研究生: |
曾聯心 Tseng, Lien-Sing |
---|---|
論文名稱: |
在高離子濃度下進行DNA感測之CMOS 32 x 32 延伸閘極場效電晶體陣列 A CMOS 32 x 32 Extended Gate Field-Effect Transistors Array for DNA Detection at High Ionic Strength |
指導教授: |
盧向成
Lu, Shiang-Cheng |
口試委員: |
鄭裕庭
Cheng, Yu-Ting 劉承賢 Liu, Cheng-Hsien |
學位類別: |
碩士 Master |
系所名稱: |
電機資訊學院 - 電子工程研究所 Institute of Electronics Engineering |
論文出版年: | 2023 |
畢業學年度: | 111 |
語文別: | 中文 |
論文頁數: | 71 |
中文關鍵詞: | 延伸閘極場效電晶體陣列 |
外文關鍵詞: | Extended Gate Field-Effect Transistors Array |
相關次數: | 點閱:2 下載:0 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
在這個半導體產業迅速發展的時代,晶片的設計結合了人類生活的應用,日常中感測器與我們形影不離,例如:觸覺感測器、生物感測器、氣體感測器、光感測器、聲音感測器、動態感測器等等,而近年來由於疫情的影響,為了能更快速且便利的檢測病毒和疾病,生醫感測器更是一個熱門的應用,利用可以與CMOS製程整合的電路設計,結合電化學的應用,製作出微機電系統整合的晶片,可大幅縮小感測器尺寸且提高精準度。
本研究使用延伸電極場效電晶體(Extended Gate Field Effect Transistors, EGFET)作為感測元件,檢測相似於人體血液濃度中的B型肝炎病毒DNA 載量(fM等級),透過將化學訊號轉為電路訊號以此作為感測機制,但由於在接近人體血液濃度中會有因溶液中離子所造成的電荷遮蔽效應,此效應會使得感測訊號受到干擾,因此如何解決電荷遮蔽的效應便是本研究一個重要的課題。我們搭配電路設計,設計一個3232的感測陣列,特色為每個感測器的尺寸小,且為了將低晶片功耗,我們僅使用一組輸出電路,並透過將電路操作在高頻,試著打破在高離子溶液環境下電荷遮蔽的效應,提高在高離子溶液環境中對於B型肝炎(Hepatitis B virus) DNA(deoxyribonucleic acid)的感測度。在不同pH值緩衝溶液下,我們量測到pH值的感測度為37.5mV/pH。而B型肝炎DNA的量測,我們感測〖10〗^(-16)M~〖10〗^(-8)M的DNA分子,在0.01XPBS溶液下,EGFET的臨界電壓變化為17.2 mV/〖/log〗_10[DNA];在1XPBS溶液下,EGFET的臨界電壓變化為19.3 mV/〖/log〗_10[DNA]。
In this era of rapid development of the semiconductor industry, the applications of chip design have high connection with human life. Sensors are inseparable from us in everyday life. Tactile sensor, biological sensor, gas sensor, light sensor, sound sensor, motion sensor and many other sensors are wildly used in our daily life. Especially nowadays we suffered from pandemic, biomedical sensors highlight its value in order to detect viruses and diseases more quickly and conveniently. By integrating the CMOS circuit process and MEMS on the same chip, we can produce biomedical sensor chips with small size and high accuracy.
In this paper, we use Extended Gate Field Effect Transistors (EGFET) as our sensing element to detect very low concentrations of hepatitis B virus DNA load (fM grade) in blood. This detection method is based on converting chemical signals to electrical signals. However, detected signal in the sample solution similar to blood is limited by the ion-screening effect caused in sample solution with high ion concentration. Therefore, how to break through the limitations of biomedical sensing is an important issue in our research.
In terms of design, in order to breakthrough Debye length effect of charge screening effect in sample solution with high ion concentration, an 3232 sensor array with small pixel size and low power consumption has been developed. The high-frequency modulation is effective to reduce charge screening so as to improve the sensitivity of the sensor. In the sensing of different pH standard solutions, we measured the sensitivity of pH value to be 35.7mV/pH.In addition, we also added DNA of Hepatitis B virus for sensing DNA molecules with a concentration of 〖10〗^(-16)M~〖10〗^(-8)M.The threshold voltage change of EGFET measured in 0.01X PBS buffer solution is 17.2 mV/〖/log〗_10[DNA] and in 1X PBS buffer solution is 19.3 mV/〖/log〗_10[DNA].
[1] P. Bergveld, “Development of an ion-sensitive solid-state device for neurophysiological measurements,” IEEE Trans. Biomed Eng, vol. 17, no. 1, pp. 70-1, Jan, 1970.
[2] C. H. Lin, C. H. Hung, C. Y. Hsiao, H. C. Lin, F. H. Ko, and Y. S. Yang, “Poly-silicon nanowire field-effect transistor for ultrasensitive and label-free detection of pathogenic avian influenza DNA,” Biosensors & Bioelectronics, vol. 24, no. 10, pp. 3019-3024, Jun 15, 2009.
