Wound healing begins with traumatic events and tissue integrity is ensured with new cell formation. The wound healing process is composed of a chain of biochemical events. This process consists of 3 intertwined stages as hemostatis and inflammation, proliferation, remodeling and maturation.

Wound Healing Process

Hemostasis and inflammation

In a skin injury, bleeding immediately occurs due to the destruction of blood vessel integrity. Hemostasis is the first stage of wound healing. The first aim of this stage is to stop blood loss. Right after the injury, blood platelets come together to secrete growth factors and after that, healing process begins. Various precursor factors (fibrinogen, thrombospodia, etc.) that stimulate coagulation are released from injured cells for the onset of coagulation. The maintenance of the healing process directly depends on the hemostasis. Inflammation, neutrophils and lymphocytes are predominant cells. The inflammation phase is observed in last 3-5 days in normal conditions. Furthermore, hemostatis is the fundamental stage to make the wound ready for repairing process by preventing inflammation and providing blood platelet coagulation.

Proliferation

Proliferation begins in the third day after injury and lasts for 2-3 weeks. Proliferation phase is characterized by new vessel formation (angiogenesis) and proliferation of epithelial cells (epithelialization). In this stage, first microcirculation is arranged to meet the oxygen demand of newly formed tissues. At the same time, rapidly and large of amount collagen is synthesized from fibroblasts in the wound area. Thus, growth factor excreting fibroblasts contribute to the process of wound healing. Afterwards, the basal layer around the wound disintegrates, causing endothelial cells forming the tissue to move into the wound to form budding. The buds come together to form a capillary network after branching. At the end of the proliferation stage, tissue formation of granules occurs.

Remodeling and Maturation

The final stage of wound healing is maturation and epithelial tissue formation is observed in this stage. The range of this phase changes from 21th day to 2 years after injury. The maturation period varies depending on age, genetic structure and the type of wound. Produced collagen in proliferation stage increasingly gets strength in maturation stage. Collagen fibrils are crosslinked to form a more regular form. By this way, tension strength of the scar tissue increases with time.

The density of capillaries and the number of fibroblasts decrease during wound healing occurs. In the wound area, blood flow and metabolic activity reduce since the capillary vascular growth stops. Over the time, capillary vascular growth stops, blood flow and metabolic activity slows down. When the all stages are completed, strong and resistant scar tissue is formed.

Natural Polymers for Wound Healing Applications

Alginate, cellulose, collagen, gelatin, silk fibrin and chitosan are commonly used for wound healing applications.

Alginate

Alginate is a biodegradable polymer and obtained from brown seaweeds. It has high liquid absorption capability. Therefore, wound dressings from alginate form a hydrophilic gel when in contact with the wound. It should be replaced after taking enough liquid on the wound. If wound dressing is not changed after filling with liquid, it can damage the healthy tissue around the wound. Moist environment is required for the performance of alginate dressings.

Therefore, it should not be used in dry wounds while used in medium and heavy drainage wounds. In literature, there are numerous alginate based wound dressing studies. Various alginate dressings have been produced showing antimicrobial effect and accelerating wound healing. Mohandas et al.  prepared nano-zinc oxide loaded composite bandages having 60-70% porosity by freeze drying method.

These wound dressings showed antimicrobial activity against Escherichia coli, Staphylococcus aureus, Candida albicans, and methicillin resistant S. aureus (MRSA) bacteria. Wound dressings have been observed to be effective in wound healing for infected wounds. In another study, alginate based double layer hydrocolloid film was fabricated. The hydrocolloid film consisted of drug (ibuprofen) loaded upper layer and a speed controlling sublayer to slow drug release. Controlled release was obtained with bilayer films. At the same time, bilayer films showed better mechanical properties compared to single layer films. Drug-loaded films also accelerated the formation of granulation in tissue.

Cellulose

Cellulose is a polysaccharide based, biocompatible, biodegradable and hydrophilic biopolymer. It provides support for granulation and epithelization. Also, Biosynthetic bacterial cellulose from Acetobacter xylinum is also used in regenerative medicine. This polymer supports the healing process by reducing pain. Non-toxic microbial cellulose dressings with antimicrobial action can be applied to burn wounds.

Since bacterial cellulose fibers accelerate new tissue formation due to their similarity to ECM. Islam et al.  have fabricated bacterial cellulose- montmorillonite composite films for wound healing applications. Cellulose- MMT composite films showed antimicrobial properties against E. coli and S. aureus. In another study, the release and antimicrobial activities of cellulose hydrogels loaded with chloramphenicol (active agent) were investigated. Almost all chloramphenicol was released from the hydrogel in 24 hours. Hydrogels with active showed antimicrobial activity agent loaded against S. pneumonia, S. aureus and E. coli bacteria.

Collagen

Collagen is a protein found in human body and it is biocompatible, biodegradable and non-toxic. The collagen produced by fibroblasts have been effectively used in makes great contributions to wound healing and new tissue development. It provides support in all phases of wound healing. There are many studies about collagen based wound dressings for skin tissue regeneration. In the literature, mostly nanofibers and vascular graft forms of collagen were developed for wound healing.

