1962 - vadgama - enzyme and other biosensors evolution of a technoloav

8/13/2019 1962 - Vadgama - Enzyme and Other Biosensors Evolution of a Technoloav

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Enzyme and otherbiosensors:Evolution of a technoloavby Seamus F J Higson, Subrayal M.Reddyand Pankaj M.Vadgama

Since 1962 when thefirst enzyme electrode was reported, biosensors have been thefocus ofintensive research andhave captured the interest and imagination ofb ot h the wider scient and l y communities. Th ey have a wide

potential applicability encompacsing both biomedical and industrial areas and oJer a unique route to simplified,reagentless analysis. Financial savitgs in analysis are an importa nt motivating force for biosensor development; this

is no more so than in medical diagnostics, where, especially in th e West and jap an , a n upward dem andf orbiomedical testing has contributed to escalating health care costs. More recently, it has been recognised that with

biosensor based monitoring ofbiotechnological processes used in thefood and drink industries, a substantialenhancement in e@ciency is possible .

Introductionbiosensor is a chemical sensing device inwhich a biologically derived recognitionentity is couple d to a transducer, to allow theA uantitative determination of some com-plex biochemical param eter. This self-contained sensoror pro be relies on the specificity of the biologicalcom pon ent to achieve reliable recognition o fan analytein a mixed sample. The subsequent transductionproduces a signal that is preferably electrical and whichmay be simply related back to the analyte concentra-tion. Practical sensors have been realised by successfulcoupling and exploitation of principles derived fromphysics an d biology as well as chemistry, the result beinga multidisciplinary field in its own right.Initial progress has be en difficult, but following threedecades of intensive research in biosensors, occasionallypunctuated by interest from the popular media,biosensors have at last encroached upon the applieddisciplines, and thus they have begun to be used, forexample, in hospital departments.It cannot be overstated that for the developm ent ofpractical sensors, adequate consideration needs to begiven to the needs and requirements of the ultimateend user. All too often the academic curiosity of ascientist, albeit fully justified i ntellectual ly,hac led to the

creation of devices which remain experimental innature, an d wh ich are d ifficult to use practically. It isnow apparent that for rapid progress the en d user as wellas to some extent application engineers should beparticipants in biosensor research at the earliest stagepossible. At the very least, in this way a clear remit forsensor requirements can be established prior to anymajor research effort being expen ded.Fig. 1shows some of the possible applications forbiosensors, though this emphasises their clinical use, asthis is the area for which the m axim um research efforthas been made to date and where most experienceresides. At one extreme is a biosensor, conventionallyin the for m of a needle, designed for in vivo use, whichnust be able to operate in an intimate way with areactive body (blood/tissue) environment withminimal loss of sensor performan ce over a prespecifiedtime period. In adhtion, ethical and safety considera-tions enter into this equation, but certainly the sensormust no t indu ce a significant inflammatory response o rclotting, and must be non inm uno grni c and nontoxic'.At the other extreme, a 'one shot' biosensor designedfor disposable single use in the doctor's surgery or eventhe home may be primarily required to have anextend ed shelf life, while its resistance to biofoulin g isnot crucial and its operational lifetime is permitted tobe of the order of seconds. Alternatively, operatin g

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Fig. 1 Potential scope ofbiosensors: applicationsand environments blosensorsllnlcal nonclintcdhmonitormglong-term short-term single shot multi omlyses single analysis reactivemplantoble mvasive

conditions for biosensors for use within the foodindustry and processing industries may demandstability over widely varying solution conm tions (pH,ionic strength) and temperatures with analytemeasurement ranges that may extend well beyondthose required for medical applications.Even with careful prior design, unexpected andoften peripheral requirements may affect practicalviability In one successful system, the MedisenseExacTech pen (Fig. 2 4 for hom e glucose monitor-ing, although acceptable biomedical function wasachieved, it became apparent o nly after marketing thatmany diabetic patients with poor eyesight could notdifferentiate the readings on the small LCD displayprovided. Accordingly, the sensor has now beenredesigned with an enlarged &splay in th e shape of acredit card, the Companion system (Fig. 2b), whichstill maintains portability.The first 3 years: establishment of somebasic ground rulesHistorically, the advent of the biosensor era washeralded in 1962 by Clarke and Lyons report of thefirst enzyme electrode for the measurement of bloodglucose. This device employed an enzyme, glucoseoxidase (GOD), to catalyse the reaction for theoxidation of glucose to gluconic acid and hydrogenperoxide:

