H2S-releasing hydrogel accelerates diabetic wound closure and suppresses scarring by coordinating neurovascular, immune, and angiogenic repair.

Diabetic wound healing is severely impaired by a pathological microenvironment involving immune dysregulation, deficient angiogenesis, and compromised neural repair. Current standard-of-care often falls short in addressing these multifaceted issues, leading to chronic non-healing ulcers and significant scarring. Hydrogen sulfide (H2S), a vital gasotransmitter, is being studied for its known anti-inflammatory, pro-angiogenic, and neuroprotective properties, offering a promising mechanism to tackle the complex pathology of diabetic wound repair.

Researchers engineered a dynamic phenylboronate ester-crosslinked hyaluronic acid/poly(vinyl alcohol) (HA/PVA) hydrogel for spatiotemporally controlled delivery of a novel hydrogen sulfide (H2S) donor. This hydrogel was evaluated in diabetic models, including both in vitro assays and an in vivo diabetic rabbit ear model. The study assessed the hydrogel's function as a reactive oxygen species (ROS) scavenger and an immunomodulatory platform. Primary endpoints included wound closure rates, hypertrophic scar formation, and the modulation of underlying cellular and molecular pathways.

The H2S-releasing hydrogel demonstrated multifaceted therapeutic effects in diabetic models, functioning as both a reactive oxygen species (ROS) scavenger and an immunomodulatory platform. Sustained H2S release promoted macrophage polarization toward the pro-reparative M2 phenotype, enhancing angiogenesis through activation of the vascular endothelial growth factor (VEGF) signaling pathway. It also facilitated sensory nerve repair by restoring calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) levels. Transcriptomic analysis further revealed that H2S regulates gene networks associated with antioxidant defense, immune modulation, angiogenesis, and neuroprotection.