在醫學檢驗中，如何迅速且精確地評估患者的疾病是一個十分重要的課題。為了能夠製作迅速且精確的生醫感測，本研究採用了MEMS與CMOS電路製程整合技術的概念，作為生醫感測器的主要架構。此整合技術，能將感測單元與電路整合。除此之外，利用CMOS電路製程的情況下，感測區域的製作可以免於獨立後製程的步驟，減少感測器因後製程所帶來的不確定因素。

根據世界衛生組織WHO的統計，全世界有三分之一的人口曾經有患有B型肝炎疾病，而台灣是全世界肝炎患病率最高的地區。如果在生醫領域能有一種迅速且精確的快篩機制，用於檢測人體血液中低濃度的B型肝炎病毒，它會有助於防止B型肝炎疾病的傳染。因此本研究希望製作出檢測快速、高感測度的生醫感測器。再透過不同的表面修飾方法，可用於感測不同的生物因子之生理變化。

本研究提出以電容式感測器來檢測低濃度B型肝炎病毒的DNA基因片段。首先，在感測器的方面，是採用指叉式電極作為感測電容。接著在電路的方面，本研究則是設計了不同操作頻率的環形震盪器，利用高頻操作下，試圖對電雙層電容所帶來的Debye Length效應加以探討。並且運用電路高頻操作的特性，使得感測器能夠在高濃度的PBS緩衝溶液下，檢測到低濃度B型肝炎病毒(HBV)之DNA基因片段所帶來的電性變化。最後，利用整合的讀取電路將電訊號輸出並且加以分析。

Due to the rapid development of the semiconductor industry, the technology in CMOS (complementary metal-oxide-semiconductor) has become totally mature. Meanwhile, in order to minimize the size of CMOS chip, the technology in MEMS (Microelectromechanical Systems) starts to develop.

In medical laboratory region, how to evaluate and detect the disease precisely and rapidly is a major issue. For the sake of rapidly biomolecules sensing, we demonstrated a capacitive biosensor in array based on CMOS-MEMS technology. By using CMOS-MEMS technology, the bio-sensing chip can be built without post-CMOS processing and reduce the uncertain factors from post-CMOS processing.

Our goal is to build a bio-sensing chip with rapid detecting and high sensitivity. Depending on the surface modification, we can sense different biological molecules.
The focus of this study is to explore the mechanism of capacitive sensing by DNA hybridization process on the bio-sensing chip, and explore the way to break through the screening effect of the electrolyte caused from the phosphate buffered saline (PBS). The chip design contains the interdigitated electrodes. It is expected that when the DNA is modified on the silicon oxide layer (SiO2) above the sensing electrode, the effective capacitance value of sensing electrode will have a corresponding change due to the electric charge from the biological molecules. This biological change can be readout by the sensing circuit and record by the data acquisition card (DAQ).

摘要I
Abstract II
目錄 III
圖目錄V
表目錄 XV
第一章 緒論 1
1-1 研究動機 1
1-2 CMOS-MEMS技術簡介 7
1-3 文獻回顧 9
第二章 電路架構與模擬 28
2-1 電路架構 28
2-1-1 整體電路架構說明 28
2-1-2 環形振盪器感測單元說明 29
2-1-3 共用輸出單元說明 33
2-1-4 數位元件說明 33
2-1-5 電路模擬 37
2-2 電容感測原理 46
2-3 電容感測結構設計與模擬 48
第三章 生醫實驗介紹 54
3-1 生醫實驗介紹 54
3-2 表面修飾步驟 56
3-3 液體下電容變化 60
第四章 量測結果與分析 63
4-1 量測設備介紹 63
4-2 晶片結構檢視與PCB封裝 66
4-3 生物實驗流程與量測結果 69
4-3-1 pH值緩衝溶液感測實驗 69
4-3-2 PBS緩衝溶液感測實驗 73
4-3-3純PBS緩衝溶液長時間操作感測實驗 76
4-3-4 DNA分子感測實驗 78
第五章 結論與未來工作 110
參考文獻 117
附錄 120
附表 140

