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Guidance of Functional Peripheral Axon Subtypes Using Molecular Cues

机译：使用分子线索指导功能性外周轴突亚型

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摘要

There are approximately 1.9 million amputees in the USA, and approximately 185,000 new amputations occur every year. Recent progress in robotic limbs provides the possibility of interfacing with the peripheral nerve to replicate natural sensory and motor functions of the human hand. While robotic prosthesis has advanced significantly, providing up to 22 degrees of freedom equipped with multiple sensors for position, temperature, and pressure, eliciting naturalistic sensation has yet to be achieved. Electrodes interfaced at the somatic peripheral nerves are intended to decode motor intent and elicit sensation through selective stimulation of sensory axons. However, current peripheral nerve interfacing technology elicits unnatural sensations through fascicular stimulation of mixed modality axon bundles. In addition, recording motor intent is more difficult due to the sparse arrangement of motor neurons. Therefore, peripheral nerve interfacing technology that selectively records motor activity and elicits naturalistic sensory percepts remains a challenge. This dissertation takes a unique approach to this problem by evaluating the use of molecular cues to selectively guide regenerating motor and sensory axons into Y-shaped conduits to modulate the sensory to motor ratio of regenerative neural interfaces.;In Chapter 2 we tested the efficacy of single neurotrophic factors (NTFs) in modulating the sensory/motor axon ratio in using a Y-shaped nerve conduit. The functionality of the regenerated segments was confirmed by evoked compound nerve action potentials in 97% of the nerve fascicles. Retrograde labeling of ventral motor neurons showed that glial derived neurotrophic (GDNF) induced a 3-fold increase in motor neurons compared to bovine serum albumin (BSA) compartment, while sensory neuron regeneration showed no difference. The sensory/motor ratio however was not significantly altered by single molecular attractants.;In Chapter 3 we evaluated the response of regenerating axons using motor axon guidance molecules brain--derived neurotrophic factor (BDNF)/GDNF in one compartment and sensory axon attractants nerve growth factor (NGF) or pleiotrophin (PTN) in the adjacent arm. The combination of BDNF/GDNF versus PTN showed a significant (p< 0.05) change in the sensory/motor axon ratio between the nerve fascicles. In Chapter 4 we evaluated the effectiveness of Semaphorin3A, a nociceptive sensory axons molecular repellent, in combination with BDNF, an attractant for mechanoreceptors, in one regenerative chamber compared to an adjacent one containing NGF, an attractant for nociceptive axons. Sema3A significantly reduced the number of small myelinated axons compared to the BDNF only compartment, but also affected the NGF chamber, indicating cross-diffusion of the repellent to the other arm. In summary, this body of work supports the notion that molecular attractant cues are able to influence the regeneration of functional sensory/motor axons in nerve fascicles using a Y-conduit in vivo, in a nerve amputee model. Furthermore, chemorepellent molecules were shown to induce an inhibitory effect on small myelinated axons for the first time in a peripheral nerve regeneration paradigm. Together, this work contributes to establish the feasibility of molecularly guided regenerative peripheral neural interfaces, and to define the potential of this technology towards achieving intuitive motor control and conveying natural feel to amputee users of advanced bionic limbs.
机译：美国大约有190万被截肢者，每年大约有185,000例新截肢。机器人肢体的最新进展提供了与周围神经交界以复制人手自然的感觉和运动功能的可能性。尽管机器人假肢取得了长足的进步，但它提供了多达22个自由度，并配备了多个位置，温度和压力传感器，因此尚未引起自然的感觉。连接在体周神经上的电极旨在通过选择性刺激感觉轴突来解码运动意图并引起感觉。然而，当前的周围神经接口技术通过束缚混合形态轴突束的束缚刺激引起不自然的感觉。另外，由于运动神经元的稀疏排列，记录运动意图更加困难。因此，选择性地记录运动活动并引起自然的感觉感知的外周神经接口技术仍然是一个挑战。本论文通过评估分子线索的使用，以选择性地将再生运动轴突和感觉轴突引导到Y形导管中，以调节再生神经界面的感觉与运动比，从而采取了独特的方法。在第二章中，我们测试了单个神经营养因子（NTF）在使用Y形神经导管调节感觉/运动轴突比率中的作用。在97％的神经束中诱发了复合神经动作电位，从而证实了再生节段的功能。腹侧运动神经元的逆行标记显示，与牛血清白蛋白（BSA）区室相比，胶质细胞源性神经营养（GDNF）诱导运动神经元增加了3倍，而感觉神经元再生没有差异。然而，感觉/运动比并没有被单分子引诱剂显着改变。在第3章中，我们评估了运动轴突引导分子在一个区室中脑源性神经营养因子（BDNF）/ GDNF和感觉轴突引诱神经对再生轴突的响应。相邻臂中的生长因子（NGF）或多效蛋白（PTN）。 BDNF / GDNF与PTN的组合显示神经束之间的感觉/运动轴突比率有显着（p <0.05）变化。在第四章中，我们评估了Semaphorin3A（一种伤害性感觉轴突分子驱避剂）与BDNF（一种机械感受器引诱剂）的组合在一个再生室中的有效性，而相邻的隔室中含有NGF（一种伤害性轴突的诱剂）。与仅BDNF隔室相比，Sema3A显着减少了小髓鞘轴突的数量，但也影响了NGF腔，表明驱虫剂交叉扩散到另一只手臂。总之，这项工作支持以下观点：在神经截肢模型中，使用Y导管在体内，分子引诱剂线索能够影响神经束中功能性感觉/运动轴突的再生。此外，化学驱除剂分子在外周神经再生范例中首次显示出对小的髓鞘轴突的抑制作用。在一起，这项工作有助于建立分子引导的再生外周神经接口的可行性，并确定该技术在实现直观的运动控制和向高级仿生肢体的截肢者传达自然感觉方面的潜力。

著录项

  • 作者

    Anand, Sanjay.;

  • 作者单位

    The University of Texas at Dallas.;

  • 授予单位 The University of Texas at Dallas.;
  • 学科 Biomedical engineering.;Neurosciences.
  • 学位 Ph.D.
  • 年度 2017
  • 页码 145 p.
  • 总页数 145
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 康复医学;
  • 关键词

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