Chemical sensors based on molecularly modified metallic nanoparticles

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IOP PUBLISHING JOURNAL OF PHYSICS D: APPLIED PHYSICS

J. Phys. D: Appl. Phys. 40 (2007) 7173–7186 doi:10.1088/0022-3727/40/23/S01

Chemical sensors based on molecularlymodified metallic nanoparticlesHossam Haick

Department of Chemical Engineering and Russell Berrie Nanotechnology Institute,Technion – Israel Institute of Technology, Haifa 32000, Israel

E-mail: hhossam@technion.ac.il

Received 9 February 2007, in final form 30 March 2007Published 16 November 2007Online at stacks.iop.org/JPhysD/40/7173

AbstractThis paper presents a concise, although admittedly non-exhaustive, didacticreview of some of the main concepts and approaches related to the use ofmolecularly modified metal nanoparticles in or as chemical sensors. Thispaper attempts to pull together different views and terminologies used insensors based on molecularly modified metal nanoparticles, including thoseestablished upon electrochemical, optical, surface Plasmon resonance,piezoelectric and electrical transduction approaches. Finally, this paperdiscusses briefly the main advantages and disadvantages of each of thepresented class of sensors.

(Some figures in this article are in colour only in the electronic version)

1. Introduction

The design, preparation and study of materials that exhibitinteresting chemical, physical or spectroscopic properties arean active area of research [1]. The quest in this area is notonly for compounds that behave as classical materials, butalso to produce systems that may exhibit new (combinationsof) properties. By judicious choice of the building blocks onecan indeed combine, in the same block framework, two ormore properties that are difficult to achieve in a one-phasesystem.

Metal nanoparticles (NPs) are of great scientific interestbecause they effectively bridge between bulk materials andatomic or molecular structures [2–10]. Indeed, in contrastto bulk metals, which display constant physical propertiesregardless of its size, nanoparticles display electronicstructures owing to quantum-mechanical rules and showproperties that are neither those of bulk metal nor those ofmolecular compounds [3,4,7,11,12]. A part of the interestingcharacteristics of nanoparticles depends significantly on theirsize and shape as well as on the inter-particle distance [2, 5,6, 9, 10]. The other part of the interesting characteristics ofnanoparticles depends on their surface properties, especiallysince the percentage of atoms at the surface becomes significantas the size of the material approaches the nanoscale, and onthe nature of the capping shell [2, 5, 6, 9, 10].

Application of monolayer-capped nanoparticles (MCNPs)[13–17], in which molecular functionality is used to influencethe chemical characteristics of ‘bare’ nanoparticles and toachieve cooperative (electron transport) properties of thenanoparticles and controllable functional versatility of themolecules, has led to significantly further expectations. Thisexpressed, among others, in the fact that MCNPs imposes farfewer limitations on the choice of nanoparticles and offersthe possibility to enhance the stability and solubility of thenanoparticles [18–21]. Added advantage is that cappingthe nanoparticles with tailor-made organic ligands offers thepossibility to precisely control both the chemical and physicalparameters of the nanoparticles in both quantitative andqualitative manners [22].

The continuously increased developments over thepast few years, using mainly advanced spectroscopy,scanning probe and nanofabrication methods, have raised(more realistic) expectations that this technology mayprovide building blocks for new generations of optical,electronic, sensing, magnetic, catalytic and biomedical devices[8, 23–25]. While the use of MCNPs in each of these fieldsis a topic for an extensive review, this paper will focus onrecent advances in the use of MCNPs in or as chemicalsensors. Towards this end, a concise answer for preliminary,yet fundamental question will be provided first. The questionand answer are detailed, respectively, in the title and contentof section 2.

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Figure 1. TEM image of spherical AuNPs with a diameter of (a) 5.5 ± 0.6 nm, (b) 8.0 ± 0.8 nm, (c) 17 ± 2.5 nm, and (d) 37 ± 5 nm, andAuNPs with (e) a mixture of rod-, hexagon-, rectangle-, cube- and triangle-like shapes, (f ) homogeneous phase of hexagon-like shapes, (g)homogeneous phase of cube-like shape and (h) homogeneous phase of triangle-like shapes. The scale bar in images (e)–(h) is 100 nm.(Adapted from [64, 66], copyright (2004 and 2001, respectively), with permission from the American Chemical Society.)

2. Why to exploit metallic nanoparticles for sensingapplications?

Among the numerous reasons why exploiting (materialscomprising) MCNPs for sensing applications is promising,we note three main reasons. The first relates to thepresumed ability to synthesize, if not at will, then withmuch control, nearly any type of MCNP one wishes[6, 8, 26–28]. Several studies have shown the abilityto cap the nanoparticles with wide variety of molecularligands, including alkylthiols with C3–C24 chains [23, 24,29, 30], ω-functionalized alkanethiolates [31], arenethiolate,[23, 32] (γ -mercaptopropyl)tri-methyloxysilane [33], dialkyldisulfides [34, 35], xanthates [36], oligonucleotides [37, 38],DNA [39], proteins [40], sugars [41–44], phospholipids[45–47], enzymes [48], etc. Other studies have strengthenedthe ability to control the MCNP’s core type, starting with coresmade of Au [25] or Ag [49, 50], and continuing with Ni [51],Co [52], Pt [53,54], Pd [54], Cu [55], Al [56] and metal alloys(e.g. Au/Ag, Au/Cu [50], Au/Ag/Cu [50], Au/Pt [50], Au/Pd[50] Au/Ag/Cu/Pd [50], Pt/Rh [57], Ni/Co [58] and Pt/Ni/Fe[59]). For sensing applications, this feature implies that onecan obtain MCNPs with variety of synergetic combinations ofchemical and physical functions [8, 13, 15, 17, 60, 61], whichin turn, affect the sensitivity and selectivity of the sensors[17, 62, 63]. The second reason is expressed in the abilityto vary the particles’ size [64] and shape and, therefore, thesurface-to-volume ratio. Studies have shown that MCNPs withdiameter down to ∼1 nm [65] (for nanoparticles with sphericalarchitectures) as well as with different structural architectures,such as rod-, rectangle-, hexagon-, cube-, triangle- and star-and branched-like outlines, can be synthesized in a highyield (see figure 1) [66–68]. For sensing applications, thesefeatures allow deliberate control over the domination of surfaceproperties, and, consequently, over the interaction ‘quality’with the analyte molecules. The third reason is summarized inthe ability to prepare films of MCNPs with controllable porousproperties. This allows controllable mass transport (e.g. via

diffusion) and adsorption of analyte molecules within the film.Such ability includes the control over inter-particle distance,and thereby obtaining nearly uniform inter-particle distancesin the composite films [8,27]. The result is controllable signaland noise levels [69], which eventually improves the devicesensitivity.

As discussed in section 3 below, part of these ‘justifying’reasons, such as the type of molecular modifications and theability to prepare porous films, have been well utilized forsensing applications. The rest still waits for further advancesin synthesis, fabrication and characterization techniques.While, the well-utilized aspects of MCNPs could be touchedthroughout the stated examples in sections 3.1–3.5, thefairly-utilized ones are forthrightly mentioned and discussed.

