Chitosan-based hydrogels for diabetic ulcer therapy: Molecular mechanisms, functional synergies, and future...

Diabetic ulcers pose significant therapeutic challenges driven by hyperglycemia-induced oxidative stress, chronic inflammation, and microbial infection. While conventional dressings often fail to address these complex microenvironments, hydrogels have emerged as a premier platform for advanced wound management. Among these, chitosan-based hydrogels stand out for their intrinsic antimicrobial activity, biocompatibility, and tunable properties, enabling active orchestration of wound healing. Their therapeutic effects involve neutralizing oxidative stress, polarizing macrophages to resolve inflammation, and promoting angiogenesis for extracellular matrix remodeling. Moreover, these hydrogels can serve as multifunctional, stimuli-responsive platforms for the controlled delivery of drugs, growth factors, extracellular vesicles, nucleic acids, and even living cells, allowing precise spatiotemporal control of cargo release. This review summarizes the physicochemical properties of chitosan and systematically examines the molecular mechanisms underlying hydrogel-mediated diabetic wound repair. These include cation-mediated disruption of microbial membranes, Keap1/Nrf2-dependent antioxidant signaling, NF-κB-regulated immunomodulation, and VEGF-driven angiogenic pathways. In parallel, recent advances are critically evaluated in three key areas: stimuli-responsive delivery systems (triggered by pH, reactive oxygen species, matrix metalloproteinases, or glucose), biologically functionalized scaffolds incorporating extracellular vesicles, microRNAs, and stem cells, and 3D-bioprinted constructs tailored to individual patients. Current translational challenges are also addressed, particularly the complexity of regulatory classification and the lack of standardized preclinical models. Finally, future strategies are discussed for the rational design and clinical translation of next-generation diabetic wound dressings, with an emphasis on bridging the gap between bench research and bedside application.