Mechanobiological Risk Factors for Initiation of Post Traumatic Osteoarthritis

引发创伤后骨关节炎的机械生物学危险因素

• 批准号: 9207734
• 负责人: Suzanne A. Maher
• 金额: $ 41.05万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207734
• 关键词: Activities of Daily Living; Address; Affect; Algorithms; Anterior Cruciate Ligament; Back; Biological; Biological Markers; Bioreactors; Cartilage; Chondrocytes; Chronic; Clinical; Computer Simulation; Custom; Data; Degenerative polyarthritis; Development; Disease; Effectiveness; Enzymes; Experimental Models; Extracellular Matrix; Femur; Gait; Goals; Health; In Situ; In Vitro; Injury; Joints; Knee; Knee joint; Knowledge; Lead; Ligaments; Link; Liquid substance; Location; Maps; Measurement; Mechanics; Medial; Meniscus structure of joint; Modeling; Monitor; Nature; Operative Surgical Procedures; Organ; Patients; Pattern; Peptide Initiation Factors; Risk; Risk Factors; Series; Solid; Specificity; Statistical Data Interpretation; Stimulus; Stress; Surface; Synovial Membrane; Testing; Walking; anterior cruciate ligament rupture; articular cartilage; base; bone; cartilage degradation; design; experimental study; high risk; in vitro Model; in vivo; injured; joint stress; kinematics; ligament injury; mechanical load; mechanical properties; public health relevance; response; tibia; tissue culture

 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.

 描述(申请人提供)：创伤后骨关节炎(PTOA)是一种器官水平的疾病，软骨、骨、滑膜和半月板都会受到影响。PTOA发展的一个常见先兆是关节稳定韧带的损伤，最重要的是膝关节的前十字韧带(ACL)。越来越多的证据表明，前交叉韧带损伤会导致膝关节运动学的改变，特别是日常生活活动中股骨和胫骨之间接触位置的细微变化。虽然变化的幅度因患者而异，但即使是最细微的股骨-胫骨接触位置的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部应力)发生实质性变化。有人认为这种改变与软骨退变的发生和发展有关，但确切的关系尚不清楚。我们的目标是确定在前交叉韧带损伤的膝关节关节软骨中引起类骨关节炎生物反应的特定力学变化--即确定膝关节骨性关节炎的“机械生物学标志物”。我们假设，与膝关节其他部位的“膝关节依赖”随机应力模式不同，“非膝关节”常见应力模式的改变将导致类似于骨性关节炎的生物反应。为了验证这一假设，我们将扩展之前开发的膝关节接触应力实验模型，并使用整个关节的3D计算模型对其进行扩充，以确定关节软骨内有和没有前交叉韧带的“独立于膝关节的”常见内应力模式。定制设计的生物反应器将被用来确定哪些内部应力模式改变会在细胞外基质ECM内产生类似骨关节炎的软骨细胞分解代谢反应。产生统计学上显著的负面生物反应的变化将被归类为“ACL-PTOA机械生物学标志物”，并用于将关节应力图转换为绘制“PTOA启动可能性”的图。如果我们的假设是正确的，那么干预这种疾病的模式将会改变。任何治疗或手术干预的目标将不再仅仅是恢复关节的稳定性，而是缓解这项研究中确定的特定的高危应激模式。从长远来看，这一知识将使MOE能够全面分析每个患者发生PTOA的风险，并允许更适当地评估手术干预的好处。