Nanomaterial-based electrochemical

Nanomaterial-basedelectrochemicalbiosensors

JosephWang

DOI:10.1039/b414248a

Theuniquepropertiesofnanoscalematerialsofferexcellentprospectsfor

interfacingbiologicalrecognitioneventswithelectronicsignaltransductionandfordesigninganewgenerationofbioelectronicdevicesexhibitingnovelfunctions.InthisHighlightIaddressrecentresearchthathasledtopowerfulnanomaterial-basedelectricalbiosensingdevicesandexaminefutureprospectsandchallenges.Newnanoparticle-basedsignalamplificationandcodingstrategiesforbioaffinityassaysarediscussed,alongwithcarbon-nanotubemolecularwiresforachievingefficientelectricalcommunicationwithredoxenzymeandnanowire-basedlabel-freeDNAsensors.

1.Whynanomaterials?

Thebuzzword‘‘nanotechnology’’isnowarounduseverywhere.Nanotechnologyhasrecentlybecomeoneofthemostexcitingforefrontfieldsinanalyticalchemistry.Nanotechnologyisdefinedasthecreationoffunctionalmaterials,devicesandsystemsthroughcontrolofmatteratthe1–100nmscale.Awidevarietyofnanoscalematerialsofdiffer-entsizes,shapesandcompositionsarenowavailable.1Thehugeinterestinnanomaterialsisdrivenbytheirmanydesirableproperties.Inparticular,theabilitytotailorthesizeandstructureandhencethepropertiesofnanomaterialsoffersexcellentprospectsfordesigningnovelsensingsystemsandenhancingtheperformanceofthebioanalyticalassay.Thegoalofthisarticleistohighlightrecentadvancesinnanomaterialsforsuchelectricalsensingdevices.

2.Nanoparticles,nanowiresandnanotubes

Researcheffortsonmetalandmetalsemiconductornanoparticleshaveflour-ishedinrecentyears.2,3Metalnano-particlesaregenerallydefinedasisolableparticlesbetween1and50nminsize,thatarepreventedfromagglo-meratingbyprotectingshells.Owingtotheirsmallsizesuchnanoparticleshavephysical,electronicandchemicalproper-tiesthataredifferentfromthoseofbulkmetals.Suchpropertiesstronglydependonthenumberandkindofatomsthat

makeuptheparticle.Severalreviewshaveaddressedthesynthesisandproper-tiesofnanoparticles.2,3Typically,suchparticlesarepreparedbychemicalreduc-tionofthecorrespondingtransitionmetalsaltsinthepresenceofastabilizer(cappingagentsuchascitrateorthiol)whichbindstotheirsurfacetoimparthighstabilityandrichlinkingchemistryandprovidethedesiredchargeandsolubilityproperties.Designerparticles,includingcolloidalgoldorinorganicnanocrystalshavefoundbroadapplica-tionsinmanyformsofbiologicaltaggingschemes.Forexample,colloidalquan-tumdotshavebeenwidelyusedforopticalbioassaysbecausetheirlightemittingpropertiescanbebroadlytunedthroughsizevariation.4Recentyearshavewitnessedthedevelopmentofpowerfulelectrochemicalbioassaysbasedonnanoparticlelabelsandampli-ficationplatforms.

