Abstract

Chronic and infected wounds, particularly in diabetic patients, represent a significant therapeutic challenge due to impaired regeneration and increased risk of bacterial colonization. In this study, we developed biodegradable hydrogels composed of chitosan and starch, functionalized with copper core-shell nanoparticles (CuNp), as a multifunctional platform for wound healing. CuNp were synthesized via a chitosan-assisted method and integrated into the polymeric matrix during genipin-mediated crosslinking. Morphological and chemical characterization (TEM, AFM, SEM, EDS, FTIR) confirmed a porous hydrogel structure (10-250 mu m) with homogeneous CuNp dispersion. Antimicrobial assays revealed significant inhibition of both oxacillin-sensitive and -resistant Staphylococcus aureus, Candida albicans and Enterococcus faecalis strains at concentrations >= 150 mu g/mL. Cytocompatibility studies with human dermal fibroblasts demonstrated cell viability above 75% at all doses tested, in accordance with ISO 10993-5 standards. In vivo assays in diabetic and healthy murine models showed that CuNp-loaded hydrogels accelerated wound closure, increased epithelial thickness (>40%), and improved re-epithelialization (>50%) compared to controls and commercial dressings. Histological analysis confirmed enhanced collagen deposition and skin appendage restoration. Safety assessments in rabbits revealed no pyrogenic response or systemic toxicity, supporting the formulation's biocompatibility. These findings position the CuNp-loaded chitosan-starch hydrogel as a clinically relevant, biodegradable dressing capable of providing simultaneous antimicrobial protection and regenerative support in complex or chronic wounds.