[1] C. Laborde, F. Pittino, H. A. Verhoeven, S. G. Lemay, L. Selmi, M. A. Jongsma and F. P. Widdershoven, "Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays," Nature, Vol. 10, pp. 791-796, 2015.
[2] A. J. Bard, "Electrochemical method: fundamentals, and applications, 2nd Edition," Wiley, 2000.
[3] Jeffry J. Sniegowski, "Chemical-mechanical polishing: enhancing the manufacturability of MEMS", Proc. SPIE 2879, Micromachining and Microfabrication Process Technology II,1996.
[4] S. Kang and Y. Leblebici,” CMOS digital integrated circuits: analysis and design” McGraw-Hill, 2003.
[5] C. Berggren, B. Bjarnanson, and G. Johansson,” Capacitive Biosensors,”Electroanalysis, Vol. 13, pp. 173-180, 2001.
[6] R. Mukhopadhyay, M. Lorentzen, J. Kjems, and F. Besenbacher,” Nanomechanical Sensing of DNA Sequences Using Piezoresistive Cantilevers,” Langmuir, Vol.21, pp. 8400–8408, 2005.
[7] W. Shu, E.D. Laue, and A.A. Seshia, “Investigation of biotin-streptavidin binding interactions using microcantilever sensors,” Biosensors and Bioelectronics, Vol. 22, pp. 2003-2009, 2006.
[8] S. Dewa and W. H. Ko, “Biosensors,” Chap. 9 in “Semiconductor Sensors,” by S. M. Sze, pp. 415-472, John Wiley and Sons, 1994.
[9] J. Li, M. Xue, Z. Lu, Z. Zhang, C. Feng, and M. Chan, “A High-Density Conduction-Based Micro-DNA Identification Array Fabricated with a CMOS Compatible Process,” IEEE Trans on Electron Device, Vol. 50, No. 10, pp. 2165-2170 ,2003.
[10] R. Pei, Z. Chang, E. Wang and X. Yang,” Amplification of antigen-antibody interactions based on biotin labeled protein-streptavidin network complex using impedance spectroscopy,” Biosensors and Bioelectronics, Vol.16, pp. 355-361, 2001.
[11] A. Benvidi, N. Rajabzadeh, M. Mazloum-Ardakani, M. M. Heidari, and A. Mulchandani,“Simple and label-free electrochemical impedance Amelogenin gene hybridization biosensing based on reduced graphene oxide,” Biosensors and Bioelectronics, Vol.58, pp. 145-152, 2014.
[12] C. Stagni, C. Guiducci, L. Benini, B. Riccò, S. Carrara, B. Samorí, C. Paulus, M. Schienle, M. Augustyniak, and R. Thewes,“CMOS DNA Sensor Array With Integrated A/D Conversion Based on Label-Free Capacitance Measurement,” IEEE Journal of Solid-state Circuit, Vol. 41, No. 12, pp. 2956-2964,2006.
[13] C. Stagni, C. Guiducci, L. Benini, B. Riccò, S. Carrara, C. Paulus, M. Schienle and R. Thewes,” A Fully Electronic Label-Free DNA Sensor Chip,” IEEE Sensor Journal, Vol. 14, pp. 1608-1614,2014.
[14] A. Qureshi, J. H.Niazi, S. Kallempudi, and Y. Gurbuz,“Label-free capacitive biosensor for sensitive detection of multiple biomarkers using gold interdigitated capacitor arrays,” Biosensors and Bioelectronics, Vol.25, pp. 2318-2323, 2010.
[15] C. Dai,“A capacitive humidity sensor integrated with micro heater and ring oscillator circuit fabricated by CMOS–MEMS technique, “Sensors and Actuators B, Vol. 122, pp. 375-380,2007.
[16] E. A. Vasconcelos, N. G.Peres, C. O. Pereira, V. L.da Silva, E. F. da Silva Jr., and F.Dutra ,“Potential of a simplified measurement scheme and device structure for a low cost label-free point-of-care capacitive biosensor,” Biosensors and Bioelectronics, Vol.25, pp. 870-876, 2009.
[17] S. Prakash and P. Abshire, “On-chip capacitance sensing for cell monitoring applications,”IEEE Sensors Journal, Vol.7, pp. 440-447, 2007.
[18] S. Prakash and P. Abshire, “Tracking cancer cell proliferation on a CMOS capacitance sensor chip,” Biosensors Bioelectron., vol. 23, no.10, pp. 1449–1457, 2008.
[19] A. Numnuam, P. Kanatharana, B. Mattiasson, P. Asawatreratanakul, B. Wongkittisuksa, C. Limsakul and P. Thavarungkul,” Capacitive biosensor for quantification of trace amounts of DNA,” Biosensors and Bioelectronics, Vol.24, pp. 2559-2565, 2009.
[20] S. Carrara, V. Bhalla, C. Stagnia, L. Benini, A. Ferretti, F. Vallea, A. Gallottac, B. Riccòb, and B. Samor “Label-free cancer markers detection by capacitance biochip, “Sensors and Actuators B: Chemical, Vol.136, pp. 163-172, 2009.
[21] M. S. C. Lu, Y.-C. Chen, and P.-C. Huang, “5x5 CMOS capacitive, sensor array for detection of the neurotransmitter dopamine,” Biosensors Bioelectron., vol.26, no.3, pp.1093-1097, 2010.
[22] A. Y. Chang and M. S. C. Lu, “A CMOS magnetic microbead-based capacitive biosensor array with on-chip electromagnetic manipulation,”Biosensors Bioelectron., vol. 45, no. C, pp.6-12, 2013.
[23] C. M. Chen, and M. S. C. Lu,” A CMOS capacitive biosensor array for highly sensitive detection of pathogenic avian influenza DNA,” 2017 19th International Conference on Solid-State Sensors, Actuators and Microsystems.
[24] B. Senevirathna, S. Lu, M. Dandin, J. Basile, E. Smela and P. Abshire,” High resolution monitoring of chemotherapeutic agent potency in cancer cells using a CMOS capacitance biosensor,” Biosensors Bioelectron., vol. 142, 2019.

