Intelligent sequential degradation hydrogels by releasing bimetal-phenolic for enhanced diabetic wound healing

Abstract

Healing of diabetic wounds is significantly impeded by a complex environment comprising biofilm formation, excessive inflammation, and compromised angiogenic capacity, leading to a disordered physiological healing process. Restoration and maintenance of a normal and orderly healing process in diabetic wounds remain unmet therapeutic objectives. Herein, an innovative bimetal-phenolic network hydrogel system is designed with a concentric circular structure, enabling dual-drug delivery with differentiated release kinetics. The outer layer, Cu@TA (tannic acid)-loaded ε-PL (poly-l-lysine)-SilMA (methacrylated silk), is engineered for an initial release to scavenge reactive oxygen species and exert antibacterial and anti-inflammatory effects. The inner layer, Zn@TA-loaded ε-PL-SilMA, is designed for sustained release to promote cell migration, modulate the immune microenvironment, and induce angiogenesis. By incorporating a polyphenolic-metal network, the Cu@TA/Zn@TA/ε-PL-SilMA hydrogel can alter its degradation rate, enabling the sequential release of Cu@TA and Zn@TA. An in vivo diabetic rat wound model, transcriptomic sequencing, and histological staining analyses revealed that the Cu@TA/Zn@TA/ε-PL-SilMA hydrogel effectively activates the Wnt/β-catenin signaling pathway, synergistically promoting wound healing by accelerating angiogenesis, effectively reducing inflammation, and promoting collagen deposition. This innovative hydrogel, with sequential degradation and release properties, is broadly applicable, ensures orderly wound healing, and holds promise for accelerating diabetic wound repair.

Keywords: Angiogenesis; Antibacterial; Diabetic wound healing; Dual-drug delivery; Polyphenol metal network; Sequential release hydrogel.