A microenvironment-adaptive GelMA-ODex@RRHD hydrogel for responsive release of H2S in promoted chronic diabetic wound repair

Abstract Chronic diabetic wounds present significant treatment challenges due to their complex microenvironment, often leading to suboptimal healing outcomes. Hydrogen sulfide (H2S), a crucial gaseous signaling molecule, has shown great potential in modulating inflammation, oxidative stress and extracellular matrix remodeling, which are essential for effective wound healing. However, conventional H2S delivery systems lack the adaptability required to meet the dynamic demands of different healing stages, thereby limiting their therapeutic efficacy. To address this, we developed an injectable, ROS-responsive H2S donor system integrated within a gelatin methacryloyl (GelMA) hydrogel matrix, forming a double-network hydrogel (GelMA-ODex@RRHD). The injectability of this hydrogel allows for minimally invasive application, conforming closely to wound contours and ensuring uniform distribution. The incorporation of oxidatively modified dextran derivatives (ODex) not only preserves biocompatibility but also enables the chemical attachment of ROS-responsive H2S donors. The GelMA-ODex@RRHD hydrogel releases H2S in response to oxidative stress, optimizing the environment for cell growth, modulating macrophage polarization and supporting vascular regeneration. This innovative material effectively suppresses inflammation during the initial phase, promotes tissue regeneration in the proliferative phase and facilitates controlled matrix remodeling in later stages, ultimately enhancing wound closure and functional recovery. The H2S released by GelMA-ODex@RRHD not only expedited the process of wound healing but also improved the biomechanical characteristics of newborn skin in diabetic mice, particularly in terms of stiffness and elasticity. This enhancement resulted in the skin quality being more similar to normal skin during the wound healing process. By aligning therapeutic delivery with the natural healing process, this approach offers a promising pathway toward more effective and personalized treatments for chronic diabetic wounds.