One-dimensional(1-D)nanostruc-tures,suchascarbonnanotubes(CNT)andsemiconductor-orconducting-polymernanowires,areparticularlyattractiveforbioelectronicdetection.Becauseofthehighsurface-to-volumeratioandnovelelectrontransportpro-pertiesofthesenanostructures,theirelec-tronicconductanceisstronglyinfluencedbyminorsurfaceperturbations(suchasthoseassociatedwiththebindingofmacromolecules).Such1-Dmaterialsthusoffertheprospectofrapid(real-time)andsensitivelabel-freebioelectro-nicdetection,andmassiveredundancyinnanosensorarrays.Theextremesmallnessofthesenanomaterialswouldallowpackingahugenumberofsensingelementsontoasmallfootprintofanarraydevice.Metalandconductingpolymernanowirescanbereadilypreparedbyatemplate-directedelectro-chemicalsynthesisinvolvingelectro-depositionintotheporesofamembranetemplate.5Carbonnanotubes(CNT)areparticularlyexciting1-Dnanomaterialsthathavegeneratedaconsiderableinterestowingtotheiruniquestructure-dependentelectronicandmechanicalproperties.6CNTcanbedividedintosingle-wallcarbon-nanotubes(SWCNT)andmulti-wallcarbon-nanotubes(MWCNT).SWCNTpossessacylindricalnanostructure(withahighaspectratio),formedbyrollingupasinglegraphitesheetintoatube.SWCNTcanthusbeviewedasmolecularwireswitheveryatomonthesurface.MWCNTcompriseofanarrayofsuchnanotubesthatareconcentricallynestedlikeringsofatreetrunk.TheremarkablepropertiesofCNTsuggestthepossibilityofdevelopingsuperiorelectrochemicalsensingdevices,rangingfromamperometricenzymeelectrodestolabel-freeDNAhybridizationbio-sensors.7Thetailoredelectroniccon-ductivityofconductingpolymers,coupledwiththeireaseofprocessing/modificationandrichchemistry,makethemextremelyattractiveas1-Dsensingmaterials.NewlyintroducedCNT/conducting-polymernanowiremate-rials,8basedonincorporatingoxidizedCNTasthecharge-balancingdopants

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withinelectropolymerizedwires,shouldfurtherenhancethesensingcapabilitiesof1-Dmaterials.

InthefollowingsectionsIwilldiscusshowtheuniquepropertiesofnano-particles,nanowiresandnanotubescanenhancetheperformanceofexistingelectrochemicalsensorsandcanleadtothecreationofanewgenerationofbioelectronicdevices.

controlledsurfacearchitecturesisessen-tialforthesuccessfulrealizationofthesesensingprotocols.

Nanomaterial-basedenzymeelectrodes

Enzymeelectrodeshavebeenwidelyusedformonitoringawiderangeofclinicallyorenvironmentallyimportantsubstrates.Anextremelyimportantchallengeinamperometricenzymeelectrodesistheestablishmentofsatisfactoryelectricalcommunicationbetweentheactivesiteoftheenzymeandtheelectrodesur-face.11Theredoxcenterofmostoxido-reductasesiselectricallyinsulatedbyaproteinshell.Becauseofthisshell,theenzymecannotbeoxidizedorreducedatanelectrodeatanypotential.Thepossi-bilityofdirectelectron-transferbetweenenzymesandelectrodesurfacescouldpavethewayforsuperiorreagentlessbiosensingdevices,asitobviatestheneedforco-substratesormediatorsandallowsefficienttransductionofthebiorecogni-tionevent.‘‘Trees’’ofalignedCNTinthenanoforest,preparedbyselfassem-bly,canactasmolecularwirestoallowelectricalcommunicationbetweentheunderlyingelectrodeandredoxproteins

3.Nanomaterial-derivedelectrochemicalbiosensors

Electrochemicalsensorsofferseveraldistinctadvantages.Inparticular,suchdevicesofferelegantroutesforinterfac-ing,atthemolecularlevel,biologicalrecognitioneventsandelectronicsignal-transductionprocesses.Inaddition,electrochemicaldevicesareuniquelyqualifiedformeetingthesize,cost,low-volume,andpowerrequirementsofdecentralizedtestingandindicategreatpromiseforawiderangeofbiomedicalorenvironmentalapplications.9,10Nano-materialscanbeusedinavarietyofelectrochemicalbiosensingschemesandthepresentarticleisdividedaccordingly.Theorganizationofnanomaterialsinto

(covalentlyattachedtotheendsoftheSWNT).12,13Willner’sgroup14demon-stratedthatalignedreconstitutedglucoseoxidase(GOx)ontheedgeofSWCNTcanbelinkedtoanelectrodesurface(Fig.1).SuchenzymereconstitutionontheendofCNTrepresentsanextremelyefficientapproachfor‘plugging’anelectrodeintoGOx.Electronswerethustransportedalongdistanceshigherthan150nmwiththelengthoftheSWCNTcontrollingtherateofelectrontransport.Aninterfacialelectrontransferratecon-stantof42s21wasestimatedfor50nmlongSWCNT.Thecatalyticpropertiesofmetalnanoparticleshavealsofacilitatedtheelectricalcontactofredoxcentersofproteinswithelectrodesurfaces.Forexample,goldnanoparticleswereshowntobeextremelyusefulaselectronrelays(‘‘electricalnanoplugs’’)forthealign-mentofglucoseoxidaseonconductingsupportsandwiringitsredoxcenter.15Awiderangeofenzymeelectrodesbasedondehydrogenaseoroxidaseenzymesrelyonamperometricmonitor-ingoftheliberatedNADHorhydrogenperoxideproducts.Theanodicdetectionofthesespeciesatordinaryelectrodesisoftenhamperedbythelargeovervoltage

