科學家極力於探索大腦的奧秘，大腦利用龐大的神經網路，產生人類複雜的動作、記憶、情感和學習能力。由此，神經科學已成為近年來熱門的研究領域之一，若是能夠成功判讀神經訊號的傳遞和變化，就能重建有缺陷的神經網路，以期成為醫療界很重要的技術，譬如是人工眼、思想控制的人工義肢。目前眾多的研究團隊仍對量測神經訊號的技術，投入時間精力，欲發展出穩定性高的高感測晶片，能夠作為長時間觀察膜外神經訊號的用途。
本論文發展一個CMOS 製成相容的感測器，並且整合後端訊號放大電路在同一塊晶片上，此晶片能夠降低電極陣列的繞線困難，而且使用非侵入式的方式，能夠對培養細胞或離體組織作長時間的觀察和記錄。利用晶粒等級的微加工技術，將氧半電晶體實現成凹狀結構
的感測器，並且在後製成的蝕刻過程中不會損害到同晶片的後端電路，這種感測器的結構另外設計出不同大小和形狀，嘗試得到更好的細胞附著情況。此論文展示了微加工製程、電路設計流程和整體的電性測試。除了詳述晶片的設計過程和特性分析之外，最後還展示了生物測試的結果，此系統成功紀錄了斑馬魚的離體心臟和分離心肌細胞的自發性神經電位，這些生物測試證實了此晶片能夠應用於紀錄神經電訊號，在未來提供一個穩定的平台作為神經科學研究。

In the 21st century, researchers have endeavored to explore the mystery of human brain. Human brain has specific neural networks to accomplish complex behaviors, such as instinct, memories, learning, and emotions, etc. Therefore, neuroscience has become one of the most popular research fields. The neural signals need to be analyzed in detail to help to rehabilitate the disabled patients. The study of neuroscience facilitates the human prosthesis, artificial intelligence and electronic industry. The MicroElectrode Array (MEA) provides a non-invasive and non-toxic platform for long-term monitoring of neuron activities.
This thesis proposes a single semiconductor chip consisted of CMOS-compatible sensors and recording amplifiers monolithically. The MEA chip can alleviate the wire-routing limitation by integrating the multi-channel amplifiers into the same chip. The system is fully compatible with current VLSI technology. Moreover, it is bio-compatible and non-toxic for long-term measurement. By the die-level micromachining fabrication, the well-known MOSFET has been developed as sensors and a hole structure above the sensor has been realized to approach enhancing cell adhesion to the sensor. The thesis describes the design procedure, the post-micromaching process and electrical tests. Eventually, the MEA chip demonstrates several biological tests and is proved capable of monitoring of the electrocardiogram from isolated zebrafish heart and cardiomyocytes.

[1] A. Rodgers, Alzheimer's Disease: Unraveling the Mystery. National Institutes of Health, 2003.
[2] N. Carlson and J. Braun, Foundations of physiological psychology. Allyn and Bacon Boston, MA, 2002.
[3] T. Shafer, Whole-Cell Patch-Clamp Electrophysiology of Voltage-Sensitive Channels. Wiley Online Library.
[4] L. Berdondini, P. Massobrio, M. Chiappalone, M. Tedesco, K. Imfeld, A. Maccione, M. Gandolfo, M. Koudelka-Hep, and S. Martinoia, “Extracellular recordings from locally dense microelectrode arrays coupled to dissociated cortical cultures,” Journal of Neuroscience Methods, vol. 177, no. 2, pp. 386–396, 2009.
[5] B. Eversmann, M. Jenkner, F. Hofmann, C. Paulus, R. Brederlow, B. Holzapfl, P. Fromherz, M. Merz, M. Brenner, M. Schreiter et al., “A 128× 128 CMOS biosensor array for extracellular recording of neural activity,” IEEE J. Solid-State Circuits, vol. 38, no. 12, pp. 2306–2317, 2003.
[6] J. Ando, H. Fujita, T. Sugawara, Y. Jimbo, K. Itaka, K. Kataoka, and T. Ushida, “The State of the Art of Nanobioscience in Japan,” IEEE Transactions on NanoBio-science, vol. 5, no. 1, pp. 54–65, 2006.
