Dynamic\nHyaluronic Acid Hydrogels for Comprehensively\nRegulating Inflammation, Angiogenesis, and Metabolism to Effectively Proheal Diabetic Wounds

Despite\nthe great progress of various multifunctional wound dressings,\nit is challenging to simultaneously achieve complete healing and functional\nremodeling for diabetic foot ulcers and refractory chronic wounds.\nAiming to comprehensively regulate chronic inflammation, angiogenesis,\nand metabolism processes, herein, a novel kind of dynamic hyaluronic\nacid (HA) hydrogel was designed by combining boronate and coordination\nchemistry. Besides having injectability, self-healing, and detachment\nproperties, dynamic HA hydrogels presented diabetic wound-responsive\ndegradation and controllable H<sub>2</sub>S release. They could efficiently\npolarize M1-to-M2 polarization and regulate inflammatory cytokine\nsecretion and multiple inflammation-related mRNA expressions through\ncooperative actions of reactive oxygen species elimination + H<sub>2</sub>S release + Zn<sup>2+</sup> regulation, thus driving chronic\ninflammation into the proliferation and remodeling stages. Moreover,\nthe screened lead hydrogel HTZS could regulate angiogenesis-related\nsignaling pathways and metabolism processes to promote neovascularization\nand mature vessel formation, re-epithelization, high-level collagen-I\ndeposition, and dense hair follicle regeneration, achieving complete\nhealing and functional remodeling in diabetic wounds. Importantly,\nthis work opens a new avenue to design dynamic biopolymer hydrogels\nfor high-performance wound dressing and decipher the key role of multiple\norchestrated regulations of inflammation–angiogenesis–metabolism\non complete healing and functional remodeling in chronic and diabetic\nwounds.