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The proliferative phase involves the production of highly vascular granulation tissue (a form of connective tissue) which fills the wound and provides a scaffold for further healing. He explained: “They merely prevent the wound from worsening and patients need to be scheduled for dressing change every two or three days. It is a huge cost to our healthcare system and an inconvenience to patients.” Burns, hemostasis, tissue defects, regeneration of nerves, wound dressings, augmentation of soft tissue, artificial dermis skin replacement
Antibacterial hydrogels can also be developed by the modification of the polymers with antibacterial peptides or amphoteric compounds. These structures work similarly to the inorganic materials and chitosan as they induce physical damage to the bacterial membrane and inhibit bacterial proliferation [ 73, 74, 84]. Chemical hydrolysis, enzymatic hydrolysis, acidic/ salting out, alkaline extraction and acidic extraction.Slower degradation of the dextran hydrogel with the high content of nondegradable PEGDA and higher cross-linking density Conventional dressings do not play an active role in healing wounds,” said Assistant Professor Andy Tay, who leads the team of researchers from the NUS Institute for Health Innovation & Technology and the Department of Biomedical Engineering at NUS College of Design and Engineering. According to a 2020 review, several clinical trials have demonstrated the efficacy of garlic in treating wounds. It stated that in preclinical studies, aged garlic extract showed wound healing potential depending on the dosage. Various types of drugs and therapeutic agents can be incorporated into hydrogels for efficient wound healing [ 64, 121, 122, 123, 124]. An important aspect is to provide their controlled and sustained release from the hydrogel. The pore sizes and stiffness of the hydrogels can influence the release rate of physically encapsulated drugs. For example, larger pore sizes can decrease the efficacy of drugs via more rapid release compared to hydrogels with smaller pore sizes. Drugs can be integrated into hydrogels using covalent bonding for controlled drug release kinetics [ 125].
Anti-inflammatory hydrogels enhance the recruitment of macrophages to the wound bed and reduce ROS levels. These functions contribute to wound healing by allowing for the transition from the inflammatory to the proliferation stage, increasing the rate of healing, and minimizing the length of the healing period. Some hydrogels show intrinsic anti-inflammatory properties. For instance, CS and its derivatives can regulate the inflammation process by enhancing the secretion of TGF-β, PDGF, and IL-1, which helps accelerate angiogenesis, fibroblast proliferation, and collagen synthesis [ 92, 99]. HA, which is a major component of the skin ECM, also shows inherent anti-inflammatory properties [ 100, 101]. HA is involved in the signaling cascades that trigger the recruitment of inflammatory cells around the wound, enhance cytokine expression, and decrease inflammation to protect the tissue damage [ 102, 103]. Anti-inflammatory properties can also be added to hydrogels by chemically attaching anti-inflammatory agents, such as phenolic compounds [ 78, 93, 94, 96, 98]. Those compounds can be obtained from plant extracts, honey, or antimicrobial peptides. Anti-inflammatory compounds are mostly recognized by the immune modulatory pathways to regulate inflammation and reduce ROS levels around the wound. Stimulating the body’s innate immune system by modifying the hydrogels with targeting agents can also be used to improve anti-inflammatory properties. For example, targeting the sphingosine-1-phosphate receptor could be an approach to activate inflammatory cells [ 104], which helps the transition from the inflammatory phase to the proliferative phase of wound healing [ 105, 106, 107, 108, 109, 110]. Hydrogels containing bioceramics can also exhibit anti-inflammatory activity in wound healing applications [ 111]. For instance, the controlled release of silicon (Si) ions from bioceramic particles that were encapsulated in gelatin/PCL nanofibers reduced inflammation while increasing angiogenesis, collagen deposition, and re-epithelization [ 112, 113, 114]. Prevents dehydration, optimizes moisture microenvironment, fills cavity wounds, ease of application and cost effective.The inflammatory phase begins with hemostasis and chemotaxis. Both the white cells and thrombocytes speed up the inflammatory process by releasing more mediators and cytokines. Besides the platelet-derived growth factor, other factors promote collagen degradation, the transformation of fibroblasts, the growth of new vessels, and re-epithelialization. All of the processes occur at the same time but in a synchronized fashion. Mediators like serotonin and histamine are released from platelets and increase cellular permeability. The platelet-derived growth factor attracts fibroblasts and, along with transforming growth factor, enhances the division and multiplication of fibroblasts. The fibroblasts, in turn, synthesize collagen. AgNPs release showed rapid antibacterial activity and simultaneous deferoxamine release promoted angiogenesis by enhancing the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and VEGF In vitro biocompatibility and cytotoxicity test were done as described by Khan et al., (2012) [ 39]. To do the heparinized human blood biocompatibility assay, AM, AV and AM+AV gels were diluted with different ratios of blood. A blood sample of the same donor diluted with DW and saline water (SW) at the same ratios as done for the gels was used as a control. After an incubation time of 2h at room temperature, the blood/gel mixtures were spread on glass slides, and observed under a light microscope for possible morphological changes in the blood cells. In the pharmaceutical field, Col modified into nanospheres, nanoparticles or microspheres is used as a device for drug delivery in wound healing which may be formulated either through emulsification, desolvation, coacervation, spray drying, milling technique, fluidization, solvent precipitation method, extrusion, or interfacial polymerization [ 107]. In this form, they have been proven to be effective in penetrating into the systemic circulation with the aid of Col. This is made possible as the integration of Col has resulted in a larger wound surface area covered due to its small size, high absorption ability and capacity to form a colloidal solution [ 108]. Apart from this, the crystallite suspension in the gel aggregates emerges as a multiplex chain system in the Col fold configuration. This characteristic eases the formulation of aggregates into colloidal drug delivery carriers [ 109]. Meanwhile, the formation of nanospheres is regulated by a blend of different electronic and electrostatic forces, with sodium sulphate acting as the liquefying reagent to allow for maximum charge to charge linkages between DNA plasmid and Col, whereas for Col nanoparticles the molecular weight of the Col influences the stability of the Col nanoparticles [ 109]. Nonetheless, changes in pH and temperature have proven to have significant impact on the molecular weight of the collagen solution and the noncovalent linkage responsible for the collagen’s molecular structure during the formation of Col nanoparticles [ 110]. The H&E stained skin section of day 24 showed an increase in epithelialization level (Fig. (Fig.6a13-a16). 6a13-a16). Epithelialization score was found to be significantly increased in each treatment group compared to the control group. Among treated groups, AM+AV had a higher epithelialization ( P<0.05) rate than AV (Fig. (Fig.6b). 6b). However, at this stage inflammation in AM+AV treated group increased again, while other treatment groups showed reduced inflammation (Fig. (Fig.6c). 6c). At day 24, angiogenesis in the AV group ( P<0.05), was higher than in the AM and the AM+AV group (Fig. (Fig.6d) 6d) but all groups showed elevated levels than the control.
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