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Multichannel ISFET catheter for temporal and spatial pH variation studies in the stomach over 24 hours
332
Sensors and Actuators B, 7 (1992) 332-335
Multichannel ISFET catheter for temporal and spatial pH variation studies in the stomach over 24 hours L. Thybaud
and C. Depeursinge
Laboratoire de Ginnie Midical-EPFL,
CH-1024
Ecublens (Switzerland)
A. Grisel Microsens S.A., CH-2007 Neuchcitel (Switzerland)
C. Emde, D. Armstrong
and F. Viani
Division de Gastroentkologie - CH U V, CH- 1011 Luusanne (Switzerland)
Abstract A four channel multiple sensor based on ISFETs has been developed for medical research in gastroenterology. The ISFETs are mounted in two groups separated by 10 cm and placed as close as possible in each group. New solutions for the electrical connections by kapton tape and for the disposition of the ISFET have been developed. An increased lifetime of the sensors is achieved by a silanization procedure which promotes adhesion between the ISFET surface and the encapsulating epoxide. The lifetime has been tested for Si,N, and Al,O, ISFETs. The realized sensors have been tested in clinical conditions in a university hospital and demonstrate accurate and interesting results as well as being comfortable to use.
Introduction
Sensor realization
pH measurements for 24 h at one point in the stomach are now commonly performed in gastroenterology for diagnostic purposes [l-3]. However the spatial distribution of pH and its evolution at different positions in the stomach, over a long period of time, is still largely unknown. A catheter with multiple ISFETs has been designed to determine how the pH evolves at two points in the stomach separated by several centimeters, and at the same time how it evolves within a few millimeters (locally) at these two points by mounting them in groups of two ISFETs. A reflux episode can be observed by monitoring the pH difference between the two locations separated by 10 cm. This difference is expected to be important over quite a long time, and one of the goals of the study is to evaluate the importance of the pH gradients at a local scale. This should ensure the significance and validity of the local measurements of pH in gastroenterology. To reach this goal, a multiple ISFET sensor allowing the pH mapping over 24 h in the gastro-oesophageal tract has been designed, which takes advantage of the ISFET technology: accuracy and small size.
A four channel sensor has been developed in a single lumen catheter of 2.0 mm id. The ISFETs were mounted in two groups of two neighboring ISFETs separated by 10 cm. One group is in the upper part and the other in the lower part of the stomach. Within each group, the ISFETs were placed as close as possible ( 1.5 mm). The basic method to encapsulate the ISFETs was presented in earlier papers [ 5, 61. The major improvements which have been brought to this new probe are a different placement of the ISFETs and the use of an improved kapton tape for the interconnections. The kapton tape is now made of four parallel conducting copper tracks which are printed in a zigzag form on a kapton sheet of 50 cm length. This sheet is a kapton-glue-copper-kapton sandwich which guarantees an optimal protection of the copper tracks. The sheet is cut and the resulting tape is folded and glued to yield a kapton tape of 2 m length, with an enlargement at each end to allow an easy hand soldering. The four copper tracks, each 150 pm wide, are deposited on a 1.5 mm wide and 130 pm thick kapton tape. The
09254005/92/%5.00
@ 1992 -
Elsevier Sequoia. All rights reserved
333
10cm.
I
I ww
I j /
reference electrode
lsfet
1
I
\ lsfet 2
lsfet 3
Met 4
\
f
catheter
(4 ,
bonding wire \
1.5mm.
,
epoxide /
connections to next lsfet
CMOS lsfet @I
Fig. I. Global catheter.
