基于MEMS技术的硅微神经电极阵列的设计与制造
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摘要
随着神经生理学和微机电系统技术(micro electronic mechanical system, MEMS)的发展,生物医学用检测仪器的微型化使其研究的范围已达到了细胞和分子水平。细胞携带并表达了生物医学研究领域所感兴趣的信息。细胞受到刺激后的反应表现为:动作电位的产生。通过在所关注的生物组织植入微电极就可以获取细胞通过电化学产生的生物电位。
基于MEMS技术的硅微神经电极阵列(microelectrode array, MEA)可用于细胞外电位记录。作为一种体外检测的新型工具,其实质是使细胞通过一层薄的电解液与微电极阵列上的测点相耦合,通过细胞-电极接口,可将提取到的神经信号传递给前置放大器单元。该微电极阵列体积小,易加工,具有良好的物理和电学重复特性,可以广泛应用于神经生理学研究,包括:药物筛选、细胞生理分析、毒素检测、周围神经再生和环境监测,从而给神经修复、以及人工假体等研究领域带来了希望。
论文提出了一种基于MEMS技术的三维微电极阵列的设计及制造方法。该微电极阵列可用于动作电位的细胞外检测。本论文的主要内容和贡献在于:
1.建立细胞-电极电学耦合模型。通过研究神经细胞膜上离子通道的通透性和导电性,离子电流的特点及动作电势的形成,提出了电活性细胞-电极的电学耦合模型;从而为本文的设计提供了理论基础。也为实验结果的分析了重要依据。
2.微电极阵列的结构设计。通过对几何尺寸(探针臂横截面形状、长度和宽度,探针臂上测点的尺寸和位置)的优化设计,确保探针能在刺穿生物组织过程中不断裂、不过度弯曲,同时还能提取到高质量的神经信号。最小几何尺寸、承受力的能力以及互连线间的串扰是设计中主要考虑的问题。
3.三维微电极阵列的微加工。该电极阵列由一个微加工的硅基板、两片二维平面探针和一个隔板构成。探针通过插入基板上的槽通过隔板与基本保持正交。所有器件都是在同一块硅晶圆上采用MEMS加工工艺制作出来的,光刻技术和薄膜技术使微电极具有更加优越的物理和电学特性。
4.三维微电极阵列的微组装。三维探针阵列的微组装意味着需要考虑两个问题:一是探针和基板的垂直互连,一是三维阵列与数据处理系统(DSP)的连接。前者是在多次引线键合实验的基础上实现的。而后者的解决是定制了一块PCB转接板,解决了排线由于尺寸过大不能与基板直接相连的问题。
最后,SD大鼠实验提取到了理想的神经信号,表明整个系统是可用的,设计制作及装配是成功的。
With the development of Biomedical Engineering and micro-electronic mechanical system (MEMS), the research on micro-device of cell-based biosensor has reached on the cellular and molecular level. Cells provide and express a series of biological information which is the research target of the biology and medicine. When stimulated, the living cell responds and takes actions in the form of generation active bio-potential. It is by implanting the microelectrode into biological tissue of interest that bio-potentials generated electrochemically by cells can be obtained.
The MEMS-based microelectrode array, as a novel cell-based detecting instrument, can realize the recording of extracellular electrophysiological signals. While sites coupled with the stimulated living cells, the interface of cell-electrode can be constructed to make it feasible to extract and transfer neural signals to the amplifying units. Its small size, reproducible electrical and physical characteristics and easy fabrication make the structure a versatile tool for a variety of neurophysiological application, including pharmaceutical screening, cellular physiological analysis, toxin detecting, peripheral nerve regeneration and environment monitoring, thus they are also promising in fields of neuronal prostheses and the reconstruction of damaged sense organs.
This thesis first introduced the microelectrode array designed by ourselves for extracellular action potential recording. The major contents and contributions of this thesis are given in the following aspects:
First, the cell-electrode electrical model has been established based on the study of the conductance and permeability of cellular membrane, the characteristics of trans-membrane ionic current and the formation of the active bio-potential. It is the theoretical foundations of cell-based bio-potential instrument design and provides the premise to explain the experiment results.
Secondly, It is shown that by optimal geometry dimensions (cross section shape, length and width of the probe shank ,along with the placement and dimensions of sites integrated on the probe shank), probe can be used to penetrate a variety of biological tissues without breakage or excessive dimpling as well as acquiring the high-quality neural signal. The constraints of minimal microprobe dimension, force withstanding capabilities, and the electrodes crosstalk are the main design issues.
Thirdly, the overall structure of the 3D array consists of a silicon platform, two 2D planar probes and a spacer. The probes are inserted through slots in the platform and are held orthogonal to the platform by the spacer. All of these components are fabricated on the same silicon wafer using MEMS fabrication process. photolithographic and thin-film techniques have been used to fabricate microelectrodes with much more improved physical and electrical characteristics.
