Injectable Polysaccharide-Based Hydrogel with Glucose Responsiveness as an Immunoregulatory Platform for Enhanced Diabetic Wound Healing

Persistent excessive inflammatory response in diabetic wounds caused by the imbalance of the immune microenvironment leads to delayed or nonhealing of the wounds. Timely attenuation of inflammation through immunoregulation is a crucial strategy to accelerate diabetic wound closure. Here, the protocatechuic acid (PCA)- and deferoxamine (DFO)-loaded polysaccharide-based immunoregulatory hydrogel (POCP@D) was developed by the dual-cross-linking strategy of borate ester bonds and imine bonds to promote advanced healing of full-thickness diabetic wounds. The POCP@D hydrogel showed good tissue adhesiveness property, flexibility, mechanical strength, injectability, self-healing, and glucose-responsive drug release properties, besides strong broad-spectrum antibacterial and antioxidant activities. The POCP@D hydrogel acted as an immunoregulatory platform to remold the in vivo immune microenvironment of diabetic wounds by regulating the M2-type macrophage polarization and timely relieving wound inflammation, thus promoting collagen deposition, angiogenesis, and the development of diabetic wounds from the inflammatory stage to the proliferative stage and ultimately achieving high-quality skin tissue regeneration. Overall, our developed immunoregulatory hydrogel held great potential for refractory diabetic wound therapy in clinical settings.