Vol.:(0123456789)1 3

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 dydirectoryrc@yenepoya.edu.in T. G. Sahana sahanatg@yenepoya.edu.in1 Yenepoya Research Centre, Yenepoya University, University

Road, Deralakatte, Mangalore 575018, India

Molecular Biology Reports

1 3

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.

Molecular Biology Reports

1 3

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]

Molecular Biology Reports

1 3

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]

Molecular Biology Reports

1 3

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

Molecular Biology Reports

1 3

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.

Molecular Biology Reports

1 3

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

Molecular Biology Reports

1 3

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.

References

1. WHO (2010) Injuries and violence: The facts. http://www.who.int/viole nce_injur y_preve ntion /key_facts /en/. Accessed 8 Feb 2018

2. Dhivya S, Padma VV, Santhini E (2015) Wound dressings—a review. Biomedicine 5:24–28

3. Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746

4. Gurtner GC, Werner S, Barrandon Y, Longaker MT(2008) Wound repair and regeneration. Nature 453:314–321

5. Demidova-Rice TN, Hamblin MR, Herman IM (2012) Acute and impaired wound healing: pathophysiology and current methods for drug delivery, Part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care 25:304–315

6. Regan MC, Barbul A (1999) The cellular biology of wound heal-ing. Wound Heal 1:3–17

7. Kirsner RS, Eaglstein WH (1993) The wound healing process. Dermatol Clin 11:629–640

8. Diegelmann RF, Evans MC (2000) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 1:283–289

9. Martin P (1997) Wound healing—aiming for perfect skin regen-eration. Science 276:75–81

10. Velnar T, Bailey T, Smrkolj V (2009) The wound healing pro-cess: an overview of the cellular and molecular mechanisms. J Int Med Res 371:528–1542

11. Sezer AD, Cevher E (2011) Biopolymers as wound healing materials: challenges and new strategies. In: Pignatello R (ed) Biomaterials applications for nanomedicine. InTech, Rijeka

12. Golebiewska EM, Poole AW (2015) Platelet secretion: from hae-mostasis to wound healing and beyond. Blood Rev 29:153–162

13. Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Investig Dermatol 127:514–525

14. Stramer BM, Mori R, Martin P (2007) The inflammation–fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Investig Dermatol 127:1009–1017

15. Sephel GC, Woodward SC (2001) Repair, regeneration, and fibrosis. In: Rubin E (ed) Rubin’s pathology. Lippincott, Wil-liams and Wilkins, Baltimore, 84–117

16. Bielefeld KA, Amini-Nik S, Alman BA (2013) Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 70:2059–2081

17. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870

18. Guo SA, DiPietro LA (2010) Factors affecting wound healing. J Dent Res 89:219–229

19. Anderson K, Hamm RL (2012) Factors that impair wound heal-ing. J Am Coll Clin Wound 4:84–91

20. Jarbrink K, Ni G, Sonnergren H, Schmidtchen A, Pang C, Bajpai R, Car J (2017) The humanistic and economic burden of chronic wounds: a protocol for a systematic review. Syst Rev 6:15

21. Sarabahi S (2012) Recent advances in topical wound care. Ind J Plast Surg 45:379

22. Enoch S, Grey JE, Harding KG (2006) ABC of wound healing: non-surgical and drug treatments. BMJ 332:900

23. Dickinson LE, Gerecht S (2015) Engineered biopolymeric scaf-folds for chronic wound healing. Front Physiol 7:341

24. Hamdan S, Pastar I, Drakulich S, Dikici E, Tomic-Canic M, Deo S, Daunert S (2017) Nanotechnology-driven therapeutic inter-ventions in wound healing: potential uses and applications. ACS Cent Sci 3:163–175

25. Rehm BH (2010) Bacterial polymers: biosynthesis, modifications and applications. Nat Rev Microbiol 8:578–592

26. Nwodo UU, Green E, Okoh AI (2012) Bacterial exopoly-saccharides: functionality and prospects. Int J Mol Med 11:14002–140015

27. Laurienzo P (2010) Marine polysaccharides in pharmaceutical applications: an overview. Mar Drugs 8:2435–2465

28. Smith AM, Moxon S, Morris GA (2016) Biopolymers as wound healing materials. In: Ågren MS (ed) Wound healing biomateri-als. Woodhead Publishing, Cambridge, pp 261–287

