Table 1: Factors effecting Wound Repairing ^{2, 3}

Cellular factors
Fibroblast	Migrates to wound bed and induce the Production of essential matrix proteins Fibrin, Collagen III, Hyaluronic acid.
Neutrophils	Kills pathogen by secreting various enzymes like lysozyme, and release factors like IL-1, IL-6, elastin, TNF-α
Macrophage	Pro-inflammatory M1 type clears damaged tissue, debris and pathogen by phagocytosis M2 type activates epithelisation, keratinocytes.
TNF-α	At low concentration helps to remove dead tissue, stimulation pro-inflammatory and growth factors. Prolong release delays repairing
PDGF	In the early stage of healing it release from the de-granulated platelets and helps proliferation of fibroblast as well as other extra cellular factors.
VEGF	Helps in angiogenesis for oxygen supply.
Reactive oxygen species	Oxidative killing of bacteria, Nitric Oxide, antioxidant as well as vasodilator produce and prevent the oxidative damage of tissue.
Local factors
Oxygenation	Oxygen is essential for cell metabolism and energy formation; also stimulate bactericidal action
Pressure	Pressure more than 32 mm hg for longer time leads ischemia
Oedema	Leads to ischemia by increasing the tissue volume.
Infection	Microorganism contamination needs antibiotic therapy.
Systemic factors
Malnutrition and vitamin deficiency	Vitamin K (blood coagulation) Zinc, copper, vitamin A and C(collagen synthesis).
Age	Reconstruction of cutaneous tissue delays.
Diabetes mellitus	Hyperglycaemia results proteolysis of matrix protein like collagen and tissue ischemia.
Smoking	Nicotine and other components affect the oxygen supply in subcutaneous and cutaneous cells, leads to hypoxia
Medication	Medications like blood thinning agents or anti-coagulants and NSAIDS (Ibuprofen, Aspirin), Chemotherapeutic agents likely Adriamycin (Doxorubicin).

Table 2: List of Bio-Polymers Based on their Source, Chemical Nature and Influence in Wound Repairing ^4-16