(GOD)(1)glucose 2 H2O hydrogen peroxide(H202 ) gluconic acid

A thin layer of the enzyme in solution was entrappedbetween two polymeric membranes and then placedover either a conventional pH or an oxygen electrode.An oxygen electrode here can simply comprise anTable 1: P er ox ide - bas ed ox idas e s ens o rsEnzvme Substrate Bio -samdeglucose oxidase glucos e5 bloodlactase oxidase lactate b loodoxalate oxidase oxalates b loodh r i neascorbate o xidase a ~ o r b a t e ~ b lo odalcohol oxidase alcoholso b lood

electrode made of an inert material, at which oxygenmay be detected by the imposition of a negativevoltage, eqn. 2. Th e electrode is covered by a suitablegas permeable membrane to protect the electro-chemical surface. A p H electrode was suggested as analternative to m onitor p H change du e to theproduction of gluconic acid by the enzyme, whereasthe oxygen electrode enabled detection of changes inthe local oxygen partial pressure p 0 z ) due to oxygenconsumption by the enzymatic reaction (eqn. 1).Changes in p H are vulnerable to buffering effects, and0 2 monitoring is subject to fluctuations in ambientp02. Nevertheless measurement of the latter is quiteconvenient electrochemically:

- O0 inV vs Ag/ AgC I2 2H20 4e - 4 4 0 H - (2)

Later, Upd ike and Hicks utilised a gel (acrylamidej toentrap glucose oxidase over dual cathodicampemmetric oxygen sensors. Here, one cathode wascoated with active enzyme and the other withinactivated (heat dena tured) enzym e; the latter acted asa reference/control electrode to compensate forbackground PO? lucturations.Hydrogen peroxide (H2 02j produced from theenzynuc reaction (eqn. 1 can also be mo nitored in asimple transduction step in which the generation of acurrent is made directly proportional to glucoseconcentration,h:

3 )This method needs neither background 0 2 orrectionnor the use of tw in differential electrodes.All members of the group o f enzymes known as theoxidases act as catalysts for the production of H2 2 inthe presence o f specific substrates (an alytes). Thisfandy of enzymes has therefore provided a genericmethod of constructing a variety of enzyme electrodec,each of which is highly specific for a particular analyteor analytes. A few examples of some peroxide-basedoxidase sensors that have ~uccessfullydeveloped areyhown in Table 1.

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Fig. 2 a) Medisen se ExacTech glucose pen ; b)home mon i to r ing of bloo d glucose levels usingthe Medisense ExacTech comp anion

To date the vast majority of biosensor research hascentred around the oxidase enzymes and in particularglucose oxidase. This can be attributed largely to thestability of glucose oxidase, its stability in water andeven organic solvents, and the practical need fo r sensingtechnologies due to the prevalence of mabetes. In theUnited States diabetes has been increasing for manyyears, with an estimated 2 of the population nowsuf+ing from this disease".Fig. 3shows a schematic representation o f a typicalglucose oxidase membr ane based sensor". This sensorrelies upon the chenucal mmobihsation o fth e enzymeglucose oxidase (GOD) within an enzyme/membranelaminate. Entrapment of the enzyme could also beachieved by encapsulation or physical adsorptiontechniques, but chemical immobilisation gives more~tab i l i ty '~ .he outer covering membrane functionallyacts as the outer surface interface with a bulk analytesolution, but also frequently serves to provide asubstrate diffusion limiting barrier. In this way theenzyme encounters a locally diminished analyteconcentration so avoiding enzyme saturation at thehigher concentrations and linearising the sensor signaloutput. However, an outer membrane that also allowsfree passage of oxygen would be advantageous as itis an absolute requirement for the enzymic reaction(eqn. 1).In the hostile environment frequently encountered

