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First, using the earliest in vitro model of a simulated single\u2010leg jump landing or pivot cut with realistic knee loading rates and trans\u2010knee muscle forces, we identified the worst\u2010case dynamic knee loading that causes the greatest peak ACL strain: Combined knee compression, flexion, and internal tibial rotation. We also identified morphologic factors that help explain individual susceptibility to ACL injury. Second, using the above knee loading, we introduced a possible paradigm shift in ACL research by demonstrating that the human ACL can fail by a sudden rupture in response to repeated sub\u2010maximal knee loading. If that load is repeated often enough over a short time interval, the failure tended to occur proximally, as observed clinically. Third, we emphasize the value of a physical exam of the hip by demonstrating how limited internal axial rotation at the hip both increases the susceptibility to ACL injury in professional athletes, and also increases peak ACL strain during simulated pivot landings, thereby further increasing the risk of ACL fatigue failure. When training at\u2010risk athletes, particularly females with their smaller ACL cross\u2010sections, rationing the number and intensity of worst\u2010case knee loading cycles, such that ligament degradation is within the ACL's ability to remodel, should decrease the risk for ACL rupture due to ligament fatigue failure.\u00a9 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2059\u20132068, 2016.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jor.23441","type":"journal-article","created":{"date-parts":[[2016,9,21]],"date-time":"2016-09-21T22:02:51Z","timestamp":1474495371000},"page":"2059-2068","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["New perspectives on ACL injury: On the role of repetitive sub\u2010maximal knee loading in causing ACL fatigue failure"],"prefix":"10.1002","volume":"34","author":[{"given":"Edward M.","family":"Wojtys","sequence":"first","affiliation":[{"name":"MedSport Department of Orthopedic Surgery University of Michigan Ann Arbor Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie L.","family":"Beaulieu","sequence":"additional","affiliation":[{"name":"Biomechanics Research Laboratory Department of Mechanical Engineering University of Michigan Ann Arbor Michigan 48109"},{"name":"Department of Radiology 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