sensors
Article
Electrical Properties of Two Types of Membrane Component
Used in Taste Sensors
Zhanyi Xiang 1, *, Yifei Jing 1 , Hidekazu Ikezaki 2 and Kiyoshi Toko 3,4






Citation: Xiang, Z.; Jing, Y.;
Ikezaki, H.; Toko, K. Electrical
Properties of Two Types of Membrane
Component Used in Taste Sensors.
Sensors 2021, 21, 8343. https://
doi.org/10.3390/s21248343
Academic Editor: Manel Del Valle
Received: 8 November 2021
Accepted: 12 December 2021
Published: 14 December 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Sensors 2021, 21, 8343. https://doi.org/10.3390/s21248343
1 Graduate School of Information Science and Electrical Engineering, Kyushu University,
744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; jing.yifei.623@s.kyushu-u.ac.jp
2 Intelligent Sensor Technology, Inc., 5-1-1 Onna, Atsugi-shi 243-0032, Japan; ikezaki.hidekazu@insent.co.jp
3 Institute for Advanced Study, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan;
toko@ed.kyushu-u.ac.jp
4 Research and Development Center for Five-Sense Devices, Kyushu University, 744 Motooka, Nishi-ku,
Fukuoka 819-0395, Japan
* Correspondence: xiang.zhanyi.031@s.kyushu-u.ac.jp; Tel.: +81-92-802-3762
Abstract: The lipid phosphoric acid di-n-decyl ester (PADE) has played an important role in the
development of taste sensors. As previously reported, however, the concentration of PADE and pH
of the solution affected the dissociation of H+ , which made the measurement results less accurate
and stable. In addition, PADE caused deterioration in the response to bitterness because PADE
created the acidic environment in the membrane. To solve these problems, our past study tried to
replace the PADE with a completely dissociated substance called tetrakis [3,5-bis (trifluoromethyl)
phenyl] borate sodium salt dehydrate (TFPB) as lipid. To find out whether the two substances can
be effectively replaced, it is necessary to perform an in-depth study on the properties of the two
membranes themselves. In this study, we fabricated two types of membrane electrodes, based on
PADE or TFPB, respectively, using 2-nitrophenyl octyl ether (NPOE) as a plasticizer. We measured
the selectivity to cations such as Cs+ , K+ , Na+ and Li+ , and also the membrane impedance of the
membranes comprising PADE or TFPB of the different concentrations. As a result, we found that
any concentration of PADE membranes always had low ion selectivity, while the ion selectivity of
TFPB membranes was concentration-dependent, showing increasing ion selectivity with the TFPB
concentrations. The ion selectivity order was Cs+ > K+ > Na+ > Li+ . The hydration of ions was
considered to participate in this phenomenon. In addition, the membrane impedance decreased with
increasing PADE and TFPB concentrations, while the magnitudes differed, implying that there is
a difference in the dissociation of the two substances. The obtained results will contribute to the
development of novel receptive membranes of taste sensors.
Keywords: taste sensor; lipids; dissociation of H+ ; cation selectivity; membrane resistance; Hofmeister
series
1. Introduction
In the 1960s to 1990s, with the continuous improvement of membrane theory, many
ion-selective electrodes were invented, and are still used to distinguish different ions today.
Some of them were of the liquid-membrane type, based on lipid polymer membranes [1–6].
However, there are also lots of restrictions on the conditions, such as temperature and
pH [7–9].
Toko et al. found that lipid polymer membranes could behave in the same way as
human gustatory cells, where the membrane potential can be used to extract the information
of tastes [10–14]. They successfully developed a taste sensor equipped with lipid polymer
membranes in 1989 [13]. Different from the ion-selective sensors, the taste sensor can
distinguish and quantify five basic tastes, such as sourness, sweetness, saltiness, bitterness,
and umami. Each basic taste is measured by one kind of taste sensor where the membrane is
https://www.mdpi.com/journal/sensors
Sensors 2021, 21, 8343 2 of 14

specifically constructed to measure the taste intensity based on a large quantity of possible
substances producing tastes [10–12,15,16].
Not only can this taste sensor be used under most conditions, but it can be reused
many times without affecting the measurement accuracy [17]. However, a problem has
appeared that must be overcome in taste sensors using the membrane comprising phos-
phoric acid di-n-decyl ester (PADE) as the artificial lipid. Because of the H+ dissociation of
the phosphate group, PADE is responsible for the negative charges at the surface of the
membrane [18]. This lipid has been used in our taste sensors for more than 20 years [19].
The degree of dissociation will be influenced by the lipid concentration of the membrane
and the pH of the solution because it is a weak electrolyte. Therefore, the accuracy and
durability of sensors using such kinds of lipids can become unstable. In recent studies,
Wu et al. found that adding too much PADE can create an acidic environment, which
can lead to hydrolysis of the plasticizer, resulting in deterioration of the response to bitter
substances [10]. Nakatani et al. also found that due to the partial dissociation of PADE, the
measurements of amphoteric electrolyte samples, such as amino acids, can cause changes
in H+ dissociation of PADE, resulting in unexpected changes in membrane potential,
which affects the response [20]. They tried to improve this unfavorable response by ad-
justing the lipid concentration and plasticizer type, but none of these methods solved the
problem satisfactorily.
To find a way to improve our taste sensors, a new substance is needed to replace PADE,
and hence tetrakis [3,5-bis(trifluoromethyl)phenyl] borate sodium salt dehydrate (TFPB)
was selected as a candidate [21]. TFPB is featured with little nucleophilicity [22], and high
chemical durability because of its fluoroaromatic borate structure [23]. It is stable under
acidic environments [24]. It is often used as an anion phase-transfer catalyst or as an anion
excluder in ISEs [25]. As a completely dissociative anionic lipophilic additive, it is a good
choice for cation sensing [26]. Its completely dissociative properties make it possible for it
to stay unchanged under acidic conditions. In fact, the membrane using TFPB presented
long-term stability, and also showed high selectivity and sensitivity for pharmaceutical
bitterness [21]. As a result, the chemical durability and completely dissociative property of
TFPB can be considered to make it a candidate to solve the problems concerned on PADE,
which are used in taste sensors for sourness, bitterness, and umami [11,12].
Before TFPB is utilized in lipid polymer membranes developed for a commercialized
taste sensor, it is necessary to understand the changes in basic properties that occur when
PADE is replaced with TFPB. Here, we aim to find and compare the electrical properties of a
partially dissociated membrane using PADE and a completely dissociated one using TFPB.
For this purpose, we measured the responses to alkali metal ions with the aid of the taste
sensing machine TS-5000Z, and obtained the ion selectivity coefficients, and also measured
the membrane impedance of the two membranes. As a result, we found that the PADE
membranes showed low ion selectivity, irrespective of the contained PADE concentration
of the membrane, while the TFPB membranes showed increasing ion selectivity with
increasing TFPB concentrations. This order was Cs+ > K+ > Na+ > Li+ , in accordance
with the well-known Hofmeister series. The membrane impedance slightly decreased with
increasing PADE, while it largely decreased with TFPB concentrations. The fact that PADE
membranes with impedances as high as 106 Ω · cm2 have low ion selectivity at any PADE
concentration is in line with the TFPB membrane showing high impedance at lower TFPB
concentrations. These findings will contribute to the development of a novel taste sensor
robust against changes in the circumstance in lipid polymer membranes.