withi n biological fluids such as blood or urin e, a majorcause for loss of sensor performance is that due tobiofouling by the adhesion of proteins, platelets andother cellular components to the outer membranesurface. This deposition alters the total membranepermeability and constitutes an unpredictable andadditional difision barrier that detracts and impedesreliable sensor performance. This is somewhatequivalent to an optical window gradually cloudmgover. T he search for ever more biocompatible materialsto minimise surface fouling at the outer membranesurface has of necessity therefore been itself animportant area of research".An inner membrane needs to be located betweenthe enz yme layer and the w orkm g electrode surface forthe classical peroxide type device. The peroxideproduced is then able to traverse this inner mem branewhere it is amperometrically interrogated at theelectrode surface. With the right membrane in place,other species present in biological solution (forexample ascorbate), which may also be electro-chemically active at typical operating polarisationpotentials, can be screened out. To this effect various'permselective' membrane materials have beenreported, and their properties tailored to prevent thepassage of particular interferents while allowing thepassage of the small uncharged Hz02 molecule. Amembrane with perfect selectivity for H2 2 is of

Fig. 3 Schematicdiagram of glucosecoverlng outer membrane

lmmobillsed enzymelglutaraldehydeGODp D glucose + 02 glucanolactone + H 2 0 2 inner/membrane1 Iunderlying permselective membrane,

0 2 +, 2e-+ 2H* 2 2

PI worklng electrode +650 r n V vs AglAgCI)

oxidase membrane-based enzyme laminateelectrode

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Fig. 4 Yellow Springsglucose analyser

sulpho~ies~ave been employed with somesuc ~ e ssCharge exclusion of anions rehes onthe repulsion of negatively chargedinterferent species from an (aniomc) polymermatruc providing fixed negative chargesFortunately, inany problematic interferents insolution are anionic o r negatively charged soallowing screening of the worhng electrodeHowever, an electrocheimcally activeintederent can be less easlly differen tiated bycharge if it is only partially ionised under typicalmeasurement conditions. O n e such example is thedrug paracetamol, which may be present in blood inquite high concentrations and w hich, probably becauseof its neutral fo rm, is di5 cu lt to select against. Despitethis, sonie electropolymerised phenolic nienibranesdeposited directly over the workmg electrode provideexamples of effktive screening layers against thisdrug.The working electrode is usually a noble nietal(typically gold o r silver), but may be carbon, and isanodically polarised to allow the oxidation of H2 2with the generation o f an anodic current proportionalto the analyte concentration. This process also allowsthe generation of 0 2 (eqn. 3 ) which is then free todiffuse back into the en zym e layer, a process that maysignificantly augment the local pOz level preventinglow ambient pOz levels that cou ld comp ronllse sensorperformance. Careful choice of an underlyingiriembrane that allows relatively free passage of 2 sagain a key des@ consid eration.This structure for the glucose oxidase membranelaminate electrode forms the basis for the YellowSprings (Yellow Springs Instrument Corporation,O h i o 43587, USA gluco se analyser, Fig. 4, which hasbeen used extensively for blood glucose deternlinationsover the past twenty years with in clinical biochemistrylaboratories. As a pre stage, for research purposes,enzyme laminates may be evaluated within a simple

bench -top electrode assembly (Fig. 5.Another generic approach to the exclusion ofinterferent signals, in oxidase enzym e electrodes, hasbeen the use of chemical memators. A medlator is achemical species which fachtates electron transfer &omthe enzyme active site to the worlung electrode, soallowing the interrogation of the enzyme reaction atlowered polarisation potentials and preventing theoxidation of ot her electrochemically active interferents.O f these, ferrocene, was the first to be reported* in1984, and to date togethe r with its derivatives remainsthe most extensively used mediator compound.Typically ferrocene will allow electron transfer h mglucose oxidase a t approximately +240 niV vsAg/AgCI (cf +650 mV vs Ag/AgC1 for H202). I tshould be noted that as ferrocene now acts as theoxidant for the reduced form of the enzyme, 0 2 s nolonger a necessity for the enzyme action, socircumventing the limitations imposed by near zero