29. Rehfeld A, Nylander M, KarnovK (2017) Compendium of histol-ogy: a theoretical and practical guide. Springer, New York

Molecular Biology Reports

1 3

30. Brett D (2008) A review of collagen and collagen-based wound dressings. Wounds 20:347–356

31. Bellis SL (2011) Advantages of RGD peptides for directing cell association with biomaterials. Biomaterials 32:4205–4210

32. Pastar I, Stojadinovic O, Yin NC, Ramirez H, Nusbaum AG, Sawaya A, Patel SB, Khalid L, Isseroff RR, Tomic-Canic M (2014) Epithelialization in wound healing: a comprehensive review. Adv Wound Care 7:445–464

33. Schwartz AJ, Wilson DA, Keegan KG, Ganjam VK, Sun Y, Weber KT, Zhang J (2002) Factors regulating collagen synthesis and degradation during second-intention healing of wounds in the thoracic region and the distal aspect of the forelimb of horses. Am J Vet Res 11:1564–1570

34. Rodríguez D, Morrison CJ, Overall CM (2010) Matrix metallo-proteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Mol Cell Res 1803:9–54

35. Brett D (2008) A review of collagen and collagen-based wound dressings. Wounds 12:347–356

36. Schmidt MM, Dornelles RC, Mello RO, Kubota EH, Mazutti MA, Kempka AP, Demiate IM (2016) Collagen extraction pro-cess. Int Food Res 23:913–922

37. Chattopadhyay S, Raines RT (2014) Review collagen based bio-materials for wound healing. Biopolymers 101:821–833

38. Gilbert TW, Sellaro TL, Badylak SF (2006) Decellularization of tissues and organs. Biomaterials 27:3675–3683

39. Deeken CR, White AK, Bachman SL, Ramshaw BJ, Cleveland DS, Loy TS, Grant SA (2011) Method of preparing a decellular-ized porcine tendon using tributyl phosphate. J Biomed Mater Res Part B 96:199–206

40. Marzec E, Pietrucha K (2018) Efficacy evaluation of electric field frequency and temperature on dielectric properties of collagen cross-linked by glutaraldehyde. Colloids Surf B 162:345–350

41. Davidenko N, Schuster CF, Bax DV, Raynal N, Farndale RW, Best SM, Cameron RE (2015) Control of crosslinking for tai-loring collagen-based scaffolds stability and mechanics. Acta Biomaterial 25:131–142

42. Khew ST, Yang QJ, Tong YW (2008) Enzymatically crosslinked collagen-mimetic dendrimers that promote integrin-targeted cell adhesion. Biomaterials 29:3034–3045

43. Rho KS, Jeong L, Lee G, Seo BM, Park YJ, Hong SD, Roh S, Cho JJ, Park WH, Min BM (2006) Electrospinning of collagen nanofibers: effects on the behavior of normal human keratino-cytes and early-stage wound healing. Biomaterials 27:1452–1461

44. Kim MH, Park H, Nam HC, Park SR, Jung JY, Park WH (2018) Injectable methylcellulose hydrogel containing silver oxide nano-particles for burn wound healing. Carbohydr Polym 181:579–586

45. Gomathi K, Gopinath D, Ahmed MR, Jayakumar R (2003) Quercetin incorporated collagen matrices for dermal wound healing processes in rat. Biomaterials 24:2767–2772

46. Gopinath D, Ahmed MR, Gomathi K, Chitra K, Sehgal PK, Jaya-kumar R (2004) Dermal wound healing processes with curcumin incorporated collagen films. Biomaterials 25:1911–1917

47. Chu J, Shi P, Yan W, Fu J, Yang Z, He C, Deng X, LiuH (2018) PEGylated graphene oxide-mediated quercetin-modified collagen hybrid scaffold for enhancement of MSCs differentiation poten-tial and diabetic wound healing. Nanoscale 10:9547–9560

48. Kang L, Liu X, Yue Z, Chen Z, Baker C, Winberg PC, Wallace GG (2018) Fabrication and in vitro characterization of electro-chemically compacted collagen/sulfated xylorhamnoglycuronan matrix for wound healing applications. Polymers 10:1–13

49. Sun L, Gao W, Fu X, Shi M, Xie W, Zhang W, Zhao F, Chen X (2018) Enhanced wound healing in diabetic rats by nanofibrous scaffolds mimicking the basket weave pattern of collagen fibrils in native skin. Biomater Sci 6:340–349

