Design of Biocompatible Ion Sensors
Design of Biocompatible Ion Sensors
Design of Biocompatible Ion Sensors
I. INTRODUCTION
Potentiometric ion sensors such as ion-selective electrodes are compact and convenient
tools for ion assay in solution. Specifically, much attention has been focused on neutral-
carrier-type ion sensors owing to their high ion selectivities. Solvent-polymeric membranes
are generally required as their ion-sensing membranes. A most popular ion-sensing mem-
brane material for neutral-carrier-type ion sensors is plasticized poly(vinyl chloride)
(PVC). The solvent-polymeric ion-sensing membranes, however, have some drawbacks.
The ion-sensing membranes need high volume percentages of a special plasticizer, which is
easy to exude from the membranes to aqueous (sample) phases and thereby to deteriorate.
Not only the plasticizers but also the neutral carriers are often toxic, and PVC itself is
becoming an issue in environmental science due to the chlorinated compound. Also,
plasticized-PVC membranes do not seem to be very biocompatible because they tend to
adsorb bio-organic compounds such as proteins on serum metal-ion assay. Sometimes,
neutral-carrier-type PVC-membrane ion-selective electrodes may give some negative errors
on metal-ion assay in biological systems. It is therefore quite difficult to apply ion sensors
based on neutral-carrier-type PVC membranes to in-vivo metal-ion assay such as in-situ
ion monitoring at a bedside. In another aspect, plasticized- PVC membranes are not very
suitable for ion-sensitive field-effect transistors (ISFETs) mainly due to the poor adhesion
to the FET gate surface.
Considerable efforts are therefore required for alleviating the toxicity and promoting
the biocompatibility of the neutral-carrier-type ion sensors, in order to obtain biocompa-
tible ion sensors that are applicable in-vivo ion sensing in biological systems, especially in
clinical systems. One of the efforts is in material selection for the support polymers of the
ion-sensing membranes. That is to say, materials that are compatible with biological
systems such as human blood should be applied as the membrane support. Another effort
is in chemical bonding of active materials such as neutral carriers to the membrane sup-
ports and avoidance of special plasticizers. They would diminish the toxicity of membrane
components considerably by preventing the exudation of neutral carriers from the mem-
branes to aqueous (sample) phases.
This chapter is concerned with the recent research concerning the design of biocom-
patible ion sensors, especially the results of our research group.
585
B. Poly(dimethylsiloxane)
An alternative membrane material to PVC for ion-selective electrodes is crosslinked
poly(dimethylsiloxane), which is generally called room temperature vulcanizing-type
(RTV) silicone rubber. Formation of crosslinked poly(dimethylsiloxane) (RTV silicone
rubber) consists of two processes: (1) the hydrolysis of active end groups (alkoxy, acetoxy,
oxime, amino, amido groups, and so forth) of dimethylsiloxane oligomers, and (2) cross-
linking by condensation of the active end groups with the resulting silanol groups. Silicone
rubber has several advantages: (1) easy fabrication at ambient temperature, (2) high elasticity
at ambient temperature, (3) excellent adhesive property, especially for inorganic materials,
(4) excellent electrical property, (5) chemical inactivity, and (6) low toxicity. Silicone rubber
is, therefore, an excellent candidate for membrane materials of ion sensors. The material was
first applied to heterogeneous precipitate-based membranes for silver ion-selective electrodes
[6]. Since the polymer material is highly elastic at ambient temperature, neutral-carrier-type
ion-sensing silicone-rubber membranes do not necessarily require special plasticizers to
endow a neutral carrier with mobility enough for ion exchanges. This eliminates deteriora-
tion of the sensing membranes caused by the plasticizer exudation. Most importantly, sili-
cone-rubber-membrane ion-selective electrodes are also expected to show some
biocompatibility on practical use in biological systems [7–11]. Moreover, the excellent adhe-
sive property of silicone rubber to inorganic materials is very advantageous on its use as ion-
sensing membranes for ISFET. These characteristics of silicone rubber become great advan-
tages on the application of the silicone-rubber-membrane ion sensors to clinical analyses.