p 0 2 levels.Direct electron transfer from the enzyme to theelectrode surface has been attempted, but proveddi6cult since the active site of the enzyme is deeplyembedded on the molecular scale within the proteinmacromolecule, the latter acting as an insulatorattenuating electron exchange between the active siteand th e electrode surface.A m ediator, however, may also affect the oxidationof othe r interferent species. It has been shown that an

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formance for either typecannot be simply determinedtheoretically and requirespractical evaluation for agiven sample matrix. Despitepossible disadvantages im-posed by the use of amediator, the Medisensebiosensors, based on ferro-

placed on the electrode strip, Fig. 2b; this instrumentthereby allows a rapid (130 s) determination of bloodglucose without careful timing or sample preparation.Monitoring of blood glucose is thus sufficientlysimplified for patient use, obviating the n eed fo r a fullyequipped laboratory or coniplicated wet chemistrytechniques.Continuing research effortsAlthough the present exploitation of biosenson iscentred around oxidase enzyme electrodes, consider-able research activity has involved th e d evelopment ofother concepts which could also lead to viable sensorsfor the future.Multi-ana@ monitorsRecently it has been demonstrated that more thanone enzyme may be used within the same sensor toallow the multiple determination of analytes. Inpractice this may be achieved by the use ofo ne or moreenzymes whose reaction depends on the presence of aco-factoot; this is a compound required to give theenzyme its catalytic activity. In on e arrangement a co-factor-consuming enzyme E1 that degrades one analyteA could be held in front of a second layer containingtwo different enzymes E1 and E2 for analytesA and Bbut without co-factors. On addition of A and B acombined signal is generated, but that d ue to A can besubtracted out when the co-factor is included (Fig. 6).In this way th e co-factor operates as a switch to switchon and off the outer enzyme, which then determineswhether the analyte A can reach the second layer. Aspecific example is the hexakinase, glucoamylase/glucose oxidase sensof', for the determ inatio n ofeither glucose or maltose, where hexalunase uses theco-factor adenosine triphosphate (ATP) to degrade

through ink-jet printertechnology".Unquestionably, the de-velopment of micro-elec-tronic5 and silicon tech-possibilities for the futuredevelopment of biosensorarrays with associated in situ

P

signal

electrode

stability, high redundancy,and self interrogation for signal drift. The inherentredundancy could also be exploited to provideelements individually optimised for particularenvironmental conditions (e.g. pH , temperature andanalyte levels), so further improving sensorperformance".In vivo monitor iqA further application for miniaturised sensors hasbeen in the developm ent o f invasive sensors for in vivomonitoring. Th e most favoured approach to date hasbeen to miniaturise conventional electrodes in theform of implantable needles'", e.g. for subcutaneousinsertion. A compromise with respect to electrodematerials may be needed ifsuch devices are not to posea hazard to the patient. Th us, appropriate coating withpolymer layers may be needed to avoid adverseeffects".*', and certa inly a toxic material such as silv ei'for the reference electrode may need to be replaced bya less toxic alternative such as stainless steel".Sterilisation frequently involves heat, radiation orchemical treatment. As enzymes are biologicallyderived components their activity is often destroyedunder such condltions, but nevertheless implantationdemands sterility. To ov ercome this problem , researchhas necessarily been directed towards developingspecifically tailored procedures and protocols to allowadequate effective sterilisation (e.g. using ethyleneoxide'"), while maintaining a n acceptable degree ofenzyme activity'"-".Th ou gh not a biosensorin the formal sense, localisedmonitoring of biochemical parameters n vivo may bepossible through optical interrogation of a naturallypresent biomolecule. Ultiniately this could be anenzyme, and offers the benefits of non-invasivebiosensing. An example oft his approach is provided bycontemporary research on cerebral oxygenation. H ere,