(a) and
local
(b) arrangements
of ISFETs
in the
major advantage of this design is its adaptability to different length requirements: either one very long 2 m probe or two probes of 1 m length can easily be built, and the four tracks allow two ISFETs to be connected, reducing by a factor of two the number of tapes required. The arrangement and final assembly is sketched in Fig. 1. The ISFETs are glued onto the kapton tape in opposite directions, so that the two sensing surfaces are as close as possible. This configuration allows an easy bonding, after removal of a piece of the protecting cover-layer of the kapton tape just behind each ISFET. Elsewhere the coverlayer protects from electrical short circuits. Finally, the sensing surfaces of the two ISFETs are separated only by approximately 1.5 mm. As mentioned before, the two groups of ISFETs are separated by 10 cm. The whole assembly is mounted into a single lumen catheter of 2.0 mm i.d. A single silver-silver chloride reference electrode is mounted at the tip of the catheter. No strong biopotential, which could disturb the measurements, has been observed in the stomach. Finally, the comfort of the patient is guaranteed, by the use of floppy kapton tapes in a single supple catheter. Optimization of the sensor’s lifetime
With the present technology the construction of an ISFET multisensor is still time consuming and expensive. Repeated measurements with the same sensor have been envisaged on the same patient, in
order to know how the pH varies over 24 h, three times at intervals of several days. This means that the ISFET encapsulation must last for at least 3 days. Moreover the feasibility of the ISFET encapsulation had to be dramatically increased. We knew from previous experiments that this was not the case with our encapsulation method which guaranteed approximately a lifetime of 2 days. An improvement of the encapsulation method was required. This goal has been achieved by the use of an adhesion promoter between the ISFET surface and the epoxide. The ISFET surface was silanized according to the following method. A solution of 1% (3-aminopropyl) trimethoxysilane in dry toluene is prepared in a beaker. The ISFETs are put in the solution and brought to boiling point for about 4 h. The ISFETs are then removed and carefully rinsed in toluene to avoid the deposit of excess silane. After that the standard encapsulation method is followed without any changes. Lifetime measurements have been carried out with three series of ISFETs: first a normal Alz03 ISFET series, second a silanized AlTO3 ISFET series and third a silanized Si,N4 ISFETs series; all the ISFETs were produced at the CSEM in Neuchatel. Lifetime measurements were performed in a pH 1.09 buffer solution (Radiometer, 100 mmol of HCl in water). The results for the three different series of ISFETs are shown in Fig. 2. We observe that Al,OJ without adhesion promoter failed, except for one, before the end of the second day. Their mean lifetime was 35 h. A real improvement is clearly visible in the case of the silanized A1203 ISFETs. Although one failed during the first day, all of them worked at least 3 days. This failure on the first day can be attributed to an inadequate encapsulation manoeuvre which could have been avoided. It is still unclear why a group failed around 4 days and another after 7 to 9 days. Finally, the curve for the silanized S&N4 ISFETs is horizontal and stops after 7 days: all of them were still functioning correctly after 7 days, when we decided to stop the measurements, These results suggest that the silanized S&N4 ISFET sensor is best suited for long term use. In this case the lifetime of the reference electrode should also be taken into account. As far as accuracy is concerned, the three series under test yield the same performance level: the sensitivities were between 50 and 60 mV/pH-’ and the linearity was good between pH 1 and 10 [4]. The drift
334 10
A
100.
1
silanized Siti4
______
IPHI
lsfets
I
In the
antnun(lower pan of the stomach)
2 B P z .g 3 50.
silanized Al203 Mets
B $ E 8 b h
Ah03 lsfets O0
. 1
Fig. 2. Lifetime
2
3
4
5
6
ln~w~lu~m~s~
7Time (da&)
of three series of sensors
l/04:48:12
1/04:63:42
1/05:01:12
1/05:08:42
1/06:78:12
Time
after a settlement time of 6 to 8 h becomes stable and is typically of 0.1 pH for 24 h [ 71.
Fig. 3. In viuo measurement: 30 min episode at the end of a duodenogastric reflux during the night; the gastric acidity diminishes again to low values (normal around pH 2) after a transient peak to pH 7 (reflux from duodenum).
Security aspects
According to the international standard IEC 601-l [8] the patient leakage current allowed for sensors operating in the stomach is 100 l.tA in normal operating conditions and 500 l.~4 in a single fault condition. The conditions have been fulfilled by means of a passive current limiting device consisting of a resistance placed in the amplifier stages operating the ISFETs. The resistance limits the overall leakage current, which is able to flow out of the sensor into the body, to a maximum of 50 PA. This ensures that even if all four ISFETs should breakdown and this strong leakage current appeared, it would not exceed the allowable limit. Furthermore, the ISFET operates in a direct current mode, which yields a higher security coefficient.
In the testing
The probes constructed have been tested in uivo at the university hospital in Lausanne, where they have been used in the stomach for medical research. During the measurements the sensors are connected to the amplifier stage and a data logger, which records ambulatorily 24 h measurements. At the end, the data are evaluated after their transfer to a computer. One hour of such measurements is shown in Fig. 3. The upper two curves correspond
to the two ISFETs in the antrum, the lower part of the stomach, and the other two to the ISFETs located in the corpus, the upper part of the stomach. The upper two curves show that strong pH gradients (up to 2.5 pH units) can be observed during a reflex episode even at a distance of 1.5 mm. The two lower curves are closely correlated and show no significant difference. Quasi periodical pH fluctuations with a period of 20 s take place in the stomach, demonstrating the interest of the probe in medical research.
