Sensors and Actuators B 105 (2005) 14–27

Modeling ISFET microsensor and ISFET-based microsystems: a review

Sergio Martinoia a,∗ , Giuseppe Massobrio a , Leandro Lorenzelli b
a Department of Biophysical and Electronic Engineering (DIBE), University of Genova, Via all’Opera Pia 11/A, Genova 16145, Italy
b ITC-Irst Microsystems Division, Via Sommarive, 18, 38050 Trento, Italy

Available online 30 April 2004

Abstract

Silicon technology is one of the most promising for sensor development. Moreover, electronic simulation tools, originally introduced to
design electronic circuits, can be adapted to design silicon-based chemical- and bio-sensors. These considerations lead to the description
of the models we developed and implemented in the program SPICE for simulating ion-sensitive field-effect transistors (ISFETs) and
ISFET-based microsystems. The implementation in SPICE and the simulation results are described in terms of each model. In particular, a
new model of a Si3 N4 -gate ISFET operating under subthreshold conditions and the related electrochemical characterization are presented.
The ISFET models were then used to develop a CAD system that can be considered as a general-purpose tool for designing integrated
ISFET-based sensors and microsystems with on-chip processing and control capabilities.
© 2004 Elsevier B.V. All rights reserved.

Keywords: ISFET-based sensors; ISFET-based microsystems; ISFET technology; Multisensor chip; pH sensitivity; SPICE built-in models; SPICE
macromodels; Subthreshold condition

1. Introduction food industry, and general analytical applications [26–37]. In

Silicon technology is widely used for sensor develop-
ment; it offers the advantage to integrate, on the same chip,
different sensors and their related signal amplification and
processing circuits. Moreover, computer aids in the form of
powerful design and simulation programs are available; orig-
inally developed for designing and simulating electronic cir-
cuits, these programs can be adapted to design silicon-based
chemical- and bio-sensors. This point is considered in this re-
view, with reference to the modifications we made in the pro-
gram SPICE [1,2] to simulate the ion-sensitive field-effect
transistor (ISFET) [3–5], also operating under subthresh-
old conditions, and ISFET-based microsystems. Since the
first reports of a chemically sensitive electronic device by
Bergveld [3,4], research was carried out along three main
ways: (a) extension of the sensitivity to ions other than H+
ions [6–12], (b) explanation of the mechanisms of opera-
tion of the pH-sensitive gate ISFET [13–19], and (c) de-
velopment of physical–chemical models to be used with
semiconductor-based device simulation programs [20–25].
Initially developed for pH detection, ISFETs were also pro-
posed and used for biomedical, agriculture, environmental,
∗ Corresponding author. Tel.: +39-010-3532251;
fax: +39-010-3532133.
E-mail address: martinoia@dibe.unige.it (S. Martinoia).
particular, the compatibility with standard microelectronic
fabrication processes, and the possibility of developing in-
telligent ISFET-based microsystems, by integrating on the
same chip the sensors together with the related electronic
circuitry for signal conditioning and amplification, were also
investigated [38–40]. Nowadays, ISFETs are commercially
available from several companies (e.g. Orion, Orion Re-
search, Boston, MA; Corning, New York, NY; Sentron Inte-
grated Sensor Technology, Roden, The Netherlands). Nev-
ertheless, further improvements and investigations of ISFET
performances are needed to promote their use in microsys-
tems for specific applications. Difficulties arise not only from
technological issues, but also from the lack of considering
first-order mechanisms such as the effects of drift, hystere-
sis, and temperature. These limiting operating conditions are
particularly relevant in respect of possible applications of
ISFET-based microsystems in industrial control and moni-
toring of processes (e.g. biofermenters for biotechnological
applications) or where temperature cannot be a controlled
parameter. In this work, we considered, as a basic device,
a pH-ISFET with an insulator layer (e.g. Si3 N4 , Al2 O3 ) as
a sensitive surface. The response of this device (model) to
pH is explained by considering H+ specific binding sites
at the surface of the insulator exposed to the electrolyte.
The developed models take into account also non-ideal ef-
fects such as drift, hysteresis [41,42], the limiting case of

