因為半導體產業的快速發展，結合CMOS標準製程將傳感器與讀取分析電路做在單晶片上的生醫晶片除了應用範圍廣以外，能有高靈敏度、成本較低的優點。但在高離子濃度的溶液如血清中進行生物感測，會因為電雙層電容的影響而屏蔽了電荷造成的訊號變化。
本研究提出操作在MHz以上的CMOS指叉電容式DNA感測晶片，透過自組裝單層膜的方式，將固定probe和target DNA所需要的官能基鍵結在感測指叉電極上方的氧化層上。當兩者發生雜和反應時，會改變電極對溶液的等效電容，經由電路將電容值變化轉成電壓變化讀出。希望藉由高頻操作下，破壞電雙層電容的穩態以減緩離子遮蔽效應。
本研究在pH值標準液實驗中，晶片感測度達到35.7mV/pH；在高離子強度的磷酸緩衝液(1X PBS)感測DNA實驗中，於target DNA濃度〖10〗^(-15)M至〖10〗^(-10) M感測到了13%的電容變化。

Due to the rapid development of the semiconductor industry, the biomedical chip that combines the sensors and the reading circuit on a single chip has the advantages of high sensitivity, low cost and a wide range of applications. However, performing bio-detection of charged biomolecules in high-ionic solutions such as serum is severely limited by the charge-screening effect of the electric double layer.
This research proposes a CMOS capacitive DNA chip operating above MHz to deal with the issue. The functional groups needed for DNA detection are self assembled on the silicon dioxide layer on top of the interdigitated electrodes. The hybridization between probe and target DNA results in the capacitive change of the interdigitated electrode which is converted to a voltage change by the readout circuit. It is hoped that under high-frequency operation, the steady state of the electric double layer is perturbed to reduce the charge-screening effect.
In this study, the measured pH sensitivity reached 35.7 mV/pH. The equivalent capacitance changed by 13% target DNA concentrations from 〖10〗^(-15)M to 〖10〗^(-10)M in high ionic strength solution (1X PBS).
Keywords: capacitive biosensor, interdigitated electrode, high ionic strength, high frequency, ion shielding effect, self-assembled monolayer

[1] J. Rothberg, W. Hinz, T. Rearick, J. Schultz, W. Mileski, M. Davey, J. Leamon. K. Johnson, M. Milgrew, M. Edwards, J. Hoon, J.Simons, D. Marran, J. Myers, J. Davidson, A. Branting, J. Nobile, B. Puc, D. Light, T. Clark, M. Huber, J. Branciforte, I, Stoner, S. Cawley, M. Lyons, Y. Fu, N. Homer, M. Sedova, X. Miao, B. Reed, J. Sabina, E. Feierstein, M. Schorn, M, Alanjary, E, Dimalanta, D, Dressman, R, Kasinskas, T, Sokolsky, J. Fidanza, E, Namsaraev, K, McKernan, A, Williams, G, Roth and J, Bustillo, “An integrated semiconductor device enabling non-optical genome sequencing,” Nature, vol. 475, pp. 348−352, 2011.
[2] R. Brederlow, S. Zauner, A. Scholtz, K. Aufinger, W. Simburger. C. Paulus, A. Martin, M. Fritz, H, Timme, H, Heiss, S. Marksteiner, L. Elbrecht, R, Aigner and R. Thewes, “Biochemical sensors based on bulk acoustic wave resonators,” in IEDM Tech. Dig., 2003, pp. 992-994.
[3] K. Kirstein, Y. Li , M. Zimmermann, C. Vancura, T. Volden, W. H. Song, J. Lichtenberg, and A. Hierlemannn, “Cantilever-based biosensors in CMOS technology,” in Proc. DATE’05, 2005, vol. 2, pp. 210–214.
[4] Y. J. Huang, C. W. Huang, T. H. Lin, C. T. Lin, L. G. Chen, P. Y. Hsiao, B. R. Wu, H. T. Hsueh, B. J. Kuo, H. H. Tsai, H. H. Liao, C. K. Wang and S. S. Lu, “A CMOS cantilever-based label-free DNA SoC with improved sensitivity for hepatitis B virus detection,” IEEE Transactions on Biomedical Circuits and Systems. vol. 7, pp. 820-831, 2013.
[5] P. Bergveld, “Development, operation, and application of the ion-sensitive field-effect transistor as a tool for electrophysiology,” IEEE Transactions on Biomedical Circuits and Systems, vol. 19, no. 5, pp. 342–351, 1972.
[6] X. Huang, H. Yu, X. Liu, Y. Jiang, M. Yan and D. Wu, “A dual-mode large-arrayed CMOS ISFET sensor for accurate and high-throughput pH sensing in biomedical diagnosis,” IEEE Transactions on Biomedical Circuits and Systems, vol. 62, no. 9, pp. 2224-2233, 2015.