Fig.1AssemblyofSWCNTelectricallycontactedglucoseoxidaseelectrode:linkingthereconstitutedenzyme,ontheedgeoftheFAD-functionalizedSWCNT,totheelectrodesurface.(Basedonref.14withpermission.)

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encounteredfortheiroxidation.Thegreatlyenhancedredoxactivityofhydrogenperoxide16andNADH17atCNT-modifiedelectrodesaddressestheseovervoltagelimitationsandmakesthesenanomaterialsextremelyattractivefornumerousoxidase-anddehydrogenase-basedamperometricbiosensors.TheabilityofCNTtopromoteelectrontransferreactionsisattributedtothepresenceofedgeplanedefectsattheirendcaps.Carbon-nanotube-modifiedelectrodeshavealsobeenshowntobeextremelyusefulforcircumventingsurfacefoulingassociatedwiththeoxida-tionoftheliberatedNADHproduct.17Thedepositionofplatinumnano-particlesontoCNThasledtofurtherimprovementsinthedetectionoftheenzymatically-liberatedperoxidespe-cies.18InadditiontoCNTfilms,itispossibletouseCNT-basedinks19andpastes20fordesigningscreen-printedandbiocomposite,respectively,ampero-metricbiosensors.Theexcellentelec-trocatalyticpropertiesofmetalnanoparticles(comparedtobulkmetalelectrodes)canalsobenefitamperometricenzymeelectrodes.Forexample,Niwaandcoworkers21dispersediridiumnano-particles(2nmdiameter)ingraphite-likecarbonandusedtheresultingtransducerforimprovedamperometricbiosensingofglutamate.

Tao’sgroup22describedaconducting-polymernanosensorfordetectingglu-cosebasedonapairofnanoelectrodes,separatedwithasmall(20–60nm)gapconnectedbyapolyanaline/glucose-oxidasefilm.Theremarkablesmalldimensionsofthenewdevice,coupledwithitsveryfastresponseandminimaloxygenconsumption,makesitattractiveforin-vivomonitoringofglucose.Anotherpromisingandcontrollablerouteforpreparingconducting-polymer

nanowireenzymesensorsinvolveselec-trodepositionwithinthechannelbetweenelectrodes.23Nanomaterial-basedbioaffinityelectrochemicalsensors

ThedevelopmentofelectricalDNAhybridizationbiosensorshasattractedconsiderableresearchefforts.24,25SuchDNAsensingapplicationsrequirehighsensitivitythroughamplifiedtrans-ductionoftheoligonucleotideinterac-tion.Nanoparticle-basedamplificationschemeshaveledtoimprovedsensitivityofbioelectronicassaysbyseveralordersofmagnitude.In2001bothmygroup26andthatofLimoges27reportedontheuseofcolloidalgoldtagsforelectronicdetectionofDNAhybridization.Thisprotocolreliesoncapturingthenano-particlestothehybridizedtarget,followedbyhighlysensitiveanodic-strippingelectrochemicalmeasurementofthemetaltracer.Analogousbio-electronicmeasurementsofproteinsbasedonsandwichimmunoassaysandgoldnanoparticletracershavealsobeenreported.28ElectronicDNAhybridiza-tionassayshavebeenextendedtoothermetaltracers,includingsilver29oriron.30Commonlywerelyonthecouplingbiorecognitionelementtosurfacesofmagneticbeads,asitoffersaneffectiveminimizationofnon-specificbinding.Thehybridizationofprobe-coatedmag-neticbeadswiththemetal-taggedtargetsresultsinthree-dimensionalnetworkstructuresofmagneticbeads,crossed-linkedtogetherthroughtheDNAandgoldnanoparticles.The‘magnetic’collectionofsuchmagnetic-bead/DNA/metal-labelassemblyontotheelectrodeleadstodirectcontactofthemetallabelandthesurfaceandenablessolid-state(chronopotentiometric)measurements