0925-4005/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.snb.2004.02.046
 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27
partial insensitivity to pH, i.e. reference field-effect tran-
sistor (REFET) [5,41,43], and the effects of temperature
on the characteristics of the ISFET over user-defined pH
and temperature ranges [44–47]. This approach allowed us
to develop two kinds of models for the ISFET: a built-in
model and a macromodel. The built-in model is a sophisti-
cated physical–chemical model that fully characterizes the
ISFET behavior, but it needs the availability of the program
source and a deep knowledge of the code structure. This
model was implemented into SPICE version 2G [1] result-
ing in a new simulation program called BIOSPICE [48]. The
macromodel is a behavioral model of the ISFET, less accu-
rate than the built-in model, but more general, user-friendly,
and it can be used in conjunction with the most commer-
cially available SPICE versions, such as HSPICE [49] and
PSPICE [50]. The implementation in SPICE and the simu-
lation results are described in terms of each model. These
models were then used to develop a general and complete
CAD system [39], which makes use of an ad hoc tech-
nology [ISFET/CMNOS (ion-sensitive field-effect transis-
tor/complementary metal nitride-oxide semiconductor) tech-
nology] [51], for designing and fabricating ISFET-based mi-
crosystems. The ISFET/CMNOS technology combines IS-
FET fabrication technology and CMOS IC processes. The
developed CAD system can be considered as a general pur-
pose tool for designing integrated microsystems based on
ISFET sensors also operating under subthreshold conditions.
Specific examples of microsystems design and fabrication
oriented to biomedical applications were carried out (e.g.
on-line detection of micro-organisms in waters [38], and
on-line cell population metabolism monitoring [52]).
2. ISFET built-in model formulation
The ISFET is a MOSFET-based device (i.e. a MOSFET
without the gate metallization) that uses an exposed gate in-
sulator to measure ion concentrations or local changes of
Fig. 1. n-Channel ISFET structure. The voltage drops relevant to the model are indicated. OHP indicates the outer Helmholtz plane.
15
charge densities in electrolyte solutions (Fig. 1). The re-
sponse of the ISFET to H+ concentration (pH) is explained
using the so-called site-binding theory, which describes the
charging mechanism of an oxide as the equilibrium between
surface groups and H+ ions in the bulk of the solution. This
theory, together with the Gouy–Chapman–Stern model of
the potential profile in the electrolyte, and with the MOS-
FET physics, gives a complete description of the ISFET.
As a result, a set of equations was derived and in-
troduced into SPICE to predict the pH sensitivity and
the dependence on the physical–chemical parameters
of the ISFET. This set of equations characterizes the
electrolyte–insulator–semiconductor (EIS) structure [22,23],
which is the heart of the ISFET. A p-type semiconduc-
tor and a Si3 N4 insulator (which implies two kinds of
binding sites) exposed to an electrolyte (1:1 salt solution),
were considered. The choice of 1:1 salt solution is based
on the fact that for typical biological applications, elec-
trolyte solutions can be well approximated by a NaCl (or
KCl) solution. For more complex electrolyte solutions, the
model should be expanded in order to numerically solve
the Poisson–Boltzmann equation [53].
2.1. Static model
The goal of the model is to obtain a relationship of
the form pH = f(ϕeo ), ϕeo being the potential of the
electrolyte–insulator interface. For this purpose, we first
considered the condition of charge neutrality of the system
of Fig. 1, i.e.
σd + σ0 + σmos + σb = 0 (1)
where σ d is the charge density in the diffuse layer
(Gouy–Chapman–Stern theory [53]), σ 0 the charge den-
sity at the electrolyte–insulator interface, σ mos the charge
density in the semiconductor (derived from the physics of
the MOSFET [37]), and σ b is the charge density of the
buried layer. The buried layer consists of a small fraction of
16 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27
binding sites (about 10%) positioned about 3 nm inside the
insulator surface, so that OH− and H+ groups can react with
them at the end of a diffusion process. Then, we applied the
site-binding theory and the electrical double-layer theory
[18,53,54] to write each component of Eq. (1) as function
of the electrical–chemical parameters of the ISFET. This
approach results into a system of equations whose solution
gives the electrolyte–insulator potential ϕeo . Here, only the
charge density σ 0 is indicated (see Eq. (2)); it points out the
dependence of the electrolyte–insulator interface potential
on the chemical properties of the ISFET insulator surface.
If silanol sites and basic primary amine sites are assumed
to be present on the insulator surface after oxidation in
electrolyte solution, it can be written as:


σ0 [H+ ]2s − K+ K− Nsil
= + +
qNs [H ]s + K+ [H ]s + K+ K− Ns
2


[H+ ]s Nnit
+ (2)
[H+ ]s + KN+ Ns
where K+ , K− , and KN+ are the dissociation constants,
[H+ ]s is the proton concentration at the electrolyte–insulator
interface, Nsil and Nnit are the surface densities of silanol
sites and of primary amine sites, respectively, and Ns is the
total number of binding sites given by [23]:
Ns = (1 + η)(Nsil + Nnit )
In Eq. (3) the parameter η is the fraction of buried sites;
when η = 0 (i.e. no hysteresis present) the ideal pH-ISFET
results.
Details about the solution of the system of equations (from
now on called “EIS system”) that describes an ISFET with
two kinds of binding sites (i.e. with a Si3 N4 insulator) and
non-ideal effects can be found in [22,23,41,45,46]. The de-
veloped model was also used to simulate REFET structures
[41]. In fact, partially pH-insensitive materials such as Teflon
or Parylene can be modeled by considering the chemical
equilibrium equation between the surface sites –COOH and
–COH of the organic membrane and protons.
Finally, the electrochemical properties of the insulator
surface were combined with the physics of the MOSFET
(the starting structure of the ISFET), resulting in an expres-
sion for the ISFET threshold voltage including terms derived
from MOSFET theory as well as terms that are electrochem-
ical in nature:
Vth (ISFET) = (Eref + ϕlj ) − (ϕeo − χe )
 