[3] P. W. Yen, C. W. Huang, Y. J. Huang, M. C. Chen, H. H. Liao, S. S. Lu, and 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 & Bioelectronics, vol. 61, pp. 112-118, Nov 15, 2014.
[4] A. R. Gao, N. Lu, P. F. Dai, T. Li, H. Pei, X. L. Gao, Y. B. Gong, Y. L. Wang, and C. H. Fan, “Silicon-Nanowire-Based CMOS-Compatible Field-Effect Transistor Nanosensors for Ultrasensitive Electrical Detection of Nucleic Acids,” Nano Letters, vol. 11, no. 9, pp. 3974-3978, Sep, 2011.
[5] S. R. Chang, C. H. Chang, J. S. Lin, S. C. Lu, Y. T. Lee, S. R. Yeh, and H. Chen, “Die-level, post-CMOS processes for fabricating open-gate, field-effect biosensor arrays with on-chip circuitry,” Journal of Micromechanics and Microengineering, vol. 18, no. 11, Nov, 2008.
[6] 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, Oct, 2010.
[7] J. Bausells, J. Carrabina, A. Errachid, and A. Merlos, “Ion-sensitive field-effect transistors fabricated in a commercial CMOS technology,” Sensors and Actuators B-Chemical, vol. 57, no. 1-3, pp. 56-62, Sep 7, 1999.
[8] Y. Vlasov, A. Bratov, M. Sidorova, and Y. Tarantov, “Investigation of Ph-Sensitive Isfets with Oxide and Nitride Membranes Using Colloid Chemistry Methods,” Sensors and Actuators B-Chemical, vol. 1, no. 1-6, pp. 357-360, Jan, 1990.
[9] P. Georgiou, and C. Toumazou, “ISFET characteristics in CMOS and their application to weak inversion operation,” Sensors and Actuators B-Chemical, vol. 143, no. 1, pp. 211-217, Dec 4, 2009.
[10] J. T. Smith, S. S. Shah, M. Goryll, J. R. Stowell, and D. R. Allee, “Flexible ISFET Biosensor Using IGZO Metal Oxide TFTs and an ITO Sensing Layer,” IEEE Sensors Journal, vol. 14, no. 4, pp. 937-938, Apr, 2014.
[11] D. H. Kwon, B. W. Cho, C. S. Kim, and B. K. Sohn, “Effects of heat treatment on Ta2O5 sensing membrane for low drift and high sensitivity pH-ISFET,” Sensors and Actuators B-Chemical, vol. 34, no. 1-3, pp. 441-445, Aug, 1996.
[12] H. K. Liao, J. C. Chou, W. Y. Chung, T. P. Sun, and S. K. Hsiung, “Study of amorphous tin oxide thin films for ISFET applications,” Sensors and Actuators B-Chemical, vol. 50, no. 2, pp. 104-109, Jul 31, 1998.
[13] C. Panteli, P. Georgiou, and K. Fobelets, “Reduced Drift of CMOS ISFET pH Sensors Using Graphene Sheets,” IEEE Sensors J., vol. 21, no. 13, pp. 14609-14618, Jul 1, 2021.
[14] C. Toumazou, L. M. Shepherd, S. C. Reed, G. I. Chen, A. Patel, D. M. Garner, C. J. A. Wang, C. P. Ou, K. Amin-Desai, P. Athanasiou, H. Bai, I. M. Q. Brizido, B. Caldwell, D. Coomber-Alford, P. Georgiou, K. S. Jordan, J. C. Joyce, M. La Mura, D. Morley, S. Sathyavruthan, S. Temelso, R. E. Thomas, and L. L. Zhang, “Simultaneous DNA amplification and detection using a pH-sensing semiconductor system,” Nature Methods, vol. 10, no. 7, pp. 641-+, Jul, 2013.
[15] J. M. Rothberg, W. Hinz, T. M. Rearick, J. Schultz, W. Mileski, M. Davey, J. H. Leamon, K. Johnson, M. J. Milgrew, M. Edwards, J. Hoon, J. F. Simons, D. Marran, J. W. Myers, J. F. Davidson, A. Branting, J. R. Nobile, B. P. Puc, D. Light, T. A. Clark, M. Huber, J. T. Branciforte, I. B. Stoner, S. E. Cawley, M. Lyons, Y. T. 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. A. Fidanza, E. Namsaraev, K. J. McKernan, A. Williams, G. T. Roth, and J. Bustillo, “An integrated semiconductor device enabling non-optical genome sequencing,” Nature, vol. 475, no. 7356, pp. 348-352, Jul 21, 2011.
[16] S. Sheibani, L. Capua, S. Kamaei, S. S. A. Akbari, J. Zhang, H. Guerin, and A. M. Ionescu, “Extended gate field-effect-transistor for sensing cortisol stress hormone,” Commun Mater, vol. 2, no. 1, pp. 10, 2021.
