新型复合纳米结构及器件用于细胞膜电位检测

Nanoscale materials, structures and devices have gained enormous interests in biomedical applications recently. With the ability of large-scale, high-density array integration, nanoscale transmembrane potential detection and recording devices could have a profound impact on both fundamental neuroscience research and clinical practice of psychological diseases. In this work, we will design novel nanoscale intra- and extra-cellular transmembrane potential detection devices based on complex nanostructures, such as nanowire/nanotube, graphene nanoribbon/nanotube, backbone nanowire/branched nanowires. We will develop well-controlled, high-yield fabrication schemes for these nanoscale detection devices, and realize the fabrication of large-scale, high-density device arrays. Then we will study their electrical behavior, such as sensitivity for solution potential detection, noise level and their detection bandwidth etc., in order to further optimize their electrical performance. By using chemical modification on these nanoscale detection devices, we will control the interfacing between these devices and the living cells, such as to realize the biomimetic, spontaneous cell membrane penetration by the intracellular recording devices. In the end, we will perform both intra- and extra-cellular recording of transmembrane potential and action potential with these newly developed nanoscale devices from cardiomyocytes and neurons, and demonstrate the multi-site recording capability from difference length scales, such as from different sites in a single cell, or from different sites in a large cell network. We believe the nanoscale size and high sensitivity, high bandwidth of these devices will represent recording of minimal invasiveness, high signal-to-noise ratio, high temporal and spatial resolution, long-term stability. And the capability of making devices array will facilitate large-scale, high spatial resolution multi-site recording, which is critical to many electrophysiological studies.

纳米材料、结构和器件近年来在生物医学研究领域获得了越来越多的应用，发展纳米级小尺寸，并且能大规模、高密度阵列化的新型细胞膜电位检测器件，对推动神经科学基础研究、神经系统相关疾病的理解和治疗有重要意义。本项目将设计基于复合纳米结构，如 纳米线/纳米管、石墨烯纳米带/纳米管、主干纳米线/支叉纳米线等的新型膜电位胞内胞外检测器件，建立复合纳米结构和检测器件的可控高效制备方法，以获得纳米级检测器件的大面积、高密度阵列。对器件的电学行为，如溶液电位检测的灵敏度、噪音水平、检测带宽等进行研究，对器件的电学性质进行优化。通过器件表面的化学修饰，对器件/细胞之间的界面相互作用和界面性质进行调控，例如实现胞内检测器件对细胞膜的自发仿生穿透，实现对心肌细胞和神经细胞膜电位和动作电位的高信噪比、高时间空间分辨率、低干扰、长期稳定的记录和检测，以及大规模、高密度的多位点平行检测。

发展纳米级小尺寸，并且能大规模、高密度阵列化集成的新型电极或探针，以实现对神经细胞胞内和胞外膜电位和动作电位的高时间空间分辨、低干扰记录，对推动神经科学基础研究、脑机接口应用、以及神经系统相关疾病的理解和治疗都有重要意义。传统基于玻璃微管的膜片钳膜电位测量技术具有很高的时间空间分辨率，但存在探针尺寸偏大、难以阵列化多位点平行测量的缺点。本项目1）通过使用场效应晶体管信号转导和纳米线/纳米管三维异质支叉结构，成功制备了亚10 nm尺寸的超小细胞内检测电极，从体外培养的心肌细胞中实现了细胞内低频静息膜电位的超高空间分辨、高信噪比检测，这是目前为止所报道的最小尺寸的神经电极，发展并完善了利用纳米电极进行胞内神经信号检测的技术；2）基于纳米线/纳米线同质三维支叉结构，我们还成功制得了新型细胞外电极，从体外培养的心肌细胞中实现了细胞外动作电位长期稳定的高信噪比检测；3）通过制备石墨烯包覆的铜微丝，制备了MRI高度兼容的神经记录电极，对电极的生物安全性、生物相容性、以及电化学性质进行了表征和优化，实现了活体大鼠内局域场电位以及单细胞放电的高信噪比记录。本项目通过对电极材料、结构的合理设计，尤其是设计和使用复合纳米结构如三维支叉纳米结构，核壳结构等，实现了具有高时间空间分辨率、高生物相容性、可用于磁共振电生理结合的新型胞内胞外神经电极，这些神经电极和探针的进一步应用将会对很多神经科学研究和神经工程有推动作用，具有重要的实际应用价值。相关工作发表于PNAS、Nano Lett.、Nano today、Chem. Asian J.等，并申请了相关专利，圆满地完成了既定任务。