[7] Y. Jimbo, N. Kasai, K. Torimitsu, T. Tateno, and H. Robinson, “A system for MEAbased multisite stimulation,” Biomedical Engineering, IEEE Transactions on, vol. 50, no. 2, pp. 241–248, 2003.
[8] M. Sch¨oning and A. Poghossian, “Bio FEDs (Field-Effect Devices): State-of-the-Art and New Directions,” Electroanalysis, vol. 18, no. 19-20, pp. 1893–1900, 2006.
[9] A. Offenh¨ausser, C. Spr¨ossler, M. Matsuzawa, and W. Knoll, “Field-effect transistor array for monitoring electrical activity from mammalian neurons in culture,” Biosen-sors and Bioelectronics, vol. 12, no. 8, pp. 819–826, 1997.
[10] M. Jenkner and P. Fromherz, “Bistability of membrane conductance in cell adhesion observed in a neuron transistor,” Phys. Rev. Lett., vol. 79, no. 23, pp. 4705–4708, Dec 1997.
[11] M. Jenkner, B. M¨uller, and P. Fromherz, “Interfacing a silicon chip to pairs of snail neurons connected by electrical synapses,” Biological Cybernetics, vol. 84, no. 4, pp. 239–249, 2001.
[12] G. Zeck and P. Fromherz, “Noninvasive neuroelectronic interfacing with synaptically connected snail neurons immobilized on a semiconductor chip,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 18, p. 10457, 2001.
[13] M. Merz and P. Fromherz, “Silicon chip interfaced with a geometrically defined net of snail neurons,” Advanced Functional Materials, vol. 15, no. 5, pp. 739–744, 2005.
[14] Q. He, E. Meng, Y. Tai, C. Rutherglen, J. Erickson, and J. Pine, “Parylene neurocages for live neural networks study,” in TRANSDUCERS, Solid-State Sensors, Actuators and Microsystems, 12th International Conference on, 2003, vol. 2. IEEE,
2003, pp. 995–998.
[15] A. Tooker, J. Erickson, G. Chow, Y. Tai, and J. Pine, “Parylene Neurocages for Electrical Stimulation on Silicon and Glass Substrates,” in Engineering in Medicine and Biology Society, 2006. EMBS'06. 28th Annual International Conference of the IEEE. IEEE, 2008, pp. 4322–4325.
[16] N. Joye, A. Schmid, and Y. Leblebici, “Electrical modeling of the cell-electrode interface for recording neural activity from high-density microelectrode arrays,” Neurocomputing, vol. 73, no. 1-3, pp. 250–259, 2009.
[17] V. Kiessling, B. M¨uller, and P. Fromherz, “Extracellular resistance in cell adhesion measured with a transistor probe,” Langmuir, vol. 16, no. 7, pp. 3517–3521, 2000.
[18] U. Frey, J. Sedivy, F. Heer, R. Pedron, M. Ballini, J. Mueller, D. Bakkum, S. Hafizovic, F. Faraci, F. Greve et al., “Switch-matrix-based high-density microelectrode array in CMOS technology,” Solid-State Circuits, IEEE Journal of, vol. 45, no. 2, pp. 467–482, 2010.
[19] A. Hodgkin and A. Huxley, “A quantitative description of membrane current and its application to conduction and excitation in nerve,” The Journal of Physiology, vol. 117, no. 4, p. 500, 1952.
[20] M. Sch¨oning and A. Poghossian, “Recent advances in biologically sensitive field-effect transistors (BioFETs),” The Analyst, vol. 127, no. 9, pp. 1137–1151, 2002.
[21] A. Poghossian, S. Ingebrandt, A. Offenh¨ausser, and M. Sch¨oning, “Field-effect devices for detecting cellular signals,” in Seminars in Cell & Developmental Biology, vol. 20, no. 1. Elsevier, 2009, pp. 41–48.
[22] P. Bergveld, J. Wiersma, and H. Meertens, “Extracellular potential recordings by means of a field effect transistor without gate metal, called osfet,” Biomedical Engineering, IEEE Transactions on, vol. BME-23, no. 2, pp. 136 –144, mar. 1976.
[23] P. Fromherz, “Joining microelectronics and microionics: Nerve cells and brain tissue on semiconductor chips,” Solid-State Electronics, vol. 52, no. 9, pp. 1364–1373, 2008.
