PROJECT SUMMARY Pediatric anterior cruciate ligament (ACL) injuries and surgical intervention rates are rapidly increasing in recent years. Of particular concern, pediatric patients are approximately five times more likely than adults to experience a secondary ACL injury after surgical reconstruction. Further, sex plays a factor in injury rates, where females experience a higher risk of ACL injury than males during adolescence, but not childhood or adulthood. However, the mechanism of ACL injuries and the reasons behind these age and sex-related differences remain unclear. This is, in part, due to difficulty experimentally observing the ACL during injury and limited data regarding the function of the ACL and its anteromedial (AM) and posterolateral (PL) bundles throughout skeletal growth. ACL injuries likely occur when the ligament experiences high local stresses—forces concentrated over a small area. Preliminary data from our group has shown sex-dependent growth and function of the AM and PL bundles, so it seems likely that sex and age will impact the magnitude and location of local stresses within the ACL. Therefore, the objective of this proposal is to determine how age and sex impact local stresses in the ACL throughout skeletal growth and how partial ACL injury may affect growth and remodeling of the remaining portion of ACL and other tissues in the knee joint. Aim 1 will assess how sex and age impact regional stresses experienced in the AM and PL bundles of the ACL under applied loads. Aim 2 will assess how regional stresses change as an immediate effect of partial injury. Aim 3 will assess how long-term changes in tissue and knee joint mechanics after partial ACL injury impact growth and remodeling of the remainder of the ACL and surrounding cartilage. These aims will be accomplished by developing experimentally validated subject-specific FE models to simulate mechanical loading of the ACL in males and females at different stages of skeletal growth. Additionally, the long- term impact of partial ACL injury will be investigated in vivo using the porcine model. Growth and remodeling will be studied non-invasively using quantitative imaging techniques and computational simulations of growth in response to regional tissue stresses.