Table 2.

Analysis of recent approaches to fabricating wound healing construct using biomaterials (synthetic/natural)

Sl. No.	Authors and year	Biomaterial type	Classification	Wound type	Used case (method)	Property of the material for enhanced wound healing
1	Bienert et al. 2017 [55]	Native B. Mori silk membranes and growth factor-regulated silk membranes	Natural	A chronic wound in an in vitro model	All of the silk membranes were cytocompatible and exhibited enhanced chemokine (C-X-C motif) ligand 1 (CXCL-1) and monocyte chemo-attractant protein secretion. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF)-regulated silk membranes accelerated macrophage adhesion. Dermal equivalents had higher wound healing capacity when covered with growth factor-regulated silk membranes.	• The silk membrane stimulated growth factors that were in direct contact with the membrane • Silk membranes stimulated macrophage release of neutrophils and thus inducing factors like CXCL-1 and MCP-1 while inhibiting the production of pro-inflammatory cytokines, including interleukin (IL)-6, IL-10 and TNF-α
2	Rossi et al. 2017 [56]	Chitosan ascorbate nanoparticles loaded with amoxicillin trihydrate	Synthetic and natural	Wound due to atrophic vaginitis in an in vitro model	Chitosan ascorbate NPs interact with mucin having an inhibitory effect against Enterococcus hirae and Streptococcus pyogenes. For faster wound healing, it stimulates the growth of fibroblasts.	• Chitosan ascorbate nanoparticles were found to be highly stable and were found to be effective as a drug-delivery polymer matrix • Chitosan-based polymeric nanoparticles showed superior cellular biocompatibility and enhanced cellular migration, thus achieving faster wound healing
3	Da Fonseca et al. 2017 [53]	Adipose tissue derived mesenchymal stem cells (MSC)	Natural	Excision wound in an in-vivo model (Male Wistar Rat)	MSC derived from Adipose tissue secreted extracellular vesicles, which enhanced the proliferation of fibroblast and keratinocytes, thereby leading to healing.	• Extracellular Vesicles derived from mesenchymal stem cells activate the ATK pathway in a miR-205-independent manner and hence can accelerate wound healing
4	Abdel-Mohsen et al. 2017 [51]	Hyaluronic acid/silver nanoparticles fibre	Synthetic	Diabetic wound in chronic ulcers using an in vivo rat model	In situ synthesis increased thermal stability and antimicrobial activity against E. coli and accelerated the healing process.	• The fibres showed enhanced crystallinity and thermal stability, which is required for wound dressing materials • The silver nanoparticles enhanced the antimicrobial property of the dressing • The presence of hyaluronic acid enhances the overall wound healing process as it promotes angiogenesis and also has an antioxidant effect
5	He et al. 2018 [57]	Curcumin/polyvinyl alcohol hydrogel	Synthetic	Skin and burn wound using an in vivo rat model.	The hydrogel with optimal Cur/PVA volume (1:5 at 20% Cur/PVA) exhibited antibacterial activity to E. coli and S. aureus. At a higher volume (1:10 at 10% Cur/PVA), it accelerated wound healing and reconstructed the epidermis during the 14th day of healing.	• Polyvinyl alcohol (PVA) promotes wound healing owing to its intrinsic properties like biocompatibility and biodegradability and mechanical strength [58] • PVA, when kept hydrated, maintains its structural ability, thus requiring fewer changes in dressing, and due to its transparency, wound healing can be monitored efficiently
6	Park et al. 2018 [59]	Phlorotannins and poly (vinyl alcohol) fabricated hydrogel	Synthetic	A chronic wound using an in vitro model.	PVA/PH hydrogel showed decreased tensile strength and tensile modulus, but the swelling ratio and ultimate strain showed a significant increase. On PVA/PH hydrogel, cell attachment and proliferation were increased on the first and fifth days compared to normal PVA hydrogel.	• Phlorotannins and poly (vinyl alcohol)-based hydrogel showed better cellular proliferation • The mechanical strength of the PVA-based hydrogel film played a key role in the wound healing process
7	Dhand et al. 2018 [60]	Collagen/quaternary ammonium silane (Coll-QOS) composite scaffolds	Natural and synthetic	Dermal wound using an in vitro model	Scaffolds were estimated for biocompatibility and cellular adhesion in dermal fibroblasts and fetal osteoblasts.	• Quaternary ammonium organosilane (QOS) crosslinked collagen nanofibres showed superior flexibility and thermal stability • The mats showed antibacterial activity, thus promoting effective wound healing • Collagen is chemotactic in nature and hence attracts fibroblast at the wound site • Collagen downregulates matrix metalloproteinase (MMPS) and hence promotes faster wound healing [61]
8	Yu et al. 2018 [62]	Cell sheet composed of adipose-derived stem cells (ASC)	Natural	Full thickness wound using in vivo model (nude mice)	Adipose-derived stem cell sheets enhance the healing process by decreasing scar formation and increasing the survival rate of wounded tissues within 28 days with fewer side effects.	• The adipose-derived stem cell sheets possess antifibrotic properties • The ASC sheets’ anti-scarring action was mediated in part by an increase in hepatocyte growth factor secretion • There was a considerable increase in C1q/TNF-related protein-3 produced by ASC sheets, which may be the cause of the reduced macrophage recruitment to the wound tissues • The paracrine elements included in ASC sheets help skin repair wounds more quickly and with less scarring. This makes ASC sheets an excellent choice for topical wound therapy