3. Chemical sensors based on MCNPs

Several new approaches to design MCNPs for an entirelynew chemical sensing platforms and/or capability of anexisting sensing technique have been reported. Generallyspeaking, MCNP-based chemical sensors are employed byeither controlled assembly (i.e. aggregation) or swelling ofMCNPs, through hydrogen bonding [70], π–π [71], host-guest[72], van der Waals [73], electrostatic [74], charge-transfer,[75] or antigen-antibody [76] interactions. For example,aggregation or swelling of metallic nanoparticles linked bythe organic molecules provokes, respectively, a red-to-blue orblue-to-red colour changes that are most useful for sensingapplications [25]. The parameters that can be controlled arethe nanoparticle and/or aggregate size, inter-particle distance,composition, periodicity and the aggregate thermal stability.These parameters are organized in order to influence theoptical, mechanical and electrical properties of the MCNPs.

For chemical sensors based on MCNPs, strict ‘lock-and-key’ design, wherein a specific receptor (hereby, the ‘lock’) issynthesized in order to selectively bind the analyte of interest(hereby, the ‘key’) [77–82], can lead mostly for high sensitivity

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[83–99]. Using alternative sensor architecture where thesensing elements (i.e. the MCNPs) are not individually highlyselective towards any given analyte may limit the obtainedsensitivity. However, using this architecture relaxes thestressing constraints on the sensor’s design. The result is amulti-purpose device with low to medium level of sensitivity.In practice, most MCNP-based chemical sensors suffer fromsome interference by responding to chemical species that arestructurally or chemically similar to the desired analyte. Thisinterference is an inevitable consequence of the ‘lock’ beingable to fit a number of imperfect ‘keys’. Utilizing differentcore types (cf section 2) of the responsive MCNPs canovercome this interference. This is so because different typesof metallic cores (cf section 2) can lead, via, for example, eitherpinholes in the capping monolayer and/or temporary exchangeof physically adsorbed capping molecules, to distinctiveinteractions with otherwise similar analytes [100, 101].

The responses of the MCNPs can be obtained fromequilibrium or kinetic states, with the latter often providingadditional discriminating power. The response mechanism forsuch systems is highly varied, as described in sections 3.1–3.5.Both binding and solubility properties can be interrogated withsuch MCNPs. For example, broadly responsive MCNPs canbe employed to allow a range of structurally similar moleculesto bind, MCNP-made membranes [102] may be used as size-selective sensors and MCNPs with highly selective functionalgroups may be employed to make selections on the basis ofpolarity. Often, all these recognition mechanisms, as well asothers described in this paper, exist simultaneously in thesesystems, but with different domination ratios. The advantageof this approach is that it can yield responses to a varietyof different analytes, including those for which the MCNPswere not necessarily originally designed to detect. In otherwords, sensors that combine all these recognition approachesnaturally perform an integration to yield a unique signal forcomplex but distinctive analyte without requiring the mixtureto be broken down into its individual components prior to,or during, the analysis. This is a disadvantage when precisechemical composition of a complex mixture is required butis advantageous when the only required information is thecomposite composition of the mixture of concern.

There is some controversy in the literature regardingwhether it is (or not) advantageous to use large numberof MCNPs for obtaining chemical responses. Correlationbetween the number of elements (i.e. MCNPs) and the obtainedsensing performances might solve this query. Also, it isbeneficial to measure the response of a given number ofMCNPs in many different ways, due to noise limitations inthe practical system. For example, if a sufficient precisionof MCNPs number could be obtained, it might be possible toidentify uniquely the type and characteristics of interactionbetween the analyte(s) and MCNPs. However, it is notpractical to make such measurements with this precisionapproach of MCNPs number. Hence at lower precision ofMCNPs number, useful information on the nature of theanalyte is gained by making measurements of the molecularparameters through many independent determinations ondifferent sensor elements.

Arguments on the need of a limited number of MCNPshold only if one is asked to distinguish between a series

of pure substances that are maintained at one fixed, knownconcentration. In contrast, if the background is unknown, ifmixtures are present, or if the background gases are changing inconcentration, many more MCNPs are needed simply to avoidambiguity in interpreting the output signals, and even moreare needed if optimal discrimination is to be accomplishedbetween a given target and a wide possible range of backgroundclutter and false alarm signatures. Having large number ofMCNPs also allows redundancy, which improves the signal-to-noise ratio and provides the ability to veto the output ofpoorly performing MCNPs.

MCNPs for sensing applications can be quite diverse.MCNP elements that will be discussed in this paper arebased on electrochemical, optical, surface Plasmon resonance,piezoelectric and electrical transduction approaches. Whilethe focus of this paper is primarily on the chemistry of theseMCNPs, there are a number of application areas that mightbe of interest to the reader. These include chemical andbiochemical processing, food and beverages, environmentalmonitoring, transportation, etc. Some aspects of these areas aswell as specific examples from each of these will be illustratedin the appropriate sections of the text that follows. This paperwill briefly review the extensive use of MCNPs-based sensorsin medical diagnosis, as this has been addressed in recentreviews [103–106].

The progress and insights that have arisen from recentworks investigating the MCNPs in or as sensing devices willbe discussed in sections 3.1–3.5. In each of these sections,a brief introduction on the working principle(s) of a givenclass of MCNP-based sensors, as well as pertinent examplesof actual developments, is provided. The insight(s) of theseobservations into the fundamental principles of MCNPs in oras chemical sensors is discussed where relevant. Section 4 willprovide a summary and an outlook for further efforts that areneeded for detailed understanding of the complex interplay ofthe control parameters affecting the performance of the MCNP-based sensors.

3.1. MCNP-based electrochemical sensors

A typical electrochemical sensor consists of a sensing electrode(or working electrode) and a counter electrode separated bya thin layer of electrolyte. Compound/target that reachesthe electrode surface produces a sufficient electrical signal[107, 108]. The compounds/targets that react at the surfaceof the sensing electrode involve, mostly, either an oxidationor reduction mechanism. These reactions are catalyzedby the electrode materials specifically developed for thecompound/target of interest. With a resistor connected acrossthe electrodes, a current proportional to the compound/targetconcentration flows between the anode and the cathode. Thecurrent can be measured to determine the compound/targetconcentration.