Name	Source	Chemical nature	Mechanism of action
Alginate	Brown sea algae Pseudomonas, Azotobacter	Acidic polysaccharide, linear copolymers consist of blocks of (1, 4)-linked β-D-mannuronate (M) and α-L-guluronate (G) residues. G-blocks undergo intermolecular cross-linking with divalent cations (e.g., Ca²⁺) to form hydrogels.	Calcium alginate acts as a haemostat in a moist wound. Calcium ion is exchanged with sodium ion of wound fluid. This supply of calcium ion (cofactor IV) regulates coagulation cascade as well as trigger the formation of fibrin mesh by enhancing the proliferation of fibroblast.
Chitosan	Crustaceans animals like, Prawns: Penaeus or Fenneropenaeus Shrimp: Penaeuscarinatu sp Crab: Sesarma plicatum Fungi: Aspergillus Niger Bacteria:Salmonella typhi, Pseudomonas aeruginosa	Alkaline de-acetylated derivative of chitin known as chitosan. Basic cationic polysaccharide biopolymer structured with N-glucosamine and N-acetyl-glucosamine units.	Healing effect: Chitosan is cationic attract negatively charged platelets promote platelet aggregation. Microphage migration, fibroblast proliferation and collagen synthesis. Antimicrobial effect: Disruption of cell wall and cell membrane in both gram positive and gram negative bacteria by the electrostatic interaction.
Agarose	Red algae: Lithospermum Gracilaria	Neutral polysaccharide composed with repeating unit consisting of 3-D-galactose and 4-linked 3, 6-anhydro-1-galactose with methoxy, sulphated substitutes.	Good gelling agent and highly absorbent in nature absorbs wound fluid and maintain the moisture in the wound bed. Agar gels can mimic the properties of skin’s Extra cellular matrix and tissues.
Carrageenan	Red seaweeds:Stonecrop, Kiringa and Deerstalker	Anionic, sulphated polysaccharide consisting unit of D-galactose and 3,6 anhydrogalactose linked with α-1,3 and β-1,4 glycosides.	Ionic-carrageenan can fix the optimum ratio of coagulant and anticoagulant factors in blood. Allows gaseous exchange due to high porosity.
Fucoidan	Brown algae Laminaria, Ascophyllum and Fucus	Polysaccharide consist three sugars L-fucose, mannose, and glucose attached to a sulphate group.	Fucoidan (43% sulphated) protects wound bed from reactive oxygen damage (ROS).
Cellulose	Structural material of plant, algae, fungi cell wall. Bacteria:Gluconacetobacter, Agrobacterium, Pseudomonas, Rhizobium spp.	Neutral polysaccharide chain consist of β-(1,4)-linked d-glucose units	Carboxy Methyl Cellulose widely used as wound dressing for its excellent capabilities of absorbing exudates and also possess anti-microbial action.
Starch	Cell wall of plants, algae bacteria.	Neutral polysaccharide. Amylose+ amylopectin.	Starch - Biocompatible and nontoxic
Dextran	Bacteria: Leuconostoc spp	Polymeric homosaccharide made of glucose residue linked by α-(1,6)-glycosidic bond	Highly swell able and shows pro-angiogenic effect along with tissue regeneration.
Pullulan	Fungi: Aureobasidium pullulans	A water soluble polysaccharide formed by monomers of α-(1,6)-maltotriose with α-(1,4)-glycosidic bonds.	Anti-coagulant and anti- inflammatory
Pectin	Plant cell wall specifically from fruits like apple pomance (10-15%) Citrus peels like orange, lemon (20-30%) Other fruits like pineapple, papaya, grapes and dragon fruit and sugar beet pulp.	Polysaccharide in nature which consist of D-galacturonic acid (GalA) units linked in chains by a-(1-4) glycosidic linkage. Classification High methoxyl (HM)pectin (>50% methoxyl group) Low methoxyl (LMC) pectin (<50% methoxyl) Amidated low methoxyl (LMA)pectin-(50% methoxyl+ 5-10% amidated group	Pectin shows of rapid hydration and swelling, but poor aqueous solubility. So it is modified to amidated pectin, which can undergoes in-situ gelation crosslinking with oxidised chitosan by the help of Schiff-base and form a hydrogel for wound healing. With combination of synthetic polymers pectin also widely used to produce scaffolds for skin repairing.
Gellan gum	Aerobic fermentation of bacteria likely sphingomonas/pseudomonas thaliana	Extracellular polysaccharide made of four different monosaccharaides as repeat unit of two D-glucose, l-rhamnose and d-glucuronic acid	Gellan gums possess postoperative adhesions and prevent scar formation at the last stages of healing^11-15.
Hyaluronic acid	Bovine source, Bacillus spp., Agrobacterium spp., E. coli, Lactococcus lactis.	Anionic glycosaminoglycan (GAG) composed of alternating units of α-1,4-d-glucuronic acid and β-1,3-N-acetyl-d-glucosamineattached by β-(1,3) bond	Low molecular hyaluronic acid (<50KD) helps in angiogenesis and exerts inflammatory effect along with bacteriostatic properties.
Collagen	Bone tendons cartilage and skin Terrestrial animals (cattle and pigs) Marine source (fish scale) recombinant human collagen.	Main structural protein of the ECM of skin structure Three helically coiled linear chains of amino acids, namely glycine(25%), proline(25%),hydroxyproline	Type I collagen fragments attract neutrophils and phagocytes and mediate the immune response. Collagen Type I and III show the early stage tissue remodelling and stimulate angiogenesis. Collagen type IV shows anti-angiogenic properties inhibiting the migration and apoptosis of endothelial cells.
Gelatin	Denatured collagen	Gelatin is acid or alkali treated denatured collagen	Less immunogenic than collagen. High mechanical strength.
Keratin	Horns and wools of cattle	Structural protein of nails, horns, epidermis. Keratins composed of sulphated amino acid cysteine as structural proteins, with a large number of disulfide bonds.	Acceleration in cell growth and collagen expression. Presence of cysteine as a precursor of glutathione pathway act as antioxidant.
Silk protein (fibroin and sericin)	Cocoon of Bombyx mori	Silk fibroin consists of a heavy (H) chain and a light (L) chain linked by single disulfide bond and amino acids Glycine (43%), Alanine (30%), and Serine (12%).	Fibroin is strong, flexible, and highly compressible; shows immunogenic effect. Sericin promotes the collagen regeneration and re-epithelisation.