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near-infra-red (750-1000 nm) light is passed throughcerebral tissue, and with absorbance measurement setat appropriate wavelengths, the population ofoxygenated and deoxygenated blood in the cerebralcirculation can be determined3j.Other biosensor typesEnzyme electrodes rely on the catalytic conversionof an analyte to a product, but affinity properties ofother biomolecules which do not induce analytedegradation are also usable. Thus for exampleantibodies for antigens, or cell membrane receptorsfor neurotransmitters are all potentially exploitable bio-recognition systems. Because of the lack of a depletionproduct, however, transduction may be difficult toachieve. One convenient mechanism for immuno-sensing is to use a piezoelectric microgravimetric massdetecto r coated with antibody; specific antigen bindin gto the immobilised antibo dy at the surface of an AT cutquartz crystal"' th en a lte s the mass and this can be themeans o f transduction. T he basis of the 'transduction'of weight is that the crystal oscillates at a characteristicfreque ncyf; d epend ent on its mass when stimulated byan externally applied oscdlating voltage, causingdeformation by relative motion of two parallel crystalsuriaces. T he minu te gravimetric change o f the crystalupon surface antigedantibody binding can then berelated to the measured change, Af in the vibrationalfrequency O f biomedcal importance, piezoelectriccrystals are now bein g developed for the determ inationof proteins in complex media using crystal boundimmunochemical binding reactions. The greatestproblenls encountered by these techniques have beenerrors imposed by nonspecific surface binding byproteins and colloids. Again this shortfall could well beaddressed for the future, using multiple arrays withsystematically varied surface properties.Though not stressed in this brief review, opticalfibres with biosensors at the tip'5,36 or opticalwaveguides mounted with bioreagent at the surface"'and interacting with the evanescent wave provide apowerful means of transducing biomolecule changeson analyte binding.A further field of research, now mad e possible by theexploitation of mod ern n licroelectronics. has been thedev elo pm ent of ion-selective field effect transistors(ISFETs)lX.The device essentially comprises an r~pntransistor in wh ich th e metal gate is covered by an ion-sensitive coating. If a proton-selective surface such assilicon dioxide (SiOz) or silicon nitride (Si3N4) ispresent, then changes in adjacent solution p Hmodulate charge within this layer. This in turnregulates the flow of current throu gh t he p region fromthe source and drain n type elements. In this way themodulated current may be readily related to solutionpH . Any surface coated enzyme wh ich changes net Hconcentration can then be exploited for substrateanalysis. Such enzyme-based ISFETs have been term edENFET s"; their responses are directly related toenzymic behaviour and avoid inherent problems of

electrochemically active interferents as is the case withamperometry (e.g. peroxide measuring devices). Aswith any technique, however, there are disadvantages:an E NF ET requires a highly stable reference electrodewhich is also difficult to miniaturise using micro-electronic technology. Furthermore, problems associ-ated with gate poisoning wh en u sing biological samplesremain to be addressed properlyEnzyme catalysed reactions are usually exoth ermic(heat generating) and the heat produced may bemeasured and related to analyte concentration. Suchenzyme thermistor combinahons, e.g. in a thermalenzyme probe where the thermistor is directly coatedwith an appropriate enzyme, have wide applicabihty.As with ENFETs. however, background correction istypically required for surrounding temperaturefluctuations and they have a low sensitivity. Thereforecalorimetric"' sensors have been reported where thetherm istor is at the end of an enzyme reaction colum n;here, tnuch more heat accumulates, and manymetabolites have been m onitor ed, inclu ding plucose" ,alcoho l? and oxalate'3.Th ere are at present many different approaches beingactively explored for the development of even moreingenious an d elegant sensors with specific applicationsin mind. Although this brief description of presentresearch efforts is by no means intended to becomprehensive, some of the major approaches that arecurrently being explored have been givenconsideration, to give the reader insight into thecurren t state of the art.

