Hypoxia-mimetic activation of HIF-1α by a DMOG-loaded collagen scaffold enhances angiogenesis and tissue remodeling in type 2 diabetic wounds.

Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis, persistent inflammation, and delayed extracellular matrix remodeling. Stabilization of hypoxia-inducible factor-1 alpha (HIF-1α) represents a promising therapeutic strategy to restore pro-healing signaling in diabetic tissues. In the present study, a bioactive decellularized dermal matrix scaffold (DDMS) loaded with the hypoxia-mimetic agent dimethyloxalylglycine (DMOG) was developed and evaluated for its regenerative potential in a type 2 diabetic wound model. Type 2 diabetes was induced in Wistar rats using fructose feeding followed by streptozotocin injection. Full-thickness excisional wounds were treated with blank DDMS or DDMS/DMOG and evaluated through molecular, biochemical, histological, stereological, biomechanical, and protein-level analyses. The DMOG-loaded scaffold significantly upregulated pro-angiogenic genes (HIF-1α, VEGF, SDF-1α, and TGF-β) while downregulating inflammatory mediators (TNF-α and IL-1β). These findings were further confirmed at the protein level by ELISA, demonstrating increased levels of HIF-1α, VEGF, SDF-1α, and TGF-β, along with reduced TNF-α and IL-1β in the DDMS/DMOG group. Antioxidant defenses (CAT, SOD, and GSH) were markedly improved, accompanied by reduced lipid peroxidation. Histomorphometric assessments demonstrated enhanced neovascularization, fibroblast proliferation, and collagen deposition in the DDMS/DMOG group. Furthermore, regenerated skin treated with DDMS/DMOG exhibited superior mechanical strength. Overall, hypoxia-mimetic activation via DMOG-loaded collagen scaffolds effectively modulated the diabetic wound microenvironment and accelerated tissue regeneration. These findings suggest that this drug-delivery platform may represent a promising strategy for further development in diabetic wound therapy.