Sprayable extracellular matrix hydrogel reduces postoperative adhesion formation and protects healing tissues in preclinical models.

Tissue trauma initiates inflammation that can lead to fibrotic complications such as postoperative peritoneal adhesions, which contribute to chronic pain, infertility, and bowel obstruction. Despite their prevalence and impact, effective interventions to prevent adhesion formation remain limited. In this study, we evaluated a sprayable extracellular matrix (ECM) hydrogel as a barrier to protect healing tissues and reduce adhesion formation after abdominal surgery. In both mouse and rabbit models of colorectal and gynecologic procedures, ECM hydrogel application resulted in a substantial reduction in adhesion severity. Mechanistic studies demonstrated that the hydrogel promotes preservation or restoration of the mesothelial lining while modulating early local inflammation. Treated tissues exhibited reduced expression of inflammatory cytokines, including IL-1β, and maintained an intact mesothelial surface with fewer activated myofibroblasts compared with synthetic hydrogel and controls. Immunohistochemical analysis, transcriptomic profiling of mesothelial cells, and in vitro mechanical stretch experiments revealed that the ECM hydrogel mitigates mesothelial-to-mesenchymal transition. These findings suggest that the hydrogel not only provides a physical barrier but also serves as a biological modulator, shielding tissue from mechanical and inflammatory cues that drive adhesion formation. Overall, this study identifies a dual-function, biologically active ECM hydrogel capable of protecting healing tissues and reducing adhesion development in preclinical surgical models. These results support the potential of ECM hydrogel as a clinically translatable, biocompatible strategy for improving postsurgical healing outcomes and reducing adhesion-related complications.