withoutdissolvingthemetaltag.31This

routecouldfacilitatethecreationofmagnetically-addressableDNAarrays.Severalamplificationprocessescanbeusedfordramaticallyenhancingthesensitivityofparticle-basedbioelectronicassays.Forexample,themetalnano-particletagscanactascatalyticsitesfortheelectrolessdepositionofothermetals.Treatmentofgold-linkedDNA-hybridassemblywithsilverioninthepresenceofhydroquinonethusresultsincatalyticdepositionofsilveronthegoldtracer(actingascatalyst),leadingtoadramatic(.100fold)signalamplification.32Insteadofenlargingsphericalnano-particletags,itispossibletoenhancethesensitivitybyusinglongnanorodtracers.33Wealsodescribedatriple-amplificationbioassay,couplingthecarrier-sphereamplifyingunits(loadedwithnumerousgoldnanoparticlestags)withthe‘built-in’preconcentrationoftheelectrochemicalstrippingdetectionandacatalyticenlargementofthemulti-plegold-particletags34(Fig.2).Thesuccessoftheseandothernanoparticle-basedamplificationstrategiesdependsonourabilitytomaintainalowback-groundresponse(throughproperatten-tiontothesurface-blockingchemistryandwashconditions).

Inorganicnanocrystalsofferanelec-trodiversepopulationofelectricaltagsasneededfordesigningelectroniccoding.Wedemonstratedtheuseofdifferentinorganic-nanocrystaltracersforamulti-targetelectronicdetectionofDNA35orproteins.36Threeencodingnanoparticles(zincsulfide,cadmiumsulfideandleadsulfide)havethusbeenusedtodifferentiatethesignalsofthreeproteintargetsinconnectionwithasandwichimmunoassayandstrippingvoltammetryofthecorrespondingmetals(Fig.3).Eachbindingthusyieldsa

Fig.2AmplifiedbioelectronicdetectionofDNAhybridization,usingpolymericbeadscarryingmultiplegoldnanoparticletracers,catalyticenlargementofthegoldparticlesandastrippingvoltammetricsignaltransduction.(Basedonref.34withpermission.)

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Fig.3Multi-antigensandwichimmunoassayprotocolbasedondifferentinorganic-colloid(quantumdots)nanocrystaltracers.(Basedonref.36withpermission.)

distinctvoltammetricpeak,whoseposi-tionandsizereflecttheidentityandlevel,respectively,ofthecorrespondinganti-gen.Theconceptcanbescaledupandmultiplexedbyusingaparallelhigh-throughputautomatedmicrowellopera-tion,witheachmicrocavitycapableofcarryingoutmultiplemeasurements.Librariesofelectricalcodeshavebeencreatedbyencapsulatingdifferentpre-determinedlevelsofmultipleinorganicnanocrystalsintopolymericcarrierbeadsordepositingvariousmetaltracersontotheporesofahostmembrane.37Theresultingvoltammetricsignaturesreflectthepredeterminedproportionsofthecorrespondingmetalsinsuch‘identifica-tion’nanomaterials.

Nanoparticle-inducedchangesintheconductivityacrossamicroelectrodegapcanalsobeexploitedforhighlysensitiveandselectiveelectronicdetectionof

DNAhybridization.38,39Thecaptureofthenanoparticle-taggedDNAtargetsbyprobesconfinedtothegapbetweenthetwomicroelectrodes,andasubsequentsilverenlargement,resultsinaconduc-tivemetallayeracrossthegap,andleadstoameasurableconductivitysignal(Fig.4).TargetDNAconcentrationsdownto500fmolcanthusbedetectedwithexcellentpoint-mutationselectivity.Thislow-cost,simpleschemeoffersthepotentialofparallelreadoutofmultipleelectrodearrays.One-dimensionalnano-wirescanalsobeusedforbridgingtwoclosely-spacedelectrodesforlabel-freeDNAdetection.Forexample,ap-typesiliconnanowire—functionalizedwithPNAprobes—hasbeenshowntobeextremelyusefulforreal-timelabel-freeconductometricmonitoringofthehybri-dizationevent.40Thisreliesonthebindingofthenegatively-chargedDNA

targetthatleadstoanincreaseincon-ductance,reflectingtheincreasedsurfacecharge.

