wong et al. studied the wound healing effects of pullulan–collagen scaffold formed by salt-induced phase inversion technique on healing process. Due to a porous architecture of the scaffold, it improved fibroblast migration and viability of endothelial and mes-enchymal stem cells to enhance the healing process [131]. Beta-glucans, a polymer of glucose, is a component of cell walls of cereals, mushrooms, algae and some bacteria also produce branched chain β-glucans. A few studies have reported the wound healing potentials of these molecules. For example, Kim et al. reported the wound healing effects (fibroblast proliferation and angiogenesis) of electrospun PLGA membranes containing β-glucans in nude mice [132]. In addition to these well-studied biopolymers several terres-trial and marine bacteria produce bioactive polysaccharides and form a large group of molecules unique to the bacte-ria synthesizing it. They are made up of repeating units of common saccharide units like glucose, fructose, galactose, glucosamine along with the presence of rare sugars like fucose, rhamnose etc. Matou et al. reported the angiogenic effects of an oversulfated exopolysaccharide produced by Alteromonas infernus that could increase the expression of FGF-2 and VEGF [133]. Polysaccharide designated EPS22 isolated from Pseudomonas stutzeri AS22 showed effec-tive wound healing in rats, characterized by well-organized layers of dermis and epidermis [134]. Likewise, EPS-Ca6 produced by Lactobacillus sp. Ca6 strain showed improved re-epithelialization in animal model [135]. Studies from our group have shown in vitro wound healing activities of EPSs isolated from Nitratireductor sp. PRIM-31, Rhizobium sp. PRIM-18 that were mediated by fibroblast proliferation and migration [136, 137]. Similarly, several fungal-derived poly-saccharides are also being reported to possess wound healing activities. He et al. isolated polysaccharide from Lachnum sp. and reported its tissue repair activities [138].
Future perspective
In spite of several already existing materials, the conse-quences of healing as in chronic condition are still com-promised. The future wound care products should neces-sarily possess multiple functions and provide suitable
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micro-environment by having antimicrobial, hemostasis, bioresponsive and biomimetic properties. Advances in the understanding of the physical, chemical and mechanical properties of biopolymers will help in the exploitation of the polymers with desired properties. Recent developments in regenerative medicine, nanotechnology and bioengineering technologies aid in the development of biopolymer-based scaffolds, 3D artificial skin or equivalent substitutes, drug or growth factor loaded dressings etc. Advances in nanotech-nology and bioengineering techniques like bioprinting and 3D electrospinning allows creating 3D scaffolds or matrices mimicking the integrity of skin with desired pore size and tensile strength. This allows rapid attachment and ingrowth of cells, adequate exchange of nutrients and growth factors. Playing at the nano level of the molecules allows maximum interaction of the drug molecules with cellular components thus enhancing the efficacy of the drugs. The discoveries in regenerative medicine provide a platform to extend the knowledge of cell-based therapy, growth factor delivery, and tissue engineering to create the replacement of ECM capable of restoring the injured tissue.
Conclusion
Wound healing is a complex dynamic process wherein the interaction between the cells, secretary factors, and ECM matrices decide the fate of the healing process. Biopoly-mers of diverse origins have been widely studied because of their excellent biocompatibility and bioactivity. Cellu-lose, alginate, hyaluronate, collagen, and chitosan are the most commonly used biopolymers that dominate the current wound care industry. Convergent of technological develop-ments will shape the future smart application of biopolymers wound care products to satisfy the unmet needs.
Acknowledgements Sahana T. G. acknowledges DST-INSPIRE fellowship.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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