{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:17:55Z","timestamp":1783084675668,"version":"3.54.6"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Bone healing is a complex regenerative process regulated by interactions between skeletal and host biologic responses, and failure of bone repair remains a major challenge in orthopedic surgery. Using a murine model, this study investigated whether a preemptive priming stimulus could enhance healing of a subsequent contralateral cortical bone defect and whether the type and timing of the stimulus influenced this response. Skeletally mature male mice were randomized into six groups (n = 6\/group) receiving either no stimulus, a skin incision, skin and muscle incisions, or a unicortical femoral drill hole stimulus. A subcritical-sized 1 mm \u00d7 2 mm unicortical defect was subsequently created in the contralateral femur after intervals of 2, 6, or 12 weeks, depending on group allocation. Femora were harvested 8 weeks later for micro-computed tomography, histology, and immunofluorescence analyses. Mice undergoing muscle elevation 2 weeks prior to defect creation and mice receiving drill hole stimulus 12 weeks prior demonstrated the greatest degree of cortical regeneration and healing of the contralateral subcritical-sized defect, with normalized cortical thicknesses reaching 104% and 109% of adjacent native cortex, respectively. Histologic analysis confirmed restoration of mature cortical architecture in these groups. Immunofluorescence analysis demonstrated a relative shift toward an Arg1-associated reparative macrophage profile with reduced iNOS-associated inflammatory signaling, suggesting that modulation of the innate immune response contributed to the enhanced regenerative healing observed. These findings demonstrate that priming stimuli can enhance subsequent bone healing in a timing- and stimulus-dependent manner and may represent a novel strategy to optimize bone regeneration.<\/jats:p>","DOI":"10.3390\/life16071111","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:39:11Z","timestamp":1783078751000},"page":"1111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing Bone Healing with a Priming Stimulus"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8986-6326","authenticated-orcid":false,"given":"Michael","family":"Tanzer","sequence":"first","affiliation":[{"name":"Division of Orthopaedic Surgery, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Jo Miller Orthopaedic Research Laboratory, McGill University Health Centre, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misghana","family":"Kassa","sequence":"additional","affiliation":[{"name":"Jo Miller Orthopaedic Research Laboratory, McGill University Health Centre, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin Chandra Teja","family":"Dadi","sequence":"additional","affiliation":[{"name":"Jo Miller Orthopaedic Research Laboratory, McGill University Health Centre, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6945-2459","authenticated-orcid":false,"given":"Tarek","family":"Klaylat","sequence":"additional","affiliation":[{"name":"Regenerative Orthopaedics and Innovation Laboratory, McGill University Health Centre, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9415-1739","authenticated-orcid":false,"given":"Rahul","family":"Gawri","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Surgery, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Regenerative Orthopaedics and Innovation Laboratory, McGill University Health Centre, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Martineau","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Surgery, McGill University, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9700-4523","authenticated-orcid":false,"given":"Adam","family":"Hart","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Surgery, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Jo Miller Orthopaedic Research Laboratory, McGill University Health Centre, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3390\/surgeries5020033","article-title":"Osteoimmunology: An overview of the interplay of the immune system and the bone tissue in fracture healing","volume":"5","author":"Klaylat","year":"2024","journal-title":"Surgeries"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s11914-024-00869-z","article-title":"Osteoimmunology of Fracture Healing","volume":"22","author":"Molitoris","year":"2024","journal-title":"Curr. 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