The use of MCNPs for fabrication of electrochemicalsensing devices is an extremely promising prospect [109].Multilayers of cross-linked MCNPs give rise to a porous,high surface-area electrode, where the local microenvironmentof the metallic nanoparticles can be controlled to lead tospecific and selective interactions [110–112]. Based onthese principles, Zheng et al [102] demonstrated biomimetic

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(A)

(B)

Figure 2. (A) Schematic illustration of the void frameworks in(1 1 1)-type packing of core-shell nanoparticle network. Themagnified view illustrates the chemical properties of the shell usingcarboxylic acid terminal as the model. (B) Cyclic voltammetriccurves for film of (11-mercaptoundec-anoic acid)-capped 2 nmAuNPs coated on glassy carbon electrode in 1.0 mMFe(CN)63−/0.5 M KCl solutions at (a) pH 2.7, (b) 10.8 and (c) for abare glassy carbon, as a representative example. (Reprintedfrom [102], copyright (2000), with permission from the AmericanChemical Society.)

ion-gating properties with core-shell nanoparticle networkarchitectures, using AuNPs (with a diameter of 2 or 5 nm)capped with thiolate shell and alkylthiols terminated withcarboxylic groups as model building blocks (figure 2).The biomimetic ion-gating properties were demonstrated bymeasuring the pH-tuned network ‘open-close’ responses tocharged redox probes. The redox responses were shownto depend on the degree of protonation–deprotonation ofcarboxylic groups at the inter-particle linkages, core sizesof the nanoparticles and charges of the redox probes. Thenetwork was shown to be effectively tuned by pH between aneutral ‘close’ and an ionic ‘open’ or ‘close’ state to exhibitelectrochemical ion-gating properties (figure 2(B)). While stillfar from the real biological ion gate in cell membranes, thedemonstrated properties in this study are one important steptowards achieving biomimetic functions. Further advancesrequire, among others, increasing the detection sensitivity anddegree of selectivity between different compounds.

Highly specific interactions between the analyte speciesand tailor-made organic shell functional groups could en-hance sensitivity and increase selectivity of the electroanalyt-ical methods. A series of electrochemical sensors were con-structed by electrostatic cross-linking of AuNPs with bipyri-dinium cyclophanes or oligocationic Pd(II)-ethylenediaminebipyridine square-type complex [83–86]. The bipyridiniumcyclophanes acted as receptors for the association of π -donorsubstrates in their cavities, and the 3D-conductivity of theAuNP array permitted the electrochemical sensing of π -donorsubstrates associated with the cyclophane units. The π -donor–acceptor complexes were formed between the host-receptorand the π -donor analyte that enabled pre-concentration of theanalyte at the conductive surface. AuNPs containing a mix-ture of alkylthiol and amidoferrocenyl alkylthiol ligands wereused as exo-receptors that can selectively sense H2PO−

4 andHSO−

4 owing to their hydrogen-bonding capacity with these

Figure 3. Schematic representation of the amplified electrochemicaldetection of DNA hybridization via oxidation of the ferrocene capson the AuNP/streptavidin conjugates. For clarity, 1-hexanethiol,DNA, streptavidin and 6-ferrocenylhexanethiol molecules are notdrawn to scale. The scheme pictorially reflects the fact that onestreptavidin molecule could be linked to one or twoferrocenylalkanethiol-modified AuNPs. (Reprinted from [116],copyright (2003), with permission from the American ChemicalSociety.)

oxo-anions [87]. When these anions interacted with ferro-cenyl groups, the potential of the initial wave of these par-ticles shifted cathodically. AuNPs derivatized with diacyl-diaminopyridine were shown to interact with flavin throughnon-covalent complexation and result in a cathodical shift ofthe redox potential of flavin [88]. Based on similar ‘working’principles, high detection level using electrochemical analysisof Cu2+ ions with sensitivity below 1 ppb with improved selec-tivity in the presence of Fe3+ and Zn2+ ions was achieved usinga glassy carbon electrode functionalized with AuNPs cappedwith 11-mercaptoundecanoic acid units [89]. Also, selectiveelectrochemical analysis of dopamine and ascorbic acid wasachieved on a Au electrode functionalized with a monolayerof Au nanoparticles (AuNPs) due to a catalytic effect of theAuNPs on the ascorbic acid oxidation [90].

DNA detection probes conjugated to various nanoparticleswere shown to enhance voltammetric signals. For examples, apencil graphite electrode modified with target DNA respondedwith the appearance of a Au oxide wave at ca +1.20 V whenhybridized with complementary probes conjugated to AuNPs,in two different modes [113]: (a) Inosine-substituted probeswere covalently attached from their amino groups at the 5′

end using N-(3-dimethylamino)propyl-N’-ethylcarbodiimidehydrochloride and N-hydroxysulfosuccinimide as a couplingagent onto a carboxylate-terminated L-cysteine self-assembledmonolayer (SAM) preformed on the AuNPs, and (b) probeswith a hexanethiol group at their 5′ phosphate end formed aself-assembled monolayer on AuNPs. A promising approachto augment the voltammetric signals and the detectableconcentration levels of DNA is to incorporate electrochemical-active functional groups in the MCNPs. Baca et al [114]synthesized ferrocenealkanethiol-capped AuNP-streptavidinnanoconjugates and used them for DNA analysis in a sandwichformat [115, 116] and detection of biotinylated ODN targets(cf figure 3). Owing to the presence of a large numberof ferrocene caps on the AuNPs, the voltammetric signalswere significantly augmented and the detectable concentrationlevels were lowered. In a sandwich assay, the concentrationdetection level was around 2.0 pM, whereas that from direct

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hybridization with biotinylated target was measured as low as0.25 pM. Further amenability of this method to the analysesof polynucleotides (i.e. PCR products of the pre-S gene ofhepatitis B virus in serum samples) was also demonstrated.

DNA detection probes conjugated to various nanoparticleswas shown to enhance voltammetric signals and at the sametime offer certain advantages that cannot be achieved by theenzyme-amplified approach. For example, Wang et al [117]developed a magnetically induced solid-state electrochemicaldetection, whereby target DNAs are hybridized with probemolecules immobilized onto magnetic beads. Following asandwich hybridization scheme using ODN-detection-probe-capped AuNPs, silver particles were reduced and depositedonto the AuNPs. The final product was separated magneticallyfrom the sample medium and the silver particles were dissolvedand measured by potentiometric stripping analysis. Thismethod elegantly combines the sensitivity associated withstripping voltammetry [118] with magnetic separation forselective and trace analysis of DNA. A similar approach wasexpanded to multiplexed DNA analysis using metal-containingnanocrystals. Zinc, cadmium and lead sulfides were coveredwith detection ODN probes and utilized in a sandwich assay,allowing simultaneous detection of DNA molecules of severaldifferent sequences [119]. As a result, the sample throughputswere improved.

MCNP-based electrochemical sensors are sensitive,especially for surface adsorbates [118], and do notrequire expensive instruments. Moreover, the device(the electrochemical cell and electrodes) and measuringelectronics are cost-effective and can be easily miniaturized.Consequently, electrochemical detection is particularlyattractive for point-of-care target analysis of electrochemicallyactive compounds, but not for electrically inert compoundssuch as simple aromatics and hydrocarbons.

3.2. MCNP-based optical sensors

In optical sensors, changes/shifts in a wavelength of anoptical output signal depend on an external stimulus, suchas temperature [120], strain [120], stress [120], acceleration[121], biocoating [122], or chemical environment [122]. Byimmobilization of adsorption layers onto the optical pathway,the sensor can be tuned to distinguish between a particularanalyte or a range of analytes, suing a wide variety ofsignal transduction mechanisms, such as fluorescence intensityand lifetime [123], polarization [124], spectral shape [125],absorbance [126], wavelength [127,128] and reflectance [129].