A view to the future?It is impossible to predict what the future holds forbiosensors, and how their current status will dictatetheir development through this decade and into thenext century. However, it is certain that with an ever-increasing public awareness of environmental issues,such as river pollu tion, and the care and q uality controlof food production, simple, effective monitoring ofpollutants, industrial products and foodstuEs will beadded to the present application areas. This need forpractical biosensors may provide impetus for thedmction of future research; whereas in the over-optimistic early days exaggerated claims for the h tu relead to disappointment and subsequent pressure fromfund ing bodies for 'instant success', now there is an eraof realism which provides the best guarantee forsuccess.Acade mic research has often been aimed at showingthat a novel idea may be used as opposed to necessarilyprod ucing a viable sensor, with applications being thedominant consideration. Something of a gap hasopened up therefore, with industry frequently onlydesiring to develop a product that requires nunimalinput; the gap is currently closing and productdevelopment for Feveral biosensor systems is likely inthe next few years.As emphasised earlier, ideally an end-user should b e

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Fig. 7 Modern cl inicalbiochemistry aboratoryauto-analyser I with an

identified and consulted at the co ncepu tal phase, withearly integration of academic research effort beingvitally importan t for this burg eonin g multidisciplinaryarea. Another important point to be considered is thatif a sensor is to enjoy widespread commercial success,an end-user must first be satisfied as to the reliability ofthe new technique an d then be sufficiently motivatedto invest in the new technology. Hospital pathologylaboratories, for example, have frequently investedconsiderable capital expenditure for the purchase ofautom ated analysers (Fig. 7). Here, even with financialsavings that biosensors niay offer, the purchaser mayneed to be convinced that the new equipment warrantsthe capital outlay involved. Accordingly it will be alsonecessary to niche market devices, especially forextra-laboratory an d field use.It is hoped that as ideas become ever more tried andtested, those th at prove viable will become moreevident, leading to the realisation of more practicableand exploitable sensors. However it should beappreciated that biosensors, above all in the context ofthe effort put into oth er biochenlical techniques, are at

an early stage of development, and a review in a fewyears time may well portray a very different story, oneof much wider dversity with emphasis on practicalexploitation.

critical care profiling instrument, Clinical Chemistry, 1989,35 ( 6 ) , .10982 ME DISEN SE ExacTech blood glucose testing system(users guide), 1989 , p.93 CLARK, L. C., and LYONS, L.: Electrode system forcontinuous monitoring in cardovascular surgery, A n n .N Y Acad. SI IY62, 102 pp.29-454 UPDIKE, S.J., and HICK S, G. P.: Th e enzymr electrodr,Natirre 1967, 214. pp.986-988

5 TANG, L. X., and VADGAMA, P: Optinusation ofenzyme electrodes,Med . G Bid. B i g . G Cornprrr., 1990, 28(3). pp.B18-B246 MULLEN, W. H.. KEEDY, E H., C H U K C H O U S E , S.J.,and VAIIGAMA, F M.: Glucose enzyme rlectrodc withextended linearity-Application to undiluted bloodmeasurements,Anal. Chim. A d a , 1Y86, 183 p p . 5 9 4 67 KULYS, J., WANG, L. Z . , and MASKIMOVIENNE , A.:L-lactase oxidase electrode based on methylene grren andcarbon pdste, Anal. Clz~m cta, 1993, 274 (1). pp .5 358R BRADLEY, C. K.,a n d K E C H N I T Z , G. A.: Comparisonof oxalate enzyme electrodes for urinary oxalatedeternunation, Analyti~aal h t f e n , 1986, 19 (1&2),pp. 15 1-1 629 DAILY, S.. ARMFIELD, S ., HAGGETT, B. G. D., andD O W N S . M . E. A.: Automated enzyme packed-bed

system for th r deterimnation of vitamin C in foodxuffs,Aiialyst 1991. 116 pp.569-572

10 GIULUAUL T, G. C., DANIELSSON, B.,M A N D E N I U S ,C . E, and MOSBACH, K.: Enzyme electrode andthernustor probcs for determination of alcohols withalcohol oxidace,Anal. Chern., 1983, 55 (9). pp.1582-1585

