(Verbatim from the Applicant): The objective of this application is to study the post-impact response of articular cartilage and subchondral bone to mechanically-induced, subfracture insults that result in irreversible cartilage damage. Such subfracture joint injuries are commonly seen in individuals with acute anterior cruciate ligament (ACL) injury, where radiographs are normal but subchondral microfractures are evident by magnetic resonance (MR) imaging (bone bruises). Recent evidence indicates that, in subfracture joint injury, the initial insult causes irreversible damage to the cartilage, resulting in cartilage thinning indicative of degenerative joint disease. Surprisingly, little or no information exists on the initial damage to the articular cartilage in subfracture joint injuries, nor on the cartilage and subchondral bone post-injury response. We propose the hypothesis that there is a unique threshold of impact which will cause chondrocyte death and collagen fiber rupture, but not subchondral bone microfracture, and that these cell- and matrix-specific injuries will be irreversible and lead to further cartilage degeneration.
The specific aim of this proposal is to determine the mechanical conditions (threshold stress and stress rate) and the physical mechanisms causing macrostructural, microstructural and cellular damage in impacted articular cartilage, and to evaluate the post-impact physiological response using an in vivo rabbit model. There are three phases to this study. In Phase I, we will determine the threshold stress and stress rate that causes cell and matrix damage, and the chondrocyte, collagen and subchondral bone response at 0 and 24 hours, and 1 week after impacting viable, mature bovine articular cartilage-subchondral explants. In Phase II, we will scale the threshold parameters from Phase I to the rabbit knee in order to produce three levels of impact injury (below, at and above threshold). Finally, in Phase III, we will study the in vivo post-impact response in the rabbit knee at 1, 2, 4, 8 and 12 weeks. Our hypothesis will be tested at the cellular level by determining the mechanical factors (magnitude and rate effects) causing chondrocyte damage (recoverable vs. permanent, i.e. death), the intra-cellular location of damage (membrane, cytoskeleton, nucleus), and the cell's metabolic response (anabolic vs. catabolic), and at the structural level by determining the spatial location and cause of cell and collagen damage (zone; mechanical vs. catabolic), proteoglycan degradation and loss, subchondral bone damage, and general biomechanical properties. If our preliminary findings (hypotheses) are validated, then individuals sustaining subfracture injury would be predisposed to post-traumatic arthritis, and would dictate that new methodologies would have to be developed for the diagnosis and treatment of these types of subfracture joint impact injuries.
