Development and Evaluation of Thermosensitive Hydrogels for Hydrogen Sulfide Gas Release: A Novel Approach for Therapeutic Applications

ABSTRACT Hydrogen sulfide (H₂S) plays a critical role in regulating various pathological processes, such as protecting cells from injury and promoting tissue regeneration, making it a focus of therapeutic applications. However, the unpredictable release of H₂S donors limit its clinical use. In this study, a novel delivery system was developed by encapsulating 5‐aminopyridine‐2‐thiocarboxamide (APTC), a small‐molecule H₂S donor, into a gelatin‐Pluronic (GP) thermosensitive hydrogel. The GP hydrogel exhibited excellent thermosensitivity, transitioning from sol to gel at physiological temperature (~37°C) while maintaining its gelling temperature upon APTC addition, making it ideal for minimally invasive applications. The methylene blue assay demonstrated controlled H₂S release, with the highest cumulative release (1.2 mM) at 80 h in the GP‐APTC 15 hydrogel. Cytocompatibility and cell behavior studies using HUVECs showed that H₂S release significantly enhanced cell migration, fully covering scratched areas within 24 h. GP‐APTC hydrogels also promoted angiogenesis, evidenced by in vitro tube formation and in ovo CAM assays, with greater APTC concentrations leading to increased tube branching and denser vascular networks. This study highlights the novelty of using a thermosensitive GP‐APTC hydrogel as a controlled H₂S delivery platform, offering significant potential for various therapeutic applications, including tissue regeneration and wound healing.