Multifunctional injectable hydrogel with self-supplied H2S release and bacterial inhibition for the wound healing with enhanced macrophages polarization via interfering with PI3K/Akt pathway.

Hydrogen sulfide (H2S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo. This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-(l-lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H2S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H2S release. After mixing and gelling, H2S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H2S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H2S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H2S release for accelerating the infected wound healing.