SimilarimprovementshavebeenreportedinconnectiontonanowiresandCNTfunctionalizedwithotherreceptormolecules.Forexample,Patolskyetal.41reportedrecentlyontheuseofnanowiredevicesfordirectreal-timeelectronicdetectionofsinglevirusmole-cules.Measurementsmadewithnano-wiresmodifiedwithantibodiesforinfluenzaAshoweddistinctandrever-sibleconductivitychangesuponbind-ingandunbindingofsingleviruses.Conducting-polymernanowirebio-sensorshavealsobeenshowntobeattractiveforlabel-freebioaffinitysensing.Forexample,Ramanathanetal.42demonstratedthereal-timemonitoringofnanomolarconcentrationsofbiotinatanavidin-embeddedpoly-pyrrolenanowire.Similarly,non-covalentfunctionalizationofCNTwasshowntobeusefulforlabel-freecon-ductivitymeasurementsofantibodiesassociatedwithhumanautoimmunediseases.43Non-specificbindingontheCNTwasovercomebyimmobilizingpolyethyleneoxidechains.

CarbonnanotubescanalsoleadtoultrasensitivebioelectronicdetectionofDNAhybridization.44–47Forexample,CNTcanbeusedascarriersforseveralthousandsenzymetagsandforaccumu-latingthea-naphtholproductoftheenzymaticreaction(Fig.5).SuchaCNT-deriveddouble-stepamplificationpathway(ofboththerecognitionandtransductionevents)allowsthedetectionofDNAdowntothe1.3zmollevelandindicatesgreatpromiseforPCR-freeDNAanalysis.

TheabilityofCNTtofacilitatetheadsorptiveaccumulationoftheguaninenucleobasecanleadtoadramaticampli-ficationoflabel-freeelectricaldetec-tionprotocols,basedontheintrinsic

Fig.4Conductivitydetectionofnanoparticle-basedmicroelectrodesarrays.Thecaptureofthenanoparticle-taggedDNAtargetsbyprobesconfinedtothegap,andasubsequentsilverenlargement,electricallyshortthegapandleadtoameasurableconductivitysignal.(Basedonref.38withpermission.)

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Fig.5Ultrasensitivebioassaysofproteinsandnucleicacidsbasedontheamplificationfeaturesofcarbon-nanotubecarriersandmodifiedelectrodes.(Basedonref.44withpermission.)

electroactivityofDNA.45ThecouplingofaCNTnanoelectrodearraywiththeRu(bpy)3+2-mediatedguanineoxidationhasfacilitatedthedetectionofsubatt-molesofDNAtargets.46,47SuchaCNTarraywasalsoappliedforlabel-freedetectionofDNAPCRamplicons,andofferedthedetectionoflessthan1000targetamplicons.

4.Conclusionsandfutureprospects

Theemergenceofnanotechnologyisopeningnewhorizonsforelectrochemi-calbiosensors.Recentyearshavewit-nessedthedevelopmentofavarietyofnanomaterial-basedbioelectronicdevicesexhibitingnovelfunctions.Theuseofnanomaterialsinsuchsensingdeviceshastakenoffrapidlyandwillsurelycontinuetoexpand.Nanoparticles,nanowiresandnanotubeshavealreadymadeamajorimpactonthefieldofelectrochemicalbiosensors,rangingfromglucoseenzymeelectrodestogenoelectronicsensors.Whatdoesthefutureholdforthistechnology?Theuniquepropertiesofnanoscalematerialssuggestthatfutureinterdisciplinaryresearchcouldleadtoanewgenerationofelectrochemicalbio-sensors.Wearecurrentlyexploringnanoparticle-basedprotocolsforelectro-nicdetectionofproteins.Theuseofnanoparticletagsfordetectingandcod-ingproteinsisinitsinfancy,butthelessonslearnedinDNAdetectionshouldprovideusefulstartingpoints.Themonitoringofproteinandproteininteractionspresentsagreaterchallenge

thanthatofnucleicacids,owingtotheabsenceof(PCR-like)amplificationtechnologies,thecomplexityofproteins,andtheirstrongernon-specificbindingtosolidsupports.Nanoparticlescom-prisingofmixed(recognition/shielding)monolayersaredesiredtofullyutilizethepotentialofprotein-nanoparticlehybrids.Suchadditionofproteinanaly-sistothearsenalofparticle-basedbio-assaysrepresentsanimportantstepinthedirectionofmakingparticlebio-electronicsauniversalbiodetectionplat-form.MultipleelectrodeproteinandDNAarraysbasedonnanoparticle-amplificationplatformsarethusexpectedinthenearfuture.

