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To develop a combined barrier method and drug delivery system (“hybrid system”) for preventing postoperative peritoneal adhesions, which could combine the biocompatibility and ease of application of in situ cross-linkable hydrogels with the controlled release features of polymeric nanoparticles.Poly(lactic-co-glycolic acid) nanoparticles were dispersed in aldehyde- and hydrazide-modified hyaluronic acids (HA), then combined via a double-barreled syringe. The material was subjected to mechanical testing and was assayed for in vitro cytotoxicity to murine mesothelial cells. Subsequently, it was tested for biocompatibility by intraperitoneal injection in mice. The hybrid's effectiveness in preventing postsurgical adhesions was assessed using a rabbit sidewall defect-cecum abrasion model, where it was applied to both injured surfaces.The in situ hybrid gel system formed a flexible and durable hydrogel in less than 10 seconds. It had low in vitro cytotoxicity. In the mouse, the cross-linked HA maintained the polymeric nanoparticles in the peritoneum for 1 week, which we had previously shown would have cleared in less than 2 days, and no animals developed adhesions. Notably, the hybrid gel, even in the absence of encapsulated drug, was highly effective in preventing peritoneal adhesions in the rabbit model employed. Animals treated with the hybrid (n = 8) had no adhesions in 62.5% of cases, and none had adhesions that could only be separated by sharp dissection. In contrast, only 4.2% of untreated animals (n = 24) had no adhesions, and 58.3% developed adhesions requiring sharp dissection.The hybrid cross-linked HA-nanoparticle system described here appears to be a biocompatible and highly effective adhesion barrier, which could also deliver antiadhesion drugs.