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Existing biologic strategies for bone repair primarily focus on osteogenesis but are not designed to modulate systemic immune dysregulation, limiting their utility in the polytrauma setting. To overcome this, we developed a hyaluronic acid-based hydrogel (HA) incorporating osteogenic intrinsically disordered peptides (P2) and mesenchymal stem cells (MSCs) to promote bone regeneration and modulate inflammation simultaneously. MSCs entrapped in hydrogels containing P2 (HA\u2009+\u2009P2) exhibited increased cell viability, alkaline phosphatase activity, and calcium deposition under in vitro polytrauma conditions compared to MSCs in hydrogels alone (HA). We utilized a murine polytrauma model (4\u2009mm femoral osteotomy\u2009+\u2009blunt chest trauma) in mice. We studied the inflammatory response and bone formation over 21\u2009days in mice treated with (1) HA, (2) HA\u2009+\u2009P2, or (3) HA\u2009+\u2009P2\u2009+\u2009MSCs. We observed that adding P2 enhanced bone mineralization at the fracture site, yet transplantation of MSCs with P2 further increased mineralization. Both HA\u2009+\u2009P2 and HA\u2009+\u2009P2\u2009+\u2009MSCs groups attenuated the systemic inflammatory response to near healthy baseline values. The HA\u2009+\u2009P2 group significantly accelerated the first stages of fracture healing by upregulating genes encoding for collagen biosynthesis, modifying enzymes, and extracellular matrix (ECM)-receptor interaction. Mice treated with HA\u2009+\u2009P2\u2009+\u2009MSCs exhibited transcriptional regulation resulting in the upregulation of key repair genes related to cell cycle control, E2F transcriptional regulation, and TP53-mediated DNA repair, alongside downregulation of inflammatory pathways (IL-2, IL-3, and IL-5 signaling) and improved fracture healing. This study demonstrated that the combination of intrinsically disordered peptides and mesenchymal stem cells in HA-based hydrogels enhances bone formation, modulates both local and systemic inflammation, and improves structural organization at the fracture site in polytrauma conditions.<\/jats:p>","DOI":"10.1177\/20417314251397106","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T09:03:13Z","timestamp":1764579793000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mesenchymal stem cells delivered via a bioactive disordered peptide-hydrogel platform modulate early inflammation and enhance skeletal repair in a polytrauma model"],"prefix":"10.1177","volume":"16","author":[{"given":"Augustine Mark","family":"Saiz","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"},{"name":"Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Rahmati","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony Daniel","family":"Baldini","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"},{"name":"California Northstate University College of Medicine, Elk Grove, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesh","family":"Satish Bhat","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soren David","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"},{"name":"Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"},{"name":"California Northstate University College of Medicine, Elk Grove, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato Miguel","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shierly W.","family":"Fok","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"},{"name":"Department of Biomedical Engineering, UC Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaqif","family":"El Khassawna","sequence":"additional","affiliation":[{"name":"Experimental Trauma Surgery, Justus-Liebig University Giessen, Germany"},{"name":"School of Pharmacy, The University of Jordan, Amman, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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