Simple encapsulation or dispersion of neutral carriers in silicone rubber is an easy
way to fabricate silicone-rubber ion-sensing membranes based on neutral carriers.
FIG. 1 Potential response to Naþ activity changes of ISFETs based on silicone-rubber membranes
of calixarene neutral carriers (1)(*), (2) (*), (3) (&), and (4) (~). (From Ref. 20.)
FIG. 2 Time-course changes of sensitivity (a) and selectivity (b) for Naþ -ISFETs based on silicone
rubber – (1) (90/10 wt%) membrane (*), PVC–DOS–(1) (30/60/10 wt%) membrane (&), and PVC–
DOS–(2) (30/60/10 wt%) membrane (~). (DOS is 2-ethylhexyl sebacate.) (From Ref. 20.)
were drastically decreased in about 30 days. This occurred because the plasticizer and
neutral carrier (2) dissolved out from the membrane into the aqueous phases. In the Naþ -
ISFETs of plasticized PVC–(1) membranes, a marked deterioration started at about 50
days, that is, more gradually than in the plasticized PVC–(2) system. This implies that the
unsymmetrical calix[4]arene (1) is very superior to the symmetrical one (2) in solubility
even in plasticized PVC. Nevertheless, leaching of the plasticizer out from the plasticized
PVC–(1) membrane resulted in such ISFET deterioration. The Naþ -ISFETs containing
silicone rubber–(1) membranes, on the other hand, showed an excellent durability. In these
ISFETs, their high Naþ sensitivity and selectivity remained unchanged even after 120
days.
Silicone rubber is a polymer consisting of siloxane units, as mentioned above. It is
therefore expected that incorporation of oligosiloxane moiety to calix[4]arene neutral
carriers increases their affinity to silicone rubber and thereby to enhance their solubility
or dispersibility in the polymer matrix. Oligosiloxane-modified calix[4]arene neutral car-
riers have been designed which are unsymmetrical and symmetrical ones (5) and (6) [21]. In
the unsymmetrical oligosiloxane-modified calixarene neutral carrier (5), one may also
expect dispersibility enhancement derived from its structural asymmetry. Dispersibility
of oligosiloxane-modified calixarene neutral carriers (5) and (6) in silicone rubber was
first checked by microscopic observation. In the SEM photographs, the silicone-rubber
membranes of (5) exhibit smooth surface, which suggests high dispersibility of the oligo-
siloxane-modified calixarene neutral carriers in silicone rubber. This is also the case with
the (6)-containing silicone-rubber membranes. Membrane impedance (resistivity),
obtained by AC impedance measurements in Naþ aqueous solutions, also provided impor-
tant information concerning the membrane dispersibility of the calixarene neutral carriers
based on nonsymmetrical calixarene neutral carrier (1) and oligosiloxane-modified one (5)
are similar to that based on (2) in the Naþ selectivity against Kþ . The selectivity coefficient
for Naþ with respect to Kþ for the ISFET of (1) and (5) is about 3 103 , being sufficient
of Naþ assay in blood serum.
Silicone rubber is also applicable to membrane supports for neutral-carrier-type ion-
selective electrodes. The problem of membrane impedance is, however, more serious in the
ion-selective electrodes than in the ISFETs. High membrane impedance often leads sig-
nificantly to the low sensitivity and slow potential response in the ion-selective electrodes.
The silicone-rubber membrane based on oligosiloxane-modified calix[4]arene neutral car-
rier (5) still exhibits high performance when used for Naþ -selective electrodes [22]. Figure 5
shows a typical potential response for a silicone-rubber-membrane Naþ -selective electrode
based on calixarene neutral carrier (5), together with those for (2) and a well-known Naþ
neutral carrier, bis[(12-crown-4)methyl] dodecylmethylmalonate [bis(12-crown-4)] [23].
