本研究主題為開發一〝微型多探針電極陣列之神經訊號量測系統〞，研究最終目標將朝向腦科學生物醫學檢測運用。為了要完成此量測系統，本論文將會以微型多探針電極陣列的設計和製作為主，並進行探針電極之強度與效能測試，以利將來完整系統的研發。
人腦由超過一千億個可傳遞電信號的神經元聚集而成的複雜系統，其信號傳遞過程中屬網路型觸發。由於考慮將應用於大腦皮層神經信號量測，微探針將被刺入，故探針強度將備受考驗。在設計完整的微探針製程之前，先行以ANSYS模擬各式幾何形狀，進而得到最佳化的微探針尺寸。從模擬結果可得之，以1/4圓切加支柱的根部設計，能承受最大的穿刺力量(18.5mN)。
接下來，微機電製程技術將被運用在微探針陣列的製作上。主要架構在矽底材微機械加工基礎上，並以SOI wafer為製程基材。製程主要含括：黃光微影、高溫成長、乾式蝕刻、CVD、PVD…等基本技術、在雙層矽晶片上開發出微電極陣列之結構，其優勢為將使得製程簡易，並提高製程的良率及均勻性，其良率可達98%。製程特色上，微探針厚度將取決於Device Si Layer厚度，可達精確厚度控制。
另以電化學交流阻抗分析法為基礎，架構一系統用於量測微電極與電解液之間的阻抗與相位，進而求得電雙層電容值。此資訊有利於未來電極量測神經信號前置處理的電路架設，避免負載效應，幫助調配匹配電阻，亦使OPA自身雜訊下降和避開高通濾波器之截止頻率，進而達到原始神經信號重現。微電極在AMES溶液中，平均阻抗為2.46MΩ/ 1KHz。
未來目標，初期先行整合元件與前級電路，此重點於降低雜訊對神經信號的影響。二期目標進行生物大腦皮層實體量測實驗，量測系統架設是其關鍵。最後目標將是置入藥物傳輸的微流道，以達主動型
醫療機制。

This research is to design a “Micro Multi-Probe Electrode Arrays for Neural Signal Recording System”. The final goal is to apply the measurement system on bio-medical applications. Based on the optimal design of micro multi-probe electrodes by Ansys, the fabrication of electrodes can be accomplished by using MEMS technology. At the end, the performance of electrodes would be measured, which will be very useful for further development of measurement system.
Brain is a complicated system that sends electrical signal by thousand hundred million neurons. The process of signal is a very complicated network. As a result of the micro probe electrode would be used to measure neural signal of brain cortex, the intensity of electrode is very critical. Several kinds of geometry were applied to simulate by ANSYS before designing fabrication process. The shank geometry 1/4 Cycle (Pillar) is the proper one that can bear 18.5mN force.
MEMS technology was used to develop the fabrication of micro multi-probe electrodes, which started by using SOI wafer. Lithography, LPCVD, dry etching, PVD, etc were used to develop the micro electrodes on the SOI wafer. The yield of designed fabrication can reach 98%. The feature of process inherently can control the final probe thickness based on the thickness of device layer of the SOI wafer.
Then we used the electrochemical alternative current impedance analysis to measure the impedance and phase between electrode and electrolyte, and then to obtain the capacitance of electrode double layer. It is beneficial for us to set up the circuit of the further jobs in the future. To avoid the loading effect, it is useful to allocate the suitable matching resistance, which could be used to decrease the noise of OPamp and decide the proper cut frequency of high pass filter in order to to obtain the original neural signals.
Future work is to use current accomplished results to for developing a completed measurement circuitry. To reduce noise of the neural signal is very important. The final goal is to implant multi-channels by using developed electrode array and to inject medicine for some medical treatments.

[1] T. H. T. Ichiki, T. Ujiie, Y. Horiike, and K. Yasuda, " Development of bio-MEMS devices for single cell expression analysis," presented at Conferences of Microprocesses and Nanotechnology, Shimane, Japan, Oct., 2001.
[2] O. B. G. J. M. A. W. Miller, "A MEMS DNA replicator and sample manipulator," Proceedings of Circuits and Systems, pp. 232-235, Aug., 2000.
