A Multi‐Responsive Hydrogel Combined With Mild Heat Stimulation Promotes Diabetic Wound Healing by Regulating Inflammatory and Enhancing Angiogenesis

The repair of diabetic wound still encounters huge challenges, such as disordered inflammatory regulation and impaired neovascularization. Here, a pH/ROS/glucose responsive and photothermal hydrogel is developed for diabetic wound healing. The hydrogel is formed through cross-linkage between phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA) and oxide dextran (OXD), utilizing Schiff base and phenylboronate ester bonds. Additionally, insulin-like growth factor 1 C domain (IGF-1C) and deferoxamine-loaded polydopamine nanoparticles (D@P) are incorporated into the hydrogel. The hydrogel demonstrates sustained drug release, excellent photo thermal effect, prominent antioxidant, antibacterial and anti-inflammatory activities, desirable mechanical and tissue adhesive properties, enhanced tube formation, and cell migration. Furthermore, the hydrogel combined with mild heat treatment can regulate chronic inflammation by promoting the transformation of macrophages from M1 phenotype to M2 phenotype and enhance angiogenesis by up-regulating the expression levels of angiogenesis-related factors such as hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), CD31, and α-SMA, thus greatly accelerates the wound healing in streptozotocin (STZ)-induced diabetic mice. Therefore, this multi-responsive and multifunctional hydrogel holds potential as a therapeutic strategy for diabetic wounds.