[17] X. Xu, P. Clement, J. Eklof-Osterberg, N. Kelley-Loughnane, K. Moth-Poulsen, J. L. Chavez, and M. Palma, “Reconfigurable Carbon Nanotube Multiplexed Sensing Devices,” Nano Lett., vol. 18, no. 7, pp. 4130-4135, Jul 11, 2018.
[18] Y. Jiang, X. Liu, T. C. Dang, X. Huang, H. Feng, Q. Zhang, and H. Yu, “A High-Sensitivity Potentiometric 65-nm CMOS ISFET Sensor for Rapid E. coli Screening,” IEEE Trans. Biomed Circuits Syst, vol. 12, no. 2, pp. 402-415, Apr, 2018.
[19] O. Synhaivska, Y. Mermoud, M. Baghernejad, I. Alshanski, M. Hurevich, S. Yitzchaik, M. Wipf, and M. Calame, “Detection of Cu(2+) Ions with GGH Peptide Realized with Si-Nanoribbon ISFET,” Sensors (Basel), vol. 19, no. 18, Sep 18, 2019.
[20] X. W. Huang, H. Yu, X. Liu, Y. Jiang, M. Yan, and D. P. Wu, “A Dual-Mode Large-Arrayed CMOS ISFET Sensor for Accurate and High-Throughput pH Sensing in Biomedical Diagnosis,” IEEE Trans. on Biomedical Engineering, vol. 62, no. 9, pp. 2224-2233, Sep, 2015.
[21] H. Helmholtz, “Studien über elektrische Grenzschichten,” Annalen der Physik, vol. 7, pp. Annalen der Physik, 1879.
[22] M. Gouy, “Sur la constitution de la charge électrique à la surface d'un électrolyte,” J. de Physicque et Appliquee, vol. 9, pp. 457-468, 1910.
[23] D. L. Chapman, Phil. Mag., vol. 25, pp. 475–475, 1913.
[24] A. Gao, N. Lu, Y. Wang, P. Dai, T. Li, X. Gao, Y. Wang, and C. Fan, “Enhanced sensing of nucleic acids with silicon nanowire field effect transistor biosensors,” Nano Lett., vol. 12, no. 10, pp. 5262-8, Oct 10, 2012.
[25] M. Curreli, R. Zhang, F. N. Ishikawa, H. K. Chang, R. J. Cote, C. Zhou, and M. E. Thompson, “Real-Time, Label-Free Detection of Biological Entities Using Nanowire-Based FETs,” IEEE Trans. on Nanotechnology, vol. 7, no. 6, pp. 651-667, Nov, 2008.
[26] M. Hinnemo, A. Makaraviciute, P. Ahlberg, J. Olsson, Z. Zhang, S. L. Zhang, and Z. B. Zhang, “Protein Sensing Beyond the Debye Length Using Graphene Field-Effect Transistors,” IEEE Sensors J., vol. 18, no. 16, pp. 6497-6503, Aug 15, 2018.
[27] N. Gao, W. Zhou, X. C. Jiang, G. S. Hong, T. M. Fu, and C. M. Lieber, “General Strategy for Biodetection in High Ionic Strength Solutions Using Transistor-Based Nanoelectronic Sensors,” Nano Letters, vol. 15, no. 3, pp. 2143-2148, Mar, 2015.
[28] G. S. Kulkarni, and Z. H. Zhong, “Detection beyond the Debye Screening Length in a High-Frequency Nanoelectronic Biosensor,” Nano Letters, vol. 12, no. 2, pp. 719-723, Feb, 2012.
[29] 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, no. 9, pp. 791-+, Sep, 2015.
[30] G. Y. Xu, J. Abbott, and D. Ham, “Optimization of CMOS-ISFET-Based Biomolecular Sensing: Analysis and Demonstration in DNA Detection,” IEEE Trans. on Electron Devices, vol. 63, no. 8, pp. 3249-3256, Aug, 2016.
[31] Y. Nemirovsky, I. Brouk, and C. G. Jakobson, “1/f noise in CMOS transistors for analog applications,” IEEE Trans. on Electron Devices, vol. 48, no. 5, pp. 921-927, May, 2001.
[32] L. Bousse, N. F. Derooij, and P. Bergveld, “Operation of Chemically Sensitive Field-Effect Sensors as a Function of the Insulator-Electrolyte Interface,” IEEE Trans. on Electron Devices, vol. 30, no. 10, pp. 1263-1270, 1983.
[33] Y. W. Chen, and M. S. C. Lu, “Highly Sensitive DNA Detection Beyond the Debye Screening Length Using CMOS Field Effect Transistors,” IEEE Electron Device Letters, vol. 42, no. 8, pp. 1220-1223, Aug, 2021.
[34] C. Lee, Y. W. Chen, and M. S. C. Lu, “CMOS Biosensors for the Detection of DNA Hybridization in High Ionic-Strength Solutions,” IEEE Sensors J., vol. 21, no. 4, pp. 4135-4142, Feb 15, 2021.