Engineering Skeletal Muscle WIth Biodegradable Hydrogels

在创伤或癌症切除后的重建手术中通常需要骨骼肌组织， 申请者研究的长期目标是再生具有功能的头面部骨骼肌。这个 在组织工程中，直接机械刺激受损肌肉组织的作用在很大程度上被忽视了 以及迄今为止的再生医学努力，尽管肌肉具有明显的机械作用和响应性。 我们最近证明，周期性机械压迫显著增强肌肉。 再生导致严重损伤后快速恢复的小鼠联合直接肌肉模型 损伤和缺血。虽然这些效应背后的机制(S)尚不清楚，但 对再生的机械刺激与肌肉中免疫细胞渗透的变化相关； 此外，直接操纵损伤部位的局部免疫细胞活动可以增强肌肉的功能 再生。指导这一应用的具体假设是，通过一个 软机器人装置通过改变损伤部位的免疫细胞库来增强肌肉再生。 这一假说的目的如下：1.优化机械刺激的机制 通过开发一种新的软机器人系统应用于受伤的肌肉，这种系统允许人们同时 同时控制刺激的幅度、频率和持续时间，同时治疗多只动物。 2.描述机械驱动更新背后的机制(S)，重点是 受损组织中的免疫细胞。3.在没有机械性的情况下，重建类似的免疫细胞活性图谱 刺激，并研究对肌肉再生的影响。这些目标的成功实现将导致 损伤肌肉组织再生和恢复功能的新策略。这项工作将会有 与颅面重建手术密切相关，也适用于肌肉的再生 遍及全身。从更广泛的意义上讲，这项提案中探讨的概念可能是广义的 适用于体内其他组织和器官。

Skeletal muscle tissue is often required in reconstructive surgery following trauma or resection due to cancer, and the long-term goal of the applicants' research is to regenerate functional craniofacial skeletal muscle. The role of direct mechanical stimulation of damaged muscle tissue has largely been ignored in tissue engineering and regenerative medicine efforts to date, in spite of the clear mechanical role and responsiveness of muscle. We have recently demonstrated that cyclic mechanical compression dramatically enhances muscle regeneration, leading to rapid recovery following serious injury in a mouse model of combined direct muscle injury and ischemia. While the mechanism(s) underlying these effects remain unclear, the impact of mechanical stimulation on regeneration correlates to alterations in immune cell infiltration of the muscle; further, direct manipulation of local immune cell activity at the injury site enhances functional muscle regeneration. The specific hypothesis guiding this application is that cyclic mechanical strain imposed via a soft robotic device enhances muscle regeneration via alteration of the immune cell repertoire at the injury site. The hypothesis will be addressed with the following aims: 1. Optimize the regime of mechanical stimulation applied to injured muscle via the development of a new soft robotic system that allows one to simultaneously treat multiple animals in parallel with control over the amplitude, frequency, and duration of stimulation. 2. Delineate the mechanism(s) underlying the mechanically-driven regeneration, focusing on the role of immune cells in the damaged tissue. 3. Reconstitute a similar profile of immune cell activity without mechanical stimulation, and study the impact on muscle regeneration. The successful completion of these aims will lead to a new strategy for the regeneration and return to function of damaged muscle tissue. This work will have significant relevance in craniofacial reconstructive surgery, and also apply to the regeneration of muscle throughout the body. In a broader sense, the concepts explored in this proposal are likely to be broadly applicable to other tissues and organs in the body.