50. Berthod F, Germain L, Li H, Xu W, Damour O, Auger FA (2001) Collagen fibril network and elastic system remodeling in a recon-structed skin transplanted on nude mice. Matrix Biol 20:463–473

51. Kim JI, Kim CS (2018) Harnessing nanotopography of PCL/collagen nanocomposite membrane and changes in cell morphol-ogy coordinated with wound healing activity. Mater Sci Eng C 91:824–837

52. Bae SO, Shoda M (2005) Production of bacterial cellulose by Acetobacter xylinum BPR2001 using molasses medium in a jar fermenter. Appl Microbiol Biotechnol 67:45–51

53. Keshk SM (2014) Bacterial cellulose production and its indus-trial applications. J Bioproc Biotech 4:2

54. Czaja W, Krystynowicz A, Bielecki S, Brown RM (2006) Micro-bial cellulose—the natural power to heal wounds. Biomaterials 27:145–151

55. Sulaeva I, Henniges U, Rosenau T, Potthast A (2015) Bacte-rial cellulose as a material for wound treatment: properties and modifications. A review. Biotechnol Adv 33:1547–1571

56. Kucińska-Lipka J, Gubanska I, Janik H (2015) Bacterial cellulose in the field of wound healing and regenerative medicine of skin: recent trends and future prospective. Polym Bull 72:2399–2419

57. Miao J, Pangule RC, Paskaleva EE, Hwang EE, Kane RS, Lin-hardt RJ, Dordick JS (2011) Lysostaphin-functionalized cellulose fibers with anti-staphylococcal activity for wound healing appli-cations. Biomaterials 36:9557–9567

58. Maneerung T, Tokura S, Rujiravanit R (2008) Impregnation of silver nanoparticles into bacterial cellulose for antimicrobial wound dressing. Carbohydr Polym 72:43–51

59. Farag S, Ibrahim HM, Asker MS, Amr A, El-Shafaee A (2015) Impregnation of silver nanoparticles into bacterial cel-lulose: green synthesis and cytotoxicity. Int J PharmTech Res 12:651–661

60. Wu J, Zheng Y, Song W, Luan J, Wen X, Wu Z, Chen X, Wang Q, Guo S (2014) In situ synthesis of silver-nanoparticles/bacte-rial cellulose composites for slow-released antimicrobial wound dressing. Carbohydr Polym 102:762–771

61. Wen X, Zheng Y, Wu J, Yue L, Wang C, Luan J, Wu Z, Wang K (2015) In vitro and in vivo investigation of bacterial cellulose dressing containing uniform silver sulfadiazine nanoparticles for burn wound healing. Prog Nat Sci: Mater 25:197–203

62. Lin WC, Lien CC, Yeh HJ, Yu CM, Hsu SH (2013) Bacterial cellulose and bacterial cellulose–chitosan membranes for wound dressing applications. Carbohydr Polym 94:603–611

63. Qiu Y, Qiu L, Cui J, Wei Q (2016) Bacterial cellulose and bacte-rial cellulose-vaccarin membranes for wound healing. Mater Sci Eng C 59:303–309

64. Mishra A, Chaudhary N (2010) Study of povidone iodine loaded hydrogels as wound dressing material. Trends Biomater Artif Organs 23:122–128

65. Bajpai SK, Pathak V, Soni B (2015) Minocycline-loaded cellu-lose nano whiskers/poly (sodium acrylate) composite hydrogel films as wound dressing. Int J Biol Macromol 79:76–85

66. Mohamad N, Amin MC, Pandey M, Ahmad N, Rajab NF (2014) Bacterial cellulose/acrylic acid hydrogel synthesized via electron beam irradiation: accelerated burn wound healing in an animal model. Carbohydr Polym 114:312–320

67. Hakkarainen T, Koivuniemi R, Kosonen M, Escobedo-Lucea C, Sanz-Garcia A, Vuola J, Valtonen J, Tammela P, Mäkitie A, Luukko K, Yliperttula M (2016) Nanofibrillar cellulose wound dressing in skin graft donor site treatment. J Control Release 244:292–301

68. Wagenhäuser MU, Mulorz J, Ibing W, Simon F, Spin JM, Schel-zig H, Oberhuber A (2016) Oxidized (non)-regenerated cellulose affects fundamental cellular processes of wound healing. Sci Rep 6:32238