Generally speaking, the most intensely coloured conven-tional molecular dyes (porphyrins, azo dyes, etc.) rarelyexhibit extinction coefficients greater than 105 M−1 cm−1,thereby limiting non-instrumental colorimetric detection to ca0.5 µM. Certain non-molecular chromophores such as freeelectron metal (e.g. gold, silver, and copper) nanoparticles,however, can display visible-region extinction coefficients thatare up to several orders of magnitude higher. Several stud-ies, therefore, have reasoned that by functionalizing metalnanoparticles with appropriate receptors one can increase thesensitivity towards compounds of interest. Among others,we mention the detection of uracil-functionalized nanopar-ticles upon H-bonding with complementary polystyrene-based diblock copolymers [130], interactions between AuNPs

(A)

(B)

Figure 4. (A) Schematic illustration for heavy-metal (M2+)recognition and binding. If aggregation had been driven byheavy-metal ion recognition and binding, the colour change could beemployed for visual sensing of the ions. (B) Colorimetric responses(top panel) and corresponding spectral traces (bottom panel) from(a) Au-(mercaptoundecanoic acid), (b) Au-(mercaptoundecanoicacid)/Pb2+ and (c)–(g) Au-(mercaptoundecanoic acid)/Pb2+ andincreasing amounts of EDTA. Pb2+ concentration in sample (b) is0.67 mM; EDTA concentrations in samples (c)–(g) are 0.191, 0.284,0.376, 0.467 and 0.556 mM. (Reprinted from [92], copyright (2001),with permission from the American Chemical Society.)

stabilized by 4-(dimethylamino)pyridine-AuNP and vari-ous polyelectrolytes [131], selective interactions between4-(dimethylamino)pyridine-AuNP and poly(diallyldimethyl-ammonium chloride) and between 4-(dimethylamino)pyridine-AuNP and poly(sodium 4-styrenesulfonate), poly(allylaminehydrochloride) or poly(ethyleneimine). A significant contribu-tion and one that implies widening the detection possibilitiesof MCNP-based optical sensors comes from recent demon-strations that particles might be coaxed to function as high-intensity colorimetric reporters for otherwise spectrally silentions functionalized metal nanoparticles. For example, AuNPswere used with 15-crown-5 heavy-metal ion receptors to rec-ognize K+ in water [132], with 1,10-phenanthroline metal ionreceptors to sense Li+ [91], and with 11-mercaptoundecanoicacid metal ion receptors to selectively sense Pb2+, Hg2+

and Cd2+ (for illustrative example, see figure 4 and captiontherein) [92].

The large (optical) extension coefficients of metallicnanoparticles (e.g. Au) and their dependence on the particlessize, concentration and inter-particle distance, have been madean important tool for deliberate and amplified detection andsequencing strategies of DNA. Alivisatos et al [38] showedthat the ratio of absorbances at 280 nm and 420 nm of discretenumbers of single-stranded DNA oligonucleotides of definedlength and sequence, attached to individual 1.4 nm diameterparticles, can be indicative to spatially defined dimers andtrimers upon addition of a complementary single-strandedDNA template. Based on modifications of this approach, otherstudies have reported, amongst the rest, reliable detection(s) of

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aptamer-protein [133], single-stranded target and 2.5 nM for aduplex target oligonucleotide [134] and anti-protein A [135]interactions.

For applications where highly amplified optical transduc-tion biorecognition events are required, encapsulation of a flu-orescent marker within a nanoscale carrier was found to beuseful [137, 138]. Trau et al [137] reported on a highly sensi-tive immunoassay of proteins based on polyelectrolyte encap-sulated microcrystalline fluorescent material interfaced to theantibody. A dramatically amplified immunoassay was reportedon the release of fluorescent molecules to the detection mediumupon antibody–antigen interaction. Several reports [139,140] exploited the ability of AuNPs to quench fluorescencedyes in assays that distinguish ODNs with single-base mis-matches. A homogeneous, competitive binding immunoas-say for biotin was designed based on AuNP/polyelectrolyte-coated polystyrene particles of 488 nm diameter as quench-ing agents for a fluorescein isothiocyanate labelled anti-biotin immunoglobulin [136]. Biotin molecules were local-ized on the AuNP/polyelectrolyte-coated latexes by deposit-ing a layer of biotinylated poly(allylamine hydrochloride), andanti-biotin immunoglobulin were subsequently bound to theparticles through interaction with the biotin on biotinylatedpoly(allylamine hydrochloride). The biotin-functionalizedAuNP/polyelectrolyte-coated latexes terminated by anti-biotinimmunoglobulin exhibited a dynamic sensing range 1–50 nmol(figure 5). These results indicate that AuNP/polyelectrolyte-coated latexes can be readily used as dynamic range tunablesensors.

While most of the MCNP-based optical sensors arebased on colorimetric changes, other promising optical-based approaches for detection purposes can be utilizedtoo. In a recent study, platinum nanoparticles/EastmanAQ55D/ruthenium(II) tris(bipyridine) (PtNPs/AQ/Ru(bpy)2+

3 )

colloidal material were synthesized and deposited on thesurface of a glassy carbon electrode to produce, for thefirst time, an electrochemiluminescence solid-state sensor[141]. The electronic conductivity and electroactivityof PtNPs in composite film made the sensor exhibitedfaster electron transfer, higher electrochemiluminescenceintensity of Ru(bpy)2+

3 , and a shorter equilibration time thanRu(bpy)2+

3 immobilized in pure AQ film. Furthermore, itwas demonstrated that the combination of PtNPs and per-selective cation exchanger made the sensor exhibit excellentelectrochemiluminescence behaviour and stability and a verylow limit of detection (1 × 10−15 M) of tripropylamine withapplication prospects in bioanalysis. This approach opens newroutes for further advances and developments in the MCNP-based optical sensors field.

To summarize this section, optical sensors havemany distinct advantages in comparison to their electroniccounterparts. They are very sensitive, allow remote anddistributed sensing, can be used in harsh environments andare immune to electromagnetic interference. The maindisadvantage of optical sensors is their comparatively highcost. Current inhibitors of large scale commercial acceptanceof optical sensing are the bulkiness and high cost of theinterrogation systems that are capable of resolving the smallwavelength shifts that are typically observed from thesesensors.

Figure 5. (a) Fluorescence spectra for thebiotin-AuNP/polyelectrolyte latexes terminated with anti-biotinimmunoglobulin after titration with biotin solution. The amountindicated for each spectrum is the cumulative amount of biotinadded. (b) Titration curve of the fluorescence intensity at 522 nm.The transverse axis shows the cumulative amount of biotin added.(Reprinted from [136], copyright (2005), with permission from theAmerican Chemical Society).