2. Materials and Methods

2.1. Reagents
Phosphoric acid di-n-decyl ester (PADE) was purchased from Tokyo Chemical Indus-
try Co., Ltd. (Tokyo, Japan). Tetrakis [3,5-bis(trifluoromethyl)phenyl] borate sodium salt
dehydrate (TFPB) and polyvinyl chloride (PVC) were purchased from FUJIFILM Wako
Pure Chemical Corporation (Osaka, Japan). 2-Nitrophenyl octyl ether (NPOE) and tetrahy-

Sensors 2021, 21, 8343
salt dehydrate (TFPB) and polyvinyl chloride (PVC) were purchased from FUJIFILM
Wako Pure Chemical Corporation (Osaka, Japan). 2-Nitrophenyl octyl ether (NPOE) and
tetrahydrofuran (THF), which were used as the supporting material and the organic sol-
vent, were purchased from Sigma-Aldrich Japan G.K. (Tokyo, Japan. Figure 1 shows the
structures of these substances used to make up the membrane. 3 of 14
Measurement samples are as follows. Potassium chloride (KCl) and sodium chloride
(NaCl) were purchased from Kanto Chemical Co., Inc. (Tokyo Japan). Lithium chloride
(LiCl) and cesium
drofuran (THF), chloride
which were(CsCl)
usedwere purchased
as the from
supporting FUJIFILM
material Wako
and the Puresolvent,
organic Chemical
were
Corporation. All samples to be tested were dissolved in pure water. The details of
purchased from Sigma-Aldrich Japan G.K. (Tokyo, Japan. Figure 1 shows the structures sample of
solutions will be recorded
these substances used toinmake
Section
up 2.4.
the membrane.

(a) (b)

(c)

(d) (e)
Figure 1. Structure of membrane components: (a) TFPB; (b) NPOE; (c) PADE; (d) THF; (e) PVC.
Figure 1. Structure of membrane components: (a) TFPB; (b) NPOE; (c) PADE; (d) THF; (e) PVC.

2.2. Lipid Polymer Membrane

Measurement samples are as follows. Potassium chloride (KCl) and sodium chloride
(NaCl) were purchased
In this study, two types from Kanto
of lipid Chemical
polymer Co., Inc. were
membranes (Tokyo Japan). Lithium
fabricated; i.e., one chloride
using
(LiCl) and
a partially cesium chloride
dissociated (CsCl)called
lipids PADE, were purchased from FUJIFILM
PADE membrane, Wakousing
and the other Pure Chemical
a com-
Corporation.
pletely Alllipids
dissociated samples to be
TFPB, tested
called weremembrane.
TFPB dissolved in purethe
Both water.
PADE The details
and TFPBofmem-
sample
solutions
branes will be
contained recorded
400 μL (3 M) inNPOE
Sectionas2.4.
a plasticizer, and 200 mg PVC as a polymer sup-
porting reagent. To investigate the effect of lipid concentration on the electrical properties
of 2.2. Lipid Polymer
membranes, Membrane
the PADE membranes were fabricated with 10 different concentrations
from 0.03In mM
this study,
to 300two
mM, types
and ofthelipid
TFPBpolymer membranes
membranes weremM
from 0.01 fabricated; i.e., one
to 300 mM. using a
A blank
partially dissociated
membrane lipids without
based on NPOE PADE, called
lipidPADE membrane,
was made and the other
and measured as ausing a completely
reference. The
dissociated lipids TFPB, called TFPB membrane. Both the PADE and TFPB membranes
contained 400 µL (3 M) NPOE as a plasticizer, and 200 mg PVC as a polymer supporting
reagent. To investigate the effect of lipid concentration on the electrical properties of
membranes, the PADE membranes were fabricated with 10 different concentrations from
0.03 mM to 300 mM, and the TFPB membranes from 0.01 mM to 300 mM. A blank membrane
based on NPOE without lipid was made and measured as a reference. The PADE and TFPB
concentrations are shown in Table 1. The reason for the different concentration ranges of the
two membranes is because the ion selectivity of PADE membranes always varied less, and
hence the lower concentration experiments were not necessary, while the ion selectivity of
TFPB membranes varied more and low concentration experiments were needed to confirm
the trend. The experimental results about this point will be detailed in Sections 3.3 and 3.4.
 PADE and TFPB concentrations are shown in Table 1. The reason for the different concen-
tration ranges of the two membranes is because the ion selectivity of PADE membranes
always varied less, and hence the lower concentration experiments were not necessary,
Sensors 2021, 21, 8343 4 of 14
while the ion selectivity of TFPB membranes varied more and low concentration experi-
ments were needed to confirm the trend. The experimental results about this point will be
detailed in Sections 3.3 and 3.4.
The fabrication steps were as follows. Firstly, lipids, NPOE, and PVC were dissolved
Table
in the 1.solvent
Concentrations
THF andof TFPB and
stirred forPADE
one in membranes.
hour. Secondly, the solution was poured into a
45 mm Petri dishMembrane
and dried for three days in a draft chamberConcentration
to let the THF be volatilized.
Finally, the membranes were cut into pieces that could be pasted onto a sensor probe. An
Blank membrane 0 (NPOE + PVC)
adhesive made by mixing 10 mL THF and 800 mg PVC was used to attach the membranes
PADE membrane 0.03, 0.3, 3, 10, 20, 30, 60, 100, 200, 300 mM
to the probes. After attaching the membrane to the probe, it was necessary to wait for 24 h
TFPB membrane
to make it completely attached. From one Petri 0.01, 0.03,
dish, we0.1,
made0.3, four
1, 3, 10, 30, 100,
sensor 300 mM
electrodes to
measure the sample. The thickness of the lipid polymer membranes was about 0.35 mm.
The fabrication steps were as follows. Firstly, lipids, NPOE, and PVC were dissolved
Table 1.solvent
in the THF and
Concentrations of stirred
TFPB andforPADE
one hour. Secondly, the solution was poured into a 45
in membranes.
mm Petri dish and dried for three days in a draft chamber to let the THF be volatilized.
Membrane
Finally, the membranes were cut into pieces that could be pasted Concentration
onto a sensor probe. An
adhesive madeBlank by mixing
membrane10 mL THF and 800 mg PVC was 0used (NPOEto attach
+ PVC)the membranes
to the probes. PADE
After membrane
attaching the membrane to 0.03,the probe, it was necessary to 300
0.3, 3, 10, 20, 30, 60, 100, 200, waitmM
for 24
h to make it completely attached. From one Petri dish, we made four sensor electrodes to
TFPB membrane 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300 mM
measure the sample. The thickness of the lipid polymer membranes was about 0.35 mm.

2.3.
2.3. Measurement
Measurement Procedure
Procedure ofof Taste
TasteSensor
Sensor
In this study, a commercialized
In this study, a commercialized taste taste sensing
sensing system
system called
called TS-5000Z
TS-5000Z (Intelligent
(Intelligent Sen-
Sensor
sor Technology, Inc., Kanagawa, Japan) was used for the measurement. This measuring
Technology, Inc., Kanagawa, Japan) was used for the measurement. This measuring
instrument
instrument uses
uses the
the two-electrode
two-electrode method,
method, which
which has
has at
at most
most 44 sensor
sensor electrodes
electrodes and
and aa
reference electrode on the same measurement cell, to measure the membrane
reference electrode on the same measurement cell, to measure the membrane potential potential
differences
differences between
between sensor
sensor electrodes
electrodes and
and reference
referenceelectrode
electrodeasasoutput.
output. The
The construction
construction
of the electrochemical cell is Ag-AgCl| 3.33 M KCl + satd. AgCl|membrane|sample
of the electrochemical cell is Ag-AgCl| 3.33 M KCl + satd. AgCl|membrane|sample solu-
solution|3.33
tion|3.33 M KCl M KCl + satd.
+ satd. AgCl|AgCl-Ag,
AgCl|AgCl-Ag, and
and is is shown
shown in Figure
in Figure 2. 2.