Molecular Biology Reports

1 3

69. Lewis KM, Spazierer D, Urban MD, Lin L, Redl H, Goppelt A (2013) Comparison of regenerated and non-regenerated oxi-dized cellulose hemostatic agents. Eur Surg 45:213–220

70. Jeschke MG, Sandmann G, Schubert T, Klein D (2005) Effect of oxidized regenerated cellulose/collagen matrix on dermal and epidermal healing and growth factors in an acute wound. Wound Rep Regen 13:324–331

71. Hart J, Silcock D, Gunnigle S, Cullen B, Light ND, Watt PW (2002) The role of oxidised regenerated cellulose/collagen in wound repair: effects in vitro on fibroblast biology and in vivo in a model of compromised healing. Int J Biochem Cell Biol 34:1557–1570

72. Xu S, Willcox M, Simmons P, Vehige J, Xie T, Garrett Q (2007) Carboxymethylcellulose stimulates rabbit corneal epi-thelial wound healing. Investig Ophthalmol Vis Sci 48:796

73. Loh EYX, Mohamad N, Fauzi MB, Amin MCIM (2018) Devel-opment of a bacterial cellulose-based hydrogel cell carrier con-taining keratinocytes and fibroblasts for full-thickness wound healing. Sci Rep 8:2875

74. Pourali P, Razavianzadeh N, Khojasteh L, Yahyaei B (2018) Assessment of the cutaneous wound healing efficiency of acidic, neutral and alkaline bacterial cellulose membrane in rat. J Mater Sci: Mater Med 29:90

75. Fawal GF, Abu-Serie MM, Hassan MA, Elnouby MS (2018) Hydroxyethyl cellulose hydrogel for wound dressing: fabrica-tion, characterization and in vitro evaluation. Int J Biol Mac-romol 111:649–659

76. Liu Y, Sui Y, Liu C, Liu C, Wu M, Li Y (2018) A physically crosslinked polydopamine/nanocellulose hydrogel as potential versatile vehicles for drug delivery and wound healing. Carbo-hydr Polym 188:27–36

77. Ahn S, Chantre CO, Gannon AR, Lind JU, Campbell PH, Grevesse T, O’connor BB, Parker KK (2018) Soy protein/cel-lulose nanofiber scaffolds mimicking skin extracellular matrix for enhanced wound healing. Adv Healthc Mater. https ://doi.org/10.1002/adhm.20170 1175

78. Jones V, Grey JE, Harding KG (2006) ABC of wound healing: wound dressings. Brit Med J 332:7544–7777

79. Thomas S (2000) Alginate dressings in surgery and wound management. J Wound Care 9:56–60

80. Yang D, Jones KS (2009) Effect of alginate on innate immune activation of macrophages. J Biomed Mater Res Part B 90:411–418

81. Aderibigbe BA, Buyana B (2018) Alginate in wound dressings. Pharmaceutics. https ://doi.org/10.3390/pharm aceut ics10 02004 2

82. Rowley JA, Mooney DJ (2002) Alginate type and RGD den-sity control myoblast phenotype. J Biomed Mat Res Part A 60:217–223

83. Tarun K, Gobi N (2012) Calcium alginate/PVA blended nanofi-bre matrix for wound dressing. Indian J Fibre Text 37:127–132

84. Coşkun G, Karaca E, Ozyurtlu M, Özbek S, Yermezler A, Çavuşoğlu İ (2014) Histological evaluation of wound healing performance of electrospun poly (vinyl alcohol)/sodium alginate as wound dressing in vivo. Biomed Mater Eng 24:1527–1536

85. Pereira R, Carvalho A, Vaz DC, Gil MH, Mendes A, Bártolo P (2013) Development of novel alginate-based hydrogel films for wound healing applications. Int J Biol Macromol 52:221–230

86. Murakami K, Aoki H, Nakamura S, Nakamura SI, Takikawa M, Hanzawa M, Kishimoto S, Hattori H, Tanaka Y, Kiyosawa T, Sato Y (2010) Hydrogel blends of chitin/chitosan, fucoidan and alginate as healing-impaired wound dressings. Biomaterials 31:83–90