BIO-POLYMERS IN WOUND DRESSINGS:

1. Hydrogels dressings:

Hydrogels are composed of cross-linked polymers which construct a 3D structure that can absorb a large volume of water due to the presence of hydrophilic moiety. By tailoring the cross-linking reaction the physicochemical properties of hydrogel can be modified. Apart from highly absorbent characteristics hydrogels are highly biocompatible, biodegradable, and low immunogenic in nature. The crosslinking process is mainly of two types; Chemical (covalent bonding) and Physical (hydrogen /electrostatic bonds). The swelling phenomenon defines by the diffusion of water into hydrogels¹⁷. Water molecules from the wound bed attach to the hydrophilic groups of polymers in the hydrogel and free water moiety filled into the void spaces in between the cross-linked polymer chains. The swelling index is inversely related to the degree of cross-linking. An advanced degree of cross-linking also reduces the elasticity and leads to brittleness in the hydrogel. In spite of various advantages, hydrogels often have low mechanical strength, thus not useful for highly exuding wounds as well as accommodation of wound fluid leads to generating foul smell. Although the tight mesh likes structure of hydrogel prevents colonization of microorganisms.

Ideal characteristics of hydrogels:

· Water vapour transmission rate <35 g/m2 /hour effective to retain moisture and rapid healing.

· Rate of absorption depends on the particle size and porosity of gels.

· No alteration of pH after swelling.

· Highest level of biodegradability, after degradation no residue of toxic products.

· Stability and durability during wound healing and storage.

· Low production cost.

Nature deduced polysaccharides like alginate, chitosan and agarose, etc. are potential candidates for hydrogels as they have the high absorption capacity to minimize the wound secretion and maintain the moisture/dryness ratio throughout the treatment. These types of hydrogels are often incorporated with herbal extract (Aloe Vera), honey, antibiotic drugs, and metal ions. Blending of several polymers likely chitosan/gelatin/PVA hydrogel impregnated with honey for wound healing applications and chitosan/PVA incorporates with silver nanoparticle to formulate a hydrogel for Wound Healing^18-19. Metal ion and nanoparticles loaded gels are largely formulated for their broad spectrum of antimicrobial activity. Stimuli responsive hydrogels are one of the advanced techniques for wound management. A _PH responsive hydrogels are a category of biopolymers that exhibit desirable physical and chemical properties at specific _PH ranges. The acidic groups bound to the polymer chain donate H⁺ at high _PH and basic groups accept H⁺ at lower _PH. For example, a _PH responsive composite hydrogel made of carboxylated agarose and tannic acid, cross-linked with zinc salts for wound healing²⁰.On the other hand, thermo-responsive gels are formulated based on the theory of sol-gel transition. Polymers like sodium alginate and F-127 blended with a film former agent PVA to formulate a thermo-responsive hydrogel membrane for wound healing. Polymers like dextran undergo in situ gelation and loaded both chitosan microparticle and growth factor demonstrates a controlled release to accelerate the wound healing in vivo model^21. A wide range of hydrogel dressings is available in the market such as hydrogel loaded gauze sheet, membrane, amorphous gel, etc. ActivHeal® hydrogel is an amorphous gel contains 85% of water, Guar gum and polypropylene glycol that self-donate fluid to the dry necrosis wound, Purilon® gel that hydrate the necrotic tissue and absorb the excess fluid; remove the cell debris from the sloughy wound likely leg ulcers, diabetic foot ulcers, burn wounds. Commercially available marketed products are Nu-gel®, Hydrosorb® and Silvasorb®²².