Conclusions
The improvements brought to our probe have been shown to be successful by our in vitro and in viuo results. The lifetime increase brings a sufficient feasibility to our multi-ISFET probe for medical use. Through a careful build-up of the probe, actual measurements of the pH distribution in the gastro-oesophageal tract can be taken. The obtained probe is comfortable for the patient, because of its small size and suppleness. In conclusion this work demonstrates that the monitoring and mapping of pH over long periods is possible with carefully encapsulated sensors, and that they give accurate results for future clinical investigations.
335
Acknowledgements
This work has been supported by a grant of the FSRM (Swiss Foundation for Microtechnics and Microelectronics). We also thank Professor J. Janata for numerous and fruitful discussions.
References 1 C. Em&e, A. Garner and A. L. Blum, Technical aspects of intraluminal pH-metry in man: current status and recommendations, G~r,~28(1987) 1177-1188. 2 G. McLauchlan, J. Rawlings, M. Lucas, R. McCloy, G. Crean and K. McCall, Electrodes for 24 hour pH monitoring-a comparative study, Gur, 28 (1987) 935-939.
3 C. Fimmel, A. Etienne, T. Cilluffo, C. van Ritter, T. Gasser, J.-P. Rey, P. Caradonna-Moscatelli, F. Sabatini, F. Pace, H. W. Biihler, P. Bauerfeind and A. L. Blum, Long-term ambulatory gastric pH monitoring: validation of a new method and effect of H,-antagonists, Gastroenterology, 88 ( 1985) 1842- I85 1. 4 S. H. Marron and J. B. Lando, Fundamentals of Physical Chemistry, Collier Macmillan, New York, 1974. 5 A. Grisel, C. Francis, E. Verney and G. Mondin, Packaging technologies for integrated electrochemical sensors, Sensors and Actuators, I7 (1989) 285-295. 6 L. Thybaud, C. Depeursinge,
D. Rouiller, G. Mondin and A. Grisel, Use of Isfets for 24-h pH monitoring in the gastrooesophageal tract, Sensors and Acfuators B, I (1990) 485-487. 7 Ph. Duroux, C. Emde, P. Bauerfeind, C. Francis, A. Grisel, L. Thybaud, D. Armstrong, C. Depeursinge and A. L. Blum, The ion sensitive field effect transistor (ISFET) pH electrode: a new sensor for long term ambulatory pH monitoring, Gur, 32 (1991) 240-245. 8 International Electrotechnical Commission, International Standard: IEC 601-1, 2nd edn., Geneva, 1988.
Sensors and Actuators B, 7 (1992) 332-335
Multichannel ISFET catheter for temporal and spatial pH variation studies in the stomach over 24 hours L. Thybaud
and C. Depeursinge
Laboratoire de Ginnie Midical-EPFL,
CH-1024
Ecublens (Switzerland)
A. Grisel Microsens S.A., CH-2007 Neuchcitel (Switzerland)
C. Emde, D. Armstrong
and F. Viani
Division de Gastroentkologie - CH U V, CH- 1011 Luusanne (Switzerland)
Abstract A four channel multiple sensor based on ISFETs has been developed for medical research in gastroenterology. The ISFETs are mounted in two groups separated by 10 cm and placed as close as possible in each group. New solutions for the electrical connections by kapton tape and for the disposition of the ISFET have been developed. An increased lifetime of the sensors is achieved by a silanization procedure which promotes adhesion between the ISFET surface and the encapsulating epoxide. The lifetime has been tested for Si,N, and Al,O, ISFETs. The realized sensors have been tested in clinical conditions in a university hospital and demonstrate accurate and interesting results as well as being comfortable to use.
Introduction
Sensor realization
pH measurements for 24 h at one point in the stomach are now commonly performed in gastroenterology for diagnostic purposes [l-3]. However the spatial distribution of pH and its evolution at different positions in the stomach, over a long period of time, is still largely unknown. A catheter with multiple ISFETs has been designed to determine how the pH evolves at two points in the stomach separated by several centimeters, and at the same time how it evolves within a few millimeters (locally) at these two points by mounting them in groups of two ISFETs. A reflux episode can be observed by monitoring the pH difference between the two locations separated by 10 cm. This difference is expected to be important over quite a long time, and one of the goals of the study is to evaluate the importance of the pH gradients at a local scale. This should ensure the significance and validity of the local measurements of pH in gastroenterology. To reach this goal, a multiple ISFET sensor allowing the pH mapping over 24 h in the gastro-oesophageal tract has been designed, which takes advantage of the ISFET technology: accuracy and small size.