QSS + QSC φSC
− − 2ϕf +
Cox q The developed model takes into account also the
φm
= Vth (MOSFET)+Eref +ϕlj +χe −ϕeo −
q
In Eq. (4), ϕf is the Fermi potential of the semicon-
ductor (p-type for the n-channel ISFET considered here),
QSS is the fixed surface-state charge density per unit area
at the insulator–semiconductor interface, QSC is the semi-
conductor surface depletion region charge density per unit
area, Eref = (Erel + Eabs ) is the potential of the reference
electrode (Ag/AgCl considered here) relative to hydrogen
electrode, ϕlj is the liquid-junction potential difference be-
tween the reference solution and the electrolyte, ϕeo is the
potential of the electrolyte–insulator interface that deter-
mines the ISFET sensitivity to proton concentration, χe is
the electrolyte–insulator surface dipole potential, φSC is the
semiconductor work function, and φm is the work function of
the metal gate (reference electrode) relative to vacuum. The
terms in Eq. (4) are practically constant with respect to pH,
except the potential ϕeo that depends on the pH parameter.
Once the potential ϕeo was calculated from the solution
of the “EIS system”, the ISFET static model is obtained
by considering the threshold voltage Vth(ISFET) in the I–V
equations of the MOSFET, i.e.
Ids = 21 β(Vgs − Vth(ISFET) )2 (saturation region) (5)
 
Ids = β (Vgs − Vth(ISFET) ) − 21 Vds Vds (linear region)
(6)
where β = (µCox W/L), and µ, W, and L are the electron
mobility, the channel width, and length, respectively.
(3)
2.2. Large-signal model
The insulator capacitance of the ISFET is sensitive to the
ionic activity of the electrolyte. This capacitance consists
of two elements connected in series: the MOSFET insulator
capacitance Cox , and the Helmholtz layer capacitance CH ,
expressed as [18,23]:
εIHP εOHP
CH = (7)
εOHP dIHP + εIHP dOHP
In Eq. (7), εIHP and εOHP are the inner and the
outer Helmholtz plane dielectric constants, respectively;
dIHP and dOHP are the insulator-non-hydrated ion and
insulator-hydrated ion distances, respectively. The dielectric
constants assume, in the model, different values according
to each electrolyte solution region. The resulting equivalent
capacitance is:
Cox CH
Ceq = (8)
Cox + CH
2.3. Thermal model
temperature-dependence of the electro-chemical parameters
of the ISFET, in order to simulate the effects of temperature
(4) on the characteristics of the device over a user-defined pH
and temperature range. This thermal model is based on the
standard electrochemical and MOSFET theories, and on
previously developed theoretical models [44–46]. Details
of the thermal model can be found in [45].
 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27 17

3. ISFET built-in model in BIOSPICE 3.3. Thermal model

3.1. Static model
The equations describing the MOSFET static model in
SPICE were modified by replacing the expression of Vth of
the MOSFET with Eq. (4), and using the ϕeo value resulting
from the solution of the “EIS system”. To this goal, we mod-
ified some subroutines within SPICE, and introduced new
ones. The nonlinear “EIS system” was solved numerically
by using a first-guess value for ϕs and then by verifying the
consistency of the applied ϕg (cf., Fig. 1). Thus, in addition
to the ·MOSFET static model parameters, we introduced 14
static parameters [23] that the user of BIOSPICE can specify
in the •MODEL statement to characterize the ISFET static
behavior.
3.2. Large-signal model
The equations describing the MOSFET large-signal
model in SPICE were modified by replacing the expression
of the insulator capacitance Cox of the MOSFET with the
series of Cox and CH [Eq. (8)]. The Helmholtz capacitance
was implemented in SPICE by Eq. (7).
The ISFET parameters common to the MOSFET main-
tain the same temperature dependence. In addition, specific
temperature dependence of the electrochemical parameters
was introduced [45] in the pertinent subroutines of SPICE.
3.4. BIOSPICE simulation results
The input and output characteristics of ideal SiO2 -,
Al2 O3 -, and Si3 N4 -gate ISFETs were simulated by introduc-
ing appropriate values for the parameters that characterize
the “EIS system” via the •MODEL statement of BIOSPICE.
Fig. 2 shows, as an example, the output of a measuring cir-
cuit [21] (a feedback amplifier that measures the equivalent
gate voltage Vgs , keeping constant the drain-source current
Ids ) as a function of pH, for a Si3 N4 -gate ISFET with the
density of binding sites as sweeping parameter. The outputs
are straight lines when the electrochemical parameters listed
in Table 1 are considered. In this case, the slopes of the
curves directly give the pH sensitivities S (mV/pH). Gener-
ally, an estimate of the pH average sensitivity was obtained,
according to Eq. (4), by calculating the shifts in Vth (ISFET)
from the SPICE outputs at different pH values. The limiting