The silicone-rubber membrane of (5) afforded high electrode sensitivity with a Nernstian
slope in the wide Naþ activity range of 3 105 to 1 M. On the other hand, both the
silicone-rubber membrane electrodes based on (2) and bis(12-crown-4) possess only poor
sensitivity to Naþ activity changes and even anion response in the high NaCl concentration
range. Obviously, the poor dispersibility of neutral carriers (2) and bis(12-crown-4) in
silicone rubber and therefore the high electrical resistivity of their silicone-rubber mem-
branes lead to the low sensitivity of their Naþ -selective electrodes. A marked difference in
response time was also found among Naþ -selective electrodes with silicone-rubber mem-
branes of the three neutral carriers (Fig. 6). Fast response [2 s of response time (t90 Þ was
attained in the electrodes with silicone-rubber membranes of (5). The electrode response is,
however, sluggish in the silicone-rubber membrane system of (2) and bis(12-crown-4). The
response times in both the silicone-rubber membrane systems of (2) and bis(12-crown-4) are
in the order of 1 min. Thus, high dispersibility of oligosiloxane-modified calixarene neutral
carrier (5) in silicone rubber is reflected more remarkably in the performance of silicone-
rubber membrane Naþ -selective electrodes than the corresponding ISFETs.
C. Sol–Gel-Derived Membranes
Sol–gel chemistry enables us to design hybrid inorganic–organic materials, allowing us to
fabricate glasses and films with novel properties and functionalities [24]. The low reac-
FIG. 8 Potential response of Kþ - and Naþ -ISFETs based on optimized sol–gel-derived membranes
of valinomycin (*) and bis(12-crown-4) (*) with interlayer of polythiophene [27]. The initial
DEDMS/TEOS ratio for sol–gel processing is 3.
FIG. 9 Selectivity coefficients for Kþ - and Naþ -ISFETs based on optimized sol–gel-derived mem-
branes of valinomycin (a) and bis(12-crown-4) (b) with polythiophene interlayer. (From Ref. 27.)
FIG. 10 SEM photographs for sol–gel-derived (a) and plasticized-PVC (b) membranes encapsulat-
ing bis(12-crown-4) after protein adsorption test. (From Ref. 27.)
B. Poly(dimethylsiloxane)
Poly(dimethylsiloxane) (silicone rubber) membranes are fabricated by hydrolysis of alkox-
ysilyl terminal groups of silicone-rubber precursors [oligo(dimethylsiloxane) derivatives
and crosslinking agents], followed by condensation. Covalent bonding of neutral carriers
carrying an alkoxysilyl group to silicone rubber is, therefore, feasible by simple reaction of
the silicone-rubber precursor with alkoxysilylated neutral carriers, as schematically shown
in Scheme 1 [44].
As neutral carriers for the chemical modification, 16-crown-5 and calix[4]arene deri-
vatives possessing a triethoxysilyl group (7) and (8) were designed for Naþ sensors.
Triethoxysilylethyl-16-crown-5(7) was then mixed with a silicone-rubber precursor for
the membrane fabrication accompanying covalent bonding of the neutral carrier.
Comparison of IR spectra before and after extraction of the nonbonded neutral carrier
with benzene confirmed the covalent bonding of the 16-crown-5 derivative to silicone-
rubber membranes. In the IR spectrum for the silicone-rubber membranes fabricated
using the ethoxysilylated 16-crown-5, a significant peak assigned to C–H deformation
vibration for its 16-crown-5 ring was observed around 1350 cm1 even after benzene
extraction of (7) from the membranes for a whole day. It is obvious that a considerable
amount of 16-crown-5 moiety was bonded covalently to the silicone-rubber membranes
fabricated using (7). IR spectroscopy of the silicone-rubber membranes obtained using an
alkoxysilylated calixarene (8) also supported the covalent bonding of the calix[4]arene
neutral carrier to silicone-rubber membranes.