A four channel sensor has been developed in a single lumen catheter of 2.0 mm id. The ISFETs were mounted in two groups of two neighboring ISFETs separated by 10 cm. One group is in the upper part and the other in the lower part of the stomach. Within each group, the ISFETs were placed as close as possible ( 1.5 mm). The basic method to encapsulate the ISFETs was presented in earlier papers [ 5, 61. The major improvements which have been brought to this new probe are a different placement of the ISFETs and the use of an improved kapton tape for the interconnections. The kapton tape is now made of four parallel conducting copper tracks which are printed in a zigzag form on a kapton sheet of 50 cm length. This sheet is a kapton-glue-copper-kapton sandwich which guarantees an optimal protection of the copper tracks. The sheet is cut and the resulting tape is folded and glued to yield a kapton tape of 2 m length, with an enlargement at each end to allow an easy hand soldering. The four copper tracks, each 150 pm wide, are deposited on a 1.5 mm wide and 130 pm thick kapton tape. The
09254005/92/%5.00
@ 1992 -
Elsevier Sequoia. All rights reserved
333
10cm.
I
I ww
I j /
reference electrode
lsfet
1
I
\ lsfet 2
lsfet 3
Met 4
\
f
catheter
(4 ,
bonding wire \
1.5mm.
,
epoxide /
connections to next lsfet
CMOS lsfet @I
Fig. I. Global catheter.
(a) and
local
(b) arrangements
of ISFETs
in the
major advantage of this design is its adaptability to different length requirements: either one very long 2 m probe or two probes of 1 m length can easily be built, and the four tracks allow two ISFETs to be connected, reducing by a factor of two the number of tapes required. The arrangement and final assembly is sketched in Fig. 1. The ISFETs are glued onto the kapton tape in opposite directions, so that the two sensing surfaces are as close as possible. This configuration allows an easy bonding, after removal of a piece of the protecting cover-layer of the kapton tape just behind each ISFET. Elsewhere the coverlayer protects from electrical short circuits. Finally, the sensing surfaces of the two ISFETs are separated only by approximately 1.5 mm. As mentioned before, the two groups of ISFETs are separated by 10 cm. The whole assembly is mounted into a single lumen catheter of 2.0 mm i.d. A single silver-silver chloride reference electrode is mounted at the tip of the catheter. No strong biopotential, which could disturb the measurements, has been observed in the stomach. Finally, the comfort of the patient is guaranteed, by the use of floppy kapton tapes in a single supple catheter. Optimization of the sensor’s lifetime
With the present technology the construction of an ISFET multisensor is still time consuming and expensive. Repeated measurements with the same sensor have been envisaged on the same patient, in
order to know how the pH varies over 24 h, three times at intervals of several days. This means that the ISFET encapsulation must last for at least 3 days. Moreover the feasibility of the ISFET encapsulation had to be dramatically increased. We knew from previous experiments that this was not the case with our encapsulation method which guaranteed approximately a lifetime of 2 days. An improvement of the encapsulation method was required. This goal has been achieved by the use of an adhesion promoter between the ISFET surface and the epoxide. The ISFET surface was silanized according to the following method. A solution of 1% (3-aminopropyl) trimethoxysilane in dry toluene is prepared in a beaker. The ISFETs are put in the solution and brought to boiling point for about 4 h. The ISFETs are then removed and carefully rinsed in toluene to avoid the deposit of excess silane. After that the standard encapsulation method is followed without any changes. Lifetime measurements have been carried out with three series of ISFETs: first a normal Alz03 ISFET series, second a silanized AlTO3 ISFET series and third a silanized Si,N4 ISFETs series; all the ISFETs were produced at the CSEM in Neuchatel. Lifetime measurements were performed in a pH 1.09 buffer solution (Radiometer, 100 mmol of HCl in water). The results for the three different series of ISFETs are shown in Fig. 2. We observe that Al,OJ without adhesion promoter failed, except for one, before the end of the second day. Their mean lifetime was 35 h. A real improvement is clearly visible in the case of the silanized A1203 ISFETs. Although one failed during the first day, all of them worked at least 3 days. This failure on the first day can be attributed to an inadequate encapsulation manoeuvre which could have been avoided. It is still unclear why a group failed around 4 days and another after 7 to 9 days. Finally, the curve for the silanized S&N4 ISFETs is horizontal and stops after 7 days: all of them were still functioning correctly after 7 days, when we decided to stop the measurements, These results suggest that the silanized S&N4 ISFET sensor is best suited for long term use. In this case the lifetime of the reference electrode should also be taken into account. As far as accuracy is concerned, the three series under test yield the same performance level: the sensitivities were between 50 and 60 mV/pH-’ and the linearity was good between pH 1 and 10 [4]. The drift
334 10
A
100.
