Schiff-Base Crosslinked Stretchable Multifunctional Hydrogel Enables Combined Therapy in Diabetic Wound Healing

Diabetic wound healing remains a challenge due to persistent oxidative stress, defective angiogenesis and bacterial infection. Herein, a multifunctional hydrogel Y/PDA@HAPLL was engineered via Schiff-base crosslinking between oxidized hyaluronic acid (OHA) and ε-poly-L-lysine (ε-PLL) and incorporating Y-27632 (Y, R-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride) and polydopamine (PDA). The formulation was optimized using response surface methodology, thus achieving rapid gelation (3.8 s), strong tissue adhesion (10 kPa) and excellent stretchability. Under 808 nm laser irradiation, Y/PDA@HAPLL exhibited stable photothermal conversion and good antibacterial activity to effectively eradicate the bacterial biofilms and achieve >99% killing of S. aureus and E. coli. In vitro, skin re-epithelialization (keratinocyte proliferation and migration) and endothelial repair (tube formation) under high glucose were promoted by Y/PDA@HAPLL. In the diabetic mice with infected wounds, Y/PDA@HAPLL significantly accelerated wound closure and tissue regeneration by combining PTT antibacterial activity, ROS scavenging, endothelial repair, angiogenesis, and re-epithelialization, while concurrently downregulating ROCK1 and p-DRP1, upregulating p-eNOS and CD31, reducing mtROS, and promoting collagen deposition and remodeling. In addition, no organ damage and hepatorenal toxicity were observed during treatment period. Taken together, Y/PDA@HAPLL provided a multifunctional paradigm for the combined therapy of infected diabetic wounds by integrating rapid gelation, PTT antibacterial activity, and regeneration promotion.