11 HALL, E. A. H., in Biosensors, IYYO, Open UniversityPress Biotechnology Serie5, p.223

12 HIGSON, S. P.J., and VADGAMA, 1 M.: Diamond-likecarbon coated microporous polycarbonate as a compositebarrier for a glucosr enzyme electrode, Anal. Cliim Acta.,13 VADGAMA, F?: Biosensors in WILLIAMS, D. L., and

M A R K , V. (Eds.): Principles of clinical biochemistry(Hrinenmann Medical Books, Oxford and L ondon , 198X)

AcknowledgmentWe would like to thank the UK SERC for financialsupport to SIJH and SMR.References 1993,271, pp.125-1331 WIESE, D. A., BOWEN, T. P., and KOST,G .: Enzymeelectrode for glucose measurement in whole-blood with a

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14 TANG, L. X., KOOCHAKI, Z . B., and VADGAMA, E :Composite liquid membrane for enzyme electrodeconstruction, Anal. Chim. Acta, 19 90,23 2, (2), pp.357-36515 GOR TON , L. , KARAN, H . I., HALE, P D., INAGAKI,T . , OKAMOTO, Y . , and SKOTHEIM, T. A.: A glucoseelectrode based on carbon pastes chemically modified witha ferrocene-containing siloxane polymer and glucoseoxidase, coated with a poly(ester-sulfonic acid) cationexchanger, Anal. Chim. Aita, 1990,228, (l ) , pp.23-301 6 G O N O N , E G., FOMBARLET, C. M. , BUDA, M. J., andPUJOL, T. E: Electrochemical treatment of pyrolyticcarbon fibre electrodes, Anal. Chem., 1981, 53, (9,17 VADGAMA, P., S P O O R S , J., TANG, L. X., andBATTERSBY, C .: The needle glucose ele ct ro de in vitroperformance and optimisation for implantation,, Biomed.

Biochim. Acta, 1989, 48, pp.935-94218 CHRISTIE , I., VADGAMA, P., and LLOYD, S.:Modification ofelect rode surfaces with oxidised phenols toconfer selectivity to am perometric biosensors for glucosedeterininations. Anal. Chim. Acta, 1993, 274, pp.191-19919 HIGSON, S P J. , DESAI, M., KOOCHAKI, Z., andVADGAMA, P.: Glucose oxidase enzyme electrode:relation between inner membrane permeability andsubstrate response, Anal. Chim. Acta, 1993, 276,20 CASS, A. E. G., DAVIS, G., FRANCIS, G. D., HILL,H. A . O., ASTON , W. J., HIGGINS, I. J., PLOTKIN,E. V., SCOTT, L . D. L ., and TU RN ER , A . P. E:

Ferrocene-medated enzyme electrode for amperometricdetermination of glucose, Anal. Chem., 1984, 56, (4),pp .66747121 SCHELLER, E, PFEIFER, D . , HINTSCHE, R. ,DRANSFIELD, I., WOLLENBERGER, U , , andSCHUBERT, E: Analytical aspects of internal signal-processing in biosensors, Ann. N Acad. SCI., 990, 613,22 DAUTARTUS, M. E, and EVANS, J. E: EC catalysis ofascorbic acid oxidation using plasma polymerisedvinylferrocene film electrodes. J. Electroanalytiial Chem.,1980, 1 09, pp.301-31223 SCHELLER, E, WARSINKE. A . , LUTTER, I.,

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30 WILSON, G . S., REACH, G., and THEVENOT, D. R.:Biosensors for intracorporeal measuremen~-problemand strateg ies, BiochemicalSoc. Earn. 19, (l),pp.9-1131 BINDRA, D. S., Z H A N G , Y . N., WILSON, G . S.,STERNB ERG, R. , THEVEN OT, D . R. , MOATTI , D . ,and REACH, G.: Design and in virro studies of a needle

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EE: 1994The authors are with the Department of Medicine (Sectionof Clinical Biochemistry), University of Manchester, HopeHospital, Eccles Old Ro ad, M anchester M 6 8HD , UK.

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