1.4

1.3

1.2

1.1
Vout [V]

1.0
2
NNit = 0 [#/m ]
0.9 17 2 18 2
NNit = 1 x 10 [#/m ] NSil = 4.9 x 10 [#/m ]
17 2 18 2
NNit = 3 x 10 [#/m ] NSil = 4.7 x 10 [#/m ]
0.8
17 2 18 2
NNit = 5 x 10 [#/m ] NSil = 4.5 x 10 [#/m ]
0.7

2 4 6 8 10 12
pH
Fig. 2. BIOSPICE simulated output voltage of the measuring circuit as a function of pH of the Si3 N4 -gate ISFET under test and with the density of
binding sites as sweeping parameter.

Table 1
Insulator electrochemical parameters (25 ◦ C)
Insulator K− (mol/l) K+ (mol/l) Kn+ (mol/l) Nsil/Al (m−2 ) Nnit (m−2 ) pHpzc a

SiO2 15.8 63.1 × 10−9 – 5.0 × 1018 – 3.0

Si3 N4 15.8 63.1 × 10−9 1.0 × 10−10 4.5 × 1018 5.0 × 1017 6.8
Al2 O3 12.6 × 10−9 79.9 × 10−10 – 8.0 × 1018 – 8.5
a pHpzc = pH value at the point of zero charge σ 0 .
18 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27
Fig. 3. BIOSPICE simulated and measured input characteristics of the Si3 N4 -gate ISFET under test, at Vds = 0.1 V, pH 4 and 10, at T = 5 and 37 ◦ C.
The a-thermal point is also indicated.
condition of zero amine sites (Nnit = 0) that describes the
SiO2 -gate ISFET non-linear behavior is also shown: the
reduction in the number of amine sites induces a departure
from linearity. Fig. 3 shows the measured and simulated
input characteristics (with source and bulk grounded) for
a Si3 N4 -gate ISFET at pH 4 and 10, respectively, each at
T = 5 and 37 ◦ C. In this figure, the a-thermal point, a locus
of minimum ∂Ids /∂T , i.e. where the drain current is not
significantly thermally dependent, can be observed, both
in the measured and simulated curves. It should be noted
that the athermal point depends on the physical-geometric
parameters of the MOSFET, but, as Fig. 3 shows, it is also
strongly dependent on the pH value of the solution so that,
for strong basic solutions (pH > 10) the athermal point
tends to the off-region. This effect is of great importance
when the ISFET has to operate in environmental condi-
tions where temperature is not controlled. Other simulation
results (not shown) are detailed in [22,23].
4. ISFET macromodel formulation
In Section 3, we presented a physical–chemical model
of the ISFET to be used as built-in model in BIOSPICE,
resulting in an equation system that fully characterizes the
ISFET behavior. This approach, which leads to results that
well match experimental data, has some drawbacks, i.e. the
need of availability of the program source and a deep knowl-
edge of the code subroutines and structure. To overcome
these drawbacks, a more general and user-friendly approach
is here presented. It consists of a behavioral macromodel
that can be used in conjunction with the most commer-
cial SPICE versions. The behavior of the proposed macro-
model was validated by comparing the obtained results to the
ones obtained by the BIOSPICE physical–chemical mod-
els and experimental measurements. The proposed macro-
model was shown to operate also under subthreshold condi-
tions. The subthreshold region operation becomes a particu-
larly useful operating mode when ISFET-based applications
(e.g. biomedical and environmental) require low-power and
low-voltage working conditions, and negligible non-ideal ef-
fects. Extensive characterization simulations of the ISFET, in
both weak and moderate inversion regions, were performed
with the developed ISFET macromodel, and a comparison
between the obtained simulation results and experimental
data is presented as an example.
4.1. Model theory definition
The proposed macromodel [24] was implemented in
HSPICE [49] and in PSPICE [50]. To achieve this goal,
we considered the ISFET as two fully uncoupled (as far
as the physical point of view is concerned) stages: an
electronic stage (i.e. the MOSFET which is the starting
structure of the ISFET) and an electrochemical stage (i.e.
the electrolyte–insulator interface). This assumption con-
tradicts the condition of charge neutrality of the structure
of Fig. 1. On the other hand, by considering the charge
density in the semiconductor σ mos constant in respect of
pH, and by assuming it much smaller than the charge den-
sities σ d in the diffuse layer, and the charge density at the
insulator–electrolyte interface σ 0 [16], the charge neutrality
equation reduces to
σ0 + σ d = 0 (9)
Therefore, the electrochemical stage can be considered as
uncoupled from the electronic stage. Again, by applying the
site-binding theory and the electrical double-layer theory
[18,53,54], it is possible to solve the “EIS system”. The ap-
proach we formulated leads to the ISFET equivalent circuit
 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27 19

σd = −σ0 = −Ceq ϕeo (11)