3.3. MCNP-based surface Plasmon resonance (SPR) sensors

Surface Plasmon resonance (SPR) employs enhancement ofoptical fields that occur at metal (e.g. Au, Ag and Al)surfaces when surface Plasmon polaritons are created at themetal/dielectric interface by polarized incident light [142].The classical ‘Kretschmann configuration’ is the most oftenused arrangement in commercial and laboratory devices. Inthis configuration, p-polarized light impinges on the backof a metal film-coated glass slide that is positioned onto aprism with an index-mating material. At a certain incidentangle (resonance angle), the Plasmons1 are set to resonatewith light, resulting in absorption of light at that angle, and,therefore, the reflected light decreases sharply to a minimumdip. The reflected light intensity or the dip position is relatedto the processes occurring at the sensor/solution interface. Amolecular binding event taking place on or near the metal filmcauses a shift in the resonance angle, which can be measuredby detectors such as a CCD or diode array. The reflected

1 Plasmons are quasiparticles resulting from the quantization of plasmaoscillations. They are a hybrid of the electron plasma (in a metal orsemiconductor) and a photon. Thus, Plasmons are collective oscillations ofthe free electron gas at optical frequencies.

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light intensity or the dip position is related to the processesoccurring at the sensor/solution interface. For SPR imaging,the light source is expanded and collimated to have a parallellight beam that irradiates a large area of the metal film throughthe prism [143–153].

Similar to the case of conventional SPR sensors withspectral interrogation [154], the sensing capability of metalnanoparticles is linked to the variation in optical response withnear-field electrodynamic environment. The exact position,shape and intensity of the localized nanoparticle SPR isdetermined by such factors as particle’s morphology (size andshape), dielectric environment (coating, surrounding medium,supporting substrate), and inter-particle coupling (e.g. state ofaggregation). A nanoparticle SPR sensor can, in principle, bebased on modifications of any of those factors.

MCNPs have shown ability to serve as (exo-) receptors[155] for detecting a wide range of analytes in solution viamonitoring the Plasmon band [156]. In most cases, the MCNP-based SPR sensors were illustrated via particle–particlecoupling induced by DNA linkage [157,158], particle-surfacecoupling induced by biorecognition [159] and sensing basedon changes in the dielectric environment due to an adsorptionlayer [156, 160, 161]. Few examples include detection ofantigen–antibody affinity assays [93, 94], analysis of DNAhybridization reactions at a concentration level of 10 pM[95], hybridization of unpaired segment of DNA with ODNimmobilized on SPR sensor surface [96, 97] and detection ofother several bimolecular species at levels as low as a fewfemtomolar [98]. Other examples involve immobilizationof AuNP-coated anti-transferrin on 2-mercaptoethylamine-coated substrate as active components to detect transferrin,in real time and in concentration range 1–20, 0.1–20 and0.05–20 µg mL−1 [99].

In most cases, the signal enhancement of SPR wasattributed to a combination of increased surface massand higher refractive index of the AuNP adlayer and ofelectromagnetic coupling between the nanoparticles and theunderlying SPR Au surface [95]. The effect of interactionswithin and among the different components of a nanoparticlebased SPR sensor was studied by Hutter et al [162], usinga six-phase multilayer SPR device. The results indicate thatSAM-induced changes in the free electron properties of thesubstrate and image field effects of charged nanoparticles havea considerable influence on the SPR characteristics of thesystem.

Although modulated MCNP-based SPR technique havebeen implemented to improve the SPR detection limit, thismethod cannot be used in an array format. Fortunately, thislimitation can be ‘by-passed’ through using imaging SPR,which allows simultaneous, rapid, and highly throughputdetections of multiple analytes occurring at microarrays.Enzymatically amplified SPR imaging methods for bothDNA [163] and RNA [164, 165] at femtomolar levels ofconcentration were developed by utilizing enzyme digestionsof DNA or RNA molecules on the microarrays (cf figure 6and caption therein for an illustrative example). Thisapproach for surface amplification is a simple and extremelysensitive method for the detection of multiple DNA targetson a single chip. While this study relied on SPR imagingto detect the RNase H activity, other methods such as

Figure 6. Three-component array created using non-interactingthiol-modified RNA sequences R1, R2 and R3. (a) An SPRdifference image was obtained by subtracting images taken beforeand after the array had been exposed to a 10 fM DNA solutioncomplementary to R1 and the enzyme RNase H. A line profile wastaken across the image as drawn on the pattern in the bottom part ofthe figure. The line profile shows a decrease in percent reflectivitycorresponding to DNA hybridization and the subsequent hydrolysisof the complementary RNA probes by RNase H, while no changesfor the other array elements are observed. The array was thenwashed with 8 M urea to denature the surface. (b) An SPRdifference image showing the sequential detection of a different10 fM DNA solution (D2) onto the same array surface. A line profiletaken across the image shows a decrease in per cent reflectivity isobtained for this binding event. Approximately 2 h was required toachieve a change in percent reflectivity of −0.3% in both (a) and(b). (Reprinted from [165], copyright (2000), with permission fromthe American Chemical Society.)

fluorescence or nanoparticle labelling can be incorporated intothis amplification method. The advantages of this methodcan be extended, upon appropriate modifications, to otherbiosensing applications in the areas of bio-warfare detection,gene expression analysis and drug discovery.

SPR and its variant imaging SPR can be powerfulmethods for label-free, rapid and highly sensitive detection(bio)chemical compounds [166–168]. The low amount ofsamples required to accomplish the SPR measurements andthe possibility to miniaturize the SPR instrument make thistechnique of great technological interest [144, 146–148, 169–172]. The variety of nanoparticle constructs clearly offers anopportunity for optimization of sensitivity and optical responsethat is lacking for conventional, flat surface, SPR sensors.An added strength is the possibility to optimize for surface-enhanced spectroscopic analysis, such as surface-enhancedRaman scattering (SERS) with sensitivity approaching thesingle-molecule limit [173, 174]. Due to the large number ofpossibilities, it is clearly desirable to have accurate modelsfor the optical properties and response of different SPR

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sensors. Such models would allow researchers to optimizeand evaluate various sensor concepts prior to experiment.The challenge is to solve Maxwell’s equations for realisticSPR boundary conditions, electromagnetic environments,nanoparticle shapes and interactions.

3.4. Piezoelectric methods

Piezoelectric materials produce a voltage when mechanicalstress is applied, and vice versa. When an oscillating potentialis applied on piezoelectric materials at a frequency near theresonant frequency of a piezoelectric crystal, a variety of wavemodes can be established [175]. Two main device types havebeen used with MCNPs: quartz crystal microbalance (QCM)and bulk acoustic wave (BAW) and surface acoustic wave(SAW) resonators. In a QCM, the acoustic wave propagatesthrough the bulk of the crystal in a direction perpendicular tothe surface, with motion at the surface parallel to the surface.In a SAW device, motion occurs only at the surface, penetratingto a depth of approximately one acoustic wavelength intothe crystal. The direction of propagation is parallel to thesurface, while motion at the surface is both parallel andperpendicular to the surface. SAW devices can be constructedin two different configurations: delay line and resonator.Adding mass to the surface of acoustic resonators changestheir resonant frequency, and the resulted frequency shift canbe translated to a change in mass on the QCM surface, viaSauerbrey relation [176]. If the acoustic sensor is coated with achemically selective layer and if appropriate signal processingis used, a chemical sensor or chemsensor can be constructed,and the composition and concentration of chemical mixturescan be determined.

