This proposal challenges the current dogma that `non-contact' anterior cruciate ligament (ACL) ruptures are due to sudden awkward landing or overload event. In the past funding cycle we developed the first evidence that the ACL can also fail under repetitive sub-maximal loading (Lipps 2013), helping to explain why an ACL can fail during a routine athletic maneuver. Pilot data suggest that this fatigue failure is associated with an accumulation of microdamage near the proximal femoral enthesis. We request funds to test this hypothesis.
In AIM 1 60 pairs of knees from sex- and size-matched younger cadavers (30 males, 30 females) will be positioned at an initial flexion angle of 15o via pretensioned knee muscle-tendon equivalents that allow the knee to flex under a distal impulsive test load. ACL fatigue life will be determined via repetitive sub-maximal four-times bodyweight impulsive 3-D compound loading (compression + trans knee muscle loading + flexion moment + knee abduction moment + internal tibial axial torque) applied to each knee. A Cox regression model will be used to rank the relative importance of sex, internal femoral axial rotation range of motion (ROM) and lateral tibial slope in limiting ACL fatigue life.
In AIM 2 a we will use histological images and a binomial exact test to determine the percentage of the knees undergoing AIM 1 fatigue testing that exhibit microdamage at or near the femoral enthesis exceeding the +3*SD area found in the 32 untested, paired, control knees. Similarly, in AIM 2b we will salvage ACL femoral enthesis explants in 60 healthy young adults (30 females) aged 14-25 years undergoing routine reconstruction of their ACL and determine the percentage of explants exhibiting microdamage area exceeding the +3*SD value measured in 30 untested age- and sex-matched cadaveric controls. If greater-than-normal ACL microdamage is found in fatigue-tested knees in vitro (AIM 2a) and in ACL-injured patients in vivo (AIM 2b) this suggests the ACL can fail due to an accumulation of fatigue damage. This would imply that there may be time to modify athlete work-rest cycles to reduce ACL injury risk by arresting the injury cycle (Olsen 2006) and allowing the ACL to heal (Maekawa 1996).

Public Health Relevance

Over 250,000 anterior cruciate ligament (ACL) injuries still occur annually in the U.S., many of which result in early-onset knee arthritis within 10 years regardless of treatment. Using both cadaveric knees and the ligament-bone specimens salvaged before the surgical reconstruction of ACL tears, we will test the hypothesis that the human ACL can fail under repetitive sub-maximal loading due to an accumulation of microdamage where the ligament arises from the femur. If the hypothesis is supported, the research should introduce a paradigm shift in ACL injury prevention programs by focusing for the first time on reducing the risk of ACL fatigue failure, particularly in females.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Washabaugh, Charles H
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Luetkemeyer, Callan M; Marchi, Benjamin C; Ashton-Miller, James A et al. (2018) Femoral entheseal shape and attachment angle as potential risk factors for anterior cruciate ligament injury. J Mech Behav Biomed Mater 88:313-321
Bojicic, Katherine M; Beaulieu, Mélanie L; Imaizumi Krieger, Daniel Y et al. (2017) Association Between Lateral Posterior Tibial Slope, Body Mass Index, and ACL Injury Risk. Orthop J Sports Med 5:2325967116688664
Bedi, Asheesh; Warren, Russell F; Wojtys, Edward M et al. (2016) Restriction in hip internal rotation is associated with an increased risk of ACL injury. Knee Surg Sports Traumatol Arthrosc 24:2024-31
Beaulieu, Mélanie L; Carey, Grace E; Schlecht, Stephen H et al. (2016) On the heterogeneity of the femoral enthesis of the human ACL: microscopic anatomy and clinical implications. J Exp Orthop 3:14
Wojtys, Edward M; Beaulieu, Mélanie L; Ashton-Miller, James A (2016) New perspectives on ACL injury: On the role of repetitive sub-maximal knee loading in causing ACL fatigue failure. J Orthop Res 34:2059-2068
Beaulieu, Mélanie L; Wojtys, Edward M; Ashton-Miller, James A (2015) Risk of anterior cruciate ligament fatigue failure is increased by limited internal femoral rotation during in vitro repeated pivot landings. Am J Sports Med 43:2233-41
Beaulieu, Mélanie L; Carey, Grace E; Schlecht, Stephen H et al. (2015) Quantitative comparison of the microscopic anatomy of the human ACL femoral and tibial entheses. J Orthop Res 33:1811-7
Beaulieu, Mélanie L; Oh, Youkeun K; Bedi, Asheesh et al. (2014) Does limited internal femoral rotation increase peak anterior cruciate ligament strain during a simulated pivot landing? Am J Sports Med 42:2955-63
Lipps, David B; Oh, Youkeun K; Ashton-Miller, James A et al. (2014) Effect of increased quadriceps tensile stiffness on peak anterior cruciate ligament strain during a simulated pivot landing. J Orthop Res 32:423-30
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