Figure 2.
Figure 2. Constructions of taste sensor
sensor electrodes.
electrodes.

The lipid
lipid polymer
polymer membranes
membranes were
were pasted
pasted onto
onto aa hollow
hollow sensor
sensor probe.
probe. The
The actual
actual
2
measured area of lipid
lipid polymer
polymer membranes is about 0.4 cm cm .. Both
Both the
the sensor
sensor electrodes
electrodes
and the
the reference
reference electrodes
electrodes were
were injected
injectedwith
with200 μL3.33
200µL 3.33MMKClKCland
andsaturated
saturatedAgCl.
AgCl.
The images of the taste sensor system TS-5000Z and the measurement procedure are
shown in Figures 3 and 4, respectively. Before the measurement, we had a preconditioning
process to re-arrange the lipids in the inside of the membrane surface, so that a stable
measurement potential could be obtained. In this process, the sensor electrodes and
reference electrodes were immersed in standard solution (30 mM KCl and 0.3 mM tartaric
acid) for 72 h. In the measurement section, step 1, the measurement cell was immersed in
 The images of the taste sensor system TS-5000Z and the measurement procedure are
The images of the taste sensor system TS-5000Z and the measurement procedure are
shown in Figures 3 and 4, respectively. Before the measurement, we had a preconditioning
shown in Figures 3 and 4, respectively. Before the measurement, we had a preconditioning
Sensors 2021, 21, 8343 process to re-arrange the lipids in the inside of the membrane surface, so that a stable meas- 5 of 14
process to re-arrange the lipids in the inside of the membrane surface, so that a stable meas-
urement potential could be obtained. In this process, the sensor electrodes and reference
urement potential could be obtained. In this process, the sensor electrodes and reference
electrodes were immersed in standard solution (30 mM KCl and 0.3 mM tartaric acid) for 72
electrodes were immersed in standard solution (30 mM KCl and 0.3 mM tartaric acid) for 72
h. In the measurement section, step 1, the measurement cell was immersed in standard so-
h.standard
In the measurement
solution (30section,
mM KCl step
and 1, the measurement
0.3acid)
mM tartaric cell was immersed in standard so-
lution (30 mM KCl and 0.3 mM tartaric for 30 s toacid) fora30
obtain s to obtain
membrane a membrane
potential called
lution (30 mM
potential calledKClV rand 0.3 mM
. In step 2, thetartaric acid) forcell 30 s to obtain a membrane potential called
V r. In step 2, the measurement cellmeasurement
was immersed inwas immersed
sample solutionin sample
for 30 s solution
to obtainfor 30 s
a new
Vto
r. In step 2,a the
obtain new measurement
membrane cell wascalled
potential immersed
V . in
The sample solution
difference for
between 30
V s to
and obtain
V (V a new
− Vr )
membrane potential called Vs. The differences between Vs and Vr (Vs − Vrs) is defined r s as the
membrane
is defined potential
as the called V
relative s. The In
value. difference
this between
study, the Vs andvalue
relative Vr (Vs was
− Vr)used
is defined
to as the
obtain the
relative value. In this study, the relative value was used to obtain the response value. In step
relative
response value. In this
value. study,
In step the
3, to relative
restore value was used to obtain the response value. In step
3, to restore the electrode surface tothe
its electrode surface
pre-measurement tocondition,
its pre-measurement
the measurement condition,
cell
3,the
to restore the electrode surface to its pre-measurement condition,
measurement cell was washed with a cleaning solution (100 mM HCl and 30 vol% the measurement cell
was washed with a cleaning solution (100 mM HCl and 30 vol% ethanol) [17]. Steps 1 to 3
was washed
ethanol) [17].with a cleaning
Steps 1 to 3 weresolution
repeated (100 mM
until allHCl and 30 vol%
the samples were ethanol)
measured, [17].
andSteps 1 to 3
it is defined
were repeated until all the samples were measured, and it is defined as one measurement
were
as one repeated until allcycle.
measurement the samples were one
In this study, measured, and it is
measurement celldefined
containedas one measurement
4 sensor electrodes
cycle. In this study, one measurement cell contained 4 sensor electrodes and 1 reference
and 1Inreference
cycle. this study,electrode, and five measurement
one measurement cell contained cycles were needed
4 sensor electrodesfor one
andmeasurement
1 reference
electrode, and five measurement cycles were needed for one measurement procedure. The
procedure.
electrode, andThe five average
measurement of thecycles
third were
to fifth measurement
needed cycle was calculated
for one measurement procedure.asThe the
average of the third to fifth measurement cycle was calculated as the response value. The
response
average of value. Thetostandard
the third deviations were
fifth measurement cycle calculated from as
was calculated n= the4 (response
sensor electrodes
value. The )×
standard deviations were calculated from 𝑛 = 4 sensor electrodes × 3 cycles = 12
standard ) = 12 values
3 (cyclesdeviations werein the same way
calculated from 𝑛 = 4 sensor
as previous studieselectrodes
[10,17,20,27]. × 3 cycles = 12
values in the same way as previous studies [10,17,20,27].
values in the same way as previous studies [10,17,20,27].

Figure
Figure3.3.3.Taste
Tastesensor
sensor system
systemTS-5000Z.
TS-5000Z.One measurement cellcell
could contain at most 4 sensor elec-
Figure
trodes andTaste
1 sensor
reference system TS-5000Z.
electrode. The 4 OneOne
sensor
measurement
measurement
electrodes cell
do notcould could
need to
contain
contain
use
at 4most
at most
exactly the same
4 sensor
sensor elec-
mem-
electrodes
trodes and 1 and 1 reference
reference electrode.
electrode. The 4 sensor
The 4 sensor electrodes
electrodes do not doneednottoneed to use exactly
use exactly the samethe same
mem-
brane. In this study, the membranes used in the 4 sensor electrodes of one measurement cell were
membrane. In this study, the membranes used in the 4 sensor electrodes of one
brane. In this study, the membranes used in the 4 sensor electrodes of one measurement cell were measurement cell
the same in measuring the samples and calculating the standard deviations.
were
the sametheinsame in measuring
measuring the samples
the samples and calculating
and calculating the standard
the standard deviations.
deviations.

Figure 4. Measurement procedure of taste sensor.

Measurementprocedure
Figure4.4.Measurement
Figure procedureofoftaste
tastesensor.
sensor.

2.4.
2.4. Measurement
Measurement of of the
the Selectivity
Selectivity Coefficient
Coefficient
2.4. Measurement of the Selectivity Coefficient
To
To investigate
investigatethe theelectrical
electricalproperties
properties of of
twotwomembranes,
membranes, responses to different
responses cat-
to different
To investigate the electrical properties of two membranes, responses to different cat-
ions were
cations measured
were measured andandthe the
ion ion
selectivity waswas
selectivity calculated. TheThe
calculated. sample concentrations
sample concentrationsare
ions were measured and the ion selectivity was calculated. The sample concentrations are
are shown
shown in Table
in Table 2. All2. sample
All sample solutions
solutions werewere prepared
prepared withwith chloride
chloride anions
anions and were
and were dis-
shown in Table 2. All sample solutions were prepared with chloride anions and were dis-
dissolved
solved in pure
in pure water,
water, which
which means
means thatthat the of
the pH pHtheofsample
the sample solutions
solutions was about
was about 5.2.
5.2. The
solved in pure water, which means that the pH of the sample solutions was about 5.2. The
The selectivity
selectivity coefficients
coefficients werewere calculated
calculated using
using thethe separatesolution
separate solutionmethod
method(SSM)
(SSM) [28],
[28],
selectivity
where thecoefficients
response valueswerefrom
calculated
10 mMusing
to 1000themM separate solutionand
were utilized method (SSM)
those of [28],
potassium
chloride were adopted as the reference.
Sensors 2021, 21, 8343 6 of 14

Table 2. Concentrations of alkali metal salts samples (solvent: pure water).