One-dimensionalnanostructuresareextremelyattractiveforawiderangeofbioelectronicsensingapplications.Theabilitytomodifynanowiresandnano-tubeswithbiologicalrecognitionele-mentsimpartshighselectivityontodevicesbasedon1-Dnanomaterials.Whileseveralnovelsensingconceptsbasedon1-Dnanowireshavebeenpresented,incorporatingthesematerialsintoroutinefunctionaldevicesremainsachallenge.Thesuccessfulbioelectronicutilityof1-Dnanostructuresrequiresnewnanofabricationcapabilitiesandproperattentiontotheinterconnectionchallenge,involvingreproducibleposi-tioningofnanowiresandnanotubesbetweenclosely-spacedmicroelectrodes.Suchattentiontothenanotechnology/microtechnologyinterfaceisessentialforassemblingnanosensorsintofunctionalintegrateddevices.Properattentionshouldbegivenalsototheinterfaceof

thesedeviceswiththerealworld(i.e.,tosampledeliveryissues).Ultimately,suchactivitywillleadtopowerfulsensorarraysforparallelreal-timemonitoringofmultipleanalytes.Thecreationofsuchbiosensorarraysrequiresnewmethodsforconfiningdifferentbiomoleculesontoclosely-spaced1-Dnanostructures.

Awiderangeofnewlyintroducednanomaterialsisexpectedtoexpandtherealmofnanomaterial-basedbiosensors.Suchnanomaterials-basedelectrochemi-caldevicesareexpectedtohaveamajorimpactuponclinicaldiagnostics,environmentalmonitoring,securitysurveillance,orforensuringourfoodsafety.Itisonlyamatteroftimebeforesuchprotocolsareusedforroutinediagnosticapplications.

Acknowledgements

ThisworkwassupportedbytheNationalScienceFoundation(GrantCHE0209707),theNationalInstitutesofHealth(AwardNumberR01A1056047-01),andtheEPASTARProgram.

JosephWang

DepartmentsofChemicalandMaterials

EngineeringandChemistryandBiochemistry,BiodesignInstitute,ArizonaStateUniversity,Tempe,AZ85287-5001,USA.E-mail:joseph.wang@asu.edu;Tel:1-480-727-0399

References

1C.P.Poole,Jr.andF.J.Owens,Intro-ductiontoNanotechnology,Wiley,2003.2H.BonnemannandF.J.M.Richards,Eur.J.Inorg.Chem.,2001,2455.

3C.M.Niemeyer,Angew.Chem.Int.Ed.,2001,40,4129.

4A.M.SmithandS.Nie,Analyst,2004,129,672.

5C.R.Martin,Acc.Chem.Res.,1995,28,61.

6R.H.Baughma,C.Satishkumar,A.GovindarajandM.Nath,ChemPhysChem,2001,2,79.

7J.Wang,Electroanalysis,2005,inpress.8J.Wang,J.DaiandT.Yarlagadda,Langmuir,2005,21,9.

9J.Wang,TrendsAnal.Chem.,2002,21,226.

10J.Wang,Acc.Chem.Res.,2002,35,811.11A.Guindilis,P.AtanasovandE.Wilkins,

Electroanalysis,1997,9,661.

12J.J.Gooding,R.Wibowo,J.Q.Liu,

W.Yang,D.Losic,S.Orbons,F.J.Mearns,J.G.ShapterandD.B.Hibbert,J.Am.Chem.Soc.,2003,125,9006.

ThisjournalisßTheRoyalSocietyofChemistry2005Analyst,2005,130,421–426|425

13X.Yu,D.Chattopadhyay,I.Galeska,

F.PapadimitrakopoulosandJ.F.Rusling,Electrochem.Commun.,2003,5,408.