[3] S. M. K. Ikuta, Y. Fukaya, and T. Fujisawa, "Biochemical IC chip toward cell free DNA protein synthesis," presented at The Eleventh Annual International Workshop on Micro Electro Mechanical Systems, Heidelberg, Germany, Jan., 1998.
[4] C. D. Z. Zhan, Y. Zhongyao, and W. Li, "Biochip for PCR amplification in silicon," presented at Conferences of Microtechnologies in Medicine and Biology, Lyon, France, Oct., 2000.
[5] T. U. T. Kikuchi, T. Ichiki, and Y. Horiike, "Fabrication of quartz micro-capillary electrophoresis chips for health care devices," presented at Conferences of Microprocesses and Nanotechnology, Yokohama, Yokohama, Japan, July, 2001.
[6] K. D. Jandt, "Atomic force microscopy of biomaterials surfaces and interface," Surface Science, vol. 491, pp. 303-332, 2000.
[7] G. C. P. Vettiger, M. Despont, U. Drechsler, U. Dig, B. Gotsmann, and M. A. L. W. Herle, H. E. Rothuizen, R. Stutz and G. Binnig, "The "Millipede"-nanotechnology entering data storage," IEEE Transactions on Nanotechnology, vol. 1-1, pp. 39-55, 2002.
[8] L. L. M. Meister, and D. A. Baylor, "Concerted signaling by retinal ganglion cells," Science, vol. 270, pp. 1207-1210, 1995.
[9] D. K. W. I. H. Brivanlou, and M. Meister, "Mechanisms of concerted firing among retinal ganglion cells," Neuron, vol. 20, pp. 527-539, 1998.
[10] S. H. DeVries, "Correlated firing in rabbit retinal ganglion cells," Journal of Neurophysiol, vol. 81, pp. 908-920, 1999.
[11] "http://www.dls.ym.edu.tw/neuroscience/neurok_c.html."
[12] M. O. M. Shikida, N. Todoroki, M. Ando, Y. lshihara, T. Ando, and K. Sato, "Non-photolithographic pattern transfer for fabricating arrayed 3-D microstructures by chemical anisotropic etching," presented at IEEE The Sixteenth Annual International Conference on Micro Electro Mechanical Systems, Kyoto, Japan, Jan., 2003.
[13] a. G. S. P. Griss, "Novel, side opened out-of-plane microneedles for microfluidic transdermal interfacing," presented at The Fifteenth IEEE International Conference on Micro Electro Mechanical Systems, Las Vegas, NV, Jan., 2002.
[14] a. A. B. F. S. Chandrasekaran, "Characterization of surface micromachined hollow metallic microneedles," presented at IEEE The Sixteenth Annual International Conference on Micro Electro Mechanical Systems, Kyoto, Japan, Jan., 2003.
[15] B. S. U. Egert, S. Fennrich, W. Nisch, M. Fejtl, T. Knott, T. Muller, and H. Hammerle, "A novel organotypic long-term culture of the rat hippocampus on substrate-integrated multielectrode arrays," Brain research protocols, vol. 2, pp. pp 229-242, 1998.
[16] Multichannel systems, "http://www.multichannelsystems.com/."
[17] B. G. C. N.A. Blum, H.K. Charles, R.L. Edwards, and R.A. Meyer, "Multisite microprobes for neural recordings," IEEE Transactions on Biomedical Engineering, vol. 38, pp. 68-74, 1991.
[18] a. K. D. W. J. Ji, "An implantable CMOS circuit interface for multiplexed microelectrode recording arrays," IEEE Journal of Solid-State Circuits, vol. 27, pp. 433-443, 1992.
[19] D. J. B. G. Ensell, D.J. Ewins, W. Balachandran, and P.R. Richards, "Silicon-based microelectrodes for neurophysiology fabricated using a gold metallization/nitride passivation system," Journal of Microelectromechanical Systems, vol. 5, pp. 117-121, 1996.
