Development and Validation of a Rodent FES Bicycle System

骨丢失是严重脊髓损伤（SCI）的标志，它增加了骨折的风险，并导致脊髓损伤。 发生可加重死亡风险的医学合并症。SCI后发生的骨缺损是 由中枢神经系统（CNS）损伤和随后的肌肉骨骼卸载引起， 导致强调基于活动的物理治疗（ABPT）模式， 恢复骨骼的完整性。将ABPT与电刺激结合的策略[例如，功能性电 刺激（FES）自行车]是有趣的，因为他们改善受损肢体的肌肉恢复， 刺激肌肉进行特定任务的锻炼，并可能促进感觉运动的恢复， 留下的脊髓束然而，FES循环恢复骨密度（BMD）的能力， SCI后瘫痪的肢体仍然存在争议，特别是在股骨远端和胫骨近端部位， 最容易骨折。这些数据表明，需要优化FES参数的骨修复。的目标 该建议是开发和操作第一个用于大鼠的“人性化”FES自行车系统。我们将 然后使用我们的系统在未来的建议，以优化FES参数，骨恢复在一个'高通量' 的方式，使用我们的大鼠严重SCI模型，表现出类似的肌肉骨骼病理生理学的人， 严重创伤性脊髓损伤为了实现我们的目标，我们提出了一种新的高风险/高回报的方法， 反向翻译人类FES自行车的设计以开发用于大鼠的FES系统，其包括：1）大鼠 一种允许在曲柄轴上以可变阻力进行FES定向和机动脚踏的自行车 2）传感器，其记录踏板位置、扭矩、速度并提供关于这些的实时反馈 踏板参数到FES控制系统和记录肢体运动的摄像机，以及3）闭环 切换控制系统，精确地调节FES之间的踏板，在肌肉 有助于踏板，和电动机耦合到自行车曲轴，启动在FES "死 肌肉活动几乎不提供踩踏贡献的区域。我们的方法是创新的，因为如果 成功的，它将提供一个具有成本效益和时间效率的手段，以优化临床前FES参数， 骨修复，然后可以快速跟踪到临床试验，这将有助于开发个性化的 脊髓损伤退伍军人的康复策略。为了确保我们的成功，我们采取了关键步骤，包括：1） 构建一个机动（被动）大鼠自行车，作为我们的混合FES定向/ 电动自行车，2）开发一个闭环开关控制系统的人类FES周期，作为一个 我们的控制系统的模型，和3）表征我们的大鼠严重的运动，骨骼和肌肉缺陷 挫伤SCI模型，我们将使用它来测试和验证FES自行车。此外，我们已经证明， 电动（被动/等速）自行车使反射兴奋性正常化，并促进运动和骨骼 恢复（初步数据）在SCI大鼠，提供了理论基础的自行车作为基础ABPT模式，在我们的研究中， 提议虽然这些组成部分已经到位，但我们的建议仍然是高风险/高收益的，因为成功 需要我们修改现有的老鼠自行车，如上所述;我们设计，制造，建模， 优化一个闭环开关控制系统，精确地调节大鼠的踩踏节奏; 在我们的大鼠SCI模型中探索对重复FES循环发作的初始耐受性。根据我们的发现，系统 还可能需要改进和重新测试。为了解决这些问题，我们有两个目标： 目的1：设计并制作一个老鼠自行车和一个闭环切换控制系统， FES直接和机动控制的曲柄轴产生连续的踏板。 目的2：在严重SCI大鼠中操作、验证和测试我们的FES自行车系统。

Bone loss is a hallmark of severe spinal cord injury (SCI) that increases risk of fracture and contributes to the development of medical comorbidities that worsen mortality risk. The bone deficits occurring after SCI are precipitated by the central nervous system (CNS) insult and the subsequent musculoskeletal unloading, which has resulted in an emphasis on activity-based physical therapy (ABPT) modalities that reload the impaired limbs to restore bone integrity. Strategies that couple ABPT with electrical stimulation [e.g., functional electrical stimulation (FES) cycling] are intriguing because they improve muscle recovery in the impaired limbs by stimulating muscles to perform task-specific exercise and may promote sensorimotor recovery in the presence of some spared spinal tracts. However, the ability of FES cycling to restore bone mineral density (BMD) in the paralyzed limbs remains contentious after SCI, especially at the distal femur and proximal tibia sites that are most prone to fracture. These data indicate need to optimize FES parameters for bone restoration. The goal of this proposal is to develop and operationalize the first-ever ‘humanized’ FES bicycle system for rats. We will then use our system in future proposals to optimize FES parameters for bone recovery in a ‘high-throughput’ manner, using our rat severe SCI model that exhibits similar musculoskeletal pathophysiology to persons with severe traumatic SCI. To achieve our goal, we propose a novel high-risk / high-reward approach that will reverse-translate the design of a human FES bicycle to develop a FES system for rats consisting of 1) a rat bicycle that allows both FES directed and motorized pedaling on a crank shaft with modifiable resistance levels, 2) sensors that record pedal locations, torque, velocity and that provide real-time feedback on these pedaling parameters to a FES control system and a camera that records limb motions, and 3) a closed-loop switched control system that accurately regulates pedaling between FES, in positions where muscles contribute to pedaling, and an electrical motor coupled to the bicycle crank shaft that initiates in FES “dead zones” where muscle activity provides little pedaling contribution. Our approach is innovative because, if successful, it will provide a cost-effective and time-efficient means to optimize preclinical FES parameters for bone restoration, which can then be fast-tracked to clinical trials that will assist in developing personalized rehabilitation strategies for Veterans with SCI. To ensure our success, we have taken key steps, including: 1) constructing a motorized (passive) rat bicycle that serves as the platform for our hybrid FES directed / motorized cycle, 2) developing a closed-loop switched control system for human FES cycles that serves as a model for our control system, and 3) characterizing the locomotor, bone, and muscle deficits in our rat severe contusion SCI model, which we will use to test and validate the FES bicycle. Moreover, we have demonstrated that motorized (passive / isokinetic) cycling normalized reflex excitability and promoted locomotor and bone recovery (Preliminary Data) in SCI rats, providing rationale for cycling as the base ABPT modality in our proposal. While these components are in-place, our proposal remains high-risk / high-gain because success requires that we modify our existing rat bicycle, as described above; that we design, fabricate, model, and optimize a closed-loop switched control system that accurately regulates pedaling cadence in rats; and that we explore initial tolerability to repeated FES cycling bouts in our rat SCI model. Based on our findings, system refinement and re-testing may also be required. To address these steps, we have two Aims: Aim 1: Design and fabricate a rat bicycle and a closed-loop switched control system that alternates FES directed and motorized control of the crank shaft to produce continuous pedaling. Aim 2: Operationalize, validate, and test our FES bicycle system in rats with severe SCI.