Dynamic Hyaluronic Acid Hydrogels for Comprehensively Regulating Inflammation, Angiogenesis, and Metabolism to Effectively Proheal Diabetic Wounds

Despite the great progress of various multifunctional wound dressings, it is challenging to simultaneously achieve complete healing and functional remodeling for diabetic foot ulcers and refractory chronic wounds. Aiming to comprehensively regulate chronic inflammation, angiogenesis, and metabolism processes, herein, a novel kind of dynamic hyaluronic acid (HA) hydrogel was designed by combining boronate and coordination chemistry. Besides having injectability, self-healing, and detachment properties, dynamic HA hydrogels presented diabetic wound-responsive degradation and controllable H2S release. They could efficiently polarize M1-to-M2 polarization and regulate inflammatory cytokine secretion and multiple inflammation-related mRNA expressions through cooperative actions of reactive oxygen species elimination + H2S release + Zn2+ regulation, thus driving chronic inflammation into the proliferation and remodeling stages. Moreover, the screened lead hydrogel HTZS could regulate angiogenesis-related signaling pathways and metabolism processes to promote neovascularization and mature vessel formation, re-epithelization, high-level collagen-I deposition, and dense hair follicle regeneration, achieving complete healing and functional remodeling in diabetic wounds. Importantly, this work opens a new avenue to design dynamic biopolymer hydrogels for high-performance wound dressing and decipher the key role of multiple orchestrated regulations of inflammation–angiogenesis–metabolism on complete healing and functional remodeling in chronic and diabetic wounds.