[20] W. L. C. Xu, and C. Liu, "Design and fabrication of a high-density metal microelectrode array for neural recording," Sensors and Actuators A, vol. 96, pp. 78-85, 2002.
[21] H. M. O, M. Fejtl, M. Raggenbass, D. Bertrand, and P. Renaud, "A three-dimensional multi-electrode array for multi-site stimulation and recording in acute brain slices," Journal of Neuroscience Methods, vol. 114, pp. 135-148, 2002.
[22] A. Biosystems, "http://www.ayanda-biosys.com/lts.html."
[23] B. Technology, "http://www.bionictech.com/index.html."
[24] P. E. P. Griss, H. K. Tolvanen-Laakso, P. Merilainen, S. Ollmar, and G Stemme, "Micromachined Electrodes for Biopotential Measurements," Journal Of Microelectromechanical System, vol. 10, pp. 10-16, 2001.
[25] D. Z. A. Hung, R. Greenberg, and J. W. Judy, "Micromachined Electrodes for Retinal Prostheses," presented at IEEE-EMBS Special Topic Conference On Microtechnologies In The Medicine & Biology, Madison, Wisconsin, May, 2002.
[26] D. Z. A. Hung, R. Greenberg, and J. W. Judy, "Micromachined electrodes for high density neural stimulation systems," MEMSﾒ02, pp. 56-59, Jan, 2002.
[27] W. L. C. R. J.A. Bielen, A.W. Schmidt, and R. Weiel, "Fabrication of multi electrode array structures for intra-neural stimulation: assessment of the LIGA method," Engineering in Medicine and Biology Society, pp. 268-269, Oct, 1996.
[28] K. E. J. P. K. Campbell, R. J. Huber, K. W. Horch, and R. A. Normann, "A Silicon-Based, Three-Dimensional Neural Interface: Manufacturing Processes for an Intracortical Electrode Array," IEEE Transactions On Biomedical Engineering, vol. 38, pp. 758-768, 1991.
[29] P. K. C. K. E. Jones, and R. A. Normann, "Interelectrode Isolation in a Penetrating Intracortical Electrode Array," IEEE Engineering in Medicine and Biology Society, pp. 496-497, Nov, 1990.
[30] E. M. M. R. A. Normann, P. J. Rousche, and D. J. Warren, "A neural interface for a cortical vision eprosthesis," Vision Research, vol. 39, pp. pp 2577-2587, 1999.
[31] P. K. C. R. A. Normann, and K. E. Jones, "A Silicon Based Electrode Array for Intracortical Stimulation: Structural and Electrical Properties," IEEE Engineering in medicine & biology society, pp. 939-940, Nov, 1989.
[32] T. A. F. J.A. Bielen, and W.L.C. Rutten, "Development of a solder bump technique for contacting a three-dimensional multi electrode array," Engineering in Medicine and Biology Society, pp. pp 1101-1102, Sep, 1995.
[33] C. B. P. Thiebaud, N.F. de Rooij, and M. Koudelka-Hep, "Microfabrication of Pt-tip microelectrodes," Sensors and Actuators B, vol. 70, pp. 51-56, 2000.
[34] C. B. P. Thiebaud, M. Koudelka-Hep, M. Bove, S. Martinoia, M. Grattarola, H. Jahnsen, R. Rebaudo, M. Balestrino, J. Zimmer, and Y. Dupont, "An array of Pt-tip microelectrodes for extracellular monitoring of activity of brain slices," Biosensors & Bioelectronics, vol. 14, pp. 61-65, 1999.
[35] T. S. S. Takeuchi, K. Mabuchi, and H. Fujita, "3D flexible multichannel probe array," IEEE The Sixteenth Annual International Conference on Micro Electro Mechanical Systems, pp. 376-370, Jan., 2003.
[36] K. M. T. Suzuki, and S. Takeuchi, "A 3D flexible parylene probe array for multichannel neural recording," presented at First International IEEE EMBS Conference on Neural Engineering, Capri Island, Italy, March, 2003.
[37] K. D. W. Q. Bai, and D. J. Anderson, "A High-Yield Microassembly Structure For Three-Dimensional Microelectrode Arrays," IEEE Transactions On Biomedical Engineering, vol. 47, pp. 281-289, 2000.
