Combined Stem Cell and Rehabilitation Therapies for Osteoarthritis

骨关节炎的干细胞与康复疗法相结合

• 批准号: 9350659
• 负责人: Nick J Willett
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350659
• 关键词: Activities of Daily Living; Address; Adult; Affect; Age; Allogenic; Animal Model; Ankle; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Attenuated; Caring; Cartilage; Cell Differentiation process; Clinical; Consultations; Degenerative polyarthritis; Development; Disease; Evaluation; Exercise; Family; Fluoroscopy; Foundations; General Population; Goals; Growth Factor; Guidelines; Health; Healthcare; Hindlimb Suspension; Hip region structure; Histology; Histopathology; Image; Immunohistochemistry; Incidence; Injection of therapeutic agent; Injury; Intervention; Intra-Articular Injections; Joints; Knee; Knee Injuries; Knee Osteoarthritis; Knee joint; Knowledge; Left; Limb structure; Locomotion; Lower Extremity; Mechanical Stimulation; Medial; Medical; Mesenchymal Stem Cells; Methods; Military Personnel; Modeling; Motion; Movement; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pattern; Physical therapy; Population; Pre-Clinical Model; Protocols documentation; Publications; Quality of life; Randomized; Rattus; Recovery of Function; Regenerative Medicine; Regimen; Rehabilitation therapy; Research; Risk; Roentgen Rays; Running; Saline; Shock; Speed; Stem cells; Suspensions; System; Systems Analysis; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Veterans; Work; absorption; articular cartilage; cartilage degradation; contrast enhanced; daily functioning; design; disability; efficacy testing; functional outcomes; high risk; improved; innovation; insight; joint loading; kinematics; male; paracrine; physical therapist; regenerative; regenerative therapy; response; service member; stem cell therapy; successful intervention; survivorship; tomography; treadmill

Description: Osteoarthritis (OA) is a debilitating condition of articular joints. Arthritis is the 3rd most prevalent health problem in the Veterans population affecting 43% of VA system users and veterans are ~36% more likely to be affected by OA as compared to the general population. This proposal will utilize preclinical models of osteoarthritis and test the efficacy of regenerative stem cell therapies in combination with rehabilitation regimens. The overall objective of the proposed study is to examine the progression of cartilage degeneration and changes in functional capacities under contrasting loading conditions with and without the therapeutic benefits of MSCs using a well-established injury/surgery induced knee OA model in rats. Our overall hypothesis is that while reduced joint loading will remain detrimental to cartilage health, an elevated joint load will instead enhance the therapeutic effects of MSCs on attenuating PTOA following traumatic knee injuries. Research Plan: To address the above objective we have developed two aims: Aim 1: {To establish the effects of altered knee loading via non-weight bearing or running on cartilage degeneration, joint kinematics during locomotion, and degree of voluntary activity in rats following a medial meniscal transection (MMT) surgery. Aim 2: To examine how altered knee loading (via non-weight bearing or running) influences the efficacy of MSC treatment on cartilage degeneration, joint kinematics during locomotion, and degree of voluntary activity in rats following MMT.} Methods: The rat MMT-induced OA model will be used for this study. Allogeneic MSCs or saline (control) will be administered via intra-articular injection one day post-surgery to assess the effects on the onset of OA (Aim 1). Rats in both injection groups will then be randomly assigned to the following 3 loading conditions: 1) regular loading, 2) non-weight bearing via hind limb suspension, and 3) daily treadmill running. Rats will be tested and sacrificed at the end of the 8th week post-injury to assess the changes in 3D microstructure and composition in the knee articular cartilage using our previously developed EPIC-µCT and validated with histology. To assess functional capacities rats will be evaluated at pre-surgery and 2, 4, 6, and 8 weeks post-surgery. At each time point, we will assess the level of voluntary activity by quantifying the amount (time and distance) of running on a wheel mounted inside the cage. We will quantify 3D lower limb kinematics (i.e., hip, knee, and ankle angles) during treadmill locomotion using a high-speed X-ray motion analysis system. We anticipate the proposed research will result in new insights on regenerative rehabilitation protocols for veterans with OA and will be communicated through publications and our clinical consultants in order to impact military and Veterans care.

描述：骨关节炎 (OA) 是一种使关节衰弱的关节炎，是第三常见的关节炎。 退伍军人群体的健康问题影响了 43% 的 VA 系统用户，退伍军人的健康问题的可能性要高出约 36% 与一般人群相比，该提案将利用 OA 的临床前模型。 骨关节炎并测试再生干细胞疗法与康复相结合的功效 拟议研究的总体目标是检查软骨退化的进展。 以及在有和没有治疗的情况下对比负荷条件下功能能力的变化 MSCs 在大鼠中使用成熟的损伤/手术诱导膝关节 OA 模型的益处。 假设是，虽然减少关节负荷仍然不利于软骨健康，但关节负荷升高 相反，MSCs 会增强 MSC 对减轻膝关节创伤后 PTOA 的治疗效果。 研究计划：为了实现上述目标，我们制定了两个目标： 目标 1：{确定效果 通过非负重或跑步改变膝盖负荷，软骨退化，关节运动学 内侧半月板横断（MMT）手术后大鼠的运动和自主活动程度。 2：检查改变的膝盖负荷（通过非负重或跑步）如何影响 MSC 的功效 对大鼠软骨退变、运动过程中的关节运动学和随意活动程度的治疗 遵循 MMT。} 方法：本研究将使用大鼠 MMT 诱导的 OA 模型，同种异体 MSC 或生理盐水（对照）。 术后一天通过关节内注射给药，以评估对 OA 发病的影响（目标 1）。 然后将两个注射组的大鼠随机分配至以下 3 种负荷条件：1) 常规 将测试大鼠的负载、2)通过后肢悬挂的非负重以及3)日常跑步机跑步。 在受伤后第 8 周结束时处死，以评估 3D 微观结构和成分的变化 使用我们之前开发的 EPIC-μCT 对膝关节软骨进行评估并进行组织学验证。 将在手术前以及手术后2、4、6和8周时评估大鼠的功能能力。 点上，我们将通过量化跑步量（时间和距离）来评估自愿活动水平 我们将量化 3D 下肢运动学（即臀部、膝盖和脚踝角度）。 在跑步机运动过程中使用高速 X 射线运动分析系统。 我们预计拟议的研究将为再生康复方案带来新的见解 患有 OA 的退伍军人，并将通过出版物和我们的临床顾问进行沟通，以影响 军人和退伍军人的关怀。