Modeling and Simulation of Electrochemical Biosensors based on CMOS LSI Chips

Shigeyasu Uno1
1
Ritsumeikan University, Kusatsu, Japan, suno@fc.ritsumei.ac.jp

Abstract Potentiometric Biosensors

Modeling and simulation of electrochemical In potentiometric biosensors, change in voltage
biosensors based on CMOS LSI chips are presented. difference between the sensing electrode (working
Underlying theories, simulation methods, and our electrode: WE) and another electrode to fix the
recent research results are explained for three major potential of sample solution (reference electrode:
electrochemical methods, namely, potentiometric, RE) is measured. When the WE is directly in contact
amperometric, and impedance methods. with sample solution, voltage is mainly determined
(Keywords: Modeling, Biosensor, Electrochemical) by electron transfer due to reduction and oxidation
of molecules (redox molecules) in the sample
Introduction
solution, and it is read-out by high input impedance
Population aging in developed countries and
voltage sensor as shown in Fig. 1(a). The voltage
insufficient medical support in developing countries
dependence on redox molecule concentrations is
have given rise to the need for medical tests by
given by the Nernst equation Eq. (1) in Fig. 2, where
portable, affordable, and semi-automated devices for
V is the measured voltage, V0 is a constant, R is the
use outside large hospitals. Such testing is often
gas constant, T is the temperature, n is the number of
referred to as point-of-care testing (POCT) or
electrons transferred between a redox molecule and
over-the-counter (OCT) medicine [1]. Such devices
the WE, F is the Faraday’s constant, and Cred and Cox
can also be used as sensor nodes for the
are the concentrations of reduced and oxidized
internet-of-things (IoT), and the collected data are
forms of the redox molecule, respectively.
used to improve unhealthy lifestyle or to
Meanwhile, when the WE is covered by an
prevent/predict illness in advance. Typical
ion-sensitive insulating membrane as in Fig. 1(b),
specimens of the POCT/OCT devices are blood and
the voltage is mainly affected by the ionic charging
urine, while tear, saliva, and exhaled gas are used in
at the membrane surface. The ion concentration aion
research and development stage. In such specimens,
replaces the redox molecule concentration term in
concentrations of specific analytes are of medical
the Nernst equation as shown in Eq. (2), leading to
importance. Therefore, the devices are equipped
the well-known relation for pH sensor. The
with biosensors to measure those analytes in a
ion-sensitive filed-effect transistors (ISFETs) can be
chemical manner. Among various methods,
regarded as a potentiometric sensor, where the WE
electrochemical methods offer advantages such as
is connected to (extended-gate ISFET, Fig. 1(c)) or
small equipment size and quantitative data. An
replaced by (Fig. 1(d)) a MOSFET. The voltage
electrochemical biosensor often consists of an
change occurs in the solution near the ion-sensitive
electrode in contact with specimen solution, surface
membrane, and it appears as a flatband voltage shift
modification layer for specific ion/molecule/protein
in the transistor. Therefore, in simulation of ISFET
recognition, and read-out sensor circuit. In realizing
operation, it is often sufficient to describe the
such electrochemical biosensors, a complementary
electrostatic potential distribution in the solution,
metal-oxide-semiconductor (CMOS) large-scale
which is known to be governed by the
integrated (LSI) circuit chip can be an ideal platform
Poisson-Boltzmann equation Eq. (3) [2], where ψ(x)
because of miniaturization of the electrodes,
is electrostatic potential in the solution, e the
massively-parallel sensing by microscale sensor
elementary charge, εel dielectric constant of the
array, and integration with electronic circuits. In
sample solution, c0 the ion concentration, ζ the ionic
actual R&D of electrochemical biosensors based on
valence, kB the Boltzmann constant, and T the
CMOS LSI chips, modeling and simulation of
temperature. For pH sensors, surface charge at the
electrochemical biosensors play an important role in
membrane/solution interface is given by the
prediction/optimization in sensor and circuit design.
site-binding model Eqs. (4) and (5) [3], where [H+]s
In this paper, underlying theories, practical
and [H+]b are the surface and bulk H+ concentrations,
simulation methods, and our recent research
Nsil and Nnit are the densities of –OH and –NH2 sites,
outcomes regarding the modeling and simulation of
K+, K-, KN+ are dissociation constants, and ψdl is the
electrochemical biosensors based on CMOS LSI
potential drop across the electric double layer.
chips are presented.
978-1-5386-6508-4/19/$31.00 ©2019 IEEE 2019 Electron Devices Technology and Manufacturing Conference (EDTM)
Solving Eq. (3) with the surface charge Eqs. (4) and and intuitive way is to represent the whole system
(5) at flatband condition will give flatband voltage by an equivalent electric circuit model (ECM) as
shift due to pH change. Similarly, flatband voltage shown in Fig. 1(g), where ion conduction in the bulk
shift due to charged biomolecules such as DNA or solution and ion accumulation at the
antigen/antibody on the sensing membrane can be electrode/solution interface are represented by
simulated by modeling mobile ion charge resistance and capacitance, respectively.
distribution around the charged biomolecules [4-6]. Biomolecules or cells on the WE/CE are regarded as
additional resistance or capacitance components.
Amperometric Biosensors
More rigorous method is to simulate the transport of
In amperometric biosensors, electric current
both positive and negative ions by solving the
generated by direct electron transfer due to
drift-diffusion (DD) equation with ion concentration
reduction/oxidation of redox molecules at the WE is
based on Boltzmann statistics. It gives
measured under certain voltage bias, and the
time-dependent ionic charge conduction and
measured current is converted to voltage signal
distribution under certain biomolecule model and
using trans-impedance amplifier, as shown in Fig.
electrode geometry. Simulation can be done by
1(e). The governing equation is simply the diffusion
representing the solution as a semiconductor and
equation for redox molecules Eq. (6), where CX
using TCAD device simulators. This approach is
denotes concentration of reduced/oxidized forms of
necessary only when detailed ion conduction and
redox molecules and DX the diffusion constant. The
distribution around biomolecules must be simulated
electron transfer due to the redox reaction is
down to several nano-meter scale. However, such
described by the Butler-Volmer equation Eq. (7) [7],
detailed description is not necessary for simulating
where n is the number of electrons per redox
impedance change due to living cells having a size
reaction, F the Faraday constant, k0 the electron
of approximately several decades of micro-meter.
transfer rate coefficient, R the gas constant, T the
Therefore, in simulation of such impedance change
temperature, α the transfer coefficient, and V – V0
due to living cell, ion conduction is simply
term is the voltage bias from the equilibrium
described by solving Maxwell’s equation. The ion
condition. Eq. (7) describes the current density at the
charge accumulation near the solid/liquid interface
WE due to the redox reaction, and it also describes
is simply described by a boundary condition
the conversion rate between reduced or oxidized
representing a capacitor. Such a simulation can be
forms of redox molecules at the electrode surface.
easily done with commercially-available FEM
Solving Eq. (6) with Eq. (7) will give
software such as COMSOL Multiphysics, and is
time-dependent current behavior under constant or
advantageous for three-dimensional (3D) simulation
time-varying voltage bias in a given electrode
of impedance change due to living cells near the WE.
geometry. We have simulated microscale electrode
We have recently demonstrated 3D simulation of
array used for simultaneous redox current sensing
impedance change due to single living (bacterial)
on CMOS LSI chip, and proposed a new electrode
cell on microscale electrodes on CMOS LSI chip [9].
structure for rapid/enhanced current detection [8].
As shown in Fig. 3, impedance value is affected by
Impedance Biosensors existence/absence of a tiny bacterial cell on a
In impedance biosensors, impedance between two microelectrode in 106 – 107Hz range, which might
electrodes in direct contact with the sample solution be detected by integrated impedance measurement
is measured, as shown in Fig. 1(f). The electrodes circuit on the same chip.
used are often referred to as the working electrode
WE and counter electrode CE, respectively. The AC Conclusion
The three major electrochemical biosensing methods
current conduction in the sample solution is due
have been reviewed. Our recent research results
mainly to the mobile ions, and the conduction and
regarding electrochemical impedance biosensors on
spacial distribution of such ions represent the state
CMOS LSI chips have also been presented.
of biomolecules on the sensing electrodes or living
cells nearby. Modeling and simulation of such References
impedance can be done in many ways. The simplest [1] National Institute of Health, "Fact sheet:

2019 Electron Devices Technology and Manufacturing Conference (EDTM)

 Point-of-care diagnostic testing", 2010. [7] A. J. Bard and L. R. Faulkner, “Electrochemical
[2] M. W. Shinwari et al., Microelectronics
Methods: Fundamentals and Applications”,
Reliability vol. 47, pp. 2025-2057 (2007).
[3] S. Martinoia et al., Sensors and Actuators B, John Wiley & Sons, Inc. New York (2001).
vol. 105, p. 14 (2005). [8] J. Hasegawa et al., Jpn. J. Appl. Phys., vol. 50,
[4] S. Uno et al., Jpn. J. Appl. Phys., vol. 49, no. 1, p. 04DL03 (2011).
p. 01AG07 (2010). [9] S. Uno, The 11th International Symposium on
[5] Y. Nishio et al., Jpn. J. Appl. Phys., vol. 52, p. Electrochemical Micro & Nanosystem
04CL01 (2013). Technologies (EMNT2016), Brussel, Belgium
[6] S. Uno, SPIE BIOS, San Francisco, USA (August 17-19, 2016), P-18.
(January 26, 2012) 8231-28.

(a) Redox molecules (b) (c) (d)

RE RE Ion-sensitive membrane RE Ion-sensitive membrane RE Ion-sensitive membrane
Solution Reduction/oxidation Ions Ions Ions
CMOS Passivation
WE Metal WE WE
G S D
OUT OUT Substrate
S D
Voltage sensor Voltage sensor MOSFET ISFET

(e) Redox molecules (f) Ions (g) R

RE
Solution Reduction/oxidation Biomolecules
CMOS Passivation C C
WE Metal WE CE WE CE
OUT Impedance sensing circuit
Trans-impedance amplifier

Fig. 1: Schematic diagrams of three major electrochemical biosensor operation principles.

RT  Cox  RT RT d2 2eζ c0  eζ 
V = V0 + ln   (1) V = V1 + ln ( aion ) = V1 − ln (10 ) pH  ( 2 ) ψ ( x) = sinh  ψ ( x )  ( 3)
nF  Cred  F F dx 2 ε el k
 B T 
 2
 H +  − K + K −    H +  
Qsb = eNsil  s  + eN  s
  ( 4 )  H +  =  H +  e − eψ dl kBT
 ( 5)
 H+  2 + K H+  + K K  nit
  H +  + K N +  s bulk
  s +  s + −   s 
∂CX ( x, t ) ∂ 
∂t
∂ 
+  − DX CX ( x, t )  = 0  ( 6 )
∂x  ∂x 
( 1−α ) nF (V −V0 ) RT
J = nFk0 CR ( 0, t ) e( − CO ( 0, t ) e
−α nF (V −V0 ) RT
)( 7 )
Fig. 2: Equations used in modeling and simulation of electrochemical biosensor operation.

Fig. 3: Simulation of impedance-based sensing of single bacterial cell on CMOS chip.

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