Pascual-Antón, LucíaSandoval, PilarTomero-Sanz, HenarTerri, MichelaStrippoli, RaffaeleGarcía-Sanz, ÍñigoMarín-Campos, CristinaDel Pozo, Miguel ÁngelObaid, MaryamGarcia, ValentinaSmith, Peter AlexKeane, Timothy JStevens, Molly MLópez-Cabrera, Manuel2025-12-152025-12-152025-10-08Sci Transl Med. 2025 Oct 8;17(819):eadn3179.https://hdl.handle.net/20.500.12105/27030Tissue 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.M.L.-­C. acknowledges support from the Spanish Ministry of Science and Innovation/Fondo Europeo de Desarrolo Regional (MICIN/FEDER) (PID2022-142796OB-­I00/ AEI/10.13039/501100011033) and Marie Sklodowska-­Curie Innovative Training NetworksEuropean Training Networks (no. 812699). M.L.-­C. has received sponsored research funds from TYBR Health Inc. R.S. acknowledges support from the Ministry for Health of Italy (Ricerca Corrente) linea 2. M.A.P. acknowledges support from the Spanish Ministry of Science, Innovation & Universities (MICIU)/Agencia Estatal de Investigación (AEI)/FEDER (PID2023-146414OB-­I00/AEI/10.13039/501100011033). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICIU, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S funded by MICIN/ AEI/10.13039/501100011033). T.J.K. acknowledges the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-­Curie Individual European Fellowship (no. 746980). M.M.S. acknowledges support from the UK Regenerative Medicine Platform “Acellular/Smart Materials–3D Architecture” hub (MR/R015651/1). For the purpose of open access, the author(s) has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission.engVoRhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 International41061047SCIENCE TRANSLATIONAL MEDICINEopen access