Mechanical, biological, and structural interaction in the development of osteoarthritis following anterior cruciate ligament injury and reconstruction

Osteoarthritis (OA) of the knee, characterized primarily by pain and cartilage degeneration, is one of the leading causes of disability worldwide, carrying with it a substantial economic cost and reduced quality of life. The risk factors for knee OA include aging, obesity, and traumatic knee injury. OA is particularly difficult to study because its symptoms, such as pain, stiffness, and swelling, are relatively absent until the disease has already reached an advanced state. Risk factors for OA include aging, obesity, and traumatic joint injury. As one of the most common traumatic knee injuries, anterior cruciate ligament (ACL) tear provides a valuable opportunity to study factors influencing the initiation of OA in an at-risk population. Surgical ACL reconstruction (ACLR) has managed to improve patient outcomes by stabilizing the knee and allowing return to physical activity, but has not reduced this risk of post-traumatic OA where roughly 50% of patients develop OA within 10-15 years after injury. Existing research suggests that this is likely a result of perturbations to the pre-injury knee mechanics that negatively interact with the post-injury biology and structure of the joint to disrupt cartilage homeostasis leading to premature OA in about half of patients. Lack of understanding concerning the nature of these interactions has been a critical barrier to identifying which patients will develop OA. Thus, there is a need for improved understanding of OA risk after ACLR to inform early OA risk assessment (before symptoms) that will support the development of intervention strategies to delay or prevent OA onset. This dissertation provides insight into the interaction between mechanical, biological, and structural factors on the risk of OA following ACL injury and reconstruction, and is focused on three studies completed on patients following ACLR examining relationships between these risk factors. The first study examines changes in knee kinematics occurring from 2 to 4 years after ACLR and relationships to patient reported outcomes much later at 8 years after surgery. The results suggest that a subset (approximately 50%) of patients develop increasingly abnormal kinematics that may contribute to and provide early warning of deteriorating knee function years before the onset of clinical symptoms. The second study demonstrates a relationship between cartilage matrix changes measured using a novel quantitative magnetic resonance imaging (MRI) technique and knee loading parameters known to affect OA progression at only 2 years after ACLR when the articular cartilage appeared healthy on standard clinical MRI. These results suggest that this new MRI metric may be showing early cartilage pathology that is undetectable using standard MRI methods. The final study investigates the biological response to knee loading through a walking exercise and cartilage matrix changes assessed by novel quantitative MRI at 2 years after ACLR. The results show a higher synthetic state in some patients suggestive of a repair response. However, the observed correlations with cartilage matrix changes detectable by quantitative MRI and knee loading suggest that this repair response may be related to a higher risk for future knee OA. All three studies demonstrated potential markers that separated patients into divergent groupings that suggest greater or lesser risk for developing knee OA consistent with the natural history where approximately 50% of individuals with ACL injury develop premature knee OA. The studies provide promising markers for the early detection of post-traumatic OA after ACLR and identify potential targets for intervention. It is important to note that assessing the interaction between multiple markers was an important factor in identifying the sensitivity of specific markers that would not be possible when evaluating markers independently. As such, the results of this thesis also demonstrated the importance of interdisciplinary research in evaluating biomarkers of OA risk in relationship to the complex interactions between mechanical, biological, and structural components in maintaining joint homeostasis. This knowledge will aid in the future development of personalized treatment strategies to delay or prevent the onset of post-traumatic OA after ACLR.

Keywords: Mechanical Engineering.
Advisor: Andriacchi Th. P. (Thomas P.) 
Chu Constance R.
Delp Scott