On the other hand, the Helmholtz capacitance is given by

Eq. (7), and the Gouy–Chapman capacitance, by approxi-
mating the sinh by its argument (for ϕgd 2kT/q), can be
written as [16]:
∂σd ∂   qϕ 
gd
CG = = 8εw kTc0 sinh
∂ϕgd ∂ϕgd 2kT
√
∼ q 8εw kTc0
= (12)
2kT
In Eq. (12), c0 is the ion concentration in the electrolyte, εw is
the permittivity of the electrolyte, and ϕgd is self-explanatory
in Fig. 1. Finally, the expression for the electrolyte–insulator
interface ϕeo , can be obtained as [24]:
σ0 q
ϕeo = = [Nsil fa (ϕeo , pH) + Nnit fb (ϕeo , pH)]
Ceq Ceq
(13)

The expressions of the functions fa (ϕeo , pH) and fb (ϕeo , pH)

Fig. 4. (a) Equivalent electric circuit (macromodel) of the ISFET. (b)
HSPICE/PSPICE subcircuit block showing the external connections for
the ISFET macromodel. R: reference electrode, D: drain, S: source, B:
bulk, pH: solution pH value.
(macromodel) shown in Fig. 4a. The equivalent capacitor
Ceq , which takes into account the Gouy–Chapman or diffuse
layer (CG ) and the Helmholtz layer (CH ), is:
C G CH
Ceq = (10)
CG + C H
The dependence of the diffuse layer charge density σ d on
the potential of the electrolyte–insulator interface ϕeo can
be written also in the form:
are detailed in [24]. Eq. (13) states the potential ϕeo is mod-
eled as a non-linear voltage-controlled voltage source, which
depends, in its turn, both on pH and ϕeo itself.
The electronic stage, on the other hand, is simply modeled
by using the MOSFET models available in HSPICE and
PSPICE.
4.2. HSPICE/PSPICE macromodel definition
Eqs. (10) and (13) were translated into an equivalent
circuit (the electrochemical stage of the ISFET), which was
coupled to a n-channel MOSFET (the electronic stage of
the ISFET) resulting into a behavioral macromodel which
defines the ISFET model (Fig. 4a) we implemented in

250
HSpice average sensitivity=49.6 mV/pH
Measured average sensitivity=50.1 mV/pH
200
Ids=300 µA

150
Ids [µA]

100 Measured Data pH = 4

Measured Data pH = 7
Measured Data pH = 10
50
Vds=0.1 V Simulated Data pH=4
Simulated Data pH=7
0 Simulated Data pH=10

0 1 2 3 4

Vgs [V]
Fig. 5. HSPICE simulated and measured input characteristics of the Si3 N4 -gate ISFET under test, at pH 4, 7, and 10 and at Vds = 0.1 V.
20 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27

1000
HSpice: average sensitivity=55.8 mV/pH
BioSpice: average sensitivity=57.1 mV/pH
800 Ids=300 µA

600
Ids [µA]

400 HSpice pH=4

HSpice pH=7
HSpice pH=10
200
BioSpice pH=4
BioSpice pH=7
Vds=0.5 V
0 BioSpice pH=10

0 1 2 3 4

Vgs [V]
Fig. 6. HSPICE and BIOSPICE simulated input characteristics of the Si3 N4 -gate ISFET under test at pH 4, 7, and 10 and at Vds = 0.5 V.

HSPICE and PSPICE. The equivalent circuit of the ISFET,
which models the electrochemical behavior, can be used as
a new “kind” of electronic device for designing intelligent
pH-sensors or ISFET-based microsystems. At user’s con-
venience, the macromodel was defined, in HSPICE and in
PSPICE, as a subcircuit block (Fig. 4b) where R, D, S, B,
stand for the reference electrode, the drain, the source, and
the bulk connections, respectively; pH stands for the con-
nection for the emulated pH input source, that is a chemical
input signal modeled by an independent voltage source
connected to a dummy resistor. The macromodel uses this
voltage (i.e. the pH value) as the electrochemical source
that controls the potential ϕeo in Eq. (13). The complete
HSPICE/PSPICE behavioral macromodel for a Si3 N4 -gate
ISFET is detailed in [24].
both for the curve shape and for the average sensitivity. Other
simulations are shown in [24].
The behavioral macromodel of the ISFET is then used in
PSPICE to simulate the ISFET behavior under subthresh-
old conditions. Specifically, PSPICE and HSPICE provide
a MOSFET model for low-voltage and low-current condi-
tions, based on the EPFL–EKV MOSFET model [55]. This
model can be selected by specifying the level = 5 parame-
ter in the •MODEL statement of PSPICE. (We remind the
MOSFET is the electronic stage of the developed ISFET
macromodel). The drain–source current expression is im-
plemented in PSPICE as a unique equation describing all
Table 2
PSPICE parameter values for the ISFET operating in the subthreshold
conditions

