Regenerative Rehabilitative Principles in Modulating Weight Bearing and Joint Kinematics to Delay Post-Traumatic Knee Osteoarthritis

S工程 使用 MMARY 膝关节损伤，如半月板撕裂，增加了发生创伤后骨关节炎(PTOA)的风险 至少增加了10倍。在美国，PTOA会导致残疾，每年的医疗费用高达30亿美元。 虽然受伤后需要康复，但目前的方案只涉及恢复受伤前的活动。 在如何优化早期康复工作以保存长期康复方面存在关键知识缺口 膝关节软骨健康。使用已建立的大鼠PTOA模型，我们建议表征膝关节的反应 在损伤后康复过程中常用的三个要素：1) 最初不负重的持续时间，2)体力活动水平的改变，以及3)下肢的偏差 关节运动学。临床前大鼠模型的使用提供了对疾病时间线的实验性控制 促进机械学研究，以理解PTOA。我们的总体假设是受伤后的干预 强调保持受伤前的膝关节负荷曲线(例如，最小化负重限制， 恢复体力活动水平，或减少关节运动学偏差)将延迟PTOA。我们会 使用创新的实验方法和技术系统地测试这一假设，以解决 PTOA康复文献中的知识差距，如下所述。(目标1)非重量 大鼠左后肢内侧半月板横断术后负重时间的研究 使用后肢悬吊时会有所不同。不同暴露方式对关节软骨健康影响的比较 悬吊决定了最初的非负重对PTOA进展的因果影响。使用Hind- 肢体悬吊而不是肢体固定减少了关节痉挛的有害后果，而且 与目前的做法一致的是，在膝盖受伤后开出初始不负重的处方。(目标2)受伤后 体力活动水平将通过改变每天跑步机的运动量来改变。大鼠伤前状态 首先将建立活动水平，以允许标准化量化受伤后活动修改(% MMT前)。然后可以确定损伤后活动水平对PTOA进展的因果影响。(目标 3)三维后肢关节运动学将使用多个时间点的双平面X射线运动分析进行评估 以确定早期损伤后关节运动学偏差是否可以预测 PTOA的终极严重程度。使用X射线视频直接量化3D骨骼运动可以克服 与使用皮肤标记相关的重大错误。对于所有这三个目标，我们将结合我们的对比 增强的显微CT分析与传统的组织病理学相结合，提供3D的互补评估 膝关节软骨的微结构/成分。这项创新工作的发现将为我们提供对 肢体负重和关节运动学损伤后康复治疗的潜在因果效应 PTOA进展。这些新的知识是促进我们对发病机制的理解的基础。 并开展翻译研究，通过优化创伤后康复来减少PTOA。

PROJECT S U MMARY Knee injuries, e.g., meniscus tears, increase the risk of developing post-traumatic osteoarthritis (PTOA) by at least 10 fold. PTOA leads to disability with a substantial healthcare cost of $3 billion per year in the US. Although rehabilitation is required after injury, current protocols only address the return to pre-injury activities. Critical knowledge gaps exist regarding how to optimize early rehabilitation efforts to preserve long-term knee cartilage health. Using a well-established rat PTOA model, we propose to characterize responses of knee cartilage to the manipulation of three elements commonly implemented during post-injury rehabilitation: 1) durations of initial non-weight bearing, 2) modifications of physical activity level, and 3) deviations in lower-limb joint kinematics. The use of a pre-clinical rat model provides the experimental control over disease timeline to facilitate a mechanistic study to understand PTOA. Our overall hypothesis is that post-injury interventions that emphasize maintaining pre-injury knee loading profile (e.g. minimizing weight-bearing restriction, regaining physical activity level, or reducing deviations in joint kinematics) will delay PTOA. We will systematically test this hypothesis using innovative experimental approaches and technologies to address the knowledge gaps in the PTOA rehabilitation literature as described in the following Aims. (Aim 1) Non-weight bearing durations in rats after the medial meniscal transection (MMT) surgery performed on the left hind limb will be varied using hind-limb suspension. The comparisons of cartilage health among varying exposures of suspension determines the causal effect of initial non-weight bearing on PTOA progression. The use of hind- limb suspension instead of limb immobilization reduces harmful consequences of joint contracture and is more in line with current practice of prescribing initial non-weight bearing after knee injuries. (Aim 2) Post-injury physical activity levels will be modified by varying the amount of daily treadmill running. Rats’ pre-injury activity levels will first be established to allow standardized quantification of post-injury activity modification (% of pre-MMT). The causal effect of post-injury activity level on PTOA progression can then be determined. (Aim 3) 3D hind-limb joint kinematics will be assessed using biplanar X-ray motion analysis at multiple time points before and after MMT to determine whether early post-injury joint kinematic deviations are predictive of the ultimate severity of PTOA. Using X-ray videos to directly quantify 3D bone movements can overcome the significant errors associated with the use of skin markers. For all three Aims, we will incorporate our contrast enhanced microCT analysis with conventional histopathology to provide complementary evaluations of the 3D microstructure/compositions of knee cartilage. Findings from this innovative work will provide insight into the potential causal effects of post-injury rehabilitative modifications in limb weight bearing and joint kinematics on PTOA progression. Such new knowledge is fundamental to advancing our understanding of the pathogenesis of PTOA and developing translational research to reduce PTOA by optimizing post-injury rehabilitation.