Physical and Biological Treatment Strategies to Prevent Post-Traumatic Joint Contracture

预防创伤后关节挛缩的物理和生物治疗策略

• 批准号: 9750078
• 负责人: Spencer Park Lake
• 金额: $ 33.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750078
• 关键词: Affect; Animal Model; Animals; Articular Range of Motion; Biological; Biological Response Modifier Therapy; Biology; Cell Proliferation; Cellularity; Clinical; Collagen; Combined Modality Therapy; Connective Tissue; Contracts; Contracture; Deposition; Dislocations; Dose; Drug usage; Elbow; Elbow Injury; Elbow joint structure; Engineering; Etiology; Evaluation; Exercise; Exhibits; Extracellular Matrix; Fibrosis; Fracture; Functional disorder; Gait; Health Promotion; Human; Hypertension; Hypertrophy; Immobilization; Impairment; Injury; Interdisciplinary Study; Intervention; Joint Dislocation; Joints; Lead; Losartan; Mechanics; Minor; Modeling; Motion; Operative Surgical Procedures; Pain; Pathology; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Physical Rehabilitation; Physical therapy; Predisposition; Prevention; Prevention strategy; Preventive treatment; Production; Pronation; Property; Protocols documentation; Quantitative Evaluations; Rattus; Rehabilitation therapy; Residual state; Severities; Simvastatin; Supination; System; Time; Tissue Preservation; Tissues; Treatment Protocols; Work; capsule; clinically relevant; design; disability; experience; gait symmetry; hypercholesterolemia; innovation; joint function; post-traumatic symptoms; preservation; prevent; reduce symptoms; response; standard care; tool; treadmill; treatment strategy

PROJECT SUMMARY Post-traumatic joint contracture (PTJC) often leads to debilitating impairment following injury, especially in the elbow where even minor injuries can lead to drastic disability. PTJC is a challenging clinical condition that is difficult to reverse, so preventative treatment strategies are urgently needed. Mechanisms governing successful physical therapy are poorly understood; systematic evaluation is needed to determine the potential of physical rehabilitation. Several drugs have demonstrated anti-fibrotic effects in other systems; focused studies are needed to evaluate if biological therapy using these drugs is able to reduce PTJC. Also, the potential synergistic impact of combined physical/biological therapies is unknown. The objective of this study is to utilize a validated animal model of PTJC to investigate physical and biological strategies to preserve mechanics/function (e.g., range of motion and gait patterns) of the elbow joint following injury. SA1: Determine if physical treatments can prevent PTJC and preserve mechanics/function of injured elbows. We will identify whether active motion is successful in reducing PTJC, and determine which governing principles best preserve joint mechanics. Hypothesis: Low-intensity, long-duration physical therapy will be most effective at preserving joint mechanics and function by reducing excessive ECM deposition and tissue fibrosis, while also limiting potential joint wear from high-intensity therapy. SA2: Determine if biological treatments can prevent PTJC and preserve mechanics/function of injured elbows. We will investigate whether the pleiotropic anti- fibrotic effects of simvastatin and losartan can prevent PTJC and identify which treatment protocol best preserves joint mechanics/function. Hypothesis: Both simvastatin and losartan will reduce PTJC severity but a combination of low doses of both drugs will be most effective in preserving joint mechanics and function by reducing the fibrotic response in joint tissues, especially by limiting post-traumatic collagen production. SA3: Determine if synergistic and/or compensatory effects of a combined physical-biological treatment strategy can maintain elbow joint mechanics/function at pre-injury levels. We will investigate the degree to which a well-designed physical therapy protocol (from Aim 1) combined with strategic biological intervention (from Aim 2) can eliminate symptoms of PTJC. Hypothesis: Treatment aimed at both limiting the fibrotic biological response via drug therapy and disrupting fibrosis via physical therapy will be most effective in preserving joint mechanics/function by limiting tissue fibrosis due to synergistic and compensatory benefits of combined therapy. Successful completion of this study will elucidate treatment principles that best prevent contracture and dysfunction after injury via clinically-available physical, biological, and/or combined treatment strategies. Results will be impactful for understanding etiology and pathophysiology in other articulating joints that are susceptible to contracture. This study will leverage an interdisciplinary research team to quantify the mechanical, biological, and functional aspects of PTJC prevention using tools of engineering and biology.

项目概要 创伤后关节挛缩 (PTJC) 通常会导致受伤后的衰弱性损伤，尤其是在 肘部，即使是轻微的伤害也可能导致严重的残疾。 PTJC 是一种具有挑战性的临床病症， 难以逆转，因此迫切需要预防性治疗策略。治理机制 人们对成功的物理治疗知之甚少；需要系统评估来确定潜力 的身体康复。一些药物已在其他系统中表现出抗纤维化作用；专注的 需要进行研究来评估使用这些药物的生物疗法是否能够减少 PTJC。另外， 联合物理/生物疗法的潜在协同影响尚不清楚。本研究的目的是 利用经过验证的 PTJC 动物模型来研究保护 PTJC 的物理和生物学策略 受伤后肘关节的力学/功能（例如运动范围和步态模式）。 SA1：确定 物理治疗是否可以预防 PTJC 并保留受伤肘部的力学/功能。我们将 确定主动运动是否能成功减少 PTJC，并确定哪些控制原则最好 保持关节力学。假设：低强度、长时间的物理治疗最有效 通过减少过度的 ECM 沉积和组织纤维化来保持关节力学和功能，同时还 限制高强度治疗造成的潜在关节磨损。 SA2：确定生物治疗是否可以预防 PTJC 并保留受伤肘部的力学/功能。我们将研究多效性抗 辛伐他汀和氯沙坦的纤维化作用可以预防 PTJC 并确定哪种治疗方案最好 保留关节力学/功能。假设：辛伐他汀和氯沙坦都会降低 PTJC 的严重程度，但 两种药物的低剂量组合对于保持关节力学和功能最有效 减少关节组织的纤维化反应，特别是通过限制创伤后胶原蛋白的产生。 SA3： 确定物理-生物联合治疗是否具有协同和/或补偿作用 策略可以将肘关节力学/功能维持在受伤前的水平。我们将调查学位 精心设计的物理治疗方案（来自目标 1）与战略性生物干预相结合 （来自目标 2）可以消除 PTJC 的症状。假设：治疗旨在限制纤维化 通过药物治疗的生物反应和通过物理治疗破坏纤维化将是最有效的 通过限制组织纤维化来保持关节力学/功能，这是由于协同和代偿的好处 联合治疗。这项研究的成功完成将阐明最好预防的治疗原则 通过临床上可用的物理、生物和/或综合治疗，损伤后出现挛缩和功能障碍 策略。结果将对理解其他关节的病因学和病理生理学产生影响 那些容易发生挛缩的人。这项研究将利用跨学科研究团队来量化 使用工程和生物学工具预防 PTJC 的机械、生物学和功能方面。