The Naþ -selective electrodes of the silicone-rubber membranes containing (8) with-
out any other additive exhibited a very curious potential response, especially in the Naþ
activity changes between 1 105 to 1 102 M (Fig. 11). It is probably because the
chemical modification of silicone-rubber membranes with a calixarene neutral carrier
results in high membrane impedance. Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate (TFPB) was, therefore, used to improve the electrode response. The TFPB addition to
the silicone-rubber membranes reduces the membrane impedance to about one-third of the
initial values, thus the membranes allow high sensitivity with a Nernstian slope in the Naþ
activity range of 1 105 to 1 M. TFPB is still easy to dissolve out from the membrane
because it is not bonded covalently to silicone rubber. For further durability enhancement
and toxicity alleviation of the ion-sensing membranes, sodium triphenyl-4-[3-triethoxysi-
lyl)propyloxy]phenylborate (9), together with the calixarene neutral carrier, was also used
for the immobilization of an anion excluder on silicone-rubber membranes by covalent
bonding. A decreased membrane impedance was again attained in the silicone-rubber
membranes incorporating both calixarene neutral carrier (8) and anion excluder (9).
The potential response profile for the membrane system containing both (8) and (9) is
quite similar to that for the conventional membrane system of calixarene neutral carriers
and TFPB that are not bonded covalently, showing a Nernstian response to Naþ activity
changes in the wide activity range. Response time was also improved with Naþ -selective
electrodes based on the silicone-rubber membranes modified chemically by calixarene
neutral carrier (8) and an anion excluder TFPB or alkoxysilylated sodium tetraphenylbo-
rate (9). Another way to immobilize neutral carriers to silicone rubber by covalent bond-
ing may be copolymerization of a vinyl-modified polysiloxane and neutral-carrier vinyl
monomers induced by UV-light irradiation and the resulting neutral-carrier-based mem-
branes were applied to Kþ - and Naþ -sensitive field-effect transistors (ISFETs) [45–47].
The neutral-carrier-modified silicone-rubber membranes often experience anomalous elec-
trode response, unless the ion-sensing membrane contains a lipophilic salt to overcome
their high membrane impedance. The design of an oligomeric neutral carrier with a med-
ium molecular weight and its blending with a silicone rubber might alleviate the demerits
of the silicone-rubber membranes modified chemically by a neutral carrier. The medium-
molecular-weight neutral carrier may improve the poor mobility of the covalently bonded
FIG. 11 Potential response of Naþ -selective electrodes based on silicone-rubber membranes mod-
ified chemically by triethoxysilylated calix[4]arene (8) (*) without anion excluder; (*) with TFPB;
(&) modified chemically by triethoxysilylated tetraphenylborate (9) as well. (From Ref. 44.)
neutral carriers and its outflowing from the membrane owing to its relatively high mole-
cular weight. For obtaining a medium-molecular-weight calixarene neutral carrier,
calix[4]arene tetra-allyl ester was incorporated into an oligo(methylhydrosiloxane) to
yield oligosiloxane-modified calix[4]arene neutral carrier (10) [48]. The oligosiloxane back-
bone is expected to enhance the solubility or dispersibility of the resulting calixarene
neutral carrier in silicone-rubber membranes containing dimethylsiloxane repeating
units. Calixarene oligomer (10) carries two or three calixarene units and possesses a
molecular weight of several thousands. The Naþ -selective electrodes based on silicone-
rubber membranes containing the oligomeric calixarene neutral carrier (10) in 10 wt%
exhibit a Nernstian response to tenfold Naþ activity changes in the wide activity range.