Sample Concentration
KCl 0.1, 1, 10, 100, 1000 mM
NaCl 0.1, 1, 10, 100, 1000 mM
LiCl 0.1, 1, 10, 100, 1000 mM
CsCl 0.1, 1, 10, 100, 1000 mM

2.5. Measurement of Membrane Impedance

In the measurement procedure of membrane impedance, Autolab PGSTAT302F was
used to provide the measuring environment, and the user interface NOVA was used to
automatize and analyze the measuring procedure. The details of settings are listed in Table 3.
The impedance of 0.1 Hz was used as the dedicating figure of membrane impedance.

Table 3. Measurement details and parameters of membrane impedance.

Details Parameter
Measure procedure NOVA FRA impedance potentiostatic
Electrode configuration Three electrode system
Electrolyte 30 mM KCl + 0.3 mM tartaric acid
Sweeping frequencies 0.1 Hz, 0.223 Hz, 0.5 Hz
Voltage 200 mV

3. Results and Discussion

3.1. Sensor Response to Different Alkali Metals in the PADE Membrane
Figure 5a shows the sensor response of the blank membrane containing no lipid to
different cations. Figure 5b,c show the sensor responses of membrane electrodes with low
and high PADE concentrations to different cations, respectively.
Figure 5a,b show that the membrane electrodes with low PADE concentration (0.03 mM)
and the blank membrane have almost the same response; this implies that the electrical
properties of the membrane with low PADE concentration are almost the same as those of
the blank membrane, which depends on the plasticizer NPOE. The sensor responses of both
blank membrane (a) and low-PADE membrane (b) electrodes increased logarithmically
with an increasing concentration of each alkali metal salt. It was also found that there is a
large response value for CsCl. As other research on PVC membranes have also found cation
permselectivity, it is reasonable to speculate that the rise in response is due to charged
impurities contained in the membrane components such as NPOE [29–31]. In addition,
Figure 5c shows that the sensor with high concentration of PADE membrane (30 mM) has
a higher response to alkali metals than both the low-PADE and blank membranes. The
reference potentials (V r ) of the measurements are shown in Table 4 and can be used to
calculate the response value (V s − V r ).
The KCl response (V s − V r ) of the high-PADE membrane electrodes (Figure 5c) is
about −60 mV for 30 mM KCl, which means the membrane potential V r of the reference
solution (30 mM KCl + 0.3 mM tartaric acid) is higher than that of the 30 mM KCl sample
solution. This is acceptable because the reference solution contains tartaric acid and is
weakly acidic (pH about 3.5), which leads to a decrease in the dissociation of H+ from
PADE and an increase in the surface potential of the membrane.
Sensors 2021, 21,
Sensors 2021, 21, 8343
x FOR PEER REVIEW 77 of
of 14
14

(a) (b)

(c)
Figure 5.
Figure 5. Sensor
Sensor responses
responses(V
(Vs s− −
Vr)Vto alkali metal salts samples: (a) Blank membrane; (b) low PADE concentration (0.03
r ) to alkali metal salts samples: (a) Blank membrane; (b) low PADE concentration
mM);mM);
(0.03 (c) high PADE
(c) high concentration
PADE concentration(30 mM).
(30 mM).

TableThe slope
4. The forfor
slope KCl and
KCl, selectivity
reference coefficients
potential ofselectivity
(V r ), and the sensors using blank
coefficients membrane
of the sensors. and
PADE membranes based on 0.03 mM and 30 mM are summarized in Table 4. First, the re-
Membrane
sponse slopeComponent Blank Membrane
for KCl largely increases with increasing PADE
PADE 0.03 concentration.
mM PADE
It is30quite
mM rea-
Slope
sonable for KClthat
[32,33] (mV)the increase in PADE
9.0 concentration can 9.7increase the charge 30.1
density in-
side the membrane,
V r (mV) which is closer28.5
to the ideal-type response.25.7 Next, the selectivity
−29.9 coeffi-
cients of the blank membrane and the low-PADE
Selectivity membrane
coefficients (logkK,j ) electrodes are almost the same.
pot

Last, the high-PADE membrane electrodes exhibit low selectivity for different alkali metal
K+ 0 0 0
ions, as can be+seen from the very small differences in selectivity coefficients. These facts are
Na −0.3 0.2 −0.2
detailed later in Section 3.3 in relation to the membrane impedance.
Li+ 0.5 0.5 −0.1
+ −0.1
Table 4. TheCs
slope for KCl, reference potential
1.2 (Vr), and selectivity
1.2 coefficients of the sensors.

Membrane Component Blank Membrane PADE 0.03 mM PADE 30 mM

The slope for KCl
Slope for KCl (mV) and selectivity
9.0 coefficients of the
9.7 sensors using blank membrane
30.1
and PADE membranes based on 0.03 mM and 30 mM are summarized in Table 4. First, the
Vr (mV) 28.5 25.7 −29.9
response slope for KCl largely increases with increasing PADE 𝒑𝒐𝒕 concentration. It is quite
Selectivity
reasonable [32,33] that the increase coefficients
in PADE (𝐥𝐨𝐠𝒌𝑲,𝒋
concentration can increase the charge density
K
inside the membrane, 0
which is closer to the ideal-type0 response. Next, the0 selectivity
coefficientsNa
of the blank membrane −0.3 0.2
and the low-PADE membrane −0.2
electrodes are almost the
same. Last,Lithe high-PADE membrane 0.5 electrodes exhibit low
0.5 selectivity for different
−0.1 alkali
metal ions,Csas can be seen from the1.2very small differences
1.2 in selectivity coefficients.
−0.1 These
facts are detailed later in Section 3.3 in relation to the membrane impedance.
 dissociation of TFPB is complete and is not affected by pH.
Figure 7 shows the sensor response of the membrane electrodes with high PADE and
TFPB concentrations (30 mM) to 100 mM NaCl samples at different pH levels. As the pH
decreased, the response value of the PADE membrane increased, while the TFPB mem-
brane remained unchanged. This can directly indicate the difference in dissociation of the
Sensors 2021, 21, 8343 8 of 14
two membranes as previously discussed.
Last, by comparing the response of the low-TFPB membrane (Figure 6a) with that of
the blank membrane (Figure 5a), the low-TFPB membrane shows the same value around
−100 mV at Response
3.2. Sensor 0.1 mM salts as the blank
to Different Alkalione, butinitsthe
Metals responses to higher salt concentration do
TFPB Membrane
not exactly converge to those of the blank. In fact, lower concentrations
Figure 6a,b show the sensor responses of the membrane electrodes with such as(0.03
low 0.01 mM)
mM
and 0.001 mM of TFPB membranes have also been tested experimentally, and
and high (30 mM) TFPB concentrations to different alkali metal salts, respectively. The the results
were almost
reference the same(V
potentials asr )those ofmeasurements
of the 0.03 mM of TFPB aremembrane, indicating
shown in Table 5 andthe
canTFPB mem-
be used to
brane keeps its property even at the very
calculate the response value (V s − V r ). low TFPB concentrations.

