An injectable hydrogel for localized sustained release of artesunate in postoperative fibrosis prevention after glaucoma filtration surgery

Glaucoma filtration surgery (GFS) is the definitive treatment for reducing intraocular pressure in patients with refractory glaucoma. However, postoperative scarring of the filtration tract is a major cause of surgical failure. Although artesunate (ART) exhibits significant antifibrotic efficacy, its clinical application is severely limited by poor solubility and a short half-life. This study designed and developed a new injectable hydrogel cross-linked by collagen and four-armed polyethylene glycol N-hydroxysuccinimide encapsulating ART (C-P@ART) to overcome the limitations of ART in ocular antifibrotic therapy and extensively examined its underlying mechanisms. Stable three-dimensional network structure, excellent biocompatibility, and sustained drug release characteristics of C-P@ART were validated through FTIR, rheological analysis, endotoxin-testing, scanning electron microscope (SEM), and in vitro and in vivo release assays. In a TGF-β1-induced fibroblast fibrosis model, C-P@ART significantly inhibited α-SMA expression concentration-dependently and exerted antifibrotic effects through dual regulation of TGF-β1/SMAD and PI3K/Akt pathways. Subsequently, we evaluated its antifibrotic efficacy in the rabbit GFS model, where the C-P@ART treatment group exhibited a significant reduction in postoperative collagen deposition and α-SMA-positive expression compared to the control group. C-P@ART inhibited NF-κB pathway activation and reduced inflammatory cell infiltration. In conclusion, these findings demonstrated that C-P@ART synergistically mitigates fibrosis and inflammation through sustained ART release, providing an innovative therapeutic strategy to enhance GFS outcomes.