(Invited) Electrochemical Biosensors Based on CMOS LSI Chips
Authors: Uno Shigeyasu 
Published: February 2020

Electrochemical biosensors are the sensors for bio-related substances/phenomena based on electrochemical principles. While optical and colorimetric biosensors are widely used for clinical and research purposes, electrochemical biosensors offer various advantages such as compact/affordable instrumentation and high throughput. As a platform of such electrochemical biosensors, a complementary metal-oxide-semiconductor (CMOS) large-scale integrated (LSI) circuit chip can be an ideal platform for its microscale structures and electronic circuit integration. In this paper, general overview and some examples of such CMOS-based electrochemical sensing experiments/simulations are presented.
The electrochemical methods can be categorized into three types, that is, (i) amperometoric and voltammetric method, (ii) potentiometric method, and (iii) impedance method. In the amperometric method, electrochemical current is measured as a function of time under constant voltage application, while voltammetric method often means that the voltage is swept and current vs. voltage is plotted. On the other hand, in potentiometric method, no voltage is applied and therefore no current will be induced. Instead, open-circuit potential of a floating electrode in contact with sample solution is measured. Finally, in impedance method, the relation between sinusoidal voltage applied to the sample solution and resulting sinusoidal current is measured as a complex valued impedance.
We have been working on various CMOS-based electrochemical biosensing experiments and simulations. Experimental demonstrations of amperometric and voltammetric methods can been seen in [1, 2], where carbon-ink electrodes are formed on CMOS chip and used to measure current under constant/swept voltages. Computer simulation of amperometric measurement using CMOS on-chip electrode has also been presented in [3]. As for the potentiometric method, we have demonstrated a potentiometric glucose sensor with carbon electrode and enzyme-functionalized chromatography paper on CMOS chip [4]. Computer simulation of ion-sensitive field-effect transistors (ISFET) for DNA sensing [5, 6] and lipid bilayer (cell membrane) detection [7] have also been demonstrated. In terms of impedance measurement using CMOS, we have developed a computationally efficient three-dimensional model of electrolytic solution and living cells for finite-element method (FEM) simulation. Using this, we have demonstrated computer simulation of impedance measurement of single mammalian cell or bacterial cell using microscale electrode on CMOS chip [8, 9]. Compact formulae for equivalent circuit model of such cell/electrolyte/electrode system have demonstrated a good accuracy [9]. Our current goal is the experimental implementation of such single cell monitoring by impedance measurement using CMOS on-chip microelectrodes.
In summary, we have been developing both experimental and simulation techniques of the major electrochemical biosensing methods using CMOS on-chip microelectrodes. Such effort would lead to a comprehensive understanding of multi-modal electrochemical biosensing where CMOS LSI chips are used as a platform.
This work was partially supported by JSPS KAKENHI Grant Numbers 25220906 and 26289111, as well as VLSI Design and Education Center (VDEC), the University of Tokyo in collaboration with Synopsys, Cadence Design Systems, and Mentor Graphics.
[1] M. Miki, S. Iwahara, and S. Uno, “A hybrid system of carbon ink electrodes and chromatography paper on a CMOS chip and its application to Enzymatic glucose sensor”, Jpn. J. Appl. Phys., vol. 53, p. 04EL06 (2014).
[2] J. Eguchi, K. Yamaoka, and S. Uno, “Simultaneous Electrochemical Measurement using Paper Fluidic Channel on CMOS Chip”, TELKOMNIKA, vol. 15, no. 2, pp. 847-852 (2017).
[3] J. Hasegawa, S. Uno, and K. Nakazato, “Amperometric Electrochemical Sensor Array for On-Chip Simultaneous Imaging: Circuit and Microelectrode Design Considerations”, Jpn. J. Appl. Phys., vol. 50, p. 04DL03 (2011).
[4] K. Yamaoka, J. Eguchi, and S. Uno, “Potentiometric Glucose Detection by Paper-based Electrochemical Sensor on CMOS Chip”, TELKOMNIKA, vol. 15, no. 2, pp. 836-841 (2017).
[5] Y. Nishio, S. Uno, and K. Nakazato, “Three-Dimensional Simulation of DNA Sensing by Ion-Sensitive Field-Effect Transistor: Optimization of DNA Position and Orientation”, Jpn. J. Appl. Phys., vol. 52, p. 04CL01 (2013).
[6] S. Uno, M. Iio, H. Ozawa, and K. Nakazato, “Full Three-dimensional Simulation of ISFET Flatband Voltage Shift due to DNA Immobilization and Hybridization”, Jpn. J. Appl. Phys., vol. 49, no. 1, p. 01AG07 (2010).
[7] S. Uno, “Computer simulation of lipid bilayer detection using ion-sensitive field-effect transistors” SPIE BIOS, San Francisco, USA (January 26, 2012) 8231-28.
[8] S. Uno, “Simulation of Microelectrode Electrochemical Impedance Sensor for Single-cell Monitoring”, The 11th International Symposium on Electrochemical Micro & Nanosystem Technologies (EMNT2016), Brussel, Belgium (August 17-19, 2016), P-18.
[9] S. Uno, and K. Nakazato “Numerical and Equivalent Circuit Analysis of Electrochemical Impedance Spectroscopy of Single Bacterial Cell Detection using CMOS LSI Chip”, 11th International Symposium on Electrochemical Impedance Analysis 2017, Camogli, Italy (November 7-11, 2017).