4.3. HSPICE/PSPICE simulation results MOSFET level 5 parameters Values

L (m) 1.8 × 10−5

The developed macromodel [24] was extensively tested W (m) 8.04 × 10−4
in HSPICE and PSPICE, and the simulation results VTO (V) 0.887568
KP (A/V2 ) 1.65 × 10−5
were compared both with experimental data and with GAMMA 0.935645
the previously validated physical–chemical model results PHI (V) 0.426268
[22,23]. LAMBDA 0.5
Fig. 5 shows the HSPICE simulated input characteristics RSH (/sq) 150
of the Si3 N4 -gate ISFET under test compared with experi- IS (A) 4.17 × 10−12
TOX (m) 8.39 × 10−8
mental data at three different pH values (pH 4, 7, and 10) XJ (m) 3.00 × 10−7
and at Vds = 0.1 V. Input and output characteristics of other UCRIT (V/m) 1.04 × 106
types of ISFETs (e.g. Al2 O3 -, Ta2 O5 -gate ISFETs) can be LETA 1.25265
simulated by changing the parameter values of the surface WETA 0.25
site densities and of the dissociation constants. COX (F/m2 ) 4.12 × 10−4
EO (V/m) 1.42 × 109
Fig. 6 shows the simulated input characteristics at Vds =
0.5 V and pH 4, 7, and 10 obtained by the proposed be- Electrochemical parameters
havioral macromodel implemented in HSPICE, and by the Nsil [#/m2 ] 2.82 × 1017
Nnit [#/m2 ] 2.36 × 1017
BIOSPICE physical-model: a good agreement was observed
 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27 21

1
10 0.27

0
10 0.24

-1
10 0.21

10
-2 Measurements: 0.18 Measurements:
pH = 3.06 pH = 3.06
-3
10 pH = 6.85 0.15 pH = 6.85
pH = 10.4 pH = 10.4
Ids [mA]

Ids [mA]

-4
10 0.12

-5
Simulations: Simulations:
10 0.09
pH = 3.06 pH = 3.06
10
-6 pH = 6.85 0.06 pH = 6.85
pH = 10.4 pH = 10.4
-7
10 0.03

-8
10 0.00

-9
10 -0.03
-2 -1 0 1 2 3 4 -2 -1 0 1 2 3 4
(a) Vgs [V] (b) Vgs [V]

1800
Measurements: S = 54.2 mV/pH
PSPICE simulations: S = 55.3 mV/pH
1700

Ids = 100 mA
1600 Vds = 0.1 V
V gs [mV]

1500

1400

1300

2 3 4 5 6 7 8 9 10 11
(c) pH

Fig. 7. PSPICE simulated and measured characteristics of the Si3 N4 -gate ISFET under test operating in the subthreshold conditions at Vds = 0.1 V. (a)
Input characteristics, logarithmic scale, (b) input characteristics, linear scale, (c) gate-source voltage vs. pH at Ids = 100 ␮A.

the operating regions: weak, moderate and strong inversion,
non-saturation and saturation. A detailed description of the
equations and parameters used for the computer simulation
version of the EPFL–EKV MOSFET model can be found in
[55].
Considering the parameter values listed in Table 2, sim-
ulations of the ISFET operating in the subthreshold region
were carried out as function of the physical–chemical ISFET
parameters. In particular, Fig. 7a-c show the simulated and
measured Ids versus Vgs curves for three pH values at Vds =
0.1 V, and Vgs versus pH curves at fixed Ids = 100 ␮A and
Vds = 0.1 V. It should be noted that the simulated curves of
Fig. 7a and b are mainly influenced by the electronic com-
ponent of the ISFET macromodel, on the other hand, Fig. 7c
points out mainly the influence of the electrochemical stage
of the ISFET. However, all these curves show a good agree-
ment between PSPICE simulation results and experimental
measurements.
5. ISFET-based microsystems
The possibility of miniaturization and integration of
the ISFET, and its partial compatibility to the CMOS IC
process, makes it suitable for fabrication of multisensor
chips containing an array of chemically sensitive devices
and their related circuits. To this goal, we developed a
CAD system to realize ISFET-based microsystems with the
possibility of on-chip amplification, offset correction, and
interference reduction circuits. Fig. 8 shows the test plan
for the ISFET-based microsystem design and fabrication;
the extraction of the electrical and chemical parameters
22 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27
Fig. 8. Test plan for ISFET-based microsystem design and fabrication.
necessary to simulate the sensor behavior and to optimize
the circuit design represents the basic and fundamental
link between design and manufacturing. Two examples
of ISFET-based microsystems will be described in the
Section 5.2.
5.1. ISFET/CMNOS technology
Two main different approaches may be followed in fabri-
cating the ISFET. The first consists of modifying the ISFET
structure to adapt it to the standard self-aligned poly-Si-gate
CMOS technology [56]. The second consists of keeping the
ISFET fabrication technology and ensuring a partial com-
patibility to the CMOS IC process. This approach yielded
a solution called ISFET/CMNOS technology [39,51]. Other
approaches have been used, and details can be found in the
literature [56–58].
One of the main features of this technology is to make use
of a double-layer gate insulator. In fact, a low pressure chem-
ical vapor deposition (LPCVD) silicon nitride film grown on
the thermal gate oxide is an acceptable choice when CMOS
and ISFET technologies must be compatible. Moreover, the
deposition of this film is available as one of the standard
passivation layers in IC technology, and, at the same time,
it gives the ISFET a good proton sensitivity, good linearity,
and acceptable stability and reliability. On the other hand,
the high-temperature processing steps imposed by the Si3 N4
deposition are not easy to accommodate to a standard poly-Si
CMOS processing sequence.
5.2. Microsystem design
The microsystems were designed according to the results
of previously SPICE simulations performed in static and
transient analysis mode, by using the ISFET models previ-
ously described, and adapting the model parameter values
from the literature. At the end of the fabrication process, pa-
rameter extraction procedures and the comparison between
the estimated electrochemical behavior and the actual ex-
perimental results were used to optimize the values of pa-
rameters of the ISFET model and to close the test plan loop
shown in Fig. 8.
The first example of developed microsystem is shown in
Fig. 9(a) [39], where three blocks (sensor block, signal con-
ditioning block, test strip block) are presented. The sensor
block consists of one ISFET-based pH-sensor (a Si3 N4 -gate
ISFET, from now on simply referred to as ISFET) and two
Aluminum-gate n-channel MOSFETs (from now on simply
referred to as ALUFETs) with the same geometry as the
ISFET. The signal-conditioning block consists of a current
source and a current mirror connected to a pair of matched
ISFETs and ALUFETs resulting in a differential stage. Three
output stages, i.e. a CMOS output stage, a n-channel MOS-
FET output stage and a double n-channel MOSFET output
stage, which can be separately selected, are also available on
the same chip. When the ISFET is operating, an additional
ALUFET can be used as temperature sensor. The test strip
block includes 47 differently sized test structures, i.e. capac-
 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27 23