Coating a resonator with a film of MCNPs enhancesthe adsorption of chemical compounds on the piezoelectricmaterial, resulting a significant change in its resonantfrequency [177, 178]. For example, Yang et al[179] studied the vapour sensing properties of AuNPscoated with 2-naphthalenethiol, 2-benzothiazolethiol and 4-methoxythiolphenol by means of QCM and the results werecompared with equivalent ones, but with chemiresistor devices(cf section 3.5). By probing the sensing properties of AuNP-based QCM with various vapours (i.e. toluene, 2-butanone,iso-propanol, octane, butyl acetate, 1,2-dichloroethane,perchloroethylene, n-butanol, 1,4-dioxane and m-xylene),the different relative sensitivities among functional groupswere revealed through specific interactions. The design ofMCNPs structures created different selectivity in physicalsorption that were observed in QCM response patterns.However, it was found that structural chemical forces do notnecessarily reflect responses in chemiresistors. Luo et al[180] reported four distinctive mass response characteristicsupon pH tuning (cf figure 7) or metal ion (Li+, K+, Rb+,and, Cs+) binding at 11-mercaptoundecanoic acid linkednanoparticle assembly on quartz crystal nanobalance (QCN)electrodes. First, the protonation–deprotonation characteristicof the carboxylic acid groups in the nanostructured frameworkis dependent on particle core size and film thickness.Second, the pH-tunable cationic redox reaction across theelectrode/film/electrolyte interface is accompanied by a largecationic electrolyte mass flux. Third, the spontaneous

Figure 7. (a) Schematic illustration of possible mass fluxes at theelectrode/film/electrolyte interface. (b) Plot of total mass changeversus molar mass of the electrolyte cation for a CuII -loaded(11-mercaptoundecanoic acid)-Au2−nm film. (Reprinted from [180],copyright (2002), with permission from the American ChemicalSociety).

complexation to copper ions by the nanostructured carboxylateframework is reflected by a mass increase of the film. Fourth,the redox reaction of copper loaded in the nanostructuredfilm is accompanied by fluxes of electrolyte cations acrossthe electrode/film/electrolyte interface which compensateselectrostatically the fixed negative charges. The simplicity andlow detection limit of the QCN device, the high surface area-to-volume ratio, tunable ligand framework, and conductivityof the nanostructured materials and the nanoparticle-tailoredEQCN detection, is potentially amenable for developing asimple, rapid, sensitive and selective monitoring device forheavy metals. More experiments, though, are clearly neededto assess the analytical figures of merit and stability issues fordifferent heavy metals from environmental samples.

Kurosawa et al [181] developed QCM immunosensors forenvironmental pollutants that have extremely low molecularweight and high toxicity, e.g. dioxins and bisphenol-A.Towards this end a bio-interface of QCM immunosensorwas designed and controlled to immobilize antibody onthe QCM surface, to reduce nonspecific binding and tosuppress denaturation of immobilizing antibody by self-assembled monolayer technique and artificial phospholipidpolymer. Using a high-sensitivity immunoreaction formatsuch as a competitive immunoreaction and signal-enhancingstep, dioxin molecules and bisphenol-A were detected withextremely low detection limitations. A biosensor based onQCM using 50 nm AuNPs as the amplification probe for DNAdetection at concentration level of 10−14 M of DNA, wasreported [182]. Microcantilevers were used to detect DNAstrands with a specific sequence using AuNP-modified DNA.

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When the size of the AuNPs is 50 nm, a sensitivity of 10−15 Mfor single-base mutation detection has been achieved withthis method [183]. Dry-reagent strip-type biosensors basedon AuNP-DNA interaction enabled visual detection withinminutes, and quantitative data were obtained by densitometricanalysis [184]. AuNP-streptavidin conjugates covered with6-ferrocenylhexanethiol were attached onto a biotinylatedDNA detection probe of a sandwich DNA complex, and theamplified voltammetric signal was recorded. A detectionlevel down to 2.0 pM for oligonucleotide was obtained [116].Single-stranded and double-stranded DNA were shown byelectrophoresis and fluorescence to bind nonspecifically tothe AuNP surface, despite their negative charge [185]. Non-specific binding of biological molecules can be eliminated,however, using ethylene glycol core protection [186]. Willneret al [187] and Zhou et al [188] used DNA-capped AuNPsto amplify weak signals commonly observed for the DNAhybridization reactions with a QCM (especially when the DNAtarget concentration is quite low). Willner’s group [189]also utilized tagged liposomes to amplify DNA detectionand analysis of signal-base mismatch by QCM. Anotherinteresting approach by the same group was to take advantageof the precipitation generated from an enzyme-catalyzed redoxreaction [189]. In the presence of horseradish peroxidase, 4-chloro-1-naphthol was biocatalytically oxidized and forms aninsoluble product. Such a precipitation causes a pronouncedmass increase at the quartz crystal surface.

To sum up this section, sensing with acoustic wavedevices that are based on MCNPs appears highly promisingfor inexpensive, fast, sensitive and high resolution detection.However, as with other technologies, there remain severalproblems to be solved. These are primarily poor batch-to-batch reproducibility during manufacturing, reversibility anddependence of the response on humidity and temperature[190, 191].

3.5. Sensors based on MCNP-induced signal transduction

3.5.1. Chemiresistors. Utilizing chemiresistors for sensingpurposes has been attracting considerable attention [192]. Thiscan be attributed to many unique features that are relatedto chemiresistors (e.g. small size and weight, fast response,reliability, low-output impedance, the possibility of automaticpackaging at wafer level, on-chip integration of sensor arraysand the possibility of mass-producing portable microanalysissystems at low costs). In standard chemiresistors, the electricalresistance of a device changes in the presence of given chemicalspecies (figure 8).