(a) (b)
Figure
Figure 6.
6. Sensor
Sensor responses
responses (V
(Vss −−VV
r) to alkali metal salts samples: (a) Low TFPB concentration (0.03 mM); (b) high TFPB
r ) to alkali metal salts samples: (a) Low TFPB concentration (0.03 mM); (b) high TFPB
concentration (30 mM).
concentration (30 mM).

Table 5. The slope for KCl, reference potential (V r ), and selectivity coefficients of the sensors.

Membrane Component TFPB 0.03 mM TFPB 30 mM

Slope for KCl (mV) 14.9 51.4
V r (mV) 78.5 −109.9
pot
Selectivity coefficients (logkK,j )
K+ 0 0
Na+ −0.3 −1.8
Li+ −1 −2.7
Cs+ −0.3 1.2

First, both the responses of membrane electrodes increased logarithmically with

increasing concentrations of each alkali metal salt. The slope for KCl shown in Table 5
is 51.4 mV in 30 mM TFPB and is 14.9 mV in 0.03 mM TFPB. The response of the 30 mM
TFPB membrane is much higher than that of 30 mM PADE membrane, indicating that the
charge density of the TFPB membrane is higher than that of PADE membrane [32,33], which is
caused by the fact that TFPB is completely dissociated while the PADE is partially dissociated.
Next, Figure 6b shows that the response to 30 mM KCl is about 0 mV, which means
that the membrane potential V r of the reference solution (30 mM KCl + 0.3 mM tartaric
acid) is the same as that of 30 mM KCl sample solution. It is quite reasonable because the
dissociation of TFPB is complete and is not affected by pH.
Figure 7 shows the sensor response of the membrane electrodes with high PADE
and TFPB concentrations (30 mM) to 100 mM NaCl samples at different pH levels. As
the pH decreased, the response value of the PADE membrane increased, while the TFPB
membrane remained unchanged. This can directly indicate the difference in dissociation of
the two membranes as previously discussed.
Sensors 2021, 21, 8343 9 of 14
Sensors 2021, 21, x FOR PEER REVIEW 9 of 14

Figure
Figure7.7.Sensor
Sensorresponses
responses(V(V
s− Vr) V
s − tor 100
) to mM NaClNaCl
100 mM sample at different
sample pH. pH.
at different

Table 5 shows
Last, by the response
comparing slope for
the response KCllow-TFPB
of the and selectivity
membranecoefficients
(Figureof6a)
thewith
sensor
that of
using TFPBmembrane
the blank membrane(Figure
based on 5a),low
the(0.03 mM) and
low-TFPB high (30shows
membrane mM) concentrations.
the same valueThe around
sensor
−100 mV of 0.03 mM
at 0.1 mMTFPB has
salts asathe
lowblank
selectivity for alkali
one, but metal ions.
its responses However,
to higher the sensor of do
salt concentration
high
not exactly converge to those of the blank. In fact, lower concentrations suchand
TFPB concentration (30 mM) shows high selectivity for alkali metal ions follows
as 0.01 mM and
the Hofmeister series in the order Cs > K > Na > Li , as is
0.001 mM of TFPB membranes have also been tested experimentally, and the results also shown in Figure 5b. were
almost the same as those of 0.03 mM of TFPB membrane, indicating the TFPB membrane
Table 5. The slope for KCl, reference potential (Vr), and selectivity coefficients of the sensors.
keeps its property even at the very low TFPB concentrations.
Membrane Component Table 5 shows the response
TFPB 0.03 mM slope for KCl and selectivity TFPBcoefficients
30 mM of the sensor
Slope for KCl (mV) using TFPB membrane based14.9 on low (0.03 mM) and high (30 mM)
51.4 concentrations. The
Vr (mV) sensor of 0.03 mM TFPB has a
78.5 low selectivity for alkali metal ions. However,
−109.9 the sensor of
high TFPB concentration (30 mM) shows
Selectivity coefficients (𝐥𝐨𝐠𝒌𝑲,𝒋 high
𝒑𝒐𝒕 selectivity for alkali metal ions and follows
the Hofmeister series in the order Cs+ > K+ > Na+ > Li+ , as is also shown in Figure 5b.
K 0 0
Na 3.3. Selectivity Coefficient and −0.3
Impedance of Different Concentrations−1.8 of PADE Membrane
Li −1 pot −2.7
Figure 8 shows the selectivity coefficient (k K,j ) as a function of the PADE concentration.
Cs −0.3 1.2
It can be seen that the selectivity coefficient does not change much with increasing PADE
concentration
3.3. and always
Selectivity Coefficient andremains
Impedance around unity.Concentrations
of Different Additionally,ofaccording to Section 3.1, the
PADE Membrane
response properties of PADE membranes at low PADE concentrations tend to be similar
Figure 8 shows the selectivity coefficient (𝑘 ) as a function of the PADE concentra-
to the blank membrane and depend on NPOE;, the membranes exhibit low selectivity but
tion. It can
still can be seen that
distinguish Csthe
+ selectivity coefficient does not change much with increasing
from other alkali metal ions. At concentrations above 20 mM,
Sensors 2021, 21, x FOR PEER REVIEW PADE
however, the propertiesalways
concentration and of the remains
membranes aroundareunity.
moreAdditionally,
biased towards according
PADEtoitself,
Section
10 of 14
which
3.1, the response properties of PADE membranes at low PADE concentrations tend to be
exhibits much lower ion selectivity for these four alkali metal ions.
similar to the blank membrane and depend on NPOE; the membranes exhibit low selec-
tivity but still can distinguish Cs from other alkali metal ions. At concentrations above
20 mM, however, the properties of the membranes are more biased towards PADE itself,
which exhibits much lower ion selectivity for these four alkali metal ions.

Figure
Figure8.8.Variation
Variationof
ofthe
theselectivity
selectivitycoefficient
coefficient (𝑘
pot ) with different PADE concentrations.
, ) with different PADE concentrations.
(k K,j

Figure 9 shows the impedance of the PADE membrane with different concentrations.
The impedance decreases with increasing lipid concentration, but remained almost un-
changed beyond 3 mM. The magnitude of the impedance of PADE membranes is always
maintained above 10 Ω ⋅ cm . As the surface charge density increases with higher lipid
concentrations, the electrical conductivity of the membrane increases, and thus the im-
Sensors 2021, 21, 8343 10 of 14

Figure 8. Variation of the selectivity coefficient (𝑘 , ) with different PADE concentrations.

Figure
Figure 99shows
showsthe theimpedance
impedance of the PADE
of the PADEmembrane
membrane withwith
different concentrations.
different concentra-
The impedance decreases with increasing lipid concentration, but
tions. The impedance decreases with increasing lipid concentration, but remained remained almost un-
almost
changed beyond 3 mM. The magnitude of the impedance of PADE
unchanged beyond 3 mM. The magnitude of the impedance of PADE membranes is al- membranes is always
maintained
ways maintained 10 Ω 10
above above ⋅ cm
6 Ω. ·As
cmthe surface
2 . As chargecharge
the surface density increases
density with higher
increases lipid
with higher
concentrations, the electrical
lipid concentrations, conductivity
the electrical of theofmembrane
conductivity the membraneincreases, and and
increases, thusthus
the im-
the
pedance
impedance decreases, as expected. However, lipid molecules PADE have the property of
decreases, as expected. However, lipid molecules PADE have the property of
partial
partial dissociation
dissociation ofof HH +.. Therefore,
Therefore, the the H
H+ dissociation
dissociation was
was inhibited
inhibited when
when there
there are
are
too
too many
many lipids
lipids on
on the
the surface
surface toto reduce
reduce thethe mutual
mutual repulsion
repulsion ofof homogeneous
homogeneous charges.
charges.
As the
the impedance
impedance is is related
related toto the
the surface
surface charge
charge density,
density, even if the
the PADE
PADE concentration
increased,
increased, the impedance did not change anymore.

