Combined Regenerative and Rehabilitation Therapies for Extremity Trauma

描述：四肢创伤一直是美国武装部队战斗伤亡的主要原因 近期军事冲突中的成员。这些损伤通常会导致长期的功能障碍、疼痛和 神经功能障碍。该提案将利用四肢创伤的临床前模型并测试新组织 工程疗法与康复方案相结合。拟议研究的总体目标 是建立一个整合再生医学和康复治疗的治疗方案，以增强 严重肢体创伤后肢体功能的恢复。假设是处理大体积 多组织损伤与再生工程策略相结合，改善血运重建 低强度康复方案将增强组织再生、整合和长期功能 结果。 研究计划：我们提出以下目标： 目标 1：利用肌肉构建再生肌肉 用于体积肌损失（VML）损伤的干（卫星）细胞和微血管碎片；目标 2：在 VML 中 单独模型，确定跑步机跑步康复是否能增强治疗后大块肌肉损失的再生 具有肌肉干细胞结构；目标 3：在多组织肢体创伤模型中，评估以下方法的功效 联合跑步机跑步康复和再生疗法对肌肉和骨骼愈合的影响 方法：我们将使用四肢创伤的临床前模型，包括 VML 和多组织骨骼和肌肉 缺陷。目标 1 VML 损伤将通过再生肌肉疗法进行治疗，包括肌肉干细胞或 将在胶原水凝胶或脱细胞肌肉基质中递送的微血管碎片。瞄准 2、基于跑步机的锻炼将用于测试关键康复参数的作用，包括时间安排 移植物整合和功能的启动和强度。在目标 3 中，康复和再生疗法（如 在目标 2 中确定的血运重建效力或肌肉再生效力）将在多方面进行测试 复合骨肌肉损伤的组织损伤模型。结果措施将包括评估 肌肉和肢体结构和功能（目标 1-3）以及骨骼结构和功能（目标 3）。 我们预计拟议的工作将为严重受伤肢体的康复方案带来新的见解 并将通过出版物和我们的临床顾问进行沟通，以影响军事和退伍军人护理。

Description: Extremity trauma has been the predominant cause of combat casualties for U.S. armed forces members in recent military conflicts. These injuries often result in long-term functional disabilities, pain, and neurologic dysfunction. This proposal will utilize preclinical models of extremity trauma and test new tissue engineered therapies in combination with rehabilitation regimens. The overall objective of the proposed study is to establish an integrated regenerative medicine and rehabilitation therapy treatment protocol to enhance restoration of limb function following severe extremity trauma. The hypothesis is that treatment of large volume multi-tissue injuries with regenerative engineering strategies that improve revascularization in combination with low intensity rehabilitation regimens will enhance tissue regeneration, integration, and long term functional outcomes. Research Plan: We propose the following Aims: Aim 1: Engineer regenerative muscle constructs using muscle stem (satellite) cells and microvascular fragments for Volumetric Muscle Loss (VML) injuries; Aim 2: In a VML model alone, determine if treadmill running rehabilitation enhances the regeneration of large muscle loss treated with muscle stem cell constructs; Aim 3: In a multi-tissue extremity trauma model, assess the efficacy of combined treadmill running rehabilitation and regenerative therapies on muscle and bone healing Methods: We will use preclinical models of extremity trauma, including VML and multi-tissue bone and muscle defects. In Aim 1 VML injuries will be treated with regenerative muscle therapies including muscle stem cells or microvascular fragments which will be delivered in collagen hydrogels or decellularized muscle matrices. In Aim 2, treadmill based exercise will be used to test the role of key rehabilitation parameters including timing of initiation and intensity on graft integration and function. In Aim 3, rehabilitation and regenerative therapies (as determined in Aim 2 for re-vascularization potency or muscle regeneration potency) will be tested in a multi- tissue injury model of composite bone and muscle trauma. Outcome measures will include assessments of muscle and limb structure and function (Aim 1-3) and bone structure and function (Aim 3). We anticipate the proposed work will result in new insights on rehabilitation protocols for severely injured limbs and will be communicated through publications and our clinical consultants to impact military and veterans care.