Local stabilization of HIF-1α via deferoxamine-loaded collagen–chitosan sponge scaffold accelerates healing of type 2 diabetic wounds in rats

Diabetic wounds are characterized by impaired angiogenesis, prolonged inflammation, and delayed tissue regeneration, which often result in chronic non-healing ulcers. Hypoxia-inducible factor-1 alpha (HIF-1α) signaling plays a critical role in coordinating angiogenesis and tissue repair; however, its activity is markedly suppressed in diabetic conditions. This study aimed to evaluate the therapeutic efficacy of a collagen–chitosan sponge scaffold (CoChSS) loaded with deferoxamine (DFO) in enhancing diabetic wound healing through modulation of the hypoxic microenvironment and activation of angiogenic pathways. Type 2 diabetic rats were randomly assigned to three groups: untreated control, CoChSS scaffold alone, and DFO-loaded CoChSS (CoChSS/DFO). Full-thickness excisional wounds were created, and healing outcomes were evaluated on days 4 and 8 post-injury. Wound closure rate, mechanical properties, stereological parameters (fibroblast density, blood vessel density, and inflammatory cell infiltration), collagen deposition, gene expression (HIF-1α and SDF-1α, VEGF, TGF-β, TNF-α, IL-1β), and oxidative stress markers (CAT, SOD, GSH, and MDA) were systematically assessed. The CoChSS/DFO group exhibited significantly accelerated wound closure compared with both control and scaffold-only groups (P < 0.05). Mechanical testing demonstrated enhanced tensile strength and energy absorption in regenerated tissue following CoChSS/DFO treatment (P < 0.05). Stereological analysis revealed markedly increased angiogenesis and fibroblast proliferation, accompanied by a significant reduction in inflammatory cell infiltration (P < 0.05). Histological evaluation using Masson's trichrome staining showed enhanced collagen deposition and improved matrix organization in the CoChSS/DFO group (P < 0.05). At the molecular level, CoChSS/DFO significantly upregulated HIF-1α, SDF-1α, VEGF, and TGF-β expression, while suppressing pro-inflammatory cytokines TNF-α and IL-1β (P < 0.05). Additionally, antioxidant enzyme activities were elevated and lipid peroxidation was reduced, indicating effective mitigation of oxidative stress (P < 0.05). In conclusion, the DFO-loaded CoChSS scaffold promotes diabetic wound healing through a multimodal mechanism involving hypoxia signaling activation, angiogenesis enhancement, inflammation attenuation, oxidative stress reduction, and improved extracellular matrix remodeling. This strategy represents a promising therapeutic platform for the treatment of chronic diabetic wounds.