Fig. 9. (a) Basic block diagram of the microsystem chip, (b) fabricated chip.

itors, resistors, diodes, p-channel MOSFETs and n-channel lation were compared with the measured experimental data
MOSFETs, and it is devoted to technological evaluation, pa- obtained from the encapsulated microsystems.
rameter extraction for SPICE, and fabrication process mon- To simulate the ISFET behavior, some parameter values
itoring. were extracted by measuring test devices and some param-
The second example of developed microsystem is eter values were estimated or taken from the literature. The
shown in Fig. 10. This microsystem, designed to mon-
itor the metabolic activity of cellular populations, is a
1.75 × 1.85 cm2 die consisting of twelve ISFETs, two tem-
perature sensors, and one conductivity sensor [59]. The
ISFETs monitor, by measuring a pH variation, the medium
acidification induced by the cellular metabolic activity. The
temperature sensors verify the medium temperature imposed
by an external thermostatic system. The additional conduc-
tivity sensor, realized with an interdigitated two-electrode
structure, controls the cell culture adhesion, allowing the
use of the microsystem also for all the experimental appli-
cations where a cell population is directly grown onto the
chip surface.

5.3. Microsystem simulations and testing

As already outlined in Section 5.2, the microsystem

was designed by using the BIOSPICE built-in model, and
HSPICE/PSPICE macromodel for ISFET. SPICE allowed
us to simulate the ISFET behavior and the related inte-
grated electronic circuits by specifying the electrochemical
parameters together with the standard parameters for the
MOSFET that is the starting structure of the ISFET. At the Fig. 10. Layout of the ISFET array sensor chip for metabolic activity
end of the fabrication process, results of the SPICE simu- monitoring.
24 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27

0.08

0.06

0.04

0.02
Vout [V]

0.00

-0.02

-0.04

-0.06

-0.08

5.6 5.8 6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0
pH

Fig. 11. BIOSPICE simulated and measured characteristics of the fabricated ISFET-based microsystem in the follower configuration as function of
different pH values of the electrolyte solution.

differential stage in the follower configuration was simu-
lated and compared with experimental data (cf., Fig. 11) at
different pH values. As an example, Fig. 12 shows the sim-
ulations of the differential stage coupled to the CMOS out-
put stage at different pH values corresponding to the pH of
the buffer solutions used in the experimental measurements.
Apart from a slight offset, the CMOS output stage shows
(when both p-channel and n-channel MOSFETs operate in
saturation mode) a maximum gain value of 21.7 in accor-
dance with the experimental results. As can be seen, the lin-
earity interval of the amplifier is restricted to a narrow range
around the physiological pH.
As far as the cellular metabolism monitoring microsys-
tem is concerned [60], we used a simplified multiplexing
configuration circuit to simulate the ISFET switching be-
havior at different pH values. The ISFETs are connected in
follower mode to a common current sink (I0 = 100 ␮A), a
buffer output stage, and three n-channel MOSFET switches.
SPICE simulation results are shown in Fig. 13. The pH re-
sponse of a single ISFET was also evaluated in dependence
of the main measurement parameters.
The SPICE models have been extensively validated, and
actual deviations of the simulated results from the measured

