Multimodal wireless electrical stimulation for tissue regeneration

项目摘要 两千万美国人患有周围神经损伤，导致大约 美国每年的医疗保健费用为1500亿美元。大约一半的患者接受了治疗 神经移植物的功能不充分。两千万美国人患有外周疾病 神经损伤，导致美国每年约1500亿美元的医疗费用 各州。在众多因素中，轴突生长速度和缺乏再神经和神经肌肉 再生是两个主要的道路障碍。在许多情况下，在外周再生期间，肌肉 经历萎缩，变得不能接受再神经支配，甚至是萌芽中的轴突 跨越缝隙的再生不能形成功能性神经肌肉连接(NMJ)。虽然大多数人 以前的研究集中在加速周围神经生长，保持周围神经生长的新方法 神经肌肉的感受性和延缓肌肉的退变需要发展和整合。 因此，一种促进轴突生长与预防相结合的综合方法 需要肌肉退行性变来解决这一未得到满足的医疗需求，我们建议使用 多模式电刺激(ES)以实现这一目标。我们最近的研究表明，重复性 无论是在切断神经的近端还是远端，ES都比一次性ES更有效 为了进一步改善治疗结果，但它们对治疗的相对贡献和联合作用 在轴突生长方面，肌肉萎缩和神经再支配的减慢仍有待研究。 因此，为了研究近端和远端ES的潜在协同效应，我们假设 在坐骨神经横断损伤后，在近端和远端的可编程ES 可分别促进轴突生长和维持肌肉感受性，并协同神经肌肉 再生。我们将通过开发一种无线的、可伸展的、可生物吸收的和 允许使用多种协议的重复ES的小型化系统。为了解决上述问题， 挑战和验证我们的假设，我们组建了一个多学科团队，并进行了试点 研究论证了这一可行性。我们提出了三个具体目标：(1)发展和 一种可生物吸收、可伸展和无线的重复电生物电子设备的特征 刺激。(2)确定重复的近端和远端ES的时间周期如何调节肌肉 功能恢复。(3)探讨近端和远端ES对神经肌肉的联合作用。 再生。这一提议的项目与再生工程的最新进展相得益彰， 微/纳米技术、小型化无线医疗设备，以及可生物吸收和可伸展 电极。这一创新的生物电子设备提供了一种新颖的微创方法 神经肌肉再生，并将在再生医学和治疗中有广泛的应用。

Project Summary Twenty million Americans suffer from peripheral nerve injury, which results in approximately $150 billion health-care expenses annually in the United States. Approximately half of patients treated with nerve grafts have an inadequate level of function. Twenty million Americans suffer from peripheral nerve injury, which results in approximately $150 billion health-care expenses annually in the United States. Among various factors, axon growth rate and the lack of reinnervation and neuromuscular regeneration are two major road barriers. In many cases, during peripheral regeneration, the muscle undergoes atrophy and becomes un-receptive to reinnervation, and even the sprouting axons that regenerate across the gap cannot form functional neuromuscular junctions (NMJs). While most of the previous studies focus on accelerating peripheral nerve growth, novel approaches to maintain the neuromuscular receptivity and delay the degeneration of muscle need to be developed and integrated. Therefore, an integrative approach that combines the acceleration of axon growth and the prevention of muscle degeneration is required to address this unmet medical need, and we propose to use multimodal electrical stimulation (ES) to achieve this goal. Our recent studies have shown that repetitive ES either at the proximal or distal stumps of transected nerve can be more effective than one-time ES to further improve the therapeutic outcome, but their relative contributions to and their combined effects on axon growth, the slow-down of muscle atrophy and reinnervation remain to be investigated. Therefore, to investigate the potential synergistic effects of proximal and distal ES, we hypothesize that programmable ES at the proximal and distal stumps of sciatic nerve following a transection injury can promote axon growth and maintain muscle receptivity respectively and synergize neuromuscular regeneration. We will test this hypothesis by developing a wireless, stretchable, bioresorbable and miniaturized system that allows repetitive ES with versatile protocols. To address the aforementioned challenges and test our hypothesis, we have assembled a multidisciplinary team, and performed pilot studies to demonstrate the feasibility. We propose three Specific Aims: (1) To develop and characterize a bioresorbable, stretchable and wireless bioelectronic device for repetitive electrical stimulation. (2) To determine how the time periods of repetitive proximal and distal ES regulate muscle functional recovery. (3) To investigate the combined effects of proximal and distal ES on neuromuscular regeneration. This proposed project is timely with the recent advancement in regenerative engineering, micro/nanotechnologies, miniaturized wireless point-of-care devices, and bioresorbable and stretchable electrodes. This innovative bioelectronic device provides a novel and minimally invasive approach for neuromuscular regeneration, and will have wide applications in regenerative medicine and therapy.