[7] A. A. Ahdal, and C. Toumazou, "ISFET-based chemical switch," IEEE Sensor Journal, vol. 12, no. 5, pp. 1140-1146, 2012.
[8] M. S. Norzin, A. A. Hamzah, F. W. Yunus, J. Yunas, and B. Y. Majlis, "pH sensing characteristics of silicon nitride as sensing membrane based ISFET sensor for artificial kidney," IEEE International Conference on Semiconductor Electronics, pp. 124-127, 2018.
[9] D. Zhang, Z. Liu, C. Li, T. Tang, X. Liu, S. Han, B. Lei, and C. Zhou, “Detection of NO2 down to ppb levels using individual and multiple In2O3 nanowire devices,” Nano Lett. vol. 4, pp. 1919−1924, 2004
[10] T. Rim, K. Kim, S. Kim, C. K. Baek,, M. Meyyappan, Y. H. Jeong and J. S. Lee “Improved electrical characteristics of honeycomb nanowire ISFETs,” IEEE Electron Device Lett., vol. 34, no. 8, pp. 1059–1061, 2013.
[11] T. Wink, S. J. van Zuilen, A. Bult and W.P. van Bennekom, “Self-assembled Monolayers for Biosensors,” Analyst, vol. 122, pp. 43–50, 1997.
[12] A. Ulman, “Formation and structure of self-assembled monolayers,” Chem., vol. 96, pp. 1533–1554, 1997.
[13] A. Quershi, Y. Gurbuz, W. P. Kang, J. L. Davidson, “A novel interdigitated capacitor based biosensor for detection of cardiovascular risk marker,” Biosensors and Bioelectronics, vol. 25, pp. 877–882, 2009.
[14] V. Tsouti, C. Boutopoulos, I. Zergioti and S. Chatzandroulisa, “Capacitive microsystems for biological sensing,” Biosensors and Bioelectronics, vol. 27, pp. 1-11, 2011.
[15] C. Berggren, P. Stålhandske, J. Brundell and G. Johansson, “A feasibility study of a capacitive biosensor for direct detection of DNA hybridization,” Electroanalysis, vol. 11, pp. 156-160, 1999.
[16] C. Stagni, C. Guiducci, L. Benini, B. Ricco, S. Carrara, B, Samori, 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 SolidState Circuits, vol. 41, pp. 2956-2964, 2006.
[17] C. M. Chen, S. C. Lu, “A CMOS capacitive biosensor array for highly sensitive detection of pathogenic avian influenza DNA,” in Proc. 2017 19th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS), 2017, pp. 1632-1635.

[18] B. Lee, K. H. Lee, J. O. Lee, M. J. Sohn, S. H. Choi, S. W. Wang, J. B. Yoon and G. H. Cho, “An electronic DNA sensor chip using integrated capacitive read-out circuit,” in IEEE EMBS., 32nd, 2010, pp. 6547-6510.
[19] K. H. Lee, S. Choi, J. O. Lee, J. B. Yoon and G, H, Cho, “CMOS capacitive biosensor with enhanced sensitivity for label-free DNA detection,” in IEEE ISSCC, 2012, pp. 120-121.
[20] Z. He, F. Mansfeld, “Exploring the use of electrochemical impedance spectroscopy (EIS) in microbial fuel cell studies,” Energy Environ. Sci., vol. 2, pp. 215−219, 2009.
[21] E. B. Bahadir and M. K. Sezginturk, “A review on impedimetric biosensors,” Artificial Cells, Nanomedicine, and Biotechnology., vol. 44, pp. 248−262, 2009.
[22] J. S. Park, H. J. Kim, J. H. Lee, J. H. Park, J. Kim, K. S. Hwang and B. C. Lee, “Amyloid beta detection by faradaic electrochemical impedance spectroscopy using interdigitated microelectrodes,” Sensors., vol. 18, pp. 426, 2016.
[23] R. Faria, L. Heneine, T. Matencio and Y. Messaddeq, “Faradaic and non-faradaic electrochemical impedance spectroscopy as transduction techniques for sensing applications,” Biosensors and Bioelectronics., vol. 5, pp. 29−31, 2019.
[24] J. S. Park, H. J. Kim, J. H. Lee, J. H. Park, J. Kim, K. S. Hwang and B. C. Lee, “Amyloid beta detection by faradaic electrochemical impedance spectroscopy using interdigitated microelectrodes,” Sensors., vol. 18, pp. 1−11, 2018.
[25] S. P. Lin, L. U. Vinzons, Y. S. Kang and T. Y. Lai, “Non-faradaic electrical impedimetric investigation of the interfacial effects of neuronal cell growth and differentiation on silicon nanowire transistors,” ACS ApplMat Interfaces., vol. 7, pp. 9866-9878, 2015.
