研究生: |
賴柏亘 Lai, Po-Hsuan |
---|---|
論文名稱: |
CMOS 16x16 電容式DNA感測器陣列之開發 Development of a CMOS 16x16 capacitive DNA sensor array |
指導教授: |
盧向成
Lu, Shiang-Cheng |
口試委員: |
劉承賢
Liu, Cheng-Hsien 鄭裕庭 Cheng, Yu-Ting |
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: | 87 |
中文關鍵詞: | 電容式感測 、指叉電極 、雙重關聯式取樣電路 、DNA修飾步驟 |
外文關鍵詞: | capacitive sensing, interdigitated electrode, correlated double sampling circuit, DNA immobolization |
相關次數: | 點閱:1 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 |
隨著電路設計以及半導體製程技術發展成熟,感測器的應用也越來越多樣化。生醫感測晶片是將微機電系統與生醫晶片結合,用來感測特定生物訊號的分子。在現今疫情肆虐的世界,此種技術更能突顯其價值。但生醫感測的技術限制是其在離子濃度的溶液中時常會因離子遮蔽效應以及環境的干擾而影響到訊號的感測,因此如何突破生醫感測的限制是重要的課題。
本論文提出可以量測fM濃度DNA的CMOS指叉電容感測電路,藉由生物溶液的調製將固定probe以及target DNA需要的官能基鍵結在指叉電極上的氧化層。當兩者順利產生雜交反應後,會改變感測電極的等效電容值,此電容值轉換會變成電壓值由輸出讀出。希望藉由成功的DNA電極修飾步驟,能順利感測到低濃度的生物分子訊號。
在電路操作的部分,我們將電路分別操作於100kHz、500kHz、1MHz以及2MHz,並藉由替換不同的電容大小來實踐雙重關聯式取樣電路的架構,我們設計了50fF大小的感測電容,感測電容總共有256個,每64個感測電容共用一輸出,感測環境選用不同濃度的磷酸鹽緩衝溶液(Phosphate-buffered saline, PBS)以及pH標準液進行感測,最終的感測結果在0.01x、0.1x以及1x的PBS中0.01xPBS量測到的電容值約介於3~3.2pF,當濃度提升至1xPBS時,電容變化約為6%。在不同pH標準液的感測我們量測到pH值的感測度為76mV/pH,換算為151fF/pH的感測度。此外我們也加入了B型肝炎(Hepatitis B virus)的DNA(deoxyribonucleic acid)來進行感測,在0.01xPBS的緩衝液中加入濃度為〖10〗^(-17)M~〖10〗^(-10)M的DNA分子,在〖10〗^(-17)M量測到的初始電容值介於3.27pF~5.16pF,以10倍的濃度增加並量測至〖10〗^(-10)M的電容變化率為1.3988%/log_10[DNA],相當於每10倍濃度增加97.62fF的值,且達到R^2=0.9847的高度相關性。
關鍵字:電容式感測、指叉電極、雙重關聯式取樣電路、DNA修飾步驟
With the development of circuit design and semiconductor manufacturing technology, the applications of sensors are becoming more and more diverse. Biomedical sensing chip is a combination of micro-electromechanical system and biomedical chip to sense molecules of specific biological signals. As the pandemic is now spreading in the world, this kind of technology can highlight its value.. However, the technical limitation of biomedical sensing is that it often affects the sensing of signals due to ion-screening effect under high ionic solution and environmental interference. Therefore, how to break through the limitations of biomedical sensing is an important issue.
In this paper, a CMOS interdigitated capacitance sensing circuit that can measure fM concentration of DNA is proposed, and binds the functional groups required for immobilizing the probe and target DNA to the oxide layer on the interdigitated electrodes through the modulation of the biological solution. When the hybridization reaction is successfully generated between the two, the equivalent capacitance value of the sensing electrode will be changed, and the conversion of the capacitance value will become a voltage value to be read out by the output. It is hoped that through the successful DNA electrode modification steps, low-concentration biomolecular signals can be successfully sensed.
