Post-Traumatic Osteoarthritis (PTOA) is an organ level disease with the cartilage, bone, synovium, and menisci all affected. A common precursor to the development of PTOA is injury to the stabilizing ligaments of a joint, most important being the anterior cruciate ligament (ACL) of the knee joint. Increasing evidence suggests that ACL injury leads to changes in knee joint kinematics, specifically subtle changes in the location of contact between the femur and tibia during activities of daily living. While the magnitude of change is variable across patients, even the most subtle change in location of femoral-tibial contact can lead to substantial changes in the spatial and temporal stresses on, and within, the articular cartilage (contact and internal stresses, respectively). It has been suggested that such changes are responsible for the initiation and progression of cartilage degeneration, but the exact relationship is unclear. Our goal is to identify specific mechanical changes that result in the initiation of an OA-like biological response in the articular cartilage of ACL-injured knees - i.e. to identify mechanobiological biomarkers of PTOA. We hypothesize that changes in knee- independent common stress patterns will result in an OA-like biological response, as opposed to knee-dependent random stress patterns found on other locations in the knee. To test this hypothesis, we will expand a previously developed experimental contact stress model of the knee joint, and augment it with a 3D computational model of the whole joint to identify knee-independent common internal stress patterns within articular cartilage, with and without an ACL. Custom-designed bioreactors will be used to determine which internal stress pattern changes produce an OA- like chondrocyte catabolic response within the extracellular matrix, ECM. Changes that produce a statistically significant negative biological response will be classified as ACL-PTOA mechanobiological biomarkers and used to transform maps of joint stresses, to maps that chart likelihood of initiation of PTOA. If our hypothesis is correct, the paradigm for intervening in this disease will change. The goal of any therapy or surgical intervention will no longer be to only restore joint stability, but rather to mitigate the specifichigh-risk stress patterns identified in this study. In the long-term, this knowledge will allow for a moe comprehensive analysis of the risk of developing PTOA on a per-patient basis, and allow for the benefits of surgical intervention to be more appropriately assessed.

Public Health Relevance

This project is designed to understand the effect of anterior cruciate ligament rupture on the health of the knee joint. Our goal is to identify specific changes in mechanics that have the most profound effect on the biological response of articular cartilage. As such, we will provide an algorithm that can be used to understand how best to avoid the development of post-traumatic osteoarthritis after injury to the anterior cruciate ligament.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR066635-03
Application #
9207734
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$369,439
Indirect Cost
$129,319
Name
Hospital for Special Surgery
Department
Type
Other Domestic Non-Profits
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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Trevino, Robert L; Stoia, Jonathan; Laurent, Michel P et al. (2017) ESTABLISHING A LIVE CARTILAGE-ON-CARTILAGE INTERFACE FOR TRIBOLOGICAL TESTING. Biotribology (Oxf) 9:1-11
Khoshgoftar, Mehdi; Torzilli, Peter A; Maher, Suzanne A (2017) Influence of the pericellular and extracellular matrix structural properties on chondrocyte mechanics. J Orthop Res :
Guo, Hongqiang; Santner, Thomas J; Lerner, Amy L et al. (2017) Reducing uncertainty when using knee-specific finite element models by assessing the effect of input parameters. J Orthop Res 35:2233-2242
Sch├Ątti, Oliver R; Gallo, Luigi M; Torzilli, Peter A (2016) A Model to Study Articular Cartilage Mechanical and Biological Responses to Sliding Loads. Ann Biomed Eng 44:2577-88
Guo, Hongqiang; Torzilli, Peter A (2016) Shape of chondrocytes within articular cartilage affects the solid but not the fluid microenvironment under unconfined compression. Acta Biomater 29:170-179