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Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>\n                    Delayed and nonhealing fractures, affecting 5 to 10% of cases, are associated with prolonged disability and diminished quality of life. Although acute inflammation is required to initiate repair, persistent mechanical instability can sustain maladaptive immune and fibrotic responses that impede regeneration. Existing animal models do not adequately recapitulate mechanical instability, the principal driver of hypertrophic nonunion in clinical settings, thereby limiting translational relevance. We developed a murine model of delayed fracture healing using tunable intramedullary fixation to impose controlled interfragmentary strain. High-strain conditions (low-stiffness nail, 15 to 30% strain) produced enlarged calluses characterized by delayed ossification, increased fibrotic tissue (3.3-fold,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.0147), and reduced biomechanical integrity (1.6-fold decrease in stiffness,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.024) relative to low-strain controls (high-stiffness nail, &lt;5% strain). Spatial transcriptomic analysis identified persistent fibrotic niches in high-strain calluses enriched with fibroblast-associated genes (e.g.,\n                    <jats:italic toggle=\"yes\">Pdgfrb<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Lgals3<\/jats:italic>\n                    ) and dysregulated macrophage-fibroblast signaling (\n                    <jats:italic toggle=\"yes\">Spp1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    ). Systemically, high-strain fractures were associated with distinct immune signatures in which CD206\n                    <jats:sup>+<\/jats:sup>\n                    macrophages and CD25\n                    <jats:sup>+<\/jats:sup>\n                    regulatory T cells predicted healing outcomes (\n                    <jats:italic toggle=\"yes\">R<\/jats:italic>\n                    \u00a0=\u00a00.72,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.004), suggesting early immune polarization as a determinant of repair trajectory. Elevated CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses were observed, consistent with a sustained inflammatory state associated with impaired healing. These findings identify mechanical instability as a driver of pathological immune-stromal interactions and establish a preclinical platform for investigating mechanobiology-informed therapeutic strategies. This work supports a conceptual framework in which hypertrophic nonunion is understood as a disorder arising from dysregulated interactions between mechanical cues and immune responses.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adx7511","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:58:31Z","timestamp":1787939911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Maladaptive immune-fibrotic axis drives impaired long bone regeneration under mechanical instability"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8775-5750","authenticated-orcid":true,"given":"Matthew D.","family":"Patrick","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University at Buffalo, Buffalo, NY 14260, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-9987","authenticated-orcid":true,"given":"Jaimo","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Emory University and Grady Memorial Hospital, Atlanta, GA 30303, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6361-143X","authenticated-orcid":true,"given":"Kurt D.","family":"Hankenson","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9880-3973","authenticated-orcid":true,"given":"Ramkumar T.","family":"Annamalai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University at Buffalo, Buffalo, NY 14260, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/550S194a"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.N.01090"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00289-8"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph15122845"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.injury.2017.04.020"},{"key":"e_1_3_2_7_2","unstructured":"B. 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