生化感測器是由生化接收器及傳感器所組成，生化接收器利用特定的生物分子捕捉待測分析物，而傳感器轉譯所捕捉的待測分析物成為可量測的信號，隨著CMOS製程的演進，於矽晶片上製作積體化的傳感器成為必要發展。本論文提出了針對可攜式與可拋棄式應用的簡易讀取電路，完整的功能必須盡可能完成在單一晶片上以達到取代醫院或實驗室傳統大型裝置的目的，專題所設計的系統萃取及數位化生化感測器的導納，亦即阻抗的倒數，包含實部與虛部部分以特徵化其特性。和傳統的讀取電路相比較，所提出的改良式讀取電路其提高了製程容忍度，降低近十倍的增益誤差，所帶來的好處是毋須設計校正電路以解決製程飄移所造成錯誤的阻抗偵測，並且晶片與晶片間的阻抗結果差異可大幅縮減以提高偵測結果的可信度。晶片以台積電CMOS 0.18微米製程實現，在1.8伏特電源供應下消耗功率為36微瓦、僅佔據0.0778平方公釐的核心面積，輸出為9位元的二補數數位訊號，其對應0.9861及0.9998的振幅與相位轉換線性度。

Biosensors consist of a bio receptor and a transducer. A bio receptor captures the analytes of interest with its specific biomolecules, and a transducer translates the captured analytes into measureable signals. With the progress of CMOS process, there is a need to build an integrated transducer onto a silicon chip. In this thesis, compact readout circuit is proposed in applications of portable and disposable devices. Thus, functions must be implemented as complete as possible to replace the bulky instruments which lie in hospital or laboratory. The designed system extracts and digitizes the real and imaginary portion of admittance, the reciprocal of impedance, from biosensors to characterize its behaviors. Compared to traditional readout circuits, our proposed readout circuits enhance process tolerance, and reduce the gain error approximately 10 times lower than previous works. The benefits are more accurate impedance results over corner variations without any calibration unit, and lower difference of impedance value from chip to chip to acquire a more reliable results of detection. Fabricated in TSMC 0.18-um CMOS process, the chip consumes 36uW of power at 1.8V supply, and occupies only 0.0778 mm2 of core area. The 9-bit 2’s complement digital outputs correspond respectively to 0.98609 and 0.9998 of amplitude and phase conversion linearity.

[1] Y.-L. Liao, H. Yao, L. A. et al., “A 3-uW glucose sensor for wireless contact-lens tear glucose monitoring,” IEEE J. Solid-State Circuits, vol. 47, no. 1, pp. 335-344, Jan., 2012.
[2] W.-D. Huang, S. Deb, Y.-S. Seo et al., “A passive radio-frequency pH-sensing tag for wireless food-quality monitoring,” IEEE Sensors J., vol. 12, no. 3, pp. 487-495, Mar., 2012.
[3] H. T. Chen, K. T. Ng, A. Bermak et al., “Spike latency coding in biologically inspired microelectronic nose,” IEEE Trans. Biomedical Circuits and Systems, vol. 5, no. 2, pp. 160-168, Apr., 2011.
[4] M. Schienle, C. Paulus, A. Frey et al., “A fully electronic DNA sensor with 128 positions in-pixel ADC,” IEEE J. Solid-State Circuits, vol. 39, no. 12, pp. 2438-2445, Feb., 2004.
[5] A. Hassibi, H. Vikalo, J. L. Riechmann et al., “Real-time DNA microarray analysis,” Nucleic Acids Res, vol. 37, no. 20, pp. e132, Nov, 2009.
[6] J. S. Daniels, and N. Pourmand, “Label-free impedance biosensors: opportunities and challenges,” Electroanalysis, vol. 19, no. 12, pp. 1239-1257, May, 2007.
[7] J.-Z. Bao, C. C. Davis, and R. E. Schmukler, “Impedance spectroscopy of human erythrocytes: system calibration, and nonlinear modeling,” IEEE Trans. Biomedical Engineering, vol. 40, no. 4, pp. 364-378, Apr., 1993.
[8] M. Min, T. Parve, V. Kukk et al., “An implantable analyzer of bio-impedance dynamics mixed signal approach,” IEEE Trans. Instrum. Meas., vol. 51, no. 4, pp. 674-678, Aug., 2002.
[9] M. Min, and T. Parve, “Improvement of lock-in electrical bio-impedance analyzer for implantable medical devices,” IEEE Trans. Instrum. Meas., vol. 56, no. 3, pp. 968-974, Jun., 2007.
[10] C. Yang, D. Rairigh, and A. Mason, “Fully integrated impedance spectroscopy systems for biochemical sensor array,” in Biomedical Circuits and Systems Conf., Montreal, Canada, 2007, pp. 21-24.
[11] H. M. Jafari, and R. Genov, “CMOS impedance spectrum analyzer with dual-slope multiplying ADC,” in Biomedical Circuits and Systems Conf., San Diego, CA, 2011, pp. 361-364.
[12] C. Yang, S. R. Jadhav, R. M. Worden et al., “Compact low-power impedance-to-digital converter for sensor array microsystems,” IEEE J. Solid-State Circuits, vol. 44, no. 10, pp. 2844-2855, Oct., 2009.
[13] X. Liu, D. Rairigh, and A. Mason, “A fully integrated multi-channel impedance extraction circuit for biosensor arrays,” in Int. Symp. Circuits and Systems, Paris, 2010, pp. 3140-3143.
[14] R. Bashir, and S. Wereley, Biomolecular sensing, processing and analysis: Springer, 2006.
[15] Wikipedia. "ELISA," http://en.wikipedia.org/wiki/ELISA.