[25] J. Musayev, Y. Adlgüzel, H. Külah, S. Emino ̆glu, and T. Akln, “Label-Free DNA Detection Using a Charge Sensitive CMOS Microarray Sensor Chip,” IEEE Sensors Journal, Vol.14, No.5, pp. 1608-1616, 2014.
[26] P. W. Yen, C. W. Huang, M. C. Chen, H. H. Liao, S. S. Lu, C. T. Lin, “A device design of an integrated CMOS poly-silicon biosensor-on-chip to enhance performance of biomolecular analytes in serum samples, “Biosensors and Bioelectronics, Vol.61, pp. 112-118, 2014.
[27] Y. Jiang, X. Liu, T. C. Dang, X. W. Huang, H. Feng, Q. Zhang, and H. Yu, “A High-Sensitivity Potentiometric 65-nm CMOS ISFET Sensor for Rapid E. Coli Screening,” IEEE Transactions On Biomedical Circuits and Systems, Vol.12, No.2, pp.402-415, 2018.
[28] M. Kalofonou and C. Toumazou, " Semiconductor technology for early detection of DNA methylation for cancer:From concept to practice " Sensors and Actuators B, Vol.178, pp.572-580,2013.
[29] Y. Kagohashi, H. Ozawa, S. Uno, K. Nakazato and K. Ohdaira,” Complementary Metal–Oxide–Semiconductor Ion-Sensitive Field-Effect Transistor Sensor Array with Silicon Nitride Film Formed by Catalytic Chemical Vapor Deposition as an Ion-Sensitive Membrane,” Jpn. J. Appl. Phys., Vol. 49, 01AG06, 2010.
[30] D.C. Li, P. H. Yang, and M. S.-C. Lu, “CMOS open-gate ion-sensitive field-effect transistors for ultrasensitive dopamine detection,” IEEE Trans. on Electron Devices, Vol. 57, No. 10, pp. 2761-2767, 2010.
[31] J. Rivera-Gandía, M. d. M. Maldonado, Y. D. L. Torre-Meléndez, E. O. Ortiz-Quiles, N. M. Vargas-Barbosa, and C. R. Cabrera, “Electrochemical Capacitance DNA Sensing at Hairpin-Modified Au Electrodes, “Journal of Sensors,2011.
[32] S. O. Kelley, J. K. Barton, N. M. Jackson, L. D. McPherson, A. B. Potter, E. M. Spain, M. J. Allen, and M. G. Hill, “Orienting DNA Helices on Gold Using Applied Electric Fields,” Langmuir, Vol.14, pp. 6781–6784, 1998.
[33] J. A. Howarter and J. P. Youngblood,” Optimization of Silica Silanization by 3-Aminopropyltriethoxysilane,” Langmuir, Vol.22, no.26,pp. 11142–11147, 2006.