[26] J. Kang, J. Wen, S. H. Jayaram, A. Yu and X. Wang, “Development of an equivalent circuit model for electrochemical double layer capacitors (EDLCs) with distinct electrolytes,” Electrochimica Acta., vol. 115, pp. 587−598, 2014.
[27] S. K. Arya, P. Zhurauski, P. Jolly, M. R. Batistuti, M. Mulato and P. Estrela, “Capacitive aptasensor based on interdigitated electrode for breast cancerdetection in undiluted human serum,” Biosensors and Bioelectronics., vol. 102, pp. 106−112, 2018.
[28] P. Zhurauski, S. K. Arya, P. Jolly, C. Tiede, D. C. Tomlinson, P. K. Ferrigno and P. Estrela, “Sensitive and selective Affimer-functionalised interdigitated electrode-based capacitive biosensor for Her4 protein tumour biomarker detection,” Biosensors and Bioelectronics., vol. 108, pp. 1−8, 2018.
[29] 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.
[30] S. Suwansaard, P. Kanatharana, P. Asawatreatanakul, B. Wongkittisuksa, C. Limsakul and P. Thavarungkul, “Comparison of surface plasmon resonance and capacitive immunosensors for cancer antigen 125 detection in human serum samples,” Biosensors and Bioelectronics., vol. 24, pp. 3436−3431, 2009.
[31] A. Qureshi, Y. Gurbuz and J. H. Niazi, “Capacitive aptamer–antibody based sandwich assay for the detection of VEGF cancer biomarker in serum,” Sensors and Actuators B: Chemical., vol. 209, pp. 645−651, 2015.
[32] C. J. Chu, C. S. Yeh, C. K. Liao, L. C. Tsai, C. M. Huang, H. Y. Lin, J. J. Shyue, Y. T. Chen and C. D. Chen, “Improving nanowire sensing capability by electrical field alignment of surface probing molecules,” Nano Lett., vol. 13, pp. 2564−2569, 2013.
[33] G. Ertürk, M. Hedström, M. A. Tümer, A. Denizli and B. Mattiasson, “Real-time prostate-specific antigen detection with prostate-specific antigen imprinted capacitive biosensors,” Analytica Chimica Acta., vol. 891, pp. 120−129, 2015.
[34] S. H. Kazemi, M. Shanehsaz and M. Ghaemmaghami, “Non-Faradaic electrochemical impedance spectroscopy as a reliable and facile method: Determination of the potassium ion concentration using a guanine rich aptasensor,”
Materials Science and Engineering., vol. 52, pp. 151−154, 2015.
[35] C. Cheng, R. Oueslati, J. Wu, J. Chen and S. Eda, “Capacitive DNA sensor for rapid andsensitive detection of whole genomehuman herpesvirus-1 dsDNA in serum,” Electrophoresis., vol. 38, pp. 1617−1623, 2017.
[36] R. Deshmukh, A. K. Prusty, U. Roy and S. Bhand, “A capacitive DNA sensor for sensitive detection of Escherichia coli O157:H7 in potable water based on the z3276 genetic marker: fabrication and analytical performance, “ Analyst., vol. 145, pp. 2267−2278, 2015.
[37] N. Gao, W. Zhou, X. Jiang, G. Hong, T. M. Fu and C. M. Lieber, “General strategy for biodetection in high ionic strength solutions using transistor-based nanoelectronic sensors,” Nano Lett., vol. 15, pp. 2143−2148, 2015.
[38] R. Elnathan, M. Kwiat, A.Pevzner, Y. Engel, L. Burstein, A. Khatchtourints, A. Lichtenstein, R. Kantaev and F. Patolsky, “Biorecognition layer engineering: overcoming screening limitations of nanowire-based fet devices,” Nano Lett., vol. 12, pp. 5245-5254, 2012.
[39] G. S. Kulkarni and Z. Zhong, “Detection beyond the Debye Screening Length in a High-Frequency Nanoelectronic Biosensor,” Nano Lett., vol. 12, pp. 719-723, 2012.
[40] V. Kesler, B. Murmann and H. T. Soh, “Going beyond the Debye Length: overcomingcharge screening limitations in next-generation bioelectronic sensors,” ACS Nano. vol. 14, pp. 16194-16201, 2020.
[41] 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 nanotechnology, vol. 10, pp, 791-795, 2015.
[42] Y. W. Chen, S. C. Lu, “Highly sensitive dna detection beyond the debye screening length using cmos field effect transistors,” IEEE Electron Device Letters, 2021.
[43] M. Crescentini, M. Rossi, “AC and phase sensing of nanowires for biosensing,” Biosensors, vol. 6, pp. 1-15, 2016.
[44] H. J. Panya and J. P. Desai, “Towards an automated MEMS-based characterization of benign and cancerous breast tissue using bioimpedance measurements,” Sensors and Actuaors B: Chemical, vol. 199, pp. 259-268, 2014.