[16] S.-J. Park, T. Andrew Taton, and C. A. Mirkin, “Array-based electrical detection of DNA with nanoparticle probes,” Science, vol. 295, pp. 1503-1506, Feb., 2002.
[17] S. P., “Use of surface plasmon resonance to probe the equilibrium and dynamic aspects of interactions between biological macromolecules,” Annu Rev Biophys Biomol Struct., vol. 26, pp. 541-566, 1999.
[18] S. Susmela, C. K. O'Sullivana, and G. G. Guilbaulta, “Human cytomegalovirus detection by a quartz crystal microbalance immunosensor,” Enzyme and Microbial Technology, vol. 27, no. 9, pp. 639-645, Mar., 1999.
[19] C. Ziegler, “Cantilever-based biosensors,” Anal Bioanal Chem, vol. 379, no. 7-8, pp. 946-59, Aug., 2004.
[20] R. P. Ekins, “Ligand assays: from electrophoresis to miniaturized microarrays,” Clinical Chemistry, vol. 44, no. 9, pp. 2015-2030, Sep., 1998.
[21] K. R. Rogers, “Principles of affinity-based biosensors,” Molecular Biotechnology, vol. 14, no. 2, pp. 109-129, Feb., 2000.
[22] J. R. Macdonald, “Impedance spectroscopy,” Annals of Biomedical Engineering, vol. 20, pp. 289-305, 1992.
[23] J. Macdonald, “Impedance spectroscopy: models, data fitting, and analysis,” Solid State Ionics, vol. 176, no. 25-28, pp. 1961-1969, May, 2005.
[24] D. Rairigh, A. Mason, and C. Yang, “Analysis of on-chip impedance spectroscopy methodologies for sensor arrays,” Sensor Lett., vol. 4, no. 4, pp. 398-402, Sep., 2006.
[25] D. A. Johns, and K. Martin, "Analog integrated circuit design," 13, Wiley, 1997, p. 487.
[26] R. Schreier, and T. Caldwell. "Noise in SC circuits," http://individual.utoronto.ca/schreier/lectures/10-6.pdf.
[27] M. Waltari, and K. Halonen, “Bootstrapped switch without bulk effect in standard CMOS technology,” Electronics Lett., vol. 38, no. 12, pp. 555-557, Jun., 2002.
[28] R. J. Baker, CMOS, 3rd ed.: John Wiley & Sons, Inc., 2010.
[29] R. A. Blauschild, P. A. Tucci, R. S. Muller et al., “A new NMOS temperature-stable voltage reference,” IEEE J. Solid-State Circuits, vol. 13, no. 6, pp. 767-774, Dec., 1978.
[30] E. A. Vittoz, and O. Neyroud, “A low-voltage CMOS bandgap reference,” IEEE J. Solid-State Circuits, vol. 14, no. 3, pp. 573-579, Jun., 1979.
[31] K. Ishibashi, K. Sasaki, and H. Toyoshima, “A voltage down converter with submicroampere standby current for low-power static RAM's,” IEEE J. Solid-State Circuits, vol. 27, no. 6, pp. 920-926, Jun., 1992.
[32] A.-J. Annema, “Low-power bandgap references featuring DTMOSTs,” IEEE J. Solid-State Circuits, vol. 34, no. 7, pp. 949-955, Jul., 1999.
[33] A. Becker-Gomez, T. Lakshmi Viswanathan, and T. R. Viswanathan, “A low-supply-voltage CMOS sub-bandgap reference,” IEEE Trans. Circuits Syst. II: Express Briefs, vol. 55, no. 7, pp. 609-613, Jul., 2008.
[34] G. De Vita, and G. Iannaccone, “An ultra-low-power, temperature compensated voltage reference generator,” in Custom Integrated Circuits Conf., San Jose, CA, 2005, pp. 751-754.
[35] S. Ying, J. Song, and Z. Baoying, “A precise curvature compensated CMOS bandgap voltage reference with sub 1V supply,” in Int. Conf. Solid-State and Integrated Circuit Technology, Shanghai, 2006, pp. 1754-1756.
[36] S. Katare, “Resistorless low power voltage reference circuit,” in European Conf. Circuits and Systems for Communications, Belgrade, 2010, pp. 100-102.
[37] Y. Yang, D. M. Binkley, L. Li et al., “All-CMOS subbandgap reference circuit operating at low supply voltage,” in IEEE Int. Symp. Circuits and Systems (ISCAS), Rio de Janeiro, 2011, pp. 893-896.
[38] H. Lin, and D.-K. Chang, “A low-voltage process corner insensitive subthreshold CMOS voltage reference circuit,” in IEEE Int. Conf. Integrated Circuit Design and Technology, Padova, 2006, pp. 1-4.
[39] H. C. Lai, and Z. M. Lin, “An ultra-low temperature-coefficient CMOS voltage reference,” in IEEE Conf. Electron Devices and Solid-State Circuits, Tainan, 2007, pp. 369-372.
[40] S. K. Wadhwa, “A low voltage CMOS bandgap reference circuit,” in IEEE Int. Symp. Circuits and Systems (ISCAS), Seattle, WA, 2008, pp. 2693-2696.
[41] S. R. Tiyyagura, and S. Katare, “Low power voltage reference architectures,” in Int. Symp. Signals, Circuits and Systems Iasi, 2009, pp. 1-4.
[42] M. M. Mano, Digital design, 3rd ed., 2002.
[43] C. Yang, D. Rairigh, and A. Mason, “On-chip electrochemical impedance spectroscopy for biosensor arrays,” in Sensors, Daegu, 2006, pp. 93-96.
[44] Barnston, and A. G., “Correspondence among the correlation, RMSE, and Heidke forecast verification measures; refinement of the Heidke score,” Weather and Forecasting, vol. 7, no. 4, pp. 699-700, Dec., 1992.