87. Li X, Chen S, Zhang B, Li M, Diao K, Zhang Z, Li J, Xu Y, Wang X, Chen H (2012) In situ injectable nano-composite hydro-gel composed of curcumin, N, O-carboxymethyl chitosan and

oxidized alginate for wound healing application. Int J Pharm 7:110–119

88. Wang L, Khor E, Wee A, Lim LY (2002) Chitosan-alginate PEC membrane as a wound dressing: assessment of incisional wound healing. J Biomed Mater Res Part B 63:610–618

89. Roh DH, Kang SY, Kim JY, Kwon YB, Kweon HY, Lee KG, Park YH, Baek RM, Heo CY, Choe J, Lee JH (2006) Wound healing effect of silk fibroin/alginate-blended sponge in full thickness skin defect of rat. J Mater Sci 17:547–552

90. Xie H, Chen X, Shen X, He Y, Chen W, Luo Q, Ge W, Yuan W, Tang X, Hou D, Jiang D (2018) Preparation of chitosan-collagen-alginate composite dressing and its promoting effects on wound healing. Int J Biol Macromol 107:93–104

91. Hu Y, Zhang Z, Li Y, Ding X, Li D, Shen C, Xu FJ (2018) Dual-crosslinked amorphous polysaccharide hydrogels based on chi-tosan/alginate for wound healing applications. Macromol Rapid Commun. https ://doi.org/10.1002/marc.20180 0069

92. Zhou Q, Kang H, Bielec M, Wu X, Cheng Q, Wei W, Dai H (2018) Influence of different divalent ions cross-linking sodium alginate-polyacrylamide hydrogels on antibacterial properties and wound healing. Carbohydr Polym 197:292–304

93. Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T (2016) Hyaluronic acid in inflammation and tissue regeneration. Wounds 28:78–88

94. Trabucchi E, Pallotta S, Morini M, Corsi F, Franceschini R, Casiraghi A, Pravettoni A, Foschi D, Minghetti P (2002) Low molecular weight hyaluronic acid prevents oxygen free radical damage to granulation tissue during wound healing. Int J Tissue React 24:65–71

95. Price RD, Myers S, Leigh IM, Navsaria HA (2005) The role of hyaluronic acid in wound healing. Am J Clin Dermatol 6:393–402

96. Prosdocimi M, Bevilacqua C (2012) Exogenous hyaluronic acid and wound healing: an updated vision. Panminerva Med 54:129–135

97. Lu L, Leng Y, Cnen Y (2000) An experiment study on wound healing with exogenous hyaluronic acid. Chin J Plast Surg 16:30–33

98. Li H, Xue Y, Jia B, Bai Y, Zuo Y, Wang S, Zhao Y, Yang W, Tang H (2018) The preparation of hyaluronic acid grafted pullulan polymers and their use in the formation of novel biocompatible wound healing film. Carbohydr Polym 188:92–100

99. Huang J, Ren J, Chen G, Li Z, Liu Y, Wang G, Wu X (2018) Tunable sequential drug delivery system based on chitosan/hya-luronic acid hydrogels and PLGA microspheres for management of non-healing infected wounds. Mater Sci Eng C89:213–222

100. Chanda A, Adhikari J, Ghosh A, Chowdhury SR, Thomas S, Datta P, Saha P (2018) Electrospun chitosan/polycaprolactone-hyaluronic acid bilayered scaffold for potential wound healing applications. Int J Biol Macromol 116:774–785

101. Schanté CE, Zuber G, Herlin C, Vandamme TF (2011) Chemical modifications of hyaluronic acid for the synthesis of derivatives for a broad range of biomedical applications. Carbohydr Polym 85:469–489

102. Wang TW, Sun JS, Wu HC, Tsuang YH, Wang WH, Lin FH (2006) The effect of gelatin–chondroitin sulfate–hyaluronic acid skin substitute on wound healing in SCID mice. Biomaterials 27:5689–5697

103. Zhu J, Li F, Wang X, Yu J, Wu D (2018) Hyaluronic acid and polyethylene glycol hybrid hydrogel encapsulating nanogel with hemostasis and sustainable antibacterial property for wound heal-ing. ACS Appl Mater Interfaces 10:13304–13316

104. Hu M, Sabelman EE, Cao Y, Chang J, Hentz VR (2003) Three-dimensional hyaluronic acid grafts promote healing and reduce scar formation in skin incision wounds. J Biomed Mater Res B 67:586–592

Molecular Biology Reports

1 3

105. Yıldırım S, Özener H, Doğan B, Kuru B (2018) Effect of topi-cally applied hyaluronic acid on pain and palatal epithelial wound healing: an examiner-masked, randomized, controlled clinical trial. J Periodontol 89:36–45

