Clinically Translatable Injectable Hydrogel Platform for Dual Intraoperative Elevation and Postoperative Healing in Endoscopic Submucosal Dissection.

Abstract

Endoscopic submucosal dissection (ESD) enables en bloc resection of early gastrointestinal neoplasms but remains constrained by two critical limitations: rapid dissipation of submucosal injectates during surgery and insufficient wound management postresection. To overcome this clinical bottleneck, we develop a multifunctional, clinically translatable injectable hydrogel engineered to unify intraoperative mucosal elevation and postoperative tissue repair. This hydrogel system is synthesized via dynamic cross-linking between oxidized sodium alginate and carboxymethyl chitosan, reinforced with Ca²⁺ coordination to enhance mechanical strength and hemostasis. Phycocyanin, a natural antioxidant protein, is incorporated to provide intraoperative visual contrast and bioactive immunomodulatory properties. The formulation exhibits tunable gelation kinetics, excellent injectability, and self-healing capability compatible with endoscopic delivery. Comprehensive in vitro studies confirm the hydrogel's biocompatibility, antioxidant and anti-inflammatory activity, macrophage M2 polarization, hemostatic performance, and structural self-repair. In ex vivo porcine stomach models, the hydrogel achieves sustained mucosal elevation, significantly outperforming hyaluronic acid-based controls. In large-animal ESD models, it promotes organized collagen deposition, angiogenesis, re-epithelialization, and suppressed fibrotic α-SMA expression, collectively accelerating mucosal regeneration with reduced inflammation. This dual-function platform bridges surgical precision with postresection regeneration, offering a next-generation therapeutic material for minimally invasive gastrointestinal oncology.