[24] P. Fromherz, C. M¨uller, and R. Weis, “Neuron transistor: electrical transfer function measured by the patch-clamp technique,” Physical Review Letters, vol. 71, no. 24, pp. 4079–4082, 1993.
[25] P. Fromherz and A. Stett, “Silicon-neuron junction: capacitive stimulation of an individual neuron on a silicon chip,” Physical Review Letters, vol. 75, no. 8, pp. 1670–1673, 1995.
[26] S. Vassanelli and P. Fromherz, “Transistor records of excitable neurons from rat brain,” Applied Physics A: Materials Science & Processing, vol. 66, no. 4, pp. 459–463, 1998.
[27] P. Fromherz, “Extracellular recording with transistors and the distribution of ionic conductances in a cell membrane,” European Biophysics Journal, vol. 28, no. 3, pp. 254–258, 1999.
[28] R. Weis and P. Fromherz, “Frequency dependent signal transfer in neuron transistors,” Physical Review E, vol. 55, no. 1, pp. 877–889, 1997.
[29] P. Fromherz, “Neuroelectronic interfacing: Semiconductor chips with ion channels, nerve cells, and brain,” Nanoelectronics and Information Technology, pp. 781–810, 2003.
[30] M. Maher, J. Pine, J. Wright, and Y. Tai, “The neurochip: a new multielectrode device for stimulating and recording from cultured neurons,” Journal of Neuroscience Methods, vol. 87, no. 1, pp. 45–56, 1999.
[31] A. Tooker, E. Meng, J. Erickson, Y. Tai, and J. Pine, “Biocomplatible parylene neurocages,” Engineering in Medicine and Biology Magazine, IEEE, vol. 24, no. 6, pp. 30–33, 2005.
[32] Y. Qiu, R. Liao, and X. Zhang, “Intervention of cardiomyocyte death based on real-time monitoring of cell adhesion through impedance sensing,” Biosensors and Bioelectronics, vol. 25, no. 1, pp. 147–153, 2009.
[33] C. Lo and J. Ferrier, “Impedance analysis of fibroblastic cell layers measured by electric cell-substrate impedance sensing,” Physical Review E, vol. 57, no. 6, pp. 6982–6987, 1998.
[34] I. Giaever and C. Keese, “Micromotion of mammalian cells measured electrically,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 17, p. 7896, 1991.
[35] A. Lambacher, M. Jenkner, M. Merz, B. Eversmann, R. Kaul, F. Hofmann, R. Thewes, and P. Fromherz, “Electrical imaging of neuronal activity by multitransistor-array (MTA) recording at 7.8 _m resolution,” Applied Physics A: Materials Science & Processing, vol. 79, no. 7, pp. 1607–1611, 2004.
[36] F. Heer, S. Hafizovic, W. Franks, A. Blau, C. Ziegler, and A. Hierlemann, “CMOS microelectrode array for bidirectional interaction with neuronal networks,” Solid-State Circuits, IEEE Journal of, vol. 41, no. 7, pp. 1620–1629, 2006.
[37] B. Razavi, “Fundamentals of microelectronics,” 2009.
[38] K. Williams and R. Muller, “Etch rates for micromachining processing,” Microelec-tromechanical Systems, Journal of, vol. 5, no. 4, pp. 256–269, 1996.
[39] D. Ma, B. Wilamowski, and F. Dai, “A Tunable CMOS Resistor with Wide Tuning Range for Low Pass Filter Application,” in Silicon Monolithic Integrated Circuits in RF Systems, 2009. SiRF09. IEEE Topical Meeting on. IEEE, 2009, pp. 1–4.
[40] N. Greenwood, A. Earnshaw, and K. (Firm), “Chemistry of the Elements,” 1984.
[41] A. Reader, A. Ommen, P. Weijs, R. Wolters, and D. Oostra, “Transition metal silicides in silicon technology,” Reports on Progress in Physics, vol. 56, p. 1397, 1993.
[42] R. Harrison and C. Charles, “A low-power low-noise CMOS amplifier for neural recording applications,” IEEE Journal of Solid-State Circuits, vol. 38, no. 6, pp.958–965, 2003.
[43] R. Sorkin, A. Greenbaum, M. David-Pur, S. Anava, A. Ayali, E. Ben-Jacob, and Y. Hanein, “Process entanglement as a neuronal anchorage mechanism to rough surfaces,” Nanotechnology, vol. 20, p. 015101, 2009.