Fourthly, the micro-assembly of the 3D probe arrays means dealing with the perpendicular interconnection between the probes and the platform and the connection the 3D array to the DSP system. Orthogonal lead transfer between the probes and the platform has been realized through several times of wire bonding experiments, while using a PCB circuit as an adapter between the platform and the DSP successfully solves the problem that the arranging wire, attached on the DSP system, can not be directly bonded to the platform due to its large sizes.
At last, the SD rat experiment, implemented with the micro-machined 3D microelectrode array, has acquired the ideal neural signal; it is suggested that the whole system is available and successful.
基于MEMS技术的硅微神经电极阵列(microelectrode array, MEA)可用于细胞外电位记录。作为一种体外检测的新型工具,其实质是使细胞通过一层薄的电解液与微电极阵列上的测点相耦合,通过细胞-电极接口,可将提取到的神经信号传递给前置放大器单元。该微电极阵列体积小,易加工,具有良好的物理和电学重复特性,可以广泛应用于神经生理学研究,包括:药物筛选、细胞生理分析、毒素检测、周围神经再生和环境监测,从而给神经修复、以及人工假体等研究领域带来了希望。
论文提出了一种基于MEMS技术的三维微电极阵列的设计及制造方法。该微电极阵列可用于动作电位的细胞外检测。本论文的主要内容和贡献在于:
1.建立细胞-电极电学耦合模型。通过研究神经细胞膜上离子通道的通透性和导电性,离子电流的特点及动作电势的形成,提出了电活性细胞-电极的电学耦合模型;从而为本文的设计提供了理论基础。也为实验结果的分析了重要依据。
2.微电极阵列的结构设计。通过对几何尺寸(探针臂横截面形状、长度和宽度,探针臂上测点的尺寸和位置)的优化设计,确保探针能在刺穿生物组织过程中不断裂、不过度弯曲,同时还能提取到高质量的神经信号。最小几何尺寸、承受力的能力以及互连线间的串扰是设计中主要考虑的问题。
3.三维微电极阵列的微加工。该电极阵列由一个微加工的硅基板、两片二维平面探针和一个隔板构成。探针通过插入基板上的槽通过隔板与基本保持正交。所有器件都是在同一块硅晶圆上采用MEMS加工工艺制作出来的,光刻技术和薄膜技术使微电极具有更加优越的物理和电学特性。
4.三维微电极阵列的微组装。三维探针阵列的微组装意味着需要考虑两个问题:一是探针和基板的垂直互连,一是三维阵列与数据处理系统(DSP)的连接。前者是在多次引线键合实验的基础上实现的。而后者的解决是定制了一块PCB转接板,解决了排线由于尺寸过大不能与基板直接相连的问题。
最后,SD大鼠实验提取到了理想的神经信号,表明整个系统是可用的,设计制作及装配是成功的。
With the development of Biomedical Engineering and micro-electronic mechanical system (MEMS), the research on micro-device of cell-based biosensor has reached on the cellular and molecular level. Cells provide and express a series of biological information which is the research target of the biology and medicine. When stimulated, the living cell responds and takes actions in the form of generation active bio-potential. It is by implanting the microelectrode into biological tissue of interest that bio-potentials generated electrochemically by cells can be obtained.
The MEMS-based microelectrode array, as a novel cell-based detecting instrument, can realize the recording of extracellular electrophysiological signals. While sites coupled with the stimulated living cells, the interface of cell-electrode can be constructed to make it feasible to extract and transfer neural signals to the amplifying units. Its small size, reproducible electrical and physical characteristics and easy fabrication make the structure a versatile tool for a variety of neurophysiological application, including pharmaceutical screening, cellular physiological analysis, toxin detecting, peripheral nerve regeneration and environment monitoring, thus they are also promising in fields of neuronal prostheses and the reconstruction of damaged sense organs.
This thesis first introduced the microelectrode array designed by ourselves for extracellular action potential recording. The major contents and contributions of this thesis are given in the following aspects:
First, the cell-electrode electrical model has been established based on the study of the conductance and permeability of cellular membrane, the characteristics of trans-membrane ionic current and the formation of the active bio-potential. It is the theoretical foundations of cell-based bio-potential instrument design and provides the premise to explain the experiment results.
Secondly, It is shown that by optimal geometry dimensions (cross section shape, length and width of the probe shank ,along with the placement and dimensions of sites integrated on the probe shank), probe can be used to penetrate a variety of biological tissues without breakage or excessive dimpling as well as acquiring the high-quality neural signal. The constraints of minimal microprobe dimension, force withstanding capabilities, and the electrodes crosstalk are the main design issues.
