Combined Regenerative and Rehabilitation Therapies for Extremity Trauma

描述：四肢创伤一直是美军战斗伤亡的主要原因 最近军事冲突中的成员。这些损伤通常会导致长期的功能残疾、疼痛和 神经功能障碍。这项提议将利用肢体创伤的临床前模型，并测试新的组织 与康复疗法相结合的工程疗法。拟议研究的总体目标 是建立综合再生医学和康复治疗的治疗方案，以加强 严重肢体创伤后肢体功能的恢复。假设是大容量的治疗 多组织损伤与再生工程策略相结合改善血运重建 低强度康复疗法将增强组织再生、整合和长期功能 结果。 研究计划：我们提出以下目标：目标1：利用肌肉设计再生肌肉结构 干细胞(卫星细胞)和微血管碎片用于容积性肌肉丧失(VML)损伤；目标2：VML 单独建立模型，确定跑步机运动康复是否增强治疗后大面积肌肉损失的再生 目标3：在多组织肢体创伤模型中，评估 综合跑步机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和多组织骨和肌肉 缺陷。在AIM 1中，VML损伤将使用再生肌肉疗法治疗，包括肌肉干细胞或 微血管碎片将以胶原水凝胶或脱细胞肌肉基质的形式输送。在AIM 2、将使用基于跑步机的锻炼来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(AS 在目标2中确定的血管再形成能力或肌肉再生能力)将在多个 复合性骨和肌肉损伤的组织损伤模型。成果衡量标准将包括评估 肌肉和肢体结构和功能(目标1-3)和骨骼结构和功能(目标3)。 我们期待拟议的工作将对严重受伤肢体的康复方案产生新的见解。 并将通过出版物和我们的临床顾问进行传播，以影响军队和退伍军人的护理。

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.