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  • Gut, 1991,32,240-245

    The ion sensitive field effect transistor (ISFET) pHelectrode: a new sensor for long term ambulatory pHmonitoring

    Ph Duroux, C Emde, P Bauerfeind, C Francis, A Grisel, L Thybaud, D Armstrong,C Depeursinge, A L Blum

    Division ofGastroenterology, CentreHospitalier UniversitaireVaudois, Lausanne,SwitzerlandPh DurouxC EmdeP BauerfeindD ArmstrongA L Blum

    Centre Suissed'Electronique et deMicrotechnique,Neuchatel, SwitzerlandC FrancisA Grisel

    Institut de PhysiqueAppliquee, EcolePolytechnique FederalLausanne, SwitzerlandL ThybaudC DepeursingeCorrespondence to:Dr Ph Duroux, Division deGastroenterologie, CentreHospitalier UniversitaireVaudois (CHUV/PMU),CH-101 1 Lausanne,Switzerland.

    Accepted for publication23 April 1990

    AbstractIntraluininal pH monitoring in man should beperformed with disposable multichannelassemblies that allow recordings at multiplesites and prevent transmission of infection.Currently available glass electrodes are un-suitable for this purpose because of their sizeand price. We have thus constructed andtested a small, combined ion sensitive fieldeffect transistor (ISFET) pH electrode in-corporating an integral reference electrode. Invitro studies showed that both ISFET andglass electrodes (440-M4, Ingold, Switzerland)have a linear response over the pH range 1-3-8-0 and that they are comparable with regard toresponse time and 24 hour drift. Twenty onehour intragastric pH recordings were per-formed simultaneously in eight healthy volun-teers using a glass electrode and an ISFETelectrode, placed no more than 2 mm apart in acombined assembly. This was located in thegastric corpus under fluoroscopic control. The21 hour pH curves recorded by each electrodetype showed identical patterns: an early morn-ing rise in pH with three meal-associated pHpeaks lasting for about two to three hours. Themeans of the 21 hour pH medians were 2-09and 2.07 as measured by the glass and theISFET electrodes respectively. Thus, ISFETsare suitable for the construction ofinexpensiveand hence disposable multichannel pHmonitoring assemblies of small diameter. Pro-vided that they can be produced in largenumbers with appropriate technical support,ISFETs have the potential to replace glasselectrodes for long term monitoring of gastro-intestinal luminal acidity.

    At present, the standard electrodes for intra-luminal pH monitoring are combined glass elec-trodes which incorporate an integral referenceelectrode,'-3 but although these are highlyaccurate, they have some disadvantages. Studiesof regional pH variations in the upper gastro-intestinal tract require pH assemblies with morethan two channels which, until now, have had touse glass electrodes. These assemblies cannot,however, be passed transnasally as they are toolarge and, if they are passed orally, they cannotbe tolerated for more than a few hours, thusprecluding long term ambulatory recordingswith more than two channels.` Anotherproblem with glass electrodes is that manufac-turing costs are still so high that they are notdisposable. On the other hand, most types ofglass electrodes can only be disinfected: heat and

    gas sterilisation and the thermodisinfectionmethod newly developed for fibreopticendoscopes7 are not recommended. Therefore,transmission of infectious diseases such as hepa-titis can never completely be excluded. Becauseof this, the availability of low cost and hencedisposable electrodes is highly desirable.

    Attempts to develop a small and inexpensivepH electrode are not new; two examples are themonocrystalline antimony89 and the plastic'0'electrodes. Neither type of electrode, however,is without its problems. Although the behaviourof antimony electrodes in vivo has been reportedto be comparable with that of glass electrodes,'2they are known to be non-linear over a pH rangefrom 1 to 7 and they have a prolonged responsetime compared with glass electrodes.23 Further-more, they require an external reference elec-trode attached to the skin and they may, there-fore, suffer from the fact that the pH electrodeand the reference electrode must work inenvironments that differ in respect of ionicbackground and temperature. Although integralreference electrodes are also susceptible tochanges in the composition of gastric contents, ithas been shown that the use of a distant skin orbuccal reference electrode leads to significantdifferences in recorded pH.2 The main problemwith plastic electrodes is that they cover only aselected pH range depending on membranecomposition and other ions present in thesample. 13 Thus, their output may be predicted invitro when the composition of the measuredsolution is known but not in vivo when, forexample, the intragastric environment changesin the presence of food or refluxed duodenalcontents.We have thus developed a new type of pH

    electrode, the ISFET (ion sensitive field effecttransistor) electrode,'"'6 which is theoretically asreliable and accurate as glass electrodes with theadditional advantages that it is smaller and, ifcommercially produced, cheaper. Since com-bined glass pH electrodes represent the goldstandard for 24 hour ambulatory pH monitor-ing,2 we have compared the performance of theISFET electrode with a combined glass electrodeunder in vitro and in vivo conditions.

