pH-responsive and on-demand hydrogen sulfide-releasing injectable hydrogel for wound healing promotion

Hydrogen sulfide (H2S) has been shown to accelerate wound regeneration by promoting proliferation, angiogenesis, collagen deposition, and reducing inflammation. However, commonly used H2S donors often suffer from uncontrollable and excessive release. To address this, a pH-responsive, injectable polysaccharide hydrogel encapsulating alpha-phase manganese sulfide nanoparticles (MnS NPs) was developed to ensure controlled and on demand H2S delivery for improved wound repair. The hydrogel, termed MnS@AC, was synthesized through dynamic Schiff base crosslinking between aldehyde hyaluronic acid (AHA) and carboxymethyl chitosan (CCS). The acidic-responsive Schiff base hydrogel networks facilitated the controlled release of MnS NPs during the early stages of wound healing. The encapsulated alpha-phase MnS NPs, as pH-responsive H2S donors, provided greater structural stability than gamma-phase MnS, preventing excessive H2S release. The released H2S further contributed to reducing inflammation. MnS@AC hydrogels exhibited excellent biocompatibility, strong tissue adhesion, and effective in vivo hemostatic properties. In the full-thickness skin wound models, the wound closure rate in MnS@AC group on day 13 (94.2 f 1.1 %) was higher than in the AC group (81.1 f 5.1 %), MnS group (81.7 f 3.6 %), and control group (69.9 f 10.0 %). Further experiments demonstrated that MnS@AC hydrogels facilitated wound healing by reducing proinflammatory cytokines, enhancing proliferation, angiogenesis, and promoting collagen deposition. Interestingly, manganese ions released from MnS NPs did not induce a cGASSTING pathway-mediated inflammatory response, preventing unwanted inflammation. The pH-responsive hydrogels showed significant potential as low-toxic and comprehensive wound dressings, offering a novel approach to wound healing.