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Although mesenchymal stem cells (MSCs) have been widely explored for their regenerative properties, their therapeutic potential in polytrauma patients remains uncertain. Given the clinical interest in both systemic and localized stem cell therapies, understanding how delivery route influences MSCs biodistribution, inflammatory modulation, and therapeutic efficacy is critical for optimizing treatment strategies in polytrauma. Hence, we compared systemic versus local MSCs delivery in a polytrauma model. We evaluated inflammatory responses and bone formation in a C57BL\/6J murine model across four groups: (1) isolated fracture, (2) polytrauma (femur fracture\u2009+\u2009chest trauma), (3) polytrauma\u2009+\u2009systemic MSC delivery, and (4) polytrauma\u2009+\u2009local MSC delivery in hyaluronic acid-based hydrogels at the fracture site. Polytrauma induced a prolonged inflammatory response characterized by elevated interleukin 1 alpha and beta (IL-1\u03b1 &amp; \u03b2), tumor necrosis factor-alpha (TNF-\u03b1), interferon-gamma (IFN-\u03b3), and monocyte chemoattractant protein-1 and \u2212\u20095 (MCP-1 &amp; MCP-5). Both delivery methods significantly reduced inflammation and proinflammatory cytokines, though local delivery yielded more consistent effects. IVIS imaging confirmed MSC retention at the fracture site in the local delivery group, while systemic administration of MSCs resulted in pulmonary entrapment. Although systemic MSCs failed to enhance fracture healing significantly, local MSC delivery promoted bone formation evidenced by CT and histological characterizations. These findings demonstrate that local MSC delivery in a hydrogel scaffold represents a superior strategy for improving fracture healing in polytrauma patients compared to systemic delivery.<\/jats:p>","DOI":"10.1186\/s13036-025-00554-4","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T11:59:06Z","timestamp":1759233546000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Systemic versus local delivery of mesenchymal stem cells to improve the early stages of fracture healing in a polytrauma model"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1955-8667","authenticated-orcid":false,"given":"Augustine Mark","family":"Saiz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Rahmati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soren David","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesh Satish","family":"Bhat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony Daniel","family":"Baldini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8ystein","family":"\u00d8vreb\u00f8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liebert Parreiras","family":"Nogueira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaqif El","family":"Khassawna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"St\u00f6tzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando A.","family":"Fierro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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Stem Cell Res Ther. 2015;6:1\u201313.","journal-title":"Stem Cell Res Ther"}],"container-title":["Journal of Biological Engineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13036-025-00554-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13036-025-00554-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13036-025-00554-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T11:59:15Z","timestamp":1759233555000},"score":1,"resource":{"primary":{"URL":"https:\/\/jbioleng.biomedcentral.com\/articles\/10.1186\/s13036-025-00554-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["554"],"URL":"https:\/\/doi.org\/10.1186\/s13036-025-00554-4","relation":{},"ISSN":["1754-1611"],"issn-type":[{"value":"1754-1611","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]},"assertion":[{"value":"18 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The usage of luciferase-GFP labeled MSCs was done under an approved protocol from the UC Davis Biological Use Authorization (BUA, protocol # R3319). In addition, we performed animal surgeries in the Department of Orthopaedic Surgery, University of California, Davis in compliance with the ARRIVE guidelines under an approved protocol from the UC Davis Institutional Animal Care and Use Committee (IACUC# 23193). No other ethical approval was applicable to this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AMS \u2013 serves on committees for AO, OTA, AAOS, and ORS. MR serves on committees for ISFR ORS. The authors declared no potential conflicts of interest with respect to the research, authorship, and\/or publication of this study, except for \u00d8\u00d8 who is the inventor of the hydrogel used. The intellectual property rights and commercial rights to the material are owned by Nupep AS, where \u00d8\u00d8 is the main shareholder. Research reported in this publication was supported by the National Institute Of Arthritis And Musculoskeletal And Skin Diseases of the National Institutes of Health under Award Number K08AR084594. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosures"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"82"}}