Using an assembly of MCNPs as a medium thatcan accommodate organic materials between the particlesis a promising approach to build chemiresistors. Theconducting mechanism through MCNP film, assumingactivated tunnelling model, can be expressed as follows[29, 101]:

σ = σ0 exp(−β × δ) × exp

(− Ea

RT

)(1)

where σ is the electronic conductivity obtained at specifictemperature, β is the electron transfer coupling coefficient,δ is the edge-to-edge core separation, R is the gas constant, T

Metallic Electrode

SiSiO2

A

Metallic Electrode

SiSiO2

AA

Figure 8. Highly idealized schematic illustration of a chemiresistivefilm based monolayer-protected metallic nanoparticles (inset). Inthese films, the metallic particles provide the electric conductivityand the organic film component provides sites for the sorption ofanalyte (guest) molecules. In addition to their role as an adsorptivephase, presence of well-defined organic spacers (i.e. cappingmolecules) allows a control over the inter-particle distance, andthereby, obtaining nearly uniform inter-particle distances in thecomposite films. This allows achieving controlled signal and noiselevels [69].

is the temperature, and Ea is the activation energy for electrontransfer, which, in turn, is given by:

Ea = e2

4πεrε0r. (2)

With equations (1) and (2) in mind, the hypothesis beingchallenged in this type of chemiresistors is that cappingmonolayers of (semi-) selective molecules facilitate adsorptionof analytes in films made of MCNPs, and, as a result,induce electrical changes according to either of the followingmechanisms: (a) reduction/increment in the number ofelectrically conductive pathways between the particles, whichrepresented by changes in the core edge-to-edge distance (δ)[193] and/or (b) changes in the dielectric constant (εr), whichcan be a crucial factor during the addition of small dielectricallydifferent molecules into the MCNP media [195].

The use of MCNPs in chemiresistors was first reported byWohltjen and Snow [195], when they showed that octanethiol-encapsulated 2 nm AuNPs deposited on an inter-digitatedmicroelectrode exhibited a fast and reversible response towardstoluene, tetrachloroethene, 1-propanol and water vapour with avery high sensitivity. In the following years, other groups [100,194, 196–201] demonstrated a further development of thisconcept when they showed that the selectivity of such sensorcoatings can be tuned by introducing chemical functionalityinto the organic ligand shell for selective binding abilitiesof the molecules to be detected. Examples for the cappingligands that were reported includes alkythiols, [100, 195, 202]alkylamines, [199] para-thiophenols, [196] carboxylates [200]or cross-linked polyphenylene dendrimers [201].

The quest to understand and improve the sensingperformances of this class of sensors led to several reportsexploring the different features of MCNP-based sensors [101,194, 196–198,200,201, 203–206]. The main outcome of thesestudies was that the electronic conduction in MCNP filmsproceeds by tunnelling between metallic (nano)cores throughthe insulating thiolate ligands and is a sensitive function of thesize of the metallic (nano)core and the length and compositionof the thiolate ligands [29, 207]. Electrical and opticalresponses of thin films of MCNPs upon exposure to various

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chemical vapours were studied, and ellipsometric studiesrevealed that the film thickness increased during exposure tothe chemical vapours [196,198]. Based on the obtained results,two physical effects were assumed to play a role in determiningthe conductivity changes in MCNP-made chemiresistive films[196, 198]. Under high partial pressure, the change in thenanoparticles’ core-core separation is the main contribution tothe change in conductivity and generally leads to a reductionin the conductivity. In complementary studies, it was shownthat the linker chains appear to have sufficient flexibility in thepresence of organic vapour to collapse and fold with varieddegrees of film swelling or dryness [193]. For relatively lowpartial pressures the adsorption of vapour molecules leads topermittivity changes that tend to increase the conductivity[194]. To this end, studies have shown that for non-polarvapours sorbing into films of MCNPs having alkanethiolateligands, dielectric factors are relatively unimportant andresponses are governed by the increase in volume of the organicfraction of the film, which increases the average intercoredistances and raises the film resistivity. Vapours with dielectricconstants sufficiently greater than that of the MCNP ligandmonolayer can produce a net decrease in resistance uponsorption [195].

Few studies were performed to understand the effect ofdifferent analytes on the properties of MCNPs with differentmetallic cores. Studies by Vossmeyer and coworkers [100,101]implied that the performance of nanoparticles having differentmetallic cores (e.g. Pt and Au) comes to expression mainlyif there is a direct interaction between analyte (e.g. NH3

and CO) and the metallic core (cf figure 9 and captiontherein). This direct analyte-core interaction can occureither through pinholes in the capping monolayer and/ortemporary exchange of physically (rather than chemically)adsorbed capping molecules. These implications missed solidexperimental background and the related mechanism was notwell understood. However, a study of the conductivity ofmetallic (Pb, Cu, Pd) nanoparticles in a polymeric matrix[208] led to important conclusions in this context. Basedon such conclusions [209], it was hypothesized that directanalyte–core interaction during an uptake of electron–donormolecules (ammonia, alcohols, water) and of electron–acceptor molecules (hydrogen, dichlorobutene, chloroform)change fractal characteristics of the composites as well asthe work function of the metal nanoparticles. It is not clear,however, from a molecular electronics viewpoint, what theeffect of direct interaction is between a-polar analytes anddifferent types of metallic cores.

Several studies have shown that the resulting chemicaland physical properties of thiol-protected nanoparticles canbe correlated with the core size [30, 194, 209–213]. However,only few efforts were invested to systematically study the effectof core size on the MCNP-based chemiresistors [69, 194],especially, to determine, from signal and noise viewpoints,whether one wants larger particles with fewer tunnelling gapsor smaller particles, which would provide more tunnellingpathways. A main reason for such few efforts could beattributed to the fact that direct synthesis of MCNPs (i.e.by arrested precipitation synthetic method [23]), are, mostly,limited to a narrow range of average particle diameter [30,211].

As other transducers, the detection limit of MCNP-basedchemiresistors is given by the ratio between the sensitivity

(a)

(b)

(c)

Figure 9. Responses of (a) Au- and (b) Pt-MCNP-basedchemiresistor to exposure with 400 ppm toluene vapour (C7H8),water vapour (H2O), ammonia (NH3) and carbon monoxide (CO).(c) Illustrative drawing of a metal nanoparticle/alkanedithiolcomposite material providing three different binding sites A, B andC. Sites A are vacant sites on the metal particle surfaces. Sites B arehydrophobic alkylene chains of the linker molecules, and sites C arepolar thiol and thiolate groups of the linker molecules. (Reprintedfrom [100], copyright (2003), with permission from Elsevier.)

(i.e. response to vapour analytes) to the background noise.The higher the sensitivity and/or the lower the backgroundnoise, the higher the detection limit of the sensor. Till date,considerable efforts have been invested to achieve highersensitivity by, for example, modifying the chemical natureof the sensing material, to achieve higher affinity towardsgiven compounds. In contrast, less attention has been paidto control the noise level in these sensors, due to lack offundamental understanding of the origin of noise. Recently, itwas argued that the noise in sensing materials made of MCNPis caused by intrinsic processes, rather than extrinsic ones [69].Notwithstanding, the origin of such intrinsic processes is still

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Figure 10. Schematic representation of the functionalized ISFET device and the configuration of the sensing interface consisting of PEI/Aunanoparticle/cyclobis(paraquat-p-phenylene). (Reprinted from [218], copyright (1999), with permission from the American ChemicalSociety.)

puzzling. In a more recent work [214] it was shown thatthermal noise dominate at low voltages and high frequencies(f ), with a 1/f noise component becoming more important ata higher voltage and a lower frequency. The results impliedthat under optimum conditions, the detection limit of MCNP-based chemiresistive films can approach one part per billionby volume.

