In situ forming anti-inflammatory hydrogel attenuates esophageal stricture after endoscopic submucosal dissection via inflammation–fibrosis cascade modulation

Despite advances in therapeutic endoscopy, the development of cicatricial esophageal stenosis following extensive endoscopic submucosal dissection continues to pose a formidable clinical dilemma, with current preventive modalities demonstrating suboptimal efficacy in routine practice. Here, we developed an injectable bioadhesive hydrogel (ODA/CS-IBU) comprising oxidized dextran, chitosan, and ibuprofen-conjugated chitosan to interrupt the inflammation–fibrosis cascade underlying stricture pathogenesis. The hydrogel formed rapidly in situ (27.9 s) via dynamic Schiff base crosslinking, exhibiting robust tissue adhesion (21.35 kPa), porous architecture (pore size: 128 ± 18 μm), and sustained drug release over 28 days. In vitro studies demonstrated M1-to-M2 macrophage polarization and inhibition of fibroblast activation. In a porcine ESD model, ODA/CS-IBU reduced stricture rate to 58.96% versus 86.27% (ODA/CS) and 81.30% (saline control) at day 28 (P < 0.05), with improved swallowing function and positive weight gain. Histologically, the hydrogel promoted re-epithelialization, attenuated fibroproliferation, and optimized collagen remodeling (type I/III ratio: 1.21 versus 7.03). This bioadhesive strategy provides concurrent physical barrier protection and biological modulation of the inflammation–fibrosis axis, guiding wound healing toward a regenerative outcome.