In the circuit operation part, we operate the circuit at 100kHz, 500kHz, 1MHz and 2MHz respectively, and carry out the double correlation sampling circuit by replacing different capacitor values. We design a 50fF sensing capacitor to sense the signal and there are 256 capacitors in total. Every 64 sensing capacitor shares one output. The sensing environment uses different concentrations of Phosphate-buffered saline (PBS) and pH standard solution for sensing. For the final sensing result in 0.01x, 0.1x, 1x PBS solution, the capacitance value measured in 0.01xPBS is about 3~3.2pF. When the concentration is increased to 1xPBS, the capacitance change is about 6%. In the sensing of different pH standard solutions, we measured the sensitivity of pH value to be 76.7mV/pH which can also be transferred to 151fF/pH. In addition, we also added DNA of Hepatitis B virus for sensing. DNA molecules with a concentration of 〖10〗^(-17)M~〖10〗^(-10)M are added to the buffer solution of 0.01xPBS, and the initial capacitance value measured at 〖10〗^(-17)M was between 3.27 pF~5.16pF. The capacitance change rate was 1.3988 %/log_10[DNA] which is also eqivalent to 97.62fF value changing with a 10-fold increase in concentration and measured to〖10〗^(-10)M. Also, R^2=0.9847 which indicates the measured data is highly correlated.
Keywords: capacitive sensing, interdigitated electrode, correlated double sampling circuit, DNA immobolizaiton
1. Salve, M., Dhone, M., Rewatkar, P., Balpande, S., and Kalambe. J, “Design and sensitivity analysis of micro-cantilever based biosensor for tumor detection,” Sensor Letters, vol. 17, no. 1, pp. 64-68, 2019.
2. Sungkanak, U., Sappat, A., Wisitsoraat, A., Promptmas, C., and Tuantranont, A., “Ultrasensitive detection of Vibrio cholerae O1 using microcantilever-based biosensor with dynamic force microscopy,” Biosens. Bioelectron., vol. 26, no. 2, pp. 784-789, 2010.
3. Bergveld, P. "Development, Operation, and Application of the Ion-Sensitive Field-Effect Transistor as a Tool for Electrophysiology," IEEE Trans. Biomed. Circ. and Syst., vol. 19, no. 5, pp. 342-351, 1972
4. Gao, N., Zhou, W., Jiang, X., Hong, G., Fu, T., and Lieber, C., "General strategy for biodetection in high ionic strength solutions using transistor-based nanoelectronic sensors," Nano Lett., vol. 15, pp. 2143–2148, 2015.
5. Sedki, M., Shen, Y., and Mulchandani, A., “Nano-FET-enabled biosensors: Materials perspective and recent advances in North America,” Biosens. Bioelectron., vol. 176, 112941, 2021.
6. Sarangadharan, I., Regmi, A., Chen, Y. W., Hsu, C. P., Chen, P., Chang, W. H., Lee, G. Y., Chyi, J. I., Shiesh, S. C., Lee, G. B., and Wang, Y. L., "High sensitivity cardiac troponin I detection in physiological environment using AlGaN/GaN high electron mobility transistor (HEMT) biosensors," Biosens. Bioelectron., vol. 100, pp. 282–289, 2018.
