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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-1\u03b2, 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.<\/jats:p>","DOI":"10.1126\/scitranslmed.adn3179","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:59:46Z","timestamp":1759946386000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["Sprayable extracellular matrix hydrogel reduces postoperative adhesion formation and protects healing tissues in preclinical models"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7270-1629","authenticated-orcid":true,"given":"Luc\u00eda","family":"Pascual-Ant\u00f3n","sequence":"first","affiliation":[{"name":"Tissue and Organ Homeostasis Program, Centro de Biolog\u00eda Molecular Severo Ochoa (CBM), CSIC, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-7037","authenticated-orcid":true,"given":"Pilar","family":"Sandoval","sequence":"additional","affiliation":[{"name":"Tissue and Organ Homeostasis Program, Centro de Biolog\u00eda Molecular Severo Ochoa (CBM), CSIC, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2631-0299","authenticated-orcid":true,"given":"Henar","family":"Tomero-Sanz","sequence":"additional","affiliation":[{"name":"Tissue and Organ Homeostasis Program, Centro de Biolog\u00eda Molecular Severo Ochoa (CBM), CSIC, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1090-7012","authenticated-orcid":true,"given":"Michela","family":"Terri","sequence":"additional","affiliation":[{"name":"Mechanoadaptation and Caveolae Biology Laboratory, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain."},{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy."},{"name":"Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, 00149 Rome, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3483-8381","authenticated-orcid":true,"given":"Raffaele","family":"Strippoli","sequence":"additional","affiliation":[{"name":"Mechanoadaptation and Caveolae Biology Laboratory, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain."},{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy."},{"name":"Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, 00149 Rome, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4805-324X","authenticated-orcid":true,"given":"\u00cd\u00f1igo","family":"Garc\u00eda-Sanz","sequence":"additional","affiliation":[{"name":"Department of General and Digestive Surgery, Hospital Universitario La Princesa\u2013Instituto de Investigaci\u00f3n Sanitaria Princesa (IIS-IP), Universidad Aut\u00f3noma de Madrid, 28006 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3277-303X","authenticated-orcid":true,"given":"Cristina","family":"Mar\u00edn-Campos","sequence":"additional","affiliation":[{"name":"Department of General and Digestive Surgery, Hospital Universitario La Princesa\u2013Instituto de Investigaci\u00f3n Sanitaria Princesa (IIS-IP), Universidad Aut\u00f3noma de Madrid, 28006 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9077-391X","authenticated-orcid":true,"given":"Miguel \u00c1ngel","family":"del Pozo","sequence":"additional","affiliation":[{"name":"Mechanoadaptation and Caveolae Biology Laboratory, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Obaid","sequence":"additional","affiliation":[{"name":"TYBR Health Inc. 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