Such a curious potential response as shown in Fig. 11 was not found in the silicone-rubber
membranes containing the oligomeric calixarene neutral carrier (10). This means that the
calixarene moiety itself is more mobile and it is easier to exchange Naþ in the silicone-
rubber membranes encapsulating an oligomeric calixarene neutral carrier than in those
modified chemically with a calixarene moiety. There is another significant difference in the
sensor response time between the membranes containing oligomeric calixarene neutral
carrier (10) and incorporating a calixarene moiety by chemical bonding. The response
time (t90 ) is no shorter than 3 min in the system of the calixarene-bound membranes. In
the present membrane system containing oligomeric calixarene neutral carrier (10), on the
other hand, the response time is below 1 min. Thus, the employment of the silicone-rubber
membranes containing oligomeric calixarene neutral carrier (10) instead of the calixarene-
bound membranes can improve the electrode potential response and the response time
owing to its enhanced mobility of the calixarene moiety in the membranes. Of course, the
oligomeric calixarene neutral carrier (10) is much more insoluble in water than monomeric
calix[4]arene neutral carriers and is still not easy to exude from the membrane to aqueous
phases.
C. Sol–Gel-Derived Membranes
Appropriate fabrication of sol–gel-derived membranes encapsulating neutral carriers such
as valinomycin can afford an excellent type of neutral-carrier-type ion-sensing membranes
for ISFETs [27] as already mentioned. The simple encapsulation of neutral carriers in sol–
gel-derived membranes, however, has a drawback: the encapsulated neutral carriers are
still apt to exude from the membranes into aqueous sample solutions, which thereby
makes the resulting ion sensors less durable and more toxic. Incorporation of neutral
carriers to sol–gel-derived membranes by covalent bonding is desirable.
Sol–gel-derived membranes are generally made by hydrolysis of an alkoxysilane such
as tetraethoxysilane (TEOS), followed by condensation of the resulted silanol. So, an easy
way to incorporate a neutral carrier to sol–gel-derived membranes by covalent bonding is
sol–gel processing of the alkoxysilane together with an alkoxysilylated neutral carrier [49].
Triethoxysilylated 16-crown-5 and bis(12-crown-4) derivatives (7) and (11) were selected as
the crown-ether neutral carriers. The corresponding triethoxysilylated derivative of
sodium tetraphenylborate (9) was chosen as an anion excluder. Since sol–gel-derived
membranes made from solutions containing only TEOS are very brittle [27] sol–gel-
derived ion-sensing membranes were fabricated by using solutions containing TEOS
and diethoxydimethylsilane (DEDMS) with a 1:3 ratio. IR-spectral measurements indi-
cated that the neutral carrier and anion excluder can be covalently bonded to the mem-
branes to a great extent, by the present sol–gel processing using the alkoxysilyl-substituted
neutral carrier and anion excluder.
Typical profiles for the potential response of Naþ -ISFETs based on the sol–gel-
derived membranes modified chemically by alkoxysilylated 16-crown-5 (7) and bis(12-
crown-4) (11), together with anion excluder (9) show that both of the Naþ -ISFETs
have high sensitivity with a Nernstian response to Naþ activity changes in wide activity
ranges of 3 105 to 1 M (Fig. 12). The potential response is quite fast in the Naþ -ISFETs
in spite of the covalent bonding of the neutral carriers to the ion-sensing membranes, as
exemplified in the membrane system of the bis(12-crown-4) (11). Some mobility of the
chemically bonded neutral carriers can probably be maintained in the present sol–gel-
derived membranes. The response time (t90 Þ is several seconds for both of the Naþ -
FIG. 12 Potential response to Naþ activity changes of Naþ -ISFETs based on sol–gel-derived
membranes modified chemically by alkoxysilyl-substituted neutral carriers (7) (*) and (8) (*),
together with anion excluder (9). (From Ref. 49).
ISFETs based on the sol–gel-derived membranes of (7) and (11), being almost comparable
to that for similar ISFETs based on sol–gel-derived membranes simply encapsulating
bis[(12-crown-4-)ylmethyl]2-dodecyl-2-methylmalonate [27].