Figure
Figure 9.
9. The
Theimpedance
impedance of
of the
the PADE
PADE membrane
membrane with different PADE concentrations.
concentrations.

3.4.
3.4. Selectivity
Selectivity Coefficient
Coefficient and
and Impedance
Impedance of Different
Different Concentrations of TFPB Membrane
pot
Figure
Figure 10 shows
shows the
theselectivity
selectivitycoefficient
coefficient(k(𝑘 ) as a function of the TFPB concentra-
K,j ), as a function of the TFPB concentration.
tion. It can be seen that when the concentration of
It can be seen that when the concentration of TFPB is below TFPB is below
0.1 mM, 0.1the
mM, the membranes
membranes hardly
hardly
show ion show ion selectivity.
selectivity. BeyondBeyond
0.1 mM0.1 TFPB,
mM TFPB,
on the onother
the other hand,
hand, the the membranes
membranes start
start to
to exhibit
exhibit ion
ion selectivity,
selectivity, whichincreases,
which increases,reaching
reachingaamaximum
maximumatataaconcentration
concentration ofof 3 mM
Sensors 2021, 21, x FOR PEER REVIEW 11 of 14
and remaining essentially
and remaining essentiallyconstant.
constant.AsAs mentioned
mentioned in Section
in Section 3.2, 3.2, theselectivity
the ion ion selectivity
of TFPBof
TFPB membranes
membranes followsfollows the Hofmeister
the Hofmeister series series
in the in
order Cs+ >Cs
the order K+ > >KNa> + Na >
> Li+ .Li .

Figure pot ) with different TFPB concentrations.

Figure10.
10.Variation
Variationof
ofthe
theselectivity
selectivitycoefficient
coefficient(𝑘
(k K,j
, ) with different TFPB concentrations.

Many studies have shown that most liquid membrane electrodes such as ion-selec-
tive electrodes are ion-selective and follow the Hofmeister series [34–38]. The ion selectiv-
ity is affected by various factors such as valence, solvated equivalent volume, polarizabil-
ity, complex formation of counterions in the aqueous solution. The experimental result in
the negatively-charged monolayer [38] is typical because counterions largely affecting the
surface potential compress the molecular surface area more effectively. Among these fac-
tors affecting the Hofmeister series, the hydration of ions, i.e., hydration energy is most
important [38,39]. The order of ionic radius is Cs > K > Na > Li , which is opposite to
Sensors 2021, 21, 8343 11 of 14

Many studies have shown that most liquid membrane electrodes such as ion-selective
electrodes are ion-selective and follow the Hofmeister series [34–38]. The ion selectivity
is affected by various factors such as valence, solvated equivalent volume, polarizability,
complex formation of counterions in the aqueous solution. The experimental result in
the negatively-charged monolayer [38] is typical because counterions largely affecting
the surface potential compress the molecular surface area more effectively. Among these
factors affecting the Hofmeister series, the hydration of ions, i.e., hydration energy is most
important [38,39]. The order of ionic radius is Cs+ > K+ > Na+ > Li+ , which is opposite
to the order of hydrated radius; Li+ > Na+ > K+ > Cs+ . The larger the hydrated radius
of the ion, the stronger the binding force with water molecules (hydration energy). This
larger binding force makes it more difficult for cations to interact with negatively-charged
lipid molecules on the membrane surface, thus making the sensor response lower and
causing ion selectivity, as found in Figure 10.
The ion selectivity is remarkable at moderate or high TFPB concentrations in Figure 10
because the increase in charged sites effectively interacting with counter cations. On the
other hand, the ion selectivity kept low even at high PADE concentrations (Figure 8);
it is due to inhibition of H+ dissociation of concentrated PADE molecules, to inhibit
increasing electric repulsion between PADE molecules, resulting in effective charged sites
not increasing as much. In contrast, the ion selectivity increased in the TFPB membrane,
because TFPB molecules make complete ionization, as above.
Figure 11 shows the impedance of the TFPB membrane with different concentrations
of TFPB. As the TFPB concentration increased, the membrane impedance largely decreased
by three digits. With TFPB lower than 0.3 mM, the impedance remained above 106 Ω · cm2 ;
however, it was below 105 Ω · cm2 when TFPB was higher than 3 mM. This is because
the increasing charge density at the membrane surface with increasing concentration
of completely-dissociated TFPB resulted in an increased electrical conductivity of the
membrane. A rebound in impedance occurred when the TFPB concentration reached
300 mM. The reason for the rebounding impedance is considered to be the precipitation
Sensors 2021, 21, x FOR PEER REVIEW
of TFPB, as an oil film was observed on the membrane surface, causing a reduction 12 of of
14
electrical conductivity.

Figure
Figure 11. The
The impedance
impedance of
of the
the TFPB
TFPB membrane with different TFPB concentrations.

TheAdvantage
membranes with TFPB
impedances as high 6 Ω · cm2 showed low ion selectivity,
as 10System
3.5. The of Using in the Taste Sensing
whileBased
thoseonwith lowhas
what impedances below in
been discussed Ω · cm2 exhibited
105previous high ion
sections, TFPB canselectivity
behave infollowing
different
the Hofmeister series. This property of the TFPB membranes with high impedances
sensing patterns with its concentration being specifically controlled. The benefits of using is the
same as that of the PADE membranes showing high impedances at
TFPB as a component of the lipid polymer membrane have also been revealed. any PADE concentration.
Figure 12 shows the performance of the taste sensing system using membranes com-
posed of TFPB in comparison to other membranes developed before. Figure 12a shows
the responses of the TFPB membrane and commercialized CMTE membrane to a typical
bitter substance quinine in distilled water. The CMTE membrane is a kind of ion-exchange
membrane and is widely used in sewage disposal. The responses at all concentration steps
tended to be flat, while the TFPB membrane showed great responses when the concentra-
tion of quinine exceeds 0.1 mM, which is considered to be a decent candidate of bitterness
sensing membranes. Figure 12b shows the responses of membranes using TFPB and
Sensors 2021, 21, 8343 12 of 14
Figure 11. The impedance of the TFPB membrane with different TFPB concentrations.