2. Film dressings:

Advanced semipermeable film dressings are mainly composed of polyurethane or polyvinyl alcohol which is also biocompatible and biodegradable synthetic polymer. The adhesive transparent layer of film dressing helps in the transmission of oxygen water vapour and carbon dioxide from the wound bed to the environment. The transparency also helps to monitor the wound condition and scars without removing them. The elasticity and flexibility of the film dressings consider it as an ideal dressing for superficial and acute wounds. Film dressing is not excellent absorbent, thus not suitable for highly exuding wounds. To overcome this problem recent advancement demonstrated the blending of various biomaterials with synthetic polymers to form a multifunctional film dressing. Metallic ions are also loaded with the biopolymers to improve the bacteriostatic properties that include chitosan/gold nano composite film dressing for antibacterial activity and wound healing. Antibiotic drugs are often used to control the bacterial infection surrounding the wound bed, especially in burn cases. Silver –sulfadiazine and [(Mg-Al) LDH] loaded in alginate film as an anti-microbial wound dressing²³. Tegaderm™ is a commercially available film dressing composed with (Alginate/ CMC/ silver ionic complex).

3. Foam dressing:

Foam dressings are highly porous, absorbent steady, and durable semipermeable sheets generally composed of polyurethane or silicon-based derivatives. This dressing is applicable for traumatic, burns and chronic wounds like pressure ulcers, and diabetic foot ulcers (DFU). Foam dressing can absorb a large amount of fluid from the wound bed, permits gaseous permeation, and retain the optimum moisture balance besides it is not suitable for the dry superficial wound as too much absorption leads to tissue maceration. A secondary dressing is needed to promote flexible attachment of the foam dressing right to the wound site. It can be left for 4 to 6 days period and should change after being saturated with exudate. Synthetic polymer like Polyurethane, when incorporated with hyaluronic acid and silver sulfadiazine, exhibited a decrease in the area of wound bed around 77% after 1 week of application along with antimicrobial action²⁴. Foam dressing composed of biopolymers like alginate is also useful to load antibacterial agents like drugs(antibiotics), silver nanoparticles, herbal products (curcumin), ions like (ZnO, Cu) etc., Alginate dressing impregnated with curcumin prevented growth of viable E. faecalis in vitro. Curcumin mediated phototoxicity is less susceptible for E.Coli viable cells. But, when PEG 400 is used for solubilization dressing shows good activity against E.Coli²⁵. Another example of an antibacterial foam dressing composed of bacterial cellulose (Acetobacter xylinum) impregnated with ZnO shows action against E.Coli,^. Gastrodia elata and tea tree oil loaded in silk fibroin Foam dressing show regeneration of collagen tissue and dermis layer after 21 days in vivo model^26-27. Incorporation of various tissue growth factors like fibroblast growth factor in gelatin/hyaluronic based dressings showed sustained release of the factors for 48 hours that accelerates wound healing in the animal model²⁸.

4. Electrospun nano-fibres:

Electro spinning stands for electrostatic spinning. This is a novel technique to produce cost effective and steady nanofibres with desirable properties. Electric field is applied to attracted the charged tails of the polymers to modified them into a fibre with a nano sized diameter ranging from 5-100nm²⁹.

General process of electrospinning:

A) A syringe is loaded with the polymeric solution (moderately viscous) and placed horizontally with an installation of syringe pump.

B) The optimum voltage is applied to generate an electrical field in between the needle head and rotatory drum collector.

C) Accumulation of enough repulsive charge that exactly same as the surface tension of the solution.

D) Repulsive charges leads to form a conical shaped droplet to the edge of the needle generally termed as ‘Taylor cone’.

E) To form a taylor cone the electric field should be acting on the angle of 49.3º with respect to polymeric solution.

F) The flow volume and speed is selected in the flow rate controller device.

G) The polymeric solution is sprayed and the nanofibres are collected in the rotatory drum collector which is covered with an aluminium foil.

Figure 2: General Procedure of electrospinning.

Properties of an ideal electro spun nanofibres: ³⁰

1. Fibre Diameter: The fibre diameter is important to mimic the skin natural extracellular matrix, range from 50-500nm

2. Porosity (60-90%): Necessary for gaseous exchange and water permeation which helps in cell respiration.

3. Surface area and volume ratio: High surface area and volume ratio improve haemostasis and cell proliferation

4. Texture of Nanofibrillary matrices: Depends the drug loading and adsorption of the injury’s exudates as well with the prevention of bacterial infection.