[38] a. K. D. W. Q. Bai, "Single-Unit Neural Recording with Active Microelectrode Arrays," IEEE Transactions On Biomedical Engineering, vol. 48, pp. 911-920, 2001.
[39] a. K. D. W. A. C. Hoogerwerf, "A Three-Dimensional Microelectrode Array for Chronic Neural Recording," IEEE Transactions On Biomedical Engineering, vol. 41, pp. 1136-1146, 1994.
[40] A. C. I., "Removal of Gram-negative endotoxin from solutions by affinity," Journal of Immunological Methods, vol. 61, pp. 275-281, 1983.
[41] R. G. L. Kang Y., "Effects of ionic strength and pH on endotoxin removal efficiency and protein recovery in an affinity chromatography," Process Biochemistry, vol. 36, pp. 85-92, 2000.
[42] T. D. Amirudin A., "Review Paper: Application of electrochemical impedance spectroscopy to study the degradation of polymer-coated metals," Progress in Organic Coatings, vol. 26, pp. 1-28, 1995.
[43] K. S. Nawghare P. M., Limaye S. S., "PC based instrument for impedance analysis, cyclic voltammetry and transient analysis," Solid State Ionics, vol. 90, pp. 295-301, 1996.
[44] 田昭武著, 電化學研究方法: 科學出版社發行, 1984.
[45] A. W. B., "A.C. impedance electrochemistry," Current Separations, vol. 11, pp. 61-65, 1992.
[46] G. T. Darkow R., Albrecht W., Lützow K., Paul D., "Functionalized nanoparticles for endotoxin binding in aqueous solutions," Biomaterials, vol. 20, pp. 1277-1283, 1999.
[47] D. A. Borkholder, "Cell Based Biosensors Using Microelectrodes," Ph.D. Thesis,Stanford University, CA, 1998. 1998.
[48] Y. H. C. G. J. Schabmueller, G. Holman, K. F. Bohringer, "High-Aspect Ratio Submicrometer Needles for Intracellular Applications," Micromechanics Europe Workshop (MME '02), October 6-8, 2002.
[49] U. L. Y. Hanein, J. Theobald, R. Wyeth, T. Daniel, D. D. Denton, A. O. Willows, and K. F. Böhringer, "Intracellular Recording with High Aspect Ratio MEMS Neuronal Probes," Transducers'01 - The 11th International Conference on Solid-State Sensors and Actuators, pp. 386-389, June, 2001.
[50] D. D. D. K.F. Bohringer, Y. Hanein, G. Holman, A.O.D. Willows, and R.C. Wyeth, "Silicon micro-needles with flexible interconnections," IEEE-EMB Special Topic Conference on Microtechnologies in Medicine & Biology, pp. 255-260, May,2001.
[51] K. N. D.J. Anderson, S.J. Tanghe, D.A. Evans, K.L. Levy, J.F.Hetke, X. Xue, J.J. Zappia, and K.D. Wise, "Batch fabricated thin-filmelectrodes for stimulation of the central auditory system," IEEE Transactions on Biomedical Engineering, vol. 36, pp. 693-704, 1989.
[52] D. S. P. P.J. Rousche, D.P. Jr. Pivin, J.C. Williams, R.J. Vetter, and D.R. Kirke, "Flexible polyimide-based intracortical electrode arrays with bioactive capability," IEEE-Transactions-on-Biomedical-Engineering, vol. 48, pp. 361-371, 2001.
[53] B. G. C. N.A. Blum, H.K. Jr. Charles, R.L. Edwards, and R.A. Meyer, "Multisite microprobes for neural recordings," IEEE Transactionson Biomedical Engineering, vol. 38, pp. 68-74, 1991.
[54] H. Z. M. J.J. Mastrototaro, T.C. Pilkington and R.E. Ideker, "Rigid and flexible thin-film multielectrode arrays for transmural cardiac recording," IEEE Transactions on Biomedical Engineering, vol. 39, pp. 271-279, 1992.
[55] Madou, Fundamentals of microfabrication, p67,CRC, 1997.