A glucose-responsive nitric oxide release hydrogel for infected diabetic wounds treatment

Bacteria-infected chronic wound is one of the most serious complications of diabetes and characterized with high morbidity and risk of lower extremity amputation. Nitric oxide (NO) represents a promising strategy to accelerate wound healing through down-regulating inflammation, promoting angiogenesis and bacterial eradication. However, stimuli-responsive and control release of NO at the wound microenvironment remains a challenge. In this work, an injectable, self-healing and antibacterial hydrogel characterized with glucose-responsive and constant NO release behaviors has been engineered for diabetic wound management. The hydrogel (CAHG) is prepared by in situ crosslinking of L-arginine (L-Arg)-coupled chitosan and glucose oxidase (GOx)-modified hyaluronic acid based on Schiff-base reaction. The system is capable of mediating a continuous release of hydrogen peroxide (H2O2) and NO by the cascaded consumption of glucose and L-Arg in the presence of hyperglycemia environment. In vitro studies demonstrate that bacteria proliferation is significantly inhibited by CAHG hydrogel involving in the cascaded release of H2O2 and NO. More importantly, a full-thickness skin wound model on a diabetic mouse demonstrates that H2O2 and NO release from CAHG hydrogel exhibits a superior efficiency for wound healing through bacterial inhibition, down-regulation of pro-inflammatory factors and the elevation of M2-type macrophage, contributing to the collagen deposition and angiogenesis. In conclusion, CAHG hydrogel with excellent biocompatibility and glucose-responsive NO release characteristic can serve as a highly efficient therapeutic strategy for diabetic wound treatment.