5. 3D printed wound dressings:

3D printing is a new era of personalized regenerative medicine. It is an additive technology that can form an object in any shape and size by layer by layer deposition of material or polymer. In wound care market this technology is one of the fastest growing technique towards patient specific and customised wound dressing. Biodegradable synthetic polymers like polycaprolactone (Medical graded mPCL) dressing are formulated loaded with cryopreserved human gingival mesenchymal/ stromatal cell by melt electro-writing 3D bioprinting for skin remodelling³⁷. Various biopolymers and their modified version also shows as a potential candidate for 3D printing process which includes alginate, chitosan, cellulose, gellan gum, pectin etc.,

A classical 3D printing process essentially follows 3 steps:

1) Modelling: Virtual blue print is created with computer aided software and converted into .stl file. Then this design is sliced into distinct printable 2D layers.

2) Printing: Software controls printer movements and instruct layer by layer disposition to form the required scaffold structure.

3) Finishing: 2D layers of raw materials are fused and dried to desired 3D porous structure. Using extrusion based 3D printer Chitosan-pectin cross linked hydrogels is developed impregnated with lidocaine hydrochloride to enhance wound healing. Porous 3D printed chitosan scaffolds are prepared by fuse deposition 3D bio printing method for tissue regeneration and wound repairing³⁸. 3D printing involves the fabrication of a complex matrix called bio ink, which should be highly biocompatible, mechanical stability along with ideal rheological properties. Natural polymers or their blends or cross-linked derivatives are promising candidates for bio-ink likely collagen/chitosan, alginate/gelatin and collagen³⁹.

6. Skin substitutes using tissue engineering:

The exact replication of biological structure of skin along with dermis and epidermis layer is very difficult process. The main focuses of tissue engineering to develop durable skin substitutes which can mimic the histological structure of skin and avoid immunogenic T cell response.

Classification of skin substitutes:

1. Type I- Temporary impervious dressing materials:

a) Single layered materials: natural, biological (Amnion- semi-transparent tissue isolated from placenta) or synthetic polymer based dressings (Tegaderm®)

b) Double-layered tissue engineered materials: Combination of biopolymers and synthetic one embedded with several biological factors like growth factor, fibroblast. Eg: TransCyte® (Pig Collagen + Silicon +neonatal fibroblast)

2. Type II- Single layered steady skin substitute:

a) Epidermal layer: Apligraft® and OrCel®,Laserskin®( For Growth of keratinocytes).

b) Dermis layer: Mainly consist of biological collagen sheet. Eg: Procine dermal matrix (Permacol®), Bovine dermal matrix (Permaderm®,Matriderm®), human dermal matrix(Alloderm® freeze-dried dermis of human).

3. Type III-Composite skin substitutes:

a) Dermagraft®- human neonatal fibroblast+ PLGA scaffolds, Hyalograft-3D®- Esterified hyaluronic acid fibres.

b) Integra®- Collagen +Chondroitin +Silicon network, Biobrane®-(Nylon mesh embedded with type I collagen and fibroblast in silicon membrane)⁴⁰

Acellular dermal matrix (ADM) is widely used as dermal substitute for its excellent biocompatibility and tissue regeneration properties. Terrestrial animal (cattle, pig) tissues may risk the spread of zoonotic viruses recently scientists discover that fish skin is an appropriate candidate as they do not contain α-Gal antigen and have a low risk for virus infection. Another example is freshwater fish, tilapia (Oreochromis niloticus) which skin is used to develop a novel acellur dermal matrix by alkaline decellularization and γ-irradiation sterilization⁴¹.

Table 5: Different types of wound dressing their advantages and disadvantages^42-49

Type of dressing

Wound type

Advantages

Disadvantages

Hydrogels

1^st and 2^nd degree burn

Diabetic Foot ulcer

Surgical wound

Self -adhesive

Easy removal

Excellent moisture /dryness ratio

Antibacterial properties.

Poor air permeation to wound bed

Poor absorption of fluid.

Skin maceration

Poor mechanical properties.

Films

Dry and Superficial Wound

Transparency allows to screen and progress of wound healing

Permit vapour and O2-CO2 transfer.

Non-permeable to outer fluid and bacteria

Limited ability of absorption

Poor mechanical strength.

