Synergistic Effect of Prolonged Oxygenation and Reactive Oxygen Species Scavenging on Diabetic Wound Healing Using an Injectable Thermoresponsive Hydrogel

Diabetic wounds have complex environments, which leads to persistent inflammation caused by high level of reactive oxygen species (ROS), resulting in impeded angiogenesis and causing chronic hypoxia. Recent studies have shown that continuous oxygen supply, along with ROS reduction, can accelerate the healing process of diabetic wounds. However, the initial burst release of oxygen and poor stability of ROS scavengers have diminished therapeutic effectiveness. Moreover, a significant gap exists in research on the long-term synergistic effects of oxygenation and ROS scavenging. Herein, an injectable, thermoresponsive, oxygen-releasing, and ROS-scavenging hydrogel (ORH) system is developed based on calcium peroxide-loaded gelatin microspheres (OGMs) and chitosan-catalase complexes (CSCATs), which are incorporated into a thermoresponsive poly(organophosphazene) hydrogel. The ORH gradually releases CSCATs that lower ROS levels in wound environments and synergize with oxygen continuously released by OGMs. The ORH promoted the proliferation, migration, and tube formation by fibroblasts and endothelial cells in vitro under hypoxic conditions. In a diabetic full-thickness wound model, wound closure is significantly accelerated by ORH over the course of 14 days by alleviating ROS levels and hypoxia, which increases M2 macrophage polarization, angiogenesis, and re-epithelialization. These results introduce that the dual-action combination system significantly restores the diabetic wound healing process to near normal.