3.5. The Advantage of Using TFPB in the Taste Sensing System

3.5. The Advantage of Using TFPB in the Taste Sensing System
Based on what has been discussed in previous sections, TFPB can behave in different
Based
sensing on what
patterns has
with itsbeen discussed being
concentration in previous sections,
specifically TFPB can
controlled. behave
The in different
benefits of using
sensing
TFPB as a component of the lipid polymer membrane have also been revealed. of using
patterns with its concentration being specifically controlled. The benefits
TFPBFigure
as a component
12 shows theof the lipid polymer
performance membrane
of the havesystem
taste sensing also been revealed.
using membranes com-
Figure 12 shows the performance of the taste sensing system
posed of TFPB in comparison to other membranes developed before. Figure using membranes com-
12a shows
posed of TFPB in comparison to other membranes developed before.
the responses of the TFPB membrane and commercialized CMTE membrane to a typical Figure 12a shows
the responses of the TFPB membrane and commercialized CMTE membrane to a typical
bitter substance quinine in distilled water. The CMTE membrane is a kind of ion-exchange
bitter substance quinine in distilled water. The CMTE membrane is a kind of ion-exchange
membrane and is widely used in sewage disposal. The responses at all concentration steps
membrane and is widely used in sewage disposal. The responses at all concentration
tended to be flat, while the TFPB membrane showed great responses when the concentra-
steps tended to be flat, while the TFPB membrane showed great responses when the con-
tion of quinine exceeds 0.1 mM, which is considered to be a decent candidate of bitterness
centration of quinine exceeds 0.1 mM, which is considered to be a decent candidate of
sensing membranes. Figure 12b shows the responses of membranes using TFPB and
bitterness sensing membranes. Figure 12b shows the responses of membranes using TFPB
PADE to quinine in standard solution. It can be found that PADE is a better candidate for
and PADE to quinine in standard solution. It can be found that PADE is a better candidate
a bitterness sensing membrane, with the larger response and smoother linear shape for
for a bitterness sensing membrane, with the larger response and smoother linear shape
under 1 mM quinine, and the TFPB membrane started to behave effectively beyond 0.1
for under 1 mM quinine, and the TFPB membrane started to behave effectively beyond
mM, making it a better choice when the concentration of the solution is large.
0.1 mM, making it a better choice when the concentration of the solution is large.

(a) (b)
Figure 12.
Figure 12. The
The examples
examples using
using TFPB
TFPB membranes
membranes and
and other
other membranes
membranes to
to measure
measure bitterness
bitterness samples:
samples: (a)
(a) TFPB
TFPB (30
(30 mM)
mM)
membrane and CMTE membrane; (b) TFPB (15 mM) membrane and PADE (35 mM) membrane, respectively.
membrane and CMTE membrane; (b) TFPB (15 mM) membrane and PADE (35 mM) membrane, respectively.

4. Conclusions
4. Conclusions
In this study,
study, we
we investigated
investigated the
the differences
differences in
in electrical
electrical properties
properties of
of aa membrane
membrane
based on partially
partially dissociated PADE
PADE and
and aa membrane
membrane based
based onon completely
completely dissociated
dissociated
TFPB. The PADE membranes consistently exhibited low ion selectivity, irrespective of
the PADE concentration, whereas the TFPB membranes exhibited low ion selectivity
below 0.3 mM TFPB, and then showed significantly high ion selectivity above 1 mM and
reached a maximum at 3 mM. The sequence of ion selectivity of the TFPB membrane is
Cs+ > K+ > Na+ > Li+ , which is the same as the Hofmeister series. It can be considered
that the hydration of ions affects the electrostatic interaction with lipid molecules on the
membrane surface.
In addition, the impedance of PADE membranes decreased from 3 × 106 Ω · cm2 to
1 × 106 Ω · cm2 and remained unchanged beyond 3 mM PADE, while the TFPB membranes
continued to largely decrease from 3 × 106 Ω · cm2 to 3 × 103 Ω · cm2 . This different
property is caused by the difference in the dissociation state of the two membranes.
PADE molecules are used in the membranes of taste sensors for sourness, bitterness,
and umami [11,12]. It was already clarified [21] that the response of the membrane using
PADE to bitter substances deteriorated due to the acidic environment produced by H+
dissociation of PADE, and this problem was overcome by developing the bitterness mem-
brane using TFPB. Utilization of completely-dissociated materials such as TFPB will be also
Sensors 2021, 21, 8343 13 of 14

useful to control the sensitivity to taste substances, as discussed [21,40]. Furthermore, taste
sensors should respond to taste itself in the coexistence of various ion species; hence, those
with low hydration energy can possibly interfere with the detection of the taste produced
by other substances. Therefore, adjustment of the concentration of membrane components
and use of other lipid species with different ionization states will be effective for attaining
the purpose to quantify the taste selectively. The results obtained here will contribute to
the development of novel receptive membranes of taste sensors, the properties of which do
not change based on some real conditions such as the use time or pH.

Author Contributions: The work presented here was carried out as a collaboration between all
authors; K.T. defined the research theme; Z.X. and Y.J. carried out the experiments and analyzed the
data; Z.X. and Y.J. interpreted the results and wrote the paper; H.I. and K.T. provided directions for
the experimental methods, analysis of data, interpretation of the results, and writing of the paper.
All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by KAKENHI (21H05006).
Conflicts of Interest: Hidekazu Ikezaki is the president of Intelligent Sensor Technology, Inc., the
manufacturer of the TS-5000Z taste sensing system. Kiyoshi Toko holds stocks in Intelligent Sensor
Technology, Inc.

References
1. De Marco, R.; Clarke, G. Electrodes | Ion-selective electrodes. Encycl. Electrochem. Power Sources 2009, 103–109. [CrossRef]
2. Kimura, K.; Maeda, T.; Tamura, H.; Shono, T. Potassium-selective PVC membrane electrodes based on bis- and poly(crown
ether)s. J. Electroanal. Chem. 1979, 95, 91–101. [CrossRef]
3. Suzuki, K.; Watanabe, K.; Matsumoto, Y.; Kobayashi, M.; Sato, S.; Siswanta, D.; Hisamoto, H. Design and synthesis of calcium and
magnesium ionophores based on double-armed diazacrown ether compounds and their application to an ion sensing component
for an ion-selective electrode. Anal. Chem. 1995, 67, 324–334. [CrossRef]
4. Nishizawa, S.; Bühlmann, P.; Xiao, K.P.; Umezawa, Y. Application of a bis-thiourea ionophore for an anion selective electrode
with a remarkable sulfate selectivity. Anal. Chim. Acta 1998, 358, 35–44. [CrossRef]
5. Sutton, P.G.; Braven, J.; Ebdon, L.; Scholefield, D. Development of a sensitive nitrate-selective electrode for on-site use in fresh
waters. Analyst 1999, 124, 877–882. [CrossRef]
6. Vadgama, P. Multifunctional biosensor development and manufacture. Compr. Biotechnol. 2011, 81–94. [CrossRef]
7. Schaller, U.; Bakker, E.; Pretsch, E. Carrier mechanism of acidic ionophores in solvent polymeric membrane ion-selective electrodes.
Anal. Chem. 1995, 67, 3123–3132. [CrossRef]
8. Dimeski, G.; Badrick, T.; John, A.S. Ion selective electrodes (ISEs) and interferences—A review. Clin. Chim. Acta 2010, 411, 309–317.
[CrossRef]
9. Frag, E.Y.Z.; Ali, T.A.; Mohamed, G.G.; Awad, Y.H.H. Construction of different types of ion-selective electrodes. characteristic
performances and validation for direct potentiometric determination of orphenadrine citrate. Int. J. Electrochem. Sci. 2012, 7,
4443–4464.
10. Wu, X.; Onitake, H.; Huang, Z.; Shiino, T.; Tahara, Y.; Yatabe, R.; Ikezaki, H.; Toko, K. Improved durability and sensitivity of
bitterness-sensing membrane for medicines. Sensors 2017, 17, 2541. [CrossRef]
11. Tahara, Y.; Toko, K. Electronic tongues-a review. IEEE Sens. J. 2013, 13, 3001–3011. [CrossRef]
12. Wu, X.; Tahara, Y.; Yatabe, R.; Toko, K. Taste sensor: Electronic tongue with lipid membranes. Anal. Sci. 2020, 36, 147–159.
[CrossRef]
13. Hayashi, K.; Yamanaka, M.; Toko, K.; Yamafuji, K. Multichannel taste sensor using lipid membranes. Sens. Actuators B Chem.
1990, 2, 205–213. [CrossRef]
14. Toko, K. Taste sensor. Sens. Actuators B Chem. 2000, 64, 205–215. [CrossRef]
15. Zhang, H.; Zou, G.; Liu, W.; Zhou, Z. Beer taste detection based on electronic tongue. Sens. Mater. 2020, 32, 2949–2958. [CrossRef]
16. Hayashi, N.; Ujihara, T.; Hayakawa, F.; Nakano, Y.; Kawakami, T.; Ikezaki, H. Standardization of tomato juice tastes using a taste
sensor approach. Biosci. Biotechnol. Biochem. 2020, 84, 2569–2575. [CrossRef]
17. Wu, X.; Yuan, Y.; Tahara, Y.; Habara, M.; Ikezaki, H.; Toko, K. Reusability enhancement of taste sensor using lipid polymer
membranes by surfactant cleaning treatment. IEEE Sens. J. 2020, 20, 4579–4586. [CrossRef]
18. Kobayashi, Y.; Hamada, H.; Yamaguchi, Y.; Ikezaki, H.; Toko, K. Development of an artificial lipid-based membrane sensor
with high selectivity and sensitivity to the bitterness of drugs and with high correlation with sensory score. IEEJ Trans. Electr.
Electron. Eng. 2009, 4, 710–719. [CrossRef]
19. Uchida, T.; Kobayashi, Y.; Miyanaga, Y.; Toukubo, R.; Ikezaki, H.; Taniguchi, A.; Nishikata, M.; Matsuyama, K. A new method for
evaluating the bitterness of medicines by semi-continuous measurement of adsorption using a taste sensor. Chem. Pharm. Bull.
2001, 49, 1336–1339. [CrossRef]
Sensors 2021, 21, 8343 14 of 14