9	Ouyang et al. 2018 [52]	Chitosan-marine peptide hydrogels (CSMP)	Natural	Burn wounds using in vivo rabbit models	CSMP-treated wounds showed re-epithelialization and collagen fibre deposition on the seventh day and regeneration of epithelium on the 14th day, along with upregulating expression of FGF2 and VEGF.	• Chitosan possesses intrinsic antibacterial activity, thus promoting faster wound healing at the wound site • The hydrogel upregulates the expression of FGF2 and VEGF, which in turn can promote skin regeneration • Chitosan also reduces the inflammatory stage to start the onset of the proliferation stage [63]
10	Zhou et al. 2018 [64]	Sodium alginate-polyacrylamide based hydrogel crosslinked with novel divalent ion cross-linking (copper, zinc, strontium and calcium)	Synthetic	Full-thickness skin wounds in an in vivo rat model.	All divalent ions cross-linked hydrogels were analysed for swelling ratio, biocompatibility and antibacterial property with detection of VEGF and transforming growth factor beta (TGF-β) expression. Zinc cross-linked hydrogel showed a better response to antibacterial activities, cell viability, fibroblast migration, collagen deposition and formation of granulation tissue.	• The hydrogel crosslinked with zinc ions showed superior mechanical strength • An alginate gel may absorb wound fluid in the form of a dry powder, which can be used to keep the wound moist and reduce germs • Polyacrylamide, on the other hand, shows good skin tissue adherence and proper water absorption
11	Zhu et al. 2018 [65]	Aminoethyl methacrylate hyaluronic acid methoxy polyethylene glycol hybrid hydrogels and chlorhexidine diacetate (CHX)-loaded nanogels (Gel@CLN)	Synthetic	Skin wound at the dorsal position in a mouse model.	Gel@CLN showed swelling activity and low cytotoxicity with prolonged release of CHX. In addition to speeding up the healing process, its haemostasis abilities were quite prominent.	• Hyaluronic acid promotes wound healing by drawing fibroblasts to the wound site • HA also reduces inflammation and is responsible for the induction of the early proliferative phase [47] • Polyethylene glycol provides good mechanical support for wound dressing material • PEG also provides thermal stability to the hydrogel [30]
12	Liao et al. 2018 [66]	Hybrid alginate hydrogel crosslinked by calcium gluconate crystals deposited in PCL–PEG–PCL (PCEC) porous microspheres	Synthetic	Skin wound using an in vivo rat model	The PCEC microspheres/Alg hydrogel had compatibility and enhanced wound regeneration.	• PCL is highly viscoelastic with considerable mechanical properties making it highly suitable for wound healing applications • PCL is hydrophobic, so it is mostly blended with other materials • PCL’s high surface-to-volume ratio and porous structure improve homeostasis, cell migration and adhesion, wound exudate absorption, gas permeability for proper gas exchange, cellular migration, and proliferation [67] • PEG’s properties, like flexibility, hydrophilicity, biocompatibility and non-immunogenicity, make it highly useful for wound healing • PEG has good adhesive properties
13	Heydari et al. 2018 [68]	Novel poly (glycerol sebacate)/polyhydroxybutyrate (PGS/PHB) with simvastatin (SIM) and ciprofloxacin (CIP)	Synthetic	Skin wound	CIP loaded into the surrounding PHB part of the fibre showed burst release within 24 h that regulated wound infections. Similarly, SIM loaded to PGS core part lowered rate of release, therby providing time for wound healing.	• PGS exhibits biocompatibility and biodegradability, thus making it highly suitable for wound healing • PGS provides conducive surface for the cells to adhere to surface of the biomaterials [69]
14	Huang et al. 2018 [70]	Chitosan/hyaluronic acid hydrogels and PLGA microspheres	Synthetic	Skin wound	Chitosan/hyaluronic acid hydrogels and PLGA microspheres elevated angiogenic promoting and vascular endothelial growth factor secretion with higher antibacterial activity for wound healing.	• PLGA is a highly bio-degradable polymer; thus, it stimulates the rate of epithelization [30] • Chitosan possesses intrinsic antibacterial activity • Hyaluronic acid plays a major role in the faster completion of the inflammatory phase thus inducing the proliferative phase
15	Wang et al. 2019 [71]	Polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived MSC exosomes	Natural	Chronic nonhealing diabetic wound	FHE@exosomes hydrogel enhanced proliferation, migration and tube formation activity in umbilical vein endothelial cells with the enhanced healing process for diabetic wounds with faster angiogenesis, re-epithelization and collagen deposition.	• Poly—L-lysine (EPL) is a natural cationic polypeptide derived from Streptomyces albulus that is biodegradable, antimicrobial and biocompatible [30] • Pluronic F-127 gel is mildly inflammatory and stimulates VEGF and TGF-1 [72]