It was observed that collagen wound dressings supported the accumulation of collagen fibrils in the wound area. The epidermal growth factor-containing sponges were investigated in vitro and in vivo and shown to be effective in wound healing. In another study, collagen and a-tocopherol which is an antioxidant used in skin diseases were prepared for topical applications and this collagen-derived biomaterial was found suitable for biomedical applications.

Gelatin

Gelatin is a natural polymer produced from collagen derivatives of animal origin. It is a preferred polymer in drug delivery systems and wound healing. However, it is generally used with another polymer as gel form due to its low mechanical properties and thermal stability. Boateng et al. fabricated and characterized silver sulfadiazine-loaded alginate/gelatin composite wafers for infectious chronic wounds. Drug release from composites was observed for 7 hours to prevent bacterial infection.

In another study, effect of blending of different mass ratios of chitosan, honey and gelatin on the properties of the film was studied for burn wound dressing applications. Antimicrobial activity and rabbit’s back burn model were examined. The film at optimum composition showed antimicrobial activity against S. aureus and E. coli. Films were examined for 12 days in wound model and positive results were obtained in wound closure.

Silk Fibroin

Silk fibroin is a natural polymer used in vascular grafts, drug delivery systems and wound dressings due to its biocompatibility, biodegradability, good mechanical properties and ease of use. Silk fibroin can be processed in different forms such as film, micro-nano particle, fiber or hydrogel thanks to its easy processability. Lee and his co-workers prepared hydrocolloid films containing silk fibroin nanoparticle for burn wounds. Structural, mechanical properties and cell compatibility tests were performed and the dressings was investigated in rabbit model. Hydrocolloid films containing silk fibroin showed good mechanical properties and accelerated wound healing.

In another study, silver nanoparticle coated silk fibroin fibers were fabricated as wound dressings. It was shown that fibers exhibited antimicrobial activity against S. aureus and P. aeruginosa bacteria. In another study, silk fibroin/alginate composite membranes were tested for wound healing applications. Structural and mechanical properties, water vapor transmission rate and toxicity of membranes were investigated. As the amount of silk fibroin increased, higher mechanical strength was observed. Composite membranes were shown to be non-toxic with good swelling capacity and water transmission rate.

Chitosan

Chitosan is one of the most abundant polymers in nature. Chitin is found abundantly in shells of shellfish, and also in the cell walls of yeast and fungus. The use of chitin is limited due to its low solubility. Therefore, chitosan is obtained from chitin as its deacetylated derivative. Chitosan is dissolved in dilute acidic solutions and used in different application areas. It is biodegradable, biocompatible, non-toxic, hydrophilic and antimicrobial activity. Because of these properties, chitosan is generally preferred in biomedical applications.

Chitosan as well, has some limitations such as low stability and mechanical properties. Chitosan can form polyelectrolyte complexes with anionic alginate, gelatin, carboxymethyl cellulose to increase the stability and enhance mechanical properties. In the literature, chitosan/ alginate nanospheres and silver sulfadiazine complexes were fabricated to obtain stable biomaterials with better mechanical properties.

Crosslinkers are also used with chitosan matrix to enhance its stability. Generally, glutaraldehyde, tripolyphosphate (TPP) and genipin have been used as crosslinkers.

Glutaraldehyde which is highly reactive, may interact with cell surface and cause toxic effects result in cell death. TPP is an ionic cross-linker known as a physical cross-linker. Chemical crosslinkers are more potent binders than physical crosslinkers. The chemical crosslinking is irreversible but physical crosslinking is reversed by change in temperature or pH.

Thus, in recent years, genipin as being a natural compound with no toxic effect, has been preferred as a crosslinker for biomedical applications. In literature, it was found that genipin cross-linked nanofibers exhibited better swelling and enzymatic degradation behavior compared to non-cross-linked nanofibers. It was also observed that L929 fibroblast cells incubated on genipin cross-linked nanofibers showed favorable attachment and growth.

Another way to increase mechanical properties and stability of polymer matrix is to use nanoparticles in polymer matrix to obtain composite structures. These nanoparticles can be carbon based particles, silica based hydrophilic nanoclays or synthetic hybrid nanoparticles such as polyhedral oligomeric silsesquioxanes (POSS). Polymer composite materials with enhanced mechanical, thermal and physicochemical properties can be obtained by dispersing these nanoscale materials in polymer matrix homogenously.

Additionally, chitosan has a cationic structure. Hence, a biomaterial obtained from chitosan can easily interact with the negatively charged moieties present in the cell membrane. The anionic parts of the cell membrane and the cationic parts of the chitosan interact to prevent the formation of any bacteria. N-acetyl-β-D-glucosamine units of chitosan released by degradation induces wound healing. Chitosan helps blood clotting and chitosan bandages have been approved by the US for use in wound healing. It also supports the granulation in wound area.

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