Fig. 12. Comparison between BIOSPICE simulated and measured output voltage Vout of the ISFET-ALUFET differential stage coupled to the CMOS
output stage as function of different pH values of the electrolyte solution.
 S. Martinoia et al. / Sensors and Actuators B 105 (2005) 14–27
Fig. 13. SPICE simulation results related to the multiplexing circuit configuration of the ISFET at pH 4, 7, and 10.
ones have to be related to the non-optimized protocol used
for extracting the model parameter values.
6. Conclusions
In this paper we presented a simple and powerful approach
to developing computer models of bioelectronic devices such
as ISFETs. This approach relies on the SPICE electronic
circuit analysis program. The presented results show a good
agreement with experimental data and previously validated
analytical models proving the feasibility of the proposed
approach for modeling the electrochemical characteristics
of ISFET-based sensors. These models were then used to
develop a general and complete CAD system, which makes
use of an ad hoc technology (ISFET/CMNOS), for designing
and fabricating ISFET-based microsystems. This developed
CAD system can be considered as a general-purpose tool for
designing integrated microsystems based on ISFET sensors.
Specific examples of microsystems design and fabrication
oriented to biomedical applications were carried out (i.e.
on-line detection of micro-organisms in waters, and on-line
cell population metabolism monitoring).
This methodological approach allows joining the compu-
tational robustness of the SPICE program with the possi-
bility of simulating complex circuits involving hybrid de-
vices (e.g. chemical- and bio-sensors) and signal condition-
ing electronics.
As underlined in a recent review paper by Bergveld
[5], we believed that possible future applications of
ISFET-based sensors and ISFET-based microsystems will
be also more related to cell biosensing or generally to cel-
lular and sub-cellular studies. There are already examples
of that in literature, but detailed investigations in such a
25
field are still needed. Yet, the proposed “mixed” technology
(ISFET/CMNOS) could be considered a valuable tool for
developing multi-site sensor based systems or large sensor
arrays (i.e. high density arrays) to be used in conjunction
with excitable cells for electrophysiological measurements.
Acknowledgements
The authors wish to thank Prof. Massimo Grattarola
who first introduced them to the “world” of ISFETs and
bio-sensors; these research activities were developed under
his constant supervision and support. The authors are also
grateful to Dr. A. Adami for his assistance with PSPICE
simulations. Moreover, Dr. B. Margesin and Dr. M. Zen,
from the ITC-Irst Microsystems Division, are greatly ac-
knowledged for their contribution in developing the IS-
FET/CMNOS technology.
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Biographies
Sergio Martinoia received the Laurea degree in Electronic Engineering
from the University of Genova, Italy, in 1989 and the PhD in Bioengineer-
27
ing from the same university in 1993. He is associate professor of Bio-
engineering at the Department of Biophysical and Electronic Engineering
(DIBE) of the University of Genova, where he teaches courses on Bio-
electronics and Methods and Techniques for Neuroengineering, offered to
students of the Biomedical Engineering curricula. His research interests
are mainly in the field of Neuroengineering and they include: the devel-
opment of new electrophysiological techniques, based on the functional
coupling of neuronal populations to microelectrode array-based devices;
modeling and computer simulations of the functional coupling between
microtransducers and neuronal cells; data analysis of electrophysiological
signals from in vitro neuronal networks; design of new microelectronic
chemical and bio-sensors.
Giuseppe Massobrio received the Laurea (MSc) degree in Electronic En-
gineering from the University of Genova, Italy, in 1976. He is research
associate and adjoint professor at the Department of Biophysical and
Electronic Engineering (DIBE) of the University of Genova. Since 1976,
he has worked on semiconductor power device modeling, and circuit
design and simulation. Since 1987, he has been working on modeling
semiconductor-based biosensors, and neuronal structures. His extensive
background in microelectronic device modeling includes teaching and
research activities. In the fields of bioelectronics and of semiconduc-
tor device modeling he has contributed several papers to international
journals. He is author of the book: “Modelli dei Dispositivi a Semicon-
duttore in SPICE” (1986) published by Franco Angeli, and coauthor of
the books: “Semiconductor Device Modeling with SPICE” (1988, 1993
(2nd edition)) published by McGraw-Hill, and “Bioelectronics Handbook:
Mosfets, Biosensors, and Neurons” (1998) published by McGraw-Hill.
Leandro Lorenzelli received the Laurea degree in Electronic Engineer-
ing from the University of Genova in 1994. In 1998, received his PhD
from the University of Trento. His research activity during the PhD
concerned simulation and design of electrochemical microsensors using
CMOS foundry services. Since 1998, he is staff researcher in ITC-irst
Microsystems Division. He is involved in the design and fabrication of mi-
crosystems for biomedical analyses and environmental applications. From
2002, he is responsible for the development of silicon-based bio-inspired
microsystems.