Foams

Moderate to excessive exuding wound

Ulcers and Pressure bed sores

Excellent absorption ability

Highly porous

Application and elimination without tissue damage or trauma

Over absorption of wound fluid may cause dryness and irritation.

Require second dressing material.

Nano-fibres

Burn wound

Diabetic Foot Ulcers.

.Localized wounds

Highly Porous and large surface area

Good absorption of fluid

Drugs like antibiotics can be incorporated.

High mechanical strength.

Skin allergic reaction may occur.

3D Printed Dressing

Patient –specific wounds.

Burn wounds.

Customized and patient-specific

Modified drug release can be achieve.

Capable to develop dressings for large surface

Expensive technique and need advanced software for 3D printer.

Skin Substitute by tissue engineering

Severe wounds

2^nd and 3^rd degree burn

Mimic ECM structure of skin.

Origin is human or animal skin

High Cost

Risk of zoonotic infection and immunogenic response.

CONCLUSION:

Wound management is one of the challenging areas due to the involvement of complex cellular pathways. Additionally Non-healing chronic wounds have more complications in the case of diabetes that are associated with disrupted metabolism and weak response leads delayed in wound healing often risk of bacterial infection, nerve or blood vessel damage even loss of limbs. In the Global wound dressing market, the use of naturally occurring polymers is increasing due to their biocompatibility and structural similarity of skin histological structure. Modern wound dressings like hydrogels, films, or foams are intended to cover and conceal the wound from foreign bodies and pathogens along with accelerating the healing process by maintaining the moisture ratio and gaseous exchange. Dressing composed with biopolymers additionally has essential roles in re-epithelisation, cell proliferation, and collagen synthesis. Various cellular moieties like growth factors, fibroblasts, hyaluronic acid, or freeze dried collagens are often loaded in these dressings that fasten the healing process. The recent trends for severe burn wound care are shifted to skin substitutions that also involve epidermal or dermal matrix or collagen extracted from the animal source like bovine, porcine, or marine. Advanced techniques likely 3D bio-printing is currently elevating the interest towards customized dressing as per patient requirement. Future trends towards smart wound dressings that can monitor the wound condition by installing sensor device or using smart materials like stimuli-responsive to facilitated the skin regeneration process. From the above discussion, we can conclude that nature derived polymers with bioactive agents are the future for smart wound dressing and can bring a revolution in the wound care market.

ACKNOWLEDGEMENT:

The authors would like to thank Department of Science and Technology- Fund for improvement of science and technology infrastructure in Universities and Higher Educational Institutions (DST- FIST), New Delhi for their infrastructure support to our department.

CONFLICT OF INTEREST:

The authors state no conflicts of interest.

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Received on 18.03.2022 Modified on 11.04.2022

Research J. Pharm. and Tech 2023; 16(5):2522-2530.

DOI: 10.52711/0974-360X.2023.00415

Polymer/ Co-polymers	Method of Electro-spinning	Active molecule	Clinical Findings
Cellulose acetate/gelatin	Blend electro spinning	Berberine	Diabetic Foot ulcer in vivo model
Cellulose Acetate	Blend electro spinning	Silver sulfadiazine	Anti-bacterial wound dressing (Escherichia Coli and Bacillus Subtilis)
Alginate/PVP	Co-axial electro spinning	Dexpanthenol	Good fibroblast attachment.
Chitosan/ polyethylene oxide (PEO)	Blend electro spinning	Silver nanoparticle and ZnO	Anti-oxidant and anti-bacterial (Escherichia Coli, S. Aureus, P. Aeruginosa)
Collagen/ poly (ε-caprolactone) (PCL)(1:1)	Blend electro spinning	-	Advanced proliferation, migration, and adhesion of human adipose stromatal cell (hASC)
Collagen / hyaluronic acid	Blend electro spinning	-	Cell adhesion and proliferation
Collagen/PCL/Zein hybrid	-	Aloe Vera and zinc oxide nanoparticles	High fibroblast proliferation, antibacterial activity (Escherichia coli and Staphylococcus aureus )
Tilapia skin collagen	Blend electro spinning	-	Proliferation of human keratinocytes

Advanced Wound Care with Biopolymers