7. Novodchuk, I., Kayaharman, M., Ausri, I. R., Karimi, R., Tang, X. S., Goldthorpe, I. A., Abdel-Rahman, E., Sanderson, J., Bajcsy, M. and Yavuz, M., "An ultrasensitive heart-failure BNP biosensor using B/N co-doped graphene oxide gel FET," Biosens. Bioelectron., vol. 180, 113114, 2021
8. Newman, A. L., Hunter, K. W., and Stanbro, W. D., “The capacitive affinity sensor: a new biosensor,” In Proc. 2nd Int. Meeting Chem. Sensors, pp. 596-598, 1986
9. Bataillard, P., Gardies, F., Jaffrezic-Renault, N., Martelet, C., Colin, B., and Mandrand, B., “Direct detection of immunospecies by capacitance measurements,” Anal. Chem., vol. 60, no. 21, pp.2374-2379, 1988
10. Wei, J., “Distributed capacitance of planar electrodes in optic and acoustic surface wave devices,” IEEE J. Quantum Electronics, vol. 13, no. 4, pp. 152-158, 1977
11. Alley, G. D., “Interdigital capacitors and their application to lumped-element microwave integrated circuits,” IEEE Trans. Microwave Theory and Techniques, vol. 18, no. 12, pp. 1028-1033, 1970
12. Esfandiari, R., Maki, D. W., and Siracusa, M., “Design of interdigitated capacitors and their application to gallium arsenide monolithic filters,” IEEE Trans. Microwave Theory and Techniques, vol.31, no. 1, pp.57-64, 1983
13. Gevorgian, S. S., Martinsson, T., Linner, P. L., and Kollberg, E. L., “CAD models for multilayered substrate interdigital capacitors,” IEEE Trans. Microwave Theory and Techniques, vol. 44, no. 6, pp. 896-904, 1996
14. Chen, C. M., and Lu, M. S. C., “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), pp. 1632-1635, 2017
15. Bratov, A., Ramón-Azcón, J., Abramova, N., Merlos, A., Adrian, J., Sánchez-Baeza, F., and Domínguez, C., “Three-dimensional interdigitated electrode array as a transducer for label-free biosensors,” Biosens. Bioelectron., vol. 24, no. 4, pp. 729-735, 2008
16. Gul, O., Heves, E., Kaynak, M., Basaga, H., and Gurbuz, Y., “Label-free, capacitive immunosensor for protein detection,” Sensors, pp. 600-603, 2006
17. Varshney, M., and Li, Y., “Interdigitated array microelectrode based impedance biosensor coupled with magnetic nanoparticle–antibody conjugates for detection of Escherichia coli O157: H7 in food samples.” Biosens. Bioelectron., vol. 22, no. 11, pp. 2408-2414, 2007
18. Limbut, W., Hedström, M., Thavarungkul, P., Kanatharana, P., and Mattiasson, B., “Capacitive biosensor for detection of endotoxin,” Anal. Chem., vol. 389, pp. 517-525, 2007
19. Wang, L., Veselinovic, M., Yang, L., Geiss, B. J., Dandy, D. S. and Chen, T. “A sensitive DNA capacitive biosensor using interdigitated electrodes,” Biosens. Bioelectron., vol. 87, pp. 646–653, 2017.
20. Berggren, C., Stålhandske, P., Brundell, J., and Johansson, G., “A feasibility study of a capacitive biosensor for direct detection of DNA hybridization,” Electroanalysis: An International Journal Devoted to Fundamental and Practical Aspects of Electroanalysis, vol. 11, no. 3, pp. 156-160, 1999
21. Berney, H., West, J., Haefele, E., Alderman, J., Lane, W., and Collins, J. K., “A DNA diagnostic biosensor: development, characterisation and performance,” Sens. Actuators B (Chem.), vol. 68, pp. 100-108, 2000
22. Berdat, D., Marin, A., Herrera, F., and Gijs, M. A., “DNA biosensor using fluorescence microscopy and impedance spectroscopy,” Sens. Actuators B (Chem.), vol. 118, pp. 53-59, 2006
23. Berdat, D., Rodríguez, A. C. M., Herrera, F., and Gijs, M. A., “Label-free detection of DNA with interdigitated micro-electrodes in a fluidic cell,” Lab on a Chip, vol. 8, no. 2, pp. 302-308, 2008
24. Berggren, C., Bjarnason, B., and Johansson, G., “Capacitive biosensors”. Electroanalysis: An International Journal Devoted to Fundamental and Practical Aspects of Electroanalysis, vol.13, no. 3, pp. 173-180, 2001
25. Ghafar-Zadeh, E., Sawan, M., Chodavarapu, V. P., and Hosseini-Nia, T., “Bacteria growth monitoring through a differential CMOS capacitive sensor,” IEEE Trans. Biomed. Circ. and Syst., vol. 4, no. 4, pp. 232-238, 2010
26. Couniot, N., Francis, L. A., and Flandre, D., “A 16×16 CMOS capacitive biosensor array towards detection of single bacterial cell,” IEEE Trans. Biomed. Circ. and Syst., vol. 10, no. 2, pp. 364-374, 2015
27. Senevirathna, B. P., Lu, S., Dandin, M. P., Basile, J., Smela, E., and Abshire, P. A., “Real-time measurements of cell proliferation using a lab-on-CMOS capacitance sensor array,” IEEE Trans. Biomed. Circ. and Syst., vol. 12, no. 3, pp. 510-520, 2018
28. Abdelbaset, R., El-Sehrawy, Y., Morsy, O. E., Ghallab, Y. H., and Ismail, Y., “CMOS based capacitive sensor matrix for characterizing and tracking of biological cells,” Sci. Reports, vol. 12, no. 1, pp. 1-10, 2022
29. Laborde, C., Pittino, F., Verhoeven, H. A., Lemay, S. G., Selmi, L., Jongsma, M. A., and Widdershoven, F. P., "Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays," Nature Nanotechnol., vol. 10, pp. 791–796, 2015.
