Mechanobiological Risk Factors for Initiation of Post Traumatic Osteoarthritis

 描述（由申请人提供）：创伤后骨关节炎（PTOA）是一种器官水平疾病，软骨、骨、滑膜和滑膜均受影响。PTOA发展的常见前兆是关节稳定韧带的损伤，最重要的是膝关节的前交叉韧带（ACL）。越来越多的证据表明，ACL损伤导致膝关节运动学的变化，特别是在日常生活活动中股骨和胫骨之间的接触位置的细微变化。虽然患者之间的变化幅度是可变的，但即使是股骨-胫骨接触位置的最细微变化也会导致关节软骨上和关节软骨内的空间和时间应力（分别为接触应力和内应力）发生实质性变化。有人认为，这种变化是软骨退变的开始和进展的原因，但确切的关系尚不清楚。我们的目标是确定导致ACL损伤膝关节关节软骨中OA样生物反应启动的特定机械变化-即确定PTOA的“机械生物学生物标志物”。我们假设，“膝关节独立”的常见应力模式的变化将导致OA样生物反应，而不是在膝关节其他部位发现的“膝关节依赖性”随机应力模式。为了验证这一假设，我们将扩展先前开发的膝关节实验接触应力模型，并将其与整个关节的3D计算模型相结合，以识别关节软骨内的“膝关节独立”常见内部应力模式，有和没有ACL。将使用定制设计的生物反应器来确定哪些内部应力模式变化在细胞外基质ECM内产生OA样软骨细胞分解代谢反应。产生统计学显著性阴性生物学反应的变化将被归类为“ACL-PTOA机械生物学生物标志物”，并用于将关节应力图转换为“PTOA启动可能性”图。如果我们的假设是正确的，干预这种疾病的范例将改变。任何治疗或手术干预的目标将不再仅仅是恢复关节稳定性，而是减轻本研究中确定的特定高风险应力模式。从长远来看，这些知识将允许莫伊对每个患者发生PTOA的风险进行全面分析，并允许更适当地评估手术干预的益处。

 DESCRIPTION (provided by applicant): 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.