16	Yang et al., 2020 [73]	Human umbilical cord-derived MSC (hUCMSC)-derived exosomes (hUCMSC-exos) encapsulated in thermosensitive PF-127 hydrogel	Synthetic	Chronic refractory wounds due to diabetes mellitus	A combination of PF-127 and hUCMSC-exosomes showed a faster wound closure rate and increased expression of CD31 and Ki67 with the regeneration of granulation tissue. It also upregulated the expression of VEGF and TGFβ-1.	• At normal temperature, PF-127 hydrogel improves exosome survival • The PF-127 acted as an efficient delivery system for exosomes and hence promoted angiogenesis
17	Lu et al., 2020 [74]	Enzyme crosslinked gelatin hydrogel with human adipose-derived stem cell (hASCs) spheroid	Synthetic	Murine Burn Wound	The hASCs recognized wounded cells and elevated growth factors secretion for angiogenesis and gelatin scaffold. It also enabled cell migration by fastening tissue regeneration on the 10th day.	• Gelatin absorbs wound exudates and also keeps the wound site moist • Gelatin exhibits good attachment to fibroblast • The RGD peptide sequences found in gelatin help cells recognize their integrin receptors, which are essential for cell adhesion [75]
18	Xu et al. 2020 [54]	Modified TGFβ3 and platelet-derived growth factor (PDGF) combined with synthetic biomaterial.	Synthetic	Skin wound	TGFβ3 reduced scar formation through decreased myofibroblast proliferation with decreased collagen ratio. PDGF acted as a chemoattractant against macrophages and fibroblasts and increased the growth factor secretion for granulation tissue and matrix formation.	• PLGA is highly degradable and can efficiently deliver growth factors for faster wound healing • PLGA has tuneable and controllable mechanical properties making it highly suitable for wound dressing [30,54]
19	Ji et al. 2020 [76]	A hybrid system of PVA/gelatin hydrogel/frog egg-like microspheres	Synthetic	Skin wound	The release of Rana chensinensis skin peptides (RCSPs) elevated the healing process. H-FMS acted as a depot for the release of RCSPs over 9 days without burst release and showed biocompatibility.	• PVA increases the porosity and cell-matrix adhesion of the final material • PVA has mechanical properties mimicking that of skin [77] • Gelatin promotes cellular adhesion
20	Yu et al. 2020 [78]	Exosomes derived from bone marrow MSC pre-treated with atorvastatin (ATV)	Natural	Diabetic wound (full-thickness skin type)	Exosomes from ATV-pre-treated MSCs helped in diabetic skin defects treatment by increasing endothelial cell function through the AKT/eNOS pathway by upregulating miR-221-3p.	• Exosomes are highly efficient in cellular communication hence promoting cellular migration • MSCs induce angiogenesis • The MSC-derived exosomes were highly stable with low immune rejection
21	Zhao et al. 2020 [79]	Catechol–Fe3+ cross-linked poly (glycerol sebacate)-co-poly(ethylene glycol)-g-catechol prepolymer (PEGSD) and GTU (PEGSD-GTU) hydrogel	Synthetic	Full-thickness skin incisions	It showed rapid shape adaptation, regulated inflammatory response, accelerated collagen deposition and self-healing properties. As these hydrogels get dissolved or disintegrated in the application area, with time slight change in pH has been observed; the application of the material resulted in haemostasis of skin lesions with higher anti-bacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).	• Poly-ethylene glycol (PEG) contributes highly to the viscoelasticity of the hydrogel and makes it suitable as an injectable material • Poly (glycerol sebacate) exhibits flexible mechanical properties making it highly suitable for wound dressing material • PGS is nonimmunogenic, noncytotoxic in vitro, and elicited a modest inflammatory response in vivo with negligible fibrous capsule development [80]
22	Wang et al. 2021 [81]	Novel 3D printable bionic hydrogels	Synthetic	Large, irregular-shaped wounds	CMC/PL hydrogels with glycidyl methacrylate-modified carboxymethyl cellulose and ε-polylysine showed higher compression modulus (238 kPa), stable rheological properties and microbial inhibitory effect. They increased VEGF and CD31 expression and accelerated granulation tissue regeneration.	• The carboxymethylcellulose dressing shields the wound site from external influences that may cause discomfort, increase infection or inhibit normal wound healing • The cellulose-derived polymer carboxymethylcellulose is non-toxic, non-allergenic, water-soluble and anionic, making it highly suitable for wound healing purposes • Carboxymethylcellulose possesses high biocompatibility and superior biodegradability and also mimics tissue structure[82]
23	Ji et al. 2021 [83]	Janus-structured nanofibres loaded with R. chensinensis skin peptides and silver nanoparticles	Synthetic	Skin wound	The Janus nanofibres lowered cytotoxicity and antibacterial activity and accelerated re-epithelialization, fibroblast proliferation and regeneration of capillaries and hair follicles within 14 days.	• Polyvinylpyrrolidone (PVP) used in the fibres is soluble in water and has good film-forming properties, thus making it highly suitable for wound dressing • PVP is biocompatible, non-toxic, non-ionic, inert, temperature-resistant and pH-stable