Development and Validation of a Rodent FES Bicycle System

啮齿动物 FES 自行车系统的开发和验证

• 批准号: 10554098
• 负责人: Joshua F. Yarrow
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554098
• 关键词: Activities of Daily Living; Address; Algorithms; Bicycling; Body Composition; Bone Density; Central Nervous System; Clinical Trials; Coupled; Data; Development; Distal; Electric Stimulation; Electrodes; Eligibility Determination; Ensure; Event; Exercise; Exhibits; Feedback; Femur; Fracture; Frequencies; Functional disorder; Future; Goals; Health Expenditures; Healthcare Systems; Hospitalization; Human; Hybrids; Impairment; Incidence; Individual; Isotonic Exercise; Legal patent; Limb structure; Location; Maps; Medial; Medical; Minor; Modality; Modeling; Motion; Motor; Muscle; Musculoskeletal; Outcome; Paralysed; Persons; Physical Rehabilitation; Physical therapy; Physiologic pulse; Population; Positioning Attribute; Rattus; Records; Recovery; Reflex action; Regimen; Reporting; Resistance; Risk; Rodent; Site; Spinal Cord Contusions; Spinal cord injury; System; Testing; Time; Torque; Training; Translating; Urinary tract infection; Validation; Venous; Veterans; Width; base; bone; bone loss; cohort; comorbidity; cost effective; decubitus ulcer; design; fracture risk; functional electrical stimulation; high reward; high risk; improved; innovation; mortality risk; motor control; novel; pharmacologic; pre-clinical; prevent; primary outcome; rehabilitation strategy; respiratory; response; restoration; sensor; skeletal; spinal tract; spontaneous pain; success; tibia

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.

骨丢失是严重脊髓损伤(SCI)的一个特征，它增加了骨折的风险，并导致 导致死亡风险恶化的医疗合并症的发展。脊髓损伤后出现的骨缺陷是 由中枢神经系统(CNS)侮辱和随后的肌肉骨骼卸载引发， 导致强调以活动为基础的物理治疗(ABPT)模式，以重新加载受损的人 四肢恢复骨骼的完整性。将ABPT与电刺激[例如，功能性电刺激]相结合的策略 刺激(FES)骑自行车很有趣，因为它们通过以下方式改善受损肢体的肌肉恢复 刺激肌肉进行特定任务的运动，可能会促进感觉运动的恢复 一些备用的脊髓束。然而，FES循环恢复骨密度(BMD)的能力 脊髓损伤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，这些部位是 最容易骨折。这些数据表明需要优化FES参数以进行骨修复。的目标是 这项提议是为老鼠开发并运行第一个人性化的FES自行车系统。我们会 然后在未来的提案中使用我们的系统来优化FES参数，以实现高通量的骨回收 使用我们的大鼠严重脊髓损伤模型，其肌肉骨骼病理生理学与 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，它将 反向翻译人类FES自行车的设计，为由1)只大鼠组成的大鼠开发FES系统 允许FES在曲轴上定向和电动踏板的自行车，阻力可调 水平，2)传感器，记录踏板位置、扭矩、速度，并提供实时反馈 FES控制系统和记录肢体运动的摄像机的踏板参数，以及3)闭环系统 切换控制系统，精确地调节FE之间的踏板，在肌肉 有助于踏板，和一个电动马达耦合到自行车曲轴，启动在FES“死” 肌肉活动对踏板的贡献很小的区域。我们的方法是创新的，因为如果 如果成功，它将提供一种经济有效且省时的方法来优化临床前的FES参数 骨修复，然后可以快速进入临床试验，帮助开发个性化 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) 建造一辆电动(被动)老鼠自行车，作为我们的混合动力FES的平台 摩托车，2)开发一种用于人类FES自行车的闭环开关控制系统，作为 我们控制系统的模型，以及3)描述我们的大鼠严重的运动、骨骼和肌肉缺陷 挫伤脊髓损伤模型，我们将使用该模型来测试和验证FES自行车。此外，我们还展示了 机动化(被动/等速)自行车使反射兴奋性正常化，并促进运动和骨骼 在脊髓损伤大鼠中的恢复(初步数据)，为骑自行车作为我们的基础ABPT模式提供了理论基础 求婚。虽然这些组件已经到位，但我们的计划仍然是高风险/高收益，因为成功 要求我们修改现有的老鼠自行车，如上所述；我们设计、制造、建模和 优化闭环系统开关控制系统，准确地调节大鼠的踏板节奏；我们 在我们的大鼠脊髓损伤模型中探索对重复的FES自行车比赛的初步耐受性。根据我们的发现，系统 可能还需要改进和重新测试。为了应对这些步骤，我们有两个目标： 目标1：设计和制造一种大鼠自行车和一种交替的闭环系统开关控制系统 FES直接和电动控制曲轴，以产生连续的踏板。 目的2：在严重脊髓损伤的大鼠身上操作、验证和测试我们的FES自行车系统。