1
silanized Siti4
______
IPHI
lsfets
I
In the
antnun(lower pan of the stomach)
2 B P z .g 3 50.
silanized Al203 Mets
B $ E 8 b h
Ah03 lsfets O0
. 1
Fig. 2. Lifetime
2
3
4
5
6
ln~w~lu~m~s~
7Time (da&)
of three series of sensors
l/04:48:12
1/04:63:42
1/05:01:12
1/05:08:42
1/06:78:12
Time
after a settlement time of 6 to 8 h becomes stable and is typically of 0.1 pH for 24 h [ 71.
Fig. 3. In viuo measurement: 30 min episode at the end of a duodenogastric reflux during the night; the gastric acidity diminishes again to low values (normal around pH 2) after a transient peak to pH 7 (reflux from duodenum).
Security aspects
According to the international standard IEC 601-l [8] the patient leakage current allowed for sensors operating in the stomach is 100 l.tA in normal operating conditions and 500 l.~4 in a single fault condition. The conditions have been fulfilled by means of a passive current limiting device consisting of a resistance placed in the amplifier stages operating the ISFETs. The resistance limits the overall leakage current, which is able to flow out of the sensor into the body, to a maximum of 50 PA. This ensures that even if all four ISFETs should breakdown and this strong leakage current appeared, it would not exceed the allowable limit. Furthermore, the ISFET operates in a direct current mode, which yields a higher security coefficient.
In the testing
The probes constructed have been tested in uivo at the university hospital in Lausanne, where they have been used in the stomach for medical research. During the measurements the sensors are connected to the amplifier stage and a data logger, which records ambulatorily 24 h measurements. At the end, the data are evaluated after their transfer to a computer. One hour of such measurements is shown in Fig. 3. The upper two curves correspond
to the two ISFETs in the antrum, the lower part of the stomach, and the other two to the ISFETs located in the corpus, the upper part of the stomach. The upper two curves show that strong pH gradients (up to 2.5 pH units) can be observed during a reflex episode even at a distance of 1.5 mm. The two lower curves are closely correlated and show no significant difference. Quasi periodical pH fluctuations with a period of 20 s take place in the stomach, demonstrating the interest of the probe in medical research.
Conclusions
The improvements brought to our probe have been shown to be successful by our in vitro and in viuo results. The lifetime increase brings a sufficient feasibility to our multi-ISFET probe for medical use. Through a careful build-up of the probe, actual measurements of the pH distribution in the gastro-oesophageal tract can be taken. The obtained probe is comfortable for the patient, because of its small size and suppleness. In conclusion this work demonstrates that the monitoring and mapping of pH over long periods is possible with carefully encapsulated sensors, and that they give accurate results for future clinical investigations.
335
Acknowledgements
This work has been supported by a grant of the FSRM (Swiss Foundation for Microtechnics and Microelectronics). We also thank Professor J. Janata for numerous and fruitful discussions.
References 1 C. Em&e, A. Garner and A. L. Blum, Technical aspects of intraluminal pH-metry in man: current status and recommendations, G~r,~28(1987) 1177-1188. 2 G. McLauchlan, J. Rawlings, M. Lucas, R. McCloy, G. Crean and K. McCall, Electrodes for 24 hour pH monitoring-a comparative study, Gur, 28 (1987) 935-939.
3 C. Fimmel, A. Etienne, T. Cilluffo, C. van Ritter, T. Gasser, J.-P. Rey, P. Caradonna-Moscatelli, F. Sabatini, F. Pace, H. W. Biihler, P. Bauerfeind and A. L. Blum, Long-term ambulatory gastric pH monitoring: validation of a new method and effect of H,-antagonists, Gastroenterology, 88 ( 1985) 1842- I85 1. 4 S. H. Marron and J. B. Lando, Fundamentals of Physical Chemistry, Collier Macmillan, New York, 1974. 5 A. Grisel, C. Francis, E. Verney and G. Mondin, Packaging technologies for integrated electrochemical sensors, Sensors and Actuators, I7 (1989) 285-295. 6 L. Thybaud, C. Depeursinge,
D. Rouiller, G. Mondin and A. Grisel, Use of Isfets for 24-h pH monitoring in the gastrooesophageal tract, Sensors and Acfuators B, I (1990) 485-487. 7 Ph. Duroux, C. Emde, P. Bauerfeind, C. Francis, A. Grisel, L. Thybaud, D. Armstrong, C. Depeursinge and A. L. Blum, The ion sensitive field effect transistor (ISFET) pH electrode: a new sensor for long term ambulatory pH monitoring, Gur, 32 (1991) 240-245. 8 International Electrotechnical Commission, International Standard: IEC 601-1, 2nd edn., Geneva, 1988.