Introduction: Non-healing diabetic foot ulcers often result in amputation and reduced quality of life. The study objective was to develop and evaluate a novel fish skin-derived acellular dermal matrix (FSADM) for diabetic wound-healing applications, addressing these challenges. Methods: FSADM was fabricated from yellow fin tuna (Thunnus albacares) skin using a decellularization and lyophilization process. The matrix was characterized by Fourier-transform infrared spectroscopy (FTIR). In vitro biocompatibility was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays with L929 fibroblasts and hemocompatibility tests. In vivo, biocompatibility was evaluated through subcutaneous implantation in Sprague-Dawley rats. Wound-healing efficacy was assessed in a streptozotocin-induced diabetic rat model with full-thickness excisional wounds, comparing FSADM with commercial alternatives and untreated controls. Results: FTIR analysis confirmed the preservation of collagen structure in FSADM. In vitro studies demonstrated cytocompatibility with L929 cells and minimal haemolytic activity (0.68 ± 0.034%). Subcutaneous implantation demonstrated good biocompatibility, with a progressive reduction in the inflammatory response. In the diabetic wound model, FSADM-treated wounds exhibited significantly faster closure rates than commercial controls (p < 0.05), achieving 100% closure by day 21, compared to 90% closure in commercial controls. Histological analysis revealed enhanced epithelialization, hair follicle formation, and angiogenesis in FSADM-treated wounds. Conclusion: FSADM demonstrates excellent biocompatibility and superior wound-healing in diabetic conditions compared to commercial alternatives. It presents a promising, sustainable biomaterial for diabetic wound care. Further studies are needed to validate these findings in clinical settings and optimize their therapeutic potential.
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