Multicenter Investigation of the Mechanical Determinants of Post-Traumatic OA

描述（由申请人提供）：拟定研究的目的是证明在多中心临床研究中利用创新方法评估关节内骨折的可行性。这些研究中的一个关键挑战是，我们还不知道什么机械因素最强烈地影响创伤后骨关节炎的发展。我们的目标是扩大我们开发的量化骨折严重程度和术后接触应力挑战（来自残余表面不一致）的客观方法的使用，以提供这方面的知识，从而为关节内骨折患者的未来临床试验奠定基础。这项工作的长期目标是开发新的干预措施，预防创伤后骨关节炎的发生。 创伤后骨关节炎是一种由关节损伤引起的致残性疾病。不幸的是，现有治疗方法的持续改进未能显著降低创伤后骨关节炎的发病率和严重程度。最近的研究表明，急性冲击性关节损伤会引发一系列生物事件，导致进行性关节退行性变，从而导致创伤后骨关节炎。有相当多的证据来自外植体组织和动物研究，即创伤性损伤后不久应用于关节的新分子干预可以减轻或阻止这些不良事件，从而促进关节愈合。这些研究为关节损伤的急性治疗提供了范式转变的希望，但迫切需要对照临床试验来实现这一潜力。持续高能量关节骨折的患者是临床试验的良好候选人，因为损伤被识别并迅速治疗，关注的结果（创伤后骨关节炎）发生相对较快且频繁，并且关节炎变化易于使用标准放射摄影成像。例如，胫骨pilon骨折后，创伤后骨关节炎发生在超过50%的受影响踝关节中，并且在两年内临床上很明显。 在拟议的初步和可行性研究中，将大大扩大使用这些力学指标评价的患者范围（目标1），并将确定骨折严重程度和复位后接触应力预测创伤后骨关节炎的程度（目标2）。胫骨pilon骨折患者将从更广泛的人群基础中招募，通过联邦资助的重大创伤研究联盟（METRC）在不同部位采用不同技术治疗。METRC是美国23个核心民用创伤中心，4个军事治疗设施和38个卫星中心的合作。拟议的研究和这项合作将为未来考虑的生物干预试验提供一个强大的平台，以预防创伤后骨关节炎。 公共卫生相关性：创伤后骨关节炎是一种由关节损伤引起的致残性疾病，最常见于踝关节、膝关节或髋关节骨折后。现有治疗方法的不断改进未能降低创伤后骨关节炎的发病率和严重程度。最近的研究为关节损伤的急性治疗提供了范式转变的希望，但迫切需要通过适当控制混杂变量的临床试验来实现这一潜力。这项研究以及联邦政府资助的重大创伤研究联盟和爱荷华州大学研究翻译中心之间的合作为未来设想的生物干预试验提供了一个平台，以预防这种致残性疾病。

DESCRIPTION (provided by applicant): The objective of the proposed research is to demonstrate the feasibility of utilizing innovative methods for the assessment of intra-articular fractures in multi-center clinical studies. A key challenge in these studies is that we do not yet know what mechanical factors most strongly influence post-traumatic osteoarthritis development. We aim to scale up the use of objective methods that we have developed for quantifying fracture severity and post-operative contact stress challenge (from residual surface incongruity) to provide this knowledge, thereby laying the foundation for future clinical trials in patients with intra-articular fractures. The long-term goal of this work is to develop new interventions that forestall the onset of post-traumatic osteoarthritis. Post-traumatic osteoarthritis is a disabling condition resulting from joint injury. Unfortunately, continued refinement of existing treatment methods has failed to decrease the substantial incidence and severity of post- traumatic osteoarthritis. Recent research indicates that acute-impact joint injuries initiate a sequence of biologic events that cause the progressive joint degeneration that leads to post-traumatic osteoarthritis. There is considerable evidence emerging from explant tissue and animal studies that new molecular interventions applied to the joint soon after traumatic injury can mitigate or arrest these adverse events and thus, promote joint healing. These studies offer hope for a paradigm shift in the acute management of articular joint injury, but controlled clinical trials are desperately needed to realize this potential. Patients who sustain high-energy articular fractures are good candidates for a clinical trial because the injury is identified and treated acutely, the outcome of interest (post-traumatic osteoarthritis) occurs relatively quickly and frequently, and the arthritic changes are readily imaged using standard radiography. For instance, after tibial pilon fractures, post-traumatic osteoarthritis occurs in over fifty percent of affected ankles and is clinically evident within two years. In the proposed pilot and feasibility study the scope of patients evaluated with these mechanical metrics will be expanded considerably (Aim 1), and the extent to which fracture severity and post-reduction contact stress predict post-traumatic osteoarthritis will be determined (Aim 2). Tibial pilon fracture patients will be enrolled from a wider population base, treated with different techniques at different locations, through the federally funded Major Extremity Trauma Research Consortium (METRC). METRC is a collaboration of 23 core civilian trauma centers, 4 military treatment facilities, and 38 satellite centers throughout the United States. The proposed study and this collaboration will provide a strong platform for future contemplated trials of biologic intervention to prevent post-traumatic osteoarthritis. PUBLIC HEALTH RELEVANCE: Post-traumatic osteoarthritis is a disabling condition that results from joint injury, most predictably after fractures of joints such as the ankle, knee, or hip. Continued refinement of existing treatment methods has failed to decrease the substantial incidence and severity of post-traumatic osteoarthritis. Recent research offers hope for a paradigm shift in the acute management of articular joint injury, but clinical trials with appropriate control of confounding variables are desperately needed to realize this potential. This study and the collaboration between the federally funded Major Extremity Trauma Research Consortium and the University Of Iowa Center Of Research Translation provide a platform for future contemplated trials of biologic intervention to prevent this crippling disorder.