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Sensory nerve fibers innervate various compartments of the bone tissue, with the periosteum exhibiting the most extensive innervation that is susceptible to injury during trauma. Despite its importance, the effect of injured periosteum on fracture pain remains unknown. This study examines the impact of extensive periosteal injury on fracture pain by using a mouse model. Periosteal injury is induced by mechanical resection during unilateral transverse fracture and compared to transverse fractures with no periosteal injury. Our results demonstrate that extensive periosteal injury induces severe and long\u2010term pain, as assessed by von Frey and dynamic weight bearing measurements, for up to 12 weeks postfracture. Immunofluorescence staining revealed an increase in local neurofilament heavy polypeptide (NF200\u2009+) nerve innervation and an elevated number of calcitonin gene\u2010related peptide (CGRP\u2009+) expressing neurons in the dorsal root ganglion (DRG). Additionally, flow cytometric analyses revealed increased presence of myeloid immune cells in the DRG. Furthermore, bone healing in fractures with extensive periosteal injury exhibited reduced callus size at all time points as assessed by Faxitron X\u2010ray imaging. This study describes a previously unknown effect of extensive periosteal injury in exacerbating fracture pain and establishes a potential model to study long\u2010term orthopedic fracture pain.<\/jats:p>","DOI":"10.1002\/jor.26067","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:12:05Z","timestamp":1741738325000},"page":"1155-1163","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extensive Periosteal Injury During Fracture Induces Long\u2010Term Pain in Mice"],"prefix":"10.1002","volume":"43","author":[{"given":"Jiaoni","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Duke University Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Ru Vernon","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huchen","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell","family":"Negus","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey Bohrer","family":"Guerra","sequence":"additional","affiliation":[{"name":"Trinity College of Arts &amp; Sciences Duke University Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0004-7947","authenticated-orcid":false,"given":"Shyni","family":"Varghese","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University Durham North Carolina USA"},{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"},{"name":"Department of Mechanical Engineering and Materials Science Duke University Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.55275\/JPOSNA-2021-220"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.2007.61"},{"key":"e_1_2_8_3_2","unstructured":"discussion:288."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000005807"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0020-1383(01)00047-X"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00402-022-04717-6"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00045.2019"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1515\/sjpain-2019-0111"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/1558944720963895"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/PHM.0b013e31815e6370"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjps.2023.02.017"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000580"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.01.047"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4273"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2021.04.006"},{"key":"e_1_2_8_16_1","article-title":"Traumatized Periosteum: Its Histology, Viability, and Clinical Significance","volume":"14","author":"Patro B. 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