Oxidized Dextran/Carboxymethyl Chitosan Dynamic Schiff-Base Hydrogel for Sustained Hydrogen Sulfide Delivery and Burn Wound Microenvironment Remodeling

<b>Background</b>: Polysaccharide-based dynamic hydrogels are promising for wound management due to their biocompatibility, injectability, and tunable biofunctionality. The integration of therapeutic gasotransmitter donors offers a strategy to modulate the wound microenvironment. <b>Objectives</b>: This study aimed to develop an injectable, self-healing carbohydrate hydrogel capable of sustained hydrogen sulfide (H₂S) release for burn wound therapy, and to evaluate its physicochemical properties, in vivo efficacy, and mechanism of action. <b>Methods</b>: A dynamic hydrogel (ACMOD) was fabricated via Schiff-base crosslinking between oxidized dextran (OD) and carboxymethyl chitosan (CMCS), incorporating the H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH). Rheological and recovery tests characterized its mechanical and self-healing properties. Efficacy and mechanisms were assessed in a rat full-thickness burn model, analyzing wound closure, histology, oxidative stress, macrophage polarization, angiogenesis, and collagen deposition. <b>Results</b>: ACMOD exhibited shear-thinning, rapid self-healing, and strong tissue adherence. Sustained H₂S release from ACMOD significantly accelerated wound closure and improved tissue regeneration compared to controls. Mechanistically, H₂S attenuated oxidative stress, promoted a pro-regenerative M2 macrophage phenotype, enhanced angiogenesis via VEGF upregulation, and fostered organized collagen deposition and extracellular matrix remodeling. <b>Conclusions</b>: This work demonstrates a versatile, carbohydrate-based dynamic hydrogel platform that synergizes polymer network dynamics with bioactive H₂S delivery to effectively promote burn wound healing. The findings underscore the potential of polysaccharide hydrogels with integrated gasotransmitter release for regenerative therapy and biomaterials applications.