Selectivity coefficients for Naþ with respect to interfering cations which exist in
biological and environmental systems were determined for the Naþ -ISFETs based on
sol–gel-derived membranes incorporating neutral carriers (7) and (11) by covalent bonding
(Fig. 13). In the ISFETs of the 16-crown-5 membrane system, the Naþ selectivities against
Hþ , Liþ , NH4 þ , Mg2þ , and Ca2þ are quite good, but the selectivity against Kþ is not high
enough, especially for Naþ assay in biological systems such as blood. On the contrary,
high Naþ selectivity against Kþ as well as the other interfering ions was found in the
sensor of the bis(crown ether) membrane system. This ion sensor is of practical use in
biological systems from the standpoint of the ion selectivity.
An advantage of the ion-sensing membranes modified chemically by a neutral carrier
and an anion excluder over those simply encapsulating them is high durability of the ion-
sensing membranes and therefore of the resulted ion sensors. In the ISFETs of the mem-
branes simply encapsulating bis[(12-crown-4-)ylmethyl]2-dodecyl-2-methylmalonate and
NaTFPB, an abrupt decrease in the sensitivity was observed after 30 days (Fig. 14),
probably due to their easy extrusion from the membrane to sample solutions. In the
ISFETs of the membranes modified chemically by (11) and (9), on the other hand, the
high sensitivity of a Nernstian response was kept even after 100 days. The long lifetime for
the ISFETs of the membranes modified chemically by the neutral carrier and anion
excluder is desirable on practical applications. The high sensor durability also means
that the active materials for ion-sensing membranes hardly exude out from the membrane
to aqueous sample solutions during ion assay. This also implies the low toxicity of the ion
sensors for use in biological systems.
Quaternary alkylammonium salts are generally water-soluble surfactants. The sol–
gel-derived anion-sensing membranes encapsulating a quaternary alkylammonium salt,
especially with high contents, are easy to deteriorate due to the exudation of the cationic
site from the membrane to aqueous sample phases. Moreover, another issue concerning
the dispersibility of ammonium salts in sol–gel-derived membranes may happen when high
FIG. 13 Selectivity comparison between Naþ -ISFETs based on sol–gel-derived membranes mod-
ified chemically by alkoxysilyl-substituted neutral carriers (7) and (11). (From Ref. 49.)
FIG. 14 Time-course changes of sensitivity (slope of calibration plots) for Naþ -ISFETs based on
sol–gel-derived membranes incorporating bis(12-crown-4) by covalent bonding using (11) (*) and
by encapsulation of bis[(12-crown-4-)ylmethyl] 2-dodecyl-2-methylmalonate (*). (From Ref. 49.)
FIG. 16 Selectivity coefficients for CI with respect to other anion ISFETs based on sol–gel-
derived membranes (a) encapsulating trioctylmethylammonium chloride (b) modified chemically
by (12). (From Ref. 50.)
FIG. 17 Naþ calibration graphs and Naþ concentrations in sera obtained by Naþ -ISFETs based
on (a) silicone-rubber membrane of calixarene (5) and (b) plasticized-PVC membrane of (2). (*)
Naþ calibration plots: (~) found values for Serum I (145 mM Naþ and 4.1 mM Kþ ); (&) found
values for Serum II (124 mM Naþ and 6.5 mM Kþ ). (From Ref. 29.)
in the serum samples, obtained by the PVC-membrane Naþ -ISFET, deviate consider-
ably from the Naþ calibration [Fig. 17(b)]. The negative potential shift from the Naþ
calibration was observed in any of the serum samples. However, there is hardly any
significant deviation in the Naþ -concentration found value for the dummy samples
containing the same concentrations of Naþ and Kþ without any organic components
such as proteins. Obviously, the negative potential shift of the serum samples from the
calibration graphs is not ascribable to interference by Kþ and by organic components
(proteins) in sera. Also, for the Naþ assay in human urine samples, the calixarene-
based silicone-rubber membranes are superior to the corresponding plasticized-PVC
ones as ion-sensing membranes for Naþ -ISFETs. Thus, the silicone-rubber membrane
Naþ -ISFETs based on calixarene neutral carrier (5) are quite useful for Naþ assay in
human sera and urine, whereas the corresponding plasticized-PVC membrane ISFETs
are likely to cause significant errors on the assay.