106. Roehrs H, Stocco JG, Pott F, Blanc G, Crozeta K, Meier MJ, Dias FA (2016) Dressings and topical agents containing hyaluronic acid for chronic wound healing. The Cochrane Library

107. Shi L, Zhao Y, Xie Q, Fan C, Hilborn J, Dai J, Ossipov DA (2018) Moldable hyaluronan hydrogel enabled by dynamic metal–bisphosphonate coordination chemistry for wound heal-ing. Adv Healthc Mater 7:1700973

108. Tamer TM, Valachová K, Hassan MA, Omer AM, El-Shafeey M, Eldin MM, Šoltés L (2018) Chitosan/hyaluronan/edaravone membranes for anti-inflammatory wound dressing: in vitro and in vivo evaluation studies. Mater Sci Eng C 90:227–235

109. Ahmed S, Ikram S (2016) Chitosan based scaffolds and their applications in wound healing. Achiev Life Sci 10:27–37

110. Kozen BG, Kircher SJ, Henao J, Godinez FS, Johnson AS (2008) An alternative hemostatic dressing: comparison of CELOX, HemCon, and QuikClot. Acad Emerg Med 15:4–81

111. Raafat D, Von Bargen K, Haas A, Sahl HG (2008) Insights into the mode of action of chitosan as an antibacterial compound. Appl Environ Microbiol 74:3764–3773

112. Seyfarth F, Schliemann S, Elsner P, Hipler UC (2008) Antifungal effect of high-and low-molecular-weight chitosan hydrochloride, carboxymethyl chitosan, chitosan oligosaccharide and N-acetyl-D-glucosamine against Candida albicans, Candida kruseiand Candida glabrata. Int J Pharmacol 353:139–148

113. Ueno H, Mori T, Fujinaga T (2001) Topical formulations and wound healing applications of chitosan. Adv Drug Deliv Rev 52:105–115

114. Minagawa T, Okamura Y, Shigemasa Y, Minami S, Okamoto Y (2007) Effects of molecular weight and deacetylation degree of chitin/chitosan on wound healing. Carbohydr Polym 67:640–644

115. Tang H, Zhang P, Kieft TL, Ryan SJ, Baker SM, Wiesmann WP, Rogel S (2010) Antibacterial action of a novel functionalized chitosan-arginine against gram-negative bacteria. Acta Biomater 6:2562–2571

116. Doulabi AH, Mirzadeh H, Imani M, SamadiN (2013) Chitosan/polyethylene glycol fumarate blend film: physical and antibacte-rial properties. Carbohydr Polym 92:48–56

117. Obara K, Ishihara M, Ishizuka T, Fujita M, Ozeki Y, Maehara T, Saito Y, Yura H, Matsui T, Hattori H, Kikuchi M (2003) Photo crosslinkable chitosan hydrogel containing fibroblast growth fac-tor-2 stimulates wound healing in healing-impaired db/db mice. Biomaterials 24:3334–3337

118. Alemdaroğlu C, Değim Z, Çelebi N, Zor F, Öztürk S, Erdoğan D (2006) An investigation on burn wound healing in rats with chitosan gel formulation containing epidermal growth factor. Burns 32:319–327

119. Ong SY, Wu J, Moochhala SM, Tan MH, Lu J (2008) Develop-ment of a chitosan-based wound dressing with improved hemo-static and antimicrobial properties. Biomaterials 29:4323–4332

120. Li X, Nan K, Li L, Zhang Z, Chen H (2012) In vivo evaluation of curcumin nanoformulation loaded methoxy poly (ethylene glycol)-graft-chitosan composite film for wound healing appli-cation. Carbohydr Polym 88:84–90

121. Moura LI, Dias AM, Leal EC, Carvalho L, Sousa HC, Carvalho E (2014) Chitosan-based dressings loaded with neurotensin—an efficient strategy to improve early diabetic wound healing. Acta Biomater 10:843–857

122. Değim Z, Celebi N, Sayan H, Babül A, Erdoğan D, Take GA (2002) An investigation on skin wound healing in mice with a taurine-chitosan gel formulation. Amino Acids 22:187–198

123. Tran NQ, Joung YK, Lih E, Park KD (2011) In situ forming and rutin-releasing chitosan hydrogels as injectable dressings for dermal wound healing. Biomacromolecules 12:2872–2880

