Copper Peroxide-Loaded Dual-Responsive Hydrogel for Enhanced Diabetic Wound Healing Through Oxygen Release and Promotion of Angiogenesis

Abstract

Diabetic foot ulcers (DFUs) present a major clinical challenge because of persistent hyperglycemia, hypoxia, impaired angiogenesis, and chronic inflammation. Conventional dressings have limited capacity to modulate these pathological processes. Here, we report a glucose/pH dual-responsive hydrogel, denoted CBOD, constructed through a dynamic covalent network comprising Schiff base and boronate ester bonds between phenylboronic acid-grafted chitosan (CS-BA) and dopamine-modified oxidized sodium alginate (OSA-DA). Copper peroxide (CuO2) nanoparticles are encapsulated within this network to form CuO2/CBOD. Under acidic (pH 5.5) and high-glucose conditions, competitive binding and bond hydrolysis promote network relaxation, facilitating the stimuli-dependent release of oxygen and copper ions. In vitro assessments demonstrate good cytocompatibility and enhanced migration and tube formation of human umbilical vein endothelial cells (HUVECs). In a diabetic rat model of full-thickness excisional wounds, the hydrogel accelerates wound closure, with closure approaching 100% by day 14. Treatment is associated with reduced expression of the M1-associated markers interleukin-1β (IL-1β) and cluster of differentiation 80 (CD80), increased expression of the M2-associated markers interleukin-10 (IL-10) and cluster of differentiation 163 (CD163), and enhanced expression of the vascular markers cluster of differentiation 31 (CD31) and alpha-smooth muscle actin (α-SMA). These findings support the potential of CuO2/CBOD as a multifunctional dressing for diabetic wound management.