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Repetitive loading is known to result in fatigue damage of both ligament and tendon in the form of collagen unravelling, which can lead to structural failure. However, the relationship between tissue\u2019s structural, compositional, and mechanical changes are poorly understood. Herein we show that repetitive submaximal loading of cadaver knees causes an increase in co-localised induction of collagen unravelling and tissue compliance, especially in regions of greater mineralisation at the ACL femoral enthesis. Upon 100 cycles of 4\u00d7 bodyweight knee loading, the ACL exhibited greater unravelled collagen in highly mineralized regions across varying levels of stiffness domains as compared to unloaded controls. A decrease in the total area of the most rigid domain, and an increase in the total area of the most compliant domain was also found. The results highlight fatigue-driven changes in both protein structure and mechanics in the more mineralized regions of the ACL enthesis, a known site of clinical ACL failure. The results provide a starting point for designing studies to limit ligament overuse injury.<\/jats:p>","DOI":"10.1038\/s42003-023-04948-2","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T07:04:07Z","timestamp":1685084647000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Fatigue-driven compliance increase and collagen unravelling in mechanically tested anterior cruciate ligament"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9447-6883","authenticated-orcid":false,"given":"Kevin H.","family":"Putera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Young","family":"Baek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-927X","authenticated-orcid":false,"given":"Stephen H.","family":"Schlecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0333-5514","authenticated-orcid":false,"given":"M\u00e9lanie L.","family":"Beaulieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4630-9647","authenticated-orcid":false,"given":"Victoria","family":"Haritos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Arruda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1528-2787","authenticated-orcid":false,"given":"James A.","family":"Ashton-Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Wojtys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7759-7456","authenticated-orcid":false,"given":"Mark M.","family":"Banaszak Holl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,26]]},"reference":[{"key":"4948_CR1","doi-asserted-by":"publisher","first-page":"573","DOI":"10.3928\/0147-7447-20000601-15","volume":"23","author":"B Boden","year":"2000","unstructured":"Boden, B., Dean, G., Feagin, J. & Garrett, W. 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