Thirdly, the overall structure of the 3D array consists of a silicon platform, two 2D planar probes and a spacer. The probes are inserted through slots in the platform and are held orthogonal to the platform by the spacer. All of these components are fabricated on the same silicon wafer using MEMS fabrication process. photolithographic and thin-film techniques have been used to fabricate microelectrodes with much more improved physical and electrical characteristics.
Fourthly, the micro-assembly of the 3D probe arrays means dealing with the perpendicular interconnection between the probes and the platform and the connection the 3D array to the DSP system. Orthogonal lead transfer between the probes and the platform has been realized through several times of wire bonding experiments, while using a PCB circuit as an adapter between the platform and the DSP successfully solves the problem that the arranging wire, attached on the DSP system, can not be directly bonded to the platform due to its large sizes.
At last, the SD rat experiment, implemented with the micro-machined 3D microelectrode array, has acquired the ideal neural signal; it is suggested that the whole system is available and successful.
引文
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[2] Stephen D. Senturia,微系统设计,电子工业出版社,2004.11,
[3]徐泰然(Tai-Ran Hsu),MEMS和微系统,机械工业出版社,2004.1
[4] C Fisch,“Centennial of the String Galvanometer and the Electrocardiogram,”Journal of the American College of Cardiology, 36(6):1745, 2000
[5] E Perl,“The 1944 Nobel-Prize to Erlanger and Gasser,”FASEB Journal, 8(10):782-783, 1994
[6] Arnold C. Hoogerwerf, Kensall D. Wise. A Three-Dimensional Microelectrode Array for Chronic Neural Recording. IEEE Transactions on Biomedical Engineering. 1994, 41(12):1136-1145
[7] Qing Bai, Kensall D. Wise,David J. Anderson. A High-Yield Micro-assembly Structure For Three-Dimensional Microelectrode Arrays. IEEE Transactions on Biomedical Engineering. 2000, 47(3):281-289
[8] Y. Yao, M. N. Gulari, K. D. Wise. Micro-assembly Techniques for a Three-Dimensional Neural Stimulating Microelectrode Array. Proceedings of the 28th IEEE EMBS Annual International Conference. 2006, August30-September 3
[9]程正喜,黄维宁,周嘉,MEMS神经元微探针研究,传感技术学报,2006,19(5):1388-1394
[10]隋晓红,张若昕,裴为华,适用于神经接口的硅微电极制作,半导体学报,2006,27(10):1703-1706
[11] Apostolos P. Georgopoulos, James Ashe, Nikolaos Smyrnis, and Masato Taira, The motor cortex and coding of force, Science, 1992, 256, 1692-1695.
[12] D. M. Taylor, S. I. H. Tillery, and A. B. Schwartz, Direct cortical control of 3-D neuroprosthetic devices, Science, 2002, 296, 1829-1832.
[13]寿天德,神经生物学,高等教育出版社,2006.1,第二、三章,20-46
[14] Martinoia S,Massobrio P,Bove M,et a1.Cultured neurons coupled to microelectrode arrays:circuit models,simulations and experimental data.IEEE Trans Biomedical Engineering,2004,51(5):859
[15] Qing Bai. A Micro-machined Three-Dimensional Neural Recording Array With On-Chip CMOS Signal Processing Circuitry, Ph.D Graduation Essay, University of Michigan, 1999
[16]徐莹,余辉,张威,基于MEMS技术的微电极阵列细胞传感器,自然科学进展,2007,17(9):1265-1272
[17] Ryler DJ,Durmld DM.A slowly penetrating inter-fascicular nerve electrode for selective activation ofporipheral HelVeS[J].IEEE Trans Re.hab Eng.1997.5:51-61.
[18]杨红星,生物医学传感器与检测技术,化学工业出版社,2005.9,34-50
[19] Wang Di, Zhang Guoxiong, Li Xingfei, Design Method of Passive Multichannel Silicon Neural Microelectrode, NANOTECHNOLOGY AND PRECISION ENGINEERING, 2005, 3(2 ), 101-105.
[20] D.T. Kewley, J. M. Bower, M.D.Hills, D. A.Borkholder, I. E. Opris, N. I. Maluf, C. W. Storment, and G. T. A. Kovacs,“Plasma-Etched Neural Probes,”Sensor and Actuators A: Physical, vol. 58, no. 1, pp. 27-35, 1997
[21] P. K. Campbell, K. E. Jones, R. J. Huber, K. Horch, W., and R. A. Normann,“A Silicon-Based, Three-Dimensional Neural Interface: Manufacturing Processes for an Intracortical Eletrode Array,”IEEE Transactions on Bio-Medical Engineering, vol. 38, no. 8, pp. 758-768, 1991
[22] K. J. James and R. A. Normann,“Low-Stress Silicon Nitride for Insulating Multielectrode Arrays,”presented at Annual International Conferences of the IEEE Engineering in Medical and Biology Society, Baltimor, 1994
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