Long-term Sensing in the Brain Using Sub-cellular Edge Electrode Arrays

描述（由申请人提供）：下一代神经探针技术必须使神经科学家能够弥合神经元和神经元池之间的差距，以充分了解大脑的协调“时间动力学”。这将需要在纵向实验中进行高密度、稳定的记录。同样，如果要成功地将研究技术转化为临床领域，下一代脑机接口（BMI）必须提高记录的神经信号的寿命和可靠性。长期信号降解被广泛认为是直接相关的神经探针的存在下，细胞的反应性。 亚细胞边缘电极阵列（或“SEE”探针）被设计为减轻在常规微电极设计中明显的细胞反应性，从而解决记录技术的寿命和稳定性问题。SEE设计概念假设，如果结构特征尺寸小于反应性细胞体（<7 <m），则所产生的细胞包封将通过防止细胞扩散或粘附来减轻。这种仿生概念导致了传统探针柄的设计，该探针柄支撑仅5- 5 m厚的薄聚对二甲苯平台。4周后的组织学结果显示，相对于健康组织，薄聚对二甲苯结构边缘周围的细胞密度仅增加了129%，而传统探针柄周围的细胞密度增加了425%。本研究证明，亚细胞几何形状和适当的电极放置可以减轻组织包囊。自这项开创性的研究以来，SEE设计概念得到了进一步发展。新的初步工作提供了使用聚对二甲苯基板的电稳定性的证据，具有多边边缘几何形状的功能电极阵列，以及在急性准备中记录神经活动的能力。 SEE探头对于使用记录技术的研究工具和临床设备都具有巨大的前景。拟议的第一阶段项目将通过微加工和优化（目标1）展示SEE探针的技术优点，并提供长期的电气验证（目标2）。将在长期动物研究中清楚地证明其科学价值，该研究将使用电生理学、电极阻抗和组织学来比较同一器械上的边缘电极与平面电极（目标3）。NeuroNexus Technologies是微加工、微尺度神经探针的领先供应商，密歇根大学神经工程实验室将合作执行这一重要的科学和转化机会。 公共卫生相关性：所提出的工作的主要目标是开发和验证微电极技术，在改善生物相容性方面表现出很大的希望。这项工作将微制造一种新的仿生设计，“亚细胞边缘电极”阵列，并提供后续的长期动物研究验证。动物研究预计将显示出改善的电生理记录质量、稳定性和寿命。这种微电极技术将使神经科学家和临床医生能够在大脑中实现长期感知，这将大大提高我们对健康大脑功能的理解，并为那些患有神经系统疾病的人提供新的机会，如脊髓损伤，癫痫或ALS。

DESCRIPTION (provided by applicant): Next generation neural probe technology must enable neuroscientists to bridge the gap between neurons and neuronal pools to fully understand the orchestrated 'temporal dynamics' of the brain. This will require high-density, stable recordings in longitudinal experiments. Similarly, next generation brain machine interfaces (BMI) must improve longevity and reliability of the recorded neural signals if translation of the research technology to the clinical realm is to be successful. Long-term signal degradation is widely believed to be directly related to cellular reactivity in the presence of the neural probe. The sub-cellular edge electrode array (or "SEE" probe) was designed to mitigate the cellular reactivity evident in conventional microelectrode designs and thereby address the longevity and stability issues of recording technology. The SEE design concept hypothesized that if a structural feature size is smaller than a reactive cell body (<7 <m), the resulting cellular encapsulation would be mitigated by the prevention of cellular spreading or adhesion. This biomimetic concept resulted in the design of a conventional probe shank supporting a thin parylene platform only 5-5m thick. Histology results after 4 weeks show that cellular density surrounding the edge of the thin parylene structure had only a 129 percent increase relative to healthy tissue, versus a 425 percent increase around a conventional probe shank. This study proved that tissue encapsulation could be mitigated by a sub-cellular geometry and the appropriate electrode placement. Since this ground-breaking study, the SEE design concept has been further developed. New preliminary work has provided evidence of electrical stability using a parylene substrate, functional electrode arrays with a multi-sided edge geometry, and the ability to record neural activity in acute preparations. The SEE probe has tremendous promise for both research tools and clinical devices using recording technology. The proposed Phase I project will show the technical merit of the SEE probe through microfabrication and optimization (Aim 1), and providing long-term electrical validation (Aim 2). The scientific merit will be clearly demonstrated in chronic animal studies, which will use electrophysiology, electrode impedance, and histology to compare the edge electrodes to planar electrodes on the same device (Aim 3). NeuroNexus Technologies, a leading supplier of microfabricated, microscale neural probes, and the University of Michigan's Neural Engineering Laboratory, will collaborate to execute this important scientific and translational opportunity. PUBLIC HEALTH RELEVANCE: The primary objective of the proposed work is to develop and validate a microelectrode technology that has shown great promise in improving biocompatibility. This work will microfabricate a novel biomimetic design, the "sub-cellular edge electrode" array, and provide subsequent long-term validation in animal studies. Animal studies are expected to show improved electrophysiological recording quality, stability, and longevity. Such microelectrode technology will enable neuroscientists and clinicians to achieve long-term sensing in the brain, which would greatly improve our understanding of healthy brain function and offer new opportunities for those suffering from neurological disorders such as spinal cord injury, epilepsy, or ALS.