Adsorption of blood protein on the silicone-rubber membranes containing a neutral
carrier was tested to obtain some information about biocompatibility of the ion-sensing
membranes and therefore the resulted ISFETs on Naþ assay in blood. Comparison in the
SEM photographs for a silicone-rubber membrane and its corresponding plasticized-PVC
membrane indicates a striking difference in the protein adsorption. The silicone-rubber
membrane hardly adsorbs blood proteins, whereas a large amount of proteins can be seen
on the plasticized-PVC membrane. This indicates that the silicone-rubber ion-sensing
membranes are superior to the corresponding plasticized-PVC membranes in the blood
compatibility. The adsorption of blood organic components on plasticized-PVC ion-sen-
sing membranes often causes some negative errors on blood Naþ assay by the resulted
membrane ion sensors. The serious protein adsorption also makes it difficult to use plas-
ticized-PVC membrane ion sensors for in-vivo ion monitoring. On the contrary, this is not
the case with the silicone-rubber membranes that can alleviate markedly the protein
adsorption.
The Naþ -selective electrodes based on silicone-rubber membranes modified chemi-
cally by (8) and (9), were also investigated for Naþ assay in control serum and urine [22].
The found values for the Naþ concentrations in both of the serum and urine samples are in
good agreement with their corresponding actual values with a relative standard deviation
of about 1%. These results suggest that the Naþ -selective electrodes based on silicone-
rubber membranes modified chemically by calix[4]arene neutral carrier (8) are reliable on
assay in human body fluid.
B. Sol–Gel-Derived Membranes
The sol–gel-derived membrane ISFETs based on bis(12-crown-4) and valinomycin were
applied for Naþ and Kþ assay in blood sera [27]. For reproducibility checking, the metal-
ion assay was carried out ten times for each sample, using two different control sera. The
ISFETs gave reliable data both in Naþ and Kþ assay. The coefficient of variation ranges
between 0.45 and 0.78%, thus indicating excellent reproducibility in the serum cation
assay with the ISFETs of neutral-carrier-type sol–gel-derived membranes. The results
for real blood sera for normal human for the cation assay showed relative errors within
2% for the Naþ assay and within 4% for the Kþ assay.
The sol–gel-derived membranes incorporating the alkoxysilylated bis(crown ether)
(11) by covalent bonding were tested for their thrombogenic property. Any significant
adsorption of blood platelets was hardly observed on the membranes, as is the case with
sol–gel derived membranes encapsulating a neutral carrier [27]. Such excellent thrombo-
genic property of the sol–gel-derived membranes modified chemically by a bis(crown
ether) suggests a high possibility of their application to Naþ assay in blood sera. The
results for Naþ assay in human blood serum with the Naþ -ISFETs are given in Fig. 18,
showing that the found values for Naþ concentrations are in good agreement with the
corresponding actual values.
FIG. 18 Correlation between actual and found values of Naþ concentrations on serum assay with
ISFETs based on sol–gel-derived membranes of bis(12-crown-4) (11). (From Ref. 49.)
V. CONCLUSION
The design of biocompatible (blood compatible) potentiometric ion sensors was described
in this chapter. Sensing membranes fabricated by crosslinked poly(dimethylsiloxane) (sili-
cone rubber) and sol–gel-derived materials are excellent for potentiometric ion sensors.
Their sensor membrane properties are comparable to conventional plasticized-PVC mem-
branes, and their thrombogenic properties are superior to the PVC-based membranes.
Specifically, membranes modified chemically by neutral carriers and anion excluders are
very promising, because the toxicity is alleviated drastically. The sensor properties are still
excellent in spite of the chemical bonding of neutral carriers on membranes.
The biocompatible potentiometric ion sensors have been successfully applied for ion
assay in biological systems such as human blood. They might be used in in-vivo cation
assay in biological systems such as intra-arterial assay in the near future.
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