30. Kuo, Y. H., Chen, Y. S., Huang, P. C., and Lee, G. B., “A CMOS-based capacitive biosensor for detection of a breast cancer microRNA biomarker,” IEEE Open Journal of Nanotechnology, vol. 1, pp. 157-162, 2020
31. Alhoshany, A., Sivashankar, S., Mashraei, Y., Omran, H., and Salama, K. N., “A biosensor-CMOS platform and integrated readout circuit in 0.18-μm CMOS technology for cancer biomarker detection,” Sensors, vol. 17, no. 9, pp. 1942, 2017
32. Stagni, C., Guiducci, C., Benini, L., Riccò, B., Carrara, S., Paulus, C., and Thewes, R., “A fully electronic label-free DNA sensor chip,” IEEE Sensors J, vol. 7, no. 4, pp. 577-585, 2007
33. Musayev, J., Adlgüzel, Y., Külah, H., Eminoğlu, S., and Akln, T., “Label-free DNA detection using a charge sensitive CMOS microarray sensor chip,” IEEE Sensors J, vol. 14, no. 5, pp. 1608-1616, 2014
34. Helmholtz, H. V., “Studien über electrische Grenzschichten,” Annalen der Physik, vol. 243, no. 7, pp. 337-382, 1879
35. Gouy, M. J. J. P. T. A., “Sur la constitution de la charge électrique à la surface d'un electrolyte,” J. Phys. Theor. Appl., vol.9, no. 1, pp. 457-468, 1910
36. Chapman, D. L., “A contribution to the theory of electrocapillarity,” The London, Edinburgh, and Dublin philosophical magazine and journal of science, vol. 25, no. 148, pp. 475-481, 1913
37. Stern, O., “The theory of the electrolytic double-layer.” Z. Elektrochem, vol. 30, no. 508, pp. 1014-1020, 1924
38. Gao, N., Zhou, W., Jiang, X., Hong, G., Fu, T. M., and Lieber, C. M., “General strategy for biodetection in high ionic strength solutions using transistor-based nanoelectronic sensors,” Nano letters, vol. 15, no. 3, pp. 2143-2148, 2015
39. Elnathan, R., Kwiat, M., Pevzner, A., Engel, Y., Burstein, L., Khatchtourints, A., and Patolsky, F., “Biorecognition layer engineering: overcoming screening limitations of nanowire-based FET devices,” Nano letters, vol. 12, no. 10, pp. 5245-5254, 2012
40. Laborde, C., Pittino, F., Verhoeven, H. A., Lemay, S. G., Selmi, L., Jongsma, M. A., and Widdershoven, F. P., “Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays,” Nature nanotechnology, vol. 10, no. 9, pp. 791-795, 2015
41. Widdershoven, F., Cossettini, A., Laborde, C., Bandiziol, A., van Swinderen, P. P., Lemay, S. G., and Selmi, L., “A CMOS pixelated nanocapacitor biosensor platform for high-frequency impedance spectroscopy and imaging,” IEEE Trans. Biomed. Circ. and Syst., vol. 12, no. 6, pp. 1369-1382, 2018
42. Pandya, H. J., Kim, H. T., Roy, R., Chen, W., Cong, L., Zhong, H., and Desai, J. P., “Towards an automated MEMS-based characterization of benign and cancerous breast tissue using bioimpedance measurements,” Sens. Actuators B (Chem.), vol. 199, pp. 259-268, 2014