124. Huang X, Li LD, Lyu GM, Shen BY, Han YF, Shi JL, Teng JL, Feng L, Si SY, Wu JH, Liu YJ (2018) Chitosan-coated cerium oxide nanocubes accelerate cutaneous wound healing by curtail-ing persistent inflammation. Inorg Chem Front 5:386–393

125. Concha M, Vidal A, Giacaman A, Ojeda J, Pavicic F, Oyarzun-Ampuero FA, Torres C, Cabrera M, Moreno-Villoslada I, Orel-lana SL (2018) Aerogels made of chitosan and chondroitin sul-fate at high degree of neutralization: biological properties toward wound healing. J Biomed Mater Res B. https ://doi.org/10.1002/jbm.b.34038

126. Kim BS, Park JY, Kang HJ, Kim HJ, Lee J (2014) Fucoidan/FGF-2 induces angiogenesis through JNK- and p38-mediated activation of AKT/MMP-2 signaling. Biochem Biophys Res Commun 450:1333–1338

127. O’Leary R, Rerek M, Wood EJ (2004) Fucoidan modulates the effect of transforming growth factor (TGF)-β1 on fibroblast pro-liferation and wound repopulation in in vitro models of dermal wound repair. Biol Pharm Bull 27:266–270

128. Park JH, Choi SH, Park SJ, Lee YJ, Park JH, Song PH, Cho CM, Ku SK, Song CH (2017) Promoting wound healing using low molecular weight Fucoidan in a full-thickness dermal excision rat model. Mar Drugs 15:112

129. Zeng HY, Huang YC (2018) Basic fibroblast growth factor released from fucoidan-modified chitosan/alginate scaffolds for promoting fibroblasts migration. J Polym Res 25:83

130. Nair AV, Raman M, Doble M (2016) Cyclic β-(1→ 3)(1→ 6) glucan/carrageenan hydrogels for wound healing applications. RSC Adv 100:545–553

131. Wong VW, Rustad KC, Galvez MG, Neofytou E, Glotzbach JP, Januszyk M, Major MR, Sorkin M, Longaker MT, Rajadas J, Gurtner GC (2010) Engineered pullulan–collagen composite der-mal hydrogels improve early cutaneous wound healing. Tissue Eng A 17:631–644

132. Kim HL, Lee JH, Lee MH, Kwon BJ, Park JC (2012) Evaluation of electrospun (1, 3)-(1, 6)-β-D-glucans/biodegradable polymer as artificial skin for full-thickness wound healing. Tissue Eng A 18:2315–2322

133. Matou S, Colliec-Jouault S, Galy-Fauroux I, Ratiskol J, Sinquin C, Guezennec J, Fischer AM, Helley D (2005) Effect of an over-sulfated exopolysaccharide on angiogenesis induced by fibroblast growth factor-2 or vascular endothelial growth factor in vitro. Biochem Pharm 69:751–759

134. Maalej H, Moalla D, Boisset C, Bardaa S, Ayed HB, Sahnoun Z, Rebai T, Nasri M, Hmidet N (2014) Rhelogical, dermal wound healing and in vitro antioxidant properties of exopolysaccharide hydrogel from Pseudomonas stutzeri AS22. Colloids Surf B 123:814–824

135. Trabelsi I, Ktari N, Slima SB, Triki M, Bardaa S, Mnif H, Salah RB (2017) Evaluation of dermal wound healing activity and in vitro antibacterial and antioxidant activities of a new exopoly-saccharide produced by Lactobacillus sp. Ca6. Int J Biol Macro-mol 103:94–201

136. Priyanka P, Arun AB, Ashwini P, Rekha PD (2016) Functional and cell proliferative properties of an exopolysaccharide pro-duced by Nitratireductor sp. PRIM-31. Int J Biol Macromol 85:400–404

137. Priyanka P, Arun AB, Ashwini P, Rekha PD (2015) Versatile properties of an exopolysaccharide R-PS18 produced by Rhizo-bium sp. PRIM-18. Carbohydr Polym 126:215–221

138. He Y, Ye M, Du Z, Wang H, Wu Y, Yang L (2014) Purification, characterization and promoting effect on wound healing of an exopolysaccharide from Lachnum YM405. Carbohydr Polym 105:169–176

View publication statsView publication stats