    Methods

    ELECTRODES

    ISFET electrodeIn principle, an ISFET is a modification of thenormal field effect transistor used in many

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  • The ion sensitivefield effect transistor (ISFET)pH electrode: a new sensorfor long term ambulator pH monitoring

    Reference electroderl

    SaturatedKCI solution

    Figure 1: Encapsulation ofan ISFET in a cathetersuitablefor gastrointestinalintubation.CMOS=complementarymetal oxide silicone(integrated circuitconstruction type).

    pH -electrode_ s ... .. - -.- ............ - -...... ....... . ...... . \ . . . . ...... ............. : :...... ....... . ...................... .... s...5; ... . .. ....., _ _ .._. ........... .. _ _ .......... _ .... . .

    .. _ ..... -... ,_ ,.,.,., :-:.;;r.: .................. ......... ............. .

    I

    CMOS-I1SFET

    amplifier circuits. In the ISFET, the metal gate,which is normally used as input, is replaced by anion-sensitive membrane, the measured solution,and a reference electrode. Thus, an ISFETcombines in one device the sensing surface and asignal amplifier which produces a high current,low impedance output and allows the use ofconnecting cables without excessive shielding.The ISFET used in this study contains a pHsensitive membrane made of A1203.'7 Its ruggedsolid state structure and small size (1.5 x 0-6 x 0 3mm) permitted its encapsulation (Fig 1) in apolymer cylinder which was placed 4-5 mm fromthe tip of the catheter (1 5 mm outside diameter(OD)) just proximal to the reference electrode.The latter consisted of an AgIAgCl wireimmersed in a saturated KC1 solution behind aporous glass membrane (CSEM, Neuchatel,Switzerland). A constant-current power supplyis required for the ISFET so that it will produce avoltage that is linearly proportional to the pH ofthe surrounding fluid over the range ofpH valuesfound in the gastrointestinal tract. The be-haviour of both ISFET and glass electrodes canbe described by the Nernstian equation and thesensitivity of the ISFET electrode is, therefore,comparable with that of a glass pH electrode,although the zero point of the ISFET electrode isdifferent from that of most glass electrodes.

    This similarity in behaviour allowed a directcomparison of the electrodes using the samerecording device and evaluation program. Theonly modification required was the addition of aconstant voltage of 1600 mV to the ISFEToutput so that it was in the same range as theoutput of a glass electrode.

    Glass electrodeThe combined glass electrode used for validatingthe ISFET is commercially available (440-M4,Dr Ingold AG, Urdorf, Switzerland) and is usedroutinely for upper gastrointestinal pH monitor-ing studies. It has anOD of4mm at the tip oftheelectrode and is mounted on a polyvinyl tubewith an OD of 3 mm. The reference electrode issituated 15 mm proximal to the glass electrode.

    in a neutral buffer solution for at least six hoursbefore starting a measurement. The electrodeswere then put in a buffer of pH 4.01 (S1316,Radiometer, Copenhagen, Denmark) at 22C.The drift exhibited by ISFET electrodes has acharacteristic form with an initial exponentialchange in electrode potential followed by a muchslower but linear drift. In all cases the maximumdeviation from the initial reading was observed atthe end. Therefore, for the assessment of elec-trode drift the voltages were noted at the begin-ning and at the end of a 24 hour test period. Thedrift ofan individual electrode was defined as thedifference in voltage between first and secondmeasurements. The same procedure was used todetermine the.drift of five glass electrodes.

    Response timeResponse times were defined as the time takenfor the electrode voltage to reach 90% and 95% ofits final reading in a given neutral or acid buffersolution. The electrodes, which were connectedto a pH meter (PHM 85, Radiometer, Copen-hagen, Denmark) and thence to a chart recorder(REC 80, Radiometer, Copenhagen, Denmark),were transferred between stirred buffer solutionsof pH 7.38 and pH 1-10 at 37C (S1356 andS 1386, Radiometer). Five electrodes ofeach typewere examined and triple measurements madewith each individual electrode from which meanvalues and ranges were calculated. These data aswell as group medians are presented for eachelectrode type. Differences in response time foreach electrode type were tested statistically usingthe Wilcoxon-Mann-Whitney test.

    SensitivityElect