Water-Activated Phospholipid Phase-Separation Gel as an Immunomodulatory Anti-Adhesion Barrier for Postoperative Adhesion Prevention.

Postoperative adhesions remain a major complication after abdominal surgery, and current polymeric barriers often show limited tissue retention and biocompatibility. Here, we establish a water-activated phospholipid barrier strategy for postoperative adhesion prevention by converting a depot-forming phospholipid phase-separation gel (PPSG) into a gram-scale surgical barrier. In this study, solvent identity acts as a functional design determinant rather than a passive solubilizer, governing hydration-triggered gel reinforcement, intraperitoneal residence, and tolerability. Replacing ethanol with propylene glycol strengthened the gel matrix, improved barrier activation, and enabled gram-scale administration without hepatic toxicity associated with ethanol-based PPSG. Mechanistically, the structured phospholipid barrier retained gel-state immunomodulatory activity, attenuating macrophage-driven inflammatory responses and suppressing NF-κB-associated signaling. In a rat peritoneal-cecum abrasion model, propylene glycol-based PPSG completely prevented macroscopic adhesions. Together, these findings establish a water-activated phospholipid barrier platform for converting depot-forming phospholipid systems into active surgical barriers that combine durable physical separation with local immunomodulation.