Abstract
Diabetic wounds remain a complex clinical challenge due to impaired angiogenesis, prolonged inflammation, excessive oxidative stress, and defective extracellular matrix (ECM) remodeling. Biomaterial-based approaches that can simultaneously regulate these pathological events are highly desirable for promoting functional tissue regeneration. In this study, we developed an ECM-mimetic dermal collagen-derived hydrogel capable of co-delivering stromal cell-derived factor-1α (SDF-1α) and basic fibroblast growth factor (bFGF) to improve the healing response of type 2 diabetic wounds. A type 2 diabetic full-thickness wound model was established in male Sprague-Dawley rats using a high-fructose diet combined with streptozotocin administration. Following wound induction, animals received topical treatment with blank ECM-derived hydrogel or SDF-1α/bFGF-loaded hydrogel (GF-Hydrogel), while untreated wounds served as controls. Wound closure was monitored macroscopically, and regenerated tissues were analyzed using histological, stereological, biochemical, and biomechanical assessments. The GF-Hydrogel treatment significantly accelerated wound contraction compared with control and blank hydrogel groups. Stereological analysis demonstrated enhanced neovascularization and fibroblast accumulation accompanied by reduced inflammatory cell infiltration. Furthermore, GF-Hydrogel promoted a regenerative cytokine profile by increasing VEGF and TGF-β expression while suppressing pro-inflammatory mediators, including TNF-α and IL-1β. The treatment also restored redox balance by enhancing antioxidant defenses, including increased GSH, SOD, and CAT levels, and reducing lipid peroxidation-associated MDA accumulation. In addition, improved collagen deposition and organization were accompanied by enhanced biomechanical properties of regenerated tissues. Collectively, these findings demonstrate that an ECM-mimetic hydrogel co-delivering SDF-1α and bFGF orchestrates multiple stages of diabetic wound repair by integrating vascular regeneration, inflammation modulation, oxidative stress regulation, and extracellular matrix reconstruction. This multifunctional hydrogel platform represents a promising strategy for improving the regeneration of chronic diabetic wounds.