20. Nakatani, F.; Ienaga, T.; Wu, X.; Tahara, Y.; Ikezaki, H.; Sano, H.; Muto, Y.; Kaneda, Y.; Toko, K. Development of a sensor with
a lipid/polymer membrane comprising Na+ ionophores to evaluate the saltiness enhancement effect. Sensors 2019, 19, 5251.
[CrossRef]
21. Wu, X.; Shiino, T.; Tahara, Y.; Ikezaki, H.; Toko, K. Quantification of pharmaceutical bitterness using a membrane electrode based
on a hydrophobic tetrakis [3,5-bis (Trifluoromethyl) phenyl] borate. Chemosensors 2021, 9, 28. [CrossRef]
22. Strauss, S.H. The search for larger and more weakly coordinating anions. Chem. Rev. 1993, 93, 927–942. [CrossRef]
23. Kobayashi, H.; Sonoda, T.; Iwamoto, H.; Yoshimura, M. Tetrakis[3,5-di (F-methyl) phenyl]borate as the first efficient negatively
charged phase transfer catalyst. kinetic evidences. Chem. Lett. 1981, 10, 579–580. [CrossRef]
24. Nishida, H.; Takada, N.; Yoshimura, M.; Sonoda, T.; Kobayashi, H. Tetrakis[3,5-bis (trifluoromethyl) phenyl]borate. Highly
lipophilic stable anionic agent for solvent-extraction of cations. Bull. Chem. Soc. Jpn. 1984, 57, 2600–2604. [CrossRef]
25. Peper, S.; Gonczy, C. Potentiometric response characteristics of membrane-based Cs+ -selective electrodes containing ionophore-
functionalized polymeric microspheres. Int. J. Electrochem. 2011, 2011, 276896. [CrossRef]
26. Ying, K.S.; Heng, L.Y.; Hassan, N.I.; Hasbullah, S.A. A new copper ionophore N 1, N 3-bis [[3,5-bis (trifluoromethyl) phenyl]
carbamothioyl] isophtalamide for potentiometric sensor. Sains Malays. 2018, 47, 2657–2666. [CrossRef]
27. Yoshimatsu, J.; Toko, K.; Tahara, Y.; Ishida, M.; Habara, M.; Ikezaki, H.; Kojima, H.; Ikegami, S.; Yoshida, M.; Uchida, T.
Development of taste sensor to detect non-charged bitter substances. Sensors 2020, 20, 3455. [CrossRef]
28. Buck, R.P.; Lindner, E. Recomendations for nomenclature of ion-selective electrodes (IUPAC recommendations 1994). Pure Appl.
Chem. 1994, 66, 2527–2536. [CrossRef]
29. Van den Berg, A.; Van der Wal, P.D.; Skowronska-Ptasińska, M.; Sudhölter, E.J.; Reinhoudt, D.N.; Bergveld, P. Nature of anionic
sites in plasticized poly(vinyl chloride) membranes. Anal. Chem. 1987, 59, 2827–2829. [CrossRef]
30. Cutler, S.G.; Meares, P.; Hall, D.G. Surfactant-sensitive polymeric membrane electrodes. J. Electroanal. Chem. 1977, 85, 145–161.
[CrossRef]
31. Watanabe, M.; Toko, K.; Sato, K.; Kina, K.; Takahashi, Y.; Iiyama, S. Charged impurities of plasticizer used for ion-selective
electrode and taste sensor. Sens. Mater. 1998, 10, 103–112.
32. Teorell, T. Transport processes and electrical phenomena in ionic membranes. Prog. Biophys. Biophys. Chem. 1953, 3, 305.
[CrossRef]
33. Kobatake, Y.; Toyoshima, Y.; Takeguchi, N. Studies of membrane phenomena. II. Theoretical study of membrane potentials.
J. Phys. Chem. 1966, 70, 1187. [CrossRef]
34. Kamo, N.; Oikawa, M.; Kobatake, Y. Effective fixed charge density governing membrane phenomena. V. A reduced expression of
permselectivity. J. Phys. Chem. 1973, 77, 92–95. [CrossRef]
35. Jyo, A.; Torikai, M.; Ishibashi, N. The selectivity evaluation of an ion-selective electrode with a liquid membrane by electrode
response to a foreign ion. Bull. Chem. Soc. Jpn. 1974, 47, 2862–2868. [CrossRef]
36. Helfferich, F. Equilibria. In Ion Exchange; Dover Publications: Mineola, NY, USA, 1995; p. 624, ISBN 9780486687841.
37. Wegmann, D.; Weiss, H.; Ammann, D.; Morf, W.E.; Pretsch, E.; Sugahara, K.; Simon, W. Anion-selective liquid membrane
electrodes based on lipophilic quaternary ammonium compounds. Microchim. Acta 1984, 84, 1–16. [CrossRef]
38. Goddard, E.D.; Kao, O.; Kung, H.C. Counterion effects in charged monolayers. J. Colloid Interface Sci. 1968, 27, 616–624. [CrossRef]
39. Rais, J. Some regularities in the free enthalpies of transfer of univalent ions from water to organic polar solvents. Collect. Czechoslov.
Chem. Commun. 1971, 36, 3080–3087. [CrossRef]
40. Toko, K.; Hara, D.; Tahara, Y.; Yasuura, M.; Ikezaki, H. Relationship between the amount of bitter substances adsorbed onto
lipid/polymer membrane and the electric response of taste sensors. Sensors 2014, 14, 16274–16286. [CrossRef] [PubMed]