Chitosan based macromolecular hydrogel loaded total glycosides of paeony enhances diabetic wound healing by regulating oxidative stress microenvironment

Oxidative stress microenvironment caused by reactive oxygen species (ROS) accumulation seriously hinders wound healing in diabetes, which brings great burden to global health. Various wound dressings on the market focus on delivering active substances to promote wound healing in diabetes. However, the complex pathological microenvironment of diabetic wounds often leads to the inactivation of delivery factors, which often leads to treatment failure, and thus, emerging therapeutic approaches are urgently needed. In this study, a macromolecular hydrogel synthesized by crosslinking N-carboxyethyl chitosan, hyaluronic acid-aldehyde, and adipic acid dihydrazide, with self-healing and injectable abilities was used to deliver total glycosides of paeony (TGP). The TGP incorporated hydrogel could obviously induce fibroblasts proliferation and secretion of various extracellular matrix proteins and growth factors, induce migration and angiogenesis of vein endothelial cells, and enhance macrophages polarization to M2 phenotype by eliminating accumulated ROS. In diabetic wound models, the ROS-scavenging hydrogel efficiently enhanced proliferation, re-epithelialization, collagen deposition, as well as angiogenesis in the wound area. Besides, the dressing induced the macrophages polarization from M1 phenotype (pro-inflammatory) to M2 phenotype (anti-inflammatory) and decreased the levels of inflammatory cytokines, thereby enhancing the diabetic wound healing. The wounds treated with TGP incorporated hydrogel almost completely healed 16 days after treatment. However, the residual wound areas in the groups of Con, INTRA, and Gel are 55.2 ± 4.6 %, 33.7 ± 6.5 %, and 34.9 ± 6.1 % on the 16th day, respectively. This hydrogel with pathological microenvironment improvement ability affords a novel therapeutic strategy for enhancing healing of chronic diabetic wound.