14F.Patolsky,Y.WeizmannandI.Willner,

AngewChem.Int.Ed.,2004,43,2113.15Y.Xiao,F.Patolsky,E.Katz,

J.F.HainfeldandI.Willner,Science,2003,299,1877.

16J.Wang,M.MusamehandY.Lin,J.Am.

Chem.Soc.,2003,125,2408.

17M.Musameh,J.Wang,A.Merkociand

Y.Lin,Electrochem.Commun.,2002,4,743.

18S.Hrapovic,Y.Liu,K.Maleand

J.H.T.Luong,Anal.Chem.,2004,76,1083.

19J.WangandM.Musameh,Analyst,2004,

129,1.

20M.D.RubianesandG.A.Rivas,

Electrochem.Commun.,2003,5,6.

21T.Y.You,O.Niwa,R.Kurita,Y.Iwasaki,

K.Hayashi,K.SuzukiandS.Hirono,Electroanalysis,2004,16,.

22E.S.Forzani,H.Zhang,L.A.Nagahara,

I.Amlani,R.TsuiandN.J.Tao,NanoLett,2004,4,1785.

23K.Ramanathan,M.A.Bangar,M.Yun,

W.Chen,A.MulchandaniandN.V.Myung,NanoLett,2004,4,1237.24E.PalecekandM.Fojta,Anal.Chem.,

2000,73,75A.

25J.J.Gooding,Electroanalysis,2002,14,

1149.

26J.Wang,D.Xu,A.N.Kawdeand

R.Polsky,Anal.Chem.,2001,73,5576.27L.Authier,C.Grossiord,P.Brossierand

B.Limoges,Anal.Chem.,2001,73,4450.

28M.Dequaire,C.DegrandandB.Limoges,

Anal.Chem.,2000,72,5521.

29H.Cai,Y.Xu,N.Zhu,P.HeandY.Fang,

Analyst,2002,127,803.

30J.Wang,G.LiuandA.Merkoci,Anal.

Chim.Acta,2003,482,149.

31J.Wang,D.XuandR.Polsky,J.Am.

Chem.Soc.,2002,124,4208.

32J.Wang,R.PolskyandX.Danke,

Langmuir,2001,17,5739.

33J.Wang,G.LiuandJ.Zhou,Anal.Chem.,

2003,75,6218.

34A.KawdeandJ.Wang,Electroanalysis,

2004,16,101.

35J.Wang,G.LiuandA.Merkoc¸i,J.Am.

Chem.Soc.,2003,125,3214.

36G.Liu,J.Wang,J.KimandM.R.Jan,

Anal.Chem.,2004,76,7126.

37J.Wang,G.LiuandG.Rivas,Anal.

Chem.,2003,75,4661.38S.Park,T.A.TatonandC.A.Mirkin,

Science,2002,295,1503.

39R.Moller,A.Csaki,J.Kohlerand

W.Fritzsche,Langmuir,2001,17,26.40J.HahmandC.M.Lieber,NanoLett,

2004,4,51.

41F.Patolsky,G.Zheng,O.Hayeden,

M.Lakadamyali,X.ZhuangandC.Lieber,Proc.Natl.Acad.Sci.USA,2004,101,14017.

42K.Ramanathan,M.A.Bangar,M.Yun,

W.Chen,N.V.MyungandA.Mulchandani,J.Am.Chem.Soc.,2005,inpress.

43R.J.Chen,S.Bangsaruntip,

K.A.Drouvalakis,N.W.ShiKam,M.Shim,Y.Li,W.Kim,P.J.UtzandH.Dai,Proc.Natl.Acad.Sci.USA,2003,100,4984.

44J.Wang,G.LiuandM.Jan,J.Am.Chem.

Soc.,2004,126,3010.

45J.Wang,A.KawdeandM.Mustafa,

Analyst,2003,128,912.

46J.Li,H.T.Ng,A.Cassell,W.Fan,

H.Chen,Q.Ye,J.KoehneandM.Meyyappan,NanoLett,2003,3,597.47J.E.Koehne,H.Chen,A.M.Cassell,

Q.Yi,J.Han,M.MeyyappanandJ.Li,Clin.Chem.,2004,50,1886.

426|Analyst,2005,130,421–426ThisjournalisßTheRoyalSocietyofChemistry2005