Chitosan-Hyaluronic Acid Composite Hydrogel with Slow-Release Hydrogen Sulfide and Cerium Oxide for Multifunctional Synergy to Promote Healing of Infected Wounds

Introduction: The management of chronic infected wounds imposes a substantial economic burden on patients and significantly impairs their quality of life due to persistent wound infections and delayed healing. To address this issue, we developed a multifunctional dressing with sustained hydrogen sulfide (H 2 S) release to accelerate wound healing. Methods: Sodium hydrosulfide-loaded cerium oxide (NaSH@CeO 2 ) was synthesized via rotary evaporation and subsequently incorporated into a hydrogel dressing crosslinked with chitosan (CS) and hyaluronic acid (HA), yielding NaSH@CeO 2 /CS-HA. The composite was characterized, and H 2 S release was quantified using the methylene blue method. The biological functions of NaSH@CeO 2 /CS-HA were evaluated through CCK-8 assay, Calcein-PI staining, DCFH-DA detection, scratch assay, tube formation assay, and antibacterial tests. A methicillin-resistant Staphylococcus aureus (MRSA)-infected wound model was established in rats to assess therapeutic efficacy based on wound healing rate, hematoxylin-eosin (H&E) staining, Masson’s trichrome staining, and immunofluorescence staining. Results: NaSH@CeO 2 /CS-HA demonstrated sustained H 2 S release without cytotoxicity while effectively inhibiting Escherichia coli and MRSA. Furthermore, it reduced intracellular reactive oxygen species levels, maintained cell viability under H 2 O 2 -induced oxidative stress, promoted mouse fibroblast cells (L929 cells) migration, and enhanced tube formation in human umbilical vein endothelial cells (HUVECs). In the MRSA-infected rat wound model, the NaSH@CeO 2 /CS-HA group achieved a 98.1% wound closure rate by day 14. H&E and Masson’s staining revealed enhanced tissue healing, while immunofluorescence (CD31, Caspase-3) confirmed increased angiogenesis and reduced apoptosis at the wound site. Conclusion: The developed gel dressing (NaSH@CeO 2 /CS-HA) intelligently regulates H 2 S release, combining antioxidant, antibacterial, and wound-healing functions into one, providing a comprehensive treatment solution for chronic infectious wounds with significant clinical application potential. Keywords: wound healing, MRSA infected wound, hydrogen sulfide, cerium oxide nanoparticle, hydrogel