To summarize, most of the studies on MCNP-basedchemersistors have shown the high potential inherent in thefact that these sensor elements work at room temperature,which is usually not accessible with, for example, metaloxide sensor elements that typically work at elevatedtemperatures [215, 216]. However, a major disadvantageof these sensors is their relatively low thermal stability,as temperatures higher than, roughly speaking, 80 ◦C canaffect the organic layer irreversibly, and thus restrict theirapplications. Another important point relates to the factthat chemiresistor functions are usually analysed by directcurrent conductivity measurements. Nonetheless, futureimpedance measurements on the chemiresistors could improvethe understanding of the physical parameters operating in thesensing process. For example, impedance analyses couldindicate faradaic or non-faradaic contributions to the observedimpedance changes [217]. Also, understanding the structuraleffects on conductivity through percolated networks of orderedmaterials is an important component for achieving control overthe sorption-induced signal of chemiresistors.

3.6. Ion sensitive field-effect transistors (ISFETs)

Ion sensitive field-effect transistors (ISFETs) provide a meansto detect charged species in close proximity to a gatesurface. A charged species at the sensing interface ofsuch a device causes a change in the polarization of theunderlying semiconductor/dielectric interface (e.g. Si/SiOx).The conductance of electrons from the source electrode to thedrain electrode through the semiconductor is highly sensitiveto the gate polarization that upon chemical modification of thegate has either an attracting or repelling effect on the charge

carriers transported in the semiconductor. By measuring eitherthe source-drain current at a given gate-source potential (Vgs)

or the gate-source potential required for a given source-drainvoltage (Vsd), to retain the source-drain current (Isd), it ispossible to determine the polarization of the sensing interface.

An ISFET for small π -donors was tailored by assemblyof AuNP-adrenaline structure on Al2O3 sensing interface ofa field effect transistor (figure 10) [218, 219]. This assemblywas built up by the stepwise deposition of polyethyleneimine,AuNPs and adrenaline on the sensing interface. Theresulting sensor was able to detect any charged moleculethat complexes to the receptor, including those that are notelectrochemically active, such as serotonin. The resultscorresponding to the analysis of adrenaline were obtained oversix orders of magnitude of concentration, and the Benesi–Hildebrand analysis enabled the calculation of the bindingconstant between AuNPs and adrenaline that corresponds to200 ± 30 M−1.

4. Summary and outlook

Sensors based on MCNPs open new horizons for identifyingand quantifying many chemical and biochemical analytes, andthey certainly may be developed as detection techniques inbiomedical, environmental and related analysis. Excellentsensors are becoming available by tuning the electrical,electrochemical, spectroscopy and optical characteristics ofmetallic nanoparticles with capping ligands, including simpleor branched alkyl chains, DNA, sugars and other chemicaland biological molecules or systems. Potential exists forthe development of nanosensors based on a couple ofnanoparticles. This production of miniaturized equipmentwould be made possible by applying novel nanotechnologies.

Despite the significant innovations in MCNP-basedsensing explorations, the structure/function relationshipbetween the particle size and size distribution, configurationof the capping molecules, the MCNPs’ charge and theMCNPs’ sensing properties are not fully developed. In

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addition, there is little information on the discrimination powerbetween analytes of mixtures of closely related species. ForMCNP-based solid-state sensors, the interaction between theMCNP films and the underlying substrate need to be studiedfurther to prove the reliability for technological applications.Understanding the sensing properties of an individual oreven few single structurally well-defined nanoparticles wouldhave a major impact on the development of mechanisticunderstanding of MCNP-based sensors.

Adsorption and chemical selectivity of analyte moleculesvia MCNPs appear to be versatile but have limitations withrespect to thermal stability. Thus, compared with thehighly defined recognition process of olfactory receptors,the approach is still in its infancy [220]. The ease ofintegration into complex electronic circuitry together with therecognition chemistry of complex organic molecules underlinethe enormous potential of this approach, which still remainslargely unexploited due to the embryonic state of this concept.

Acknowledgments

The author acknowledges the Marie Curie Excellence Grant ofthe European Commission’s 6th Framework Programme, theRussell Berrie Nanotechnology Institute and the Israel CancerAssociation that made the preparation of this paper possible,and Mrs Tehila Cohen for assistance. The author holds theHorev Chair for the Leaders in Science and Technology.

References

[1] Stix G 2001 Sci. Am. 285 32[2] Zhang J Z 1997Acc. Chem. Res. 30 423[3] Khairutdinov R F 1997Colloid J. 59 535[4] Shipway A N, Katz E and Willner I 2000 Chem. Phys. Chem

1 18[5] McConnell W P, Novak J P, Brousseau L C I, Fuierer R R,

Tenent R C and Feldheim D L 2000 J. Phys. Chem. B104 8925

[6] Brust M and Kiely C J 2002 Colloids. Surf. A 202 175[7] Schmid G and Corain B 2003 Eur. J. Inorg. Chem. 17 3081[8] Marie-Christine D and Didier A 2004 Chem. Rev. 104 293[9] El-Sayed M A 2004 Acc. Chem. Res. 37 326

[10] Van Dijk M A, Tchebotareva A L, Orrit M, Lippitz M,Berciaud S, Lasne D, Cognet L and Lounis B 2006 Phys.Chem. Chem. Phys. 8 3486

[11] Landman U, Barnett R N, Cleveland C L and Cheng H P1992Int. J. Mod. Phys. B 6 3623

[12] Kelly K L, Jensen T R, Lazarides A A and Schatz G C 2002Met. Nanopart. 89

[13] Alivisatos P A et al 1998 Adv. Mater. 10 1297[14] Sanchez C, de Soler-Illia G J, Ribot F, Lalot T, Mayer C R

and Cabuil V 2001 Chem. Mater. 13 3061[15] Gomez-Romero P 2001 Adv. Mater. 13 163[16] Hay J N and Shaw S J 2003 Europhys. News 34 89[17] Cahen D and Hodes G 2002 Adv. Mater. 14 789[18] Pileni M P, Tanori J, Filankembo A, Dedieu J C and

Gulik-Krzywicki T 1998 Langmuir 14 7359[19] Schmid G, Morun B and Malm J-O 1989 Angew. Chem. Int.

Edn. 28 778[20] Cole D H, Shull K R, Baldo P and Rehn L 1999

Macromolecules 32 771[21] Bell R C, Zemski K A and Castleman A W Jr 1999 J. Phys.

Chem. A 103 1585[22] Templeton A C, Wuelfing W P and Murray R W 2000 Acc.

Chem. Res. 33 27

[23] Brust M, Fink J, Bethell D, Schiffrin D J and Kiely C J 1995J. Chem. Soc. Chem. Commun. 16 1655

[24] Brust M, Walker M, Bethell D, Schiffrin D J and Whyman R1994 J. Chem. Soc. Chem. Commun. 7 801

[25] Daniel M C and Astruc D 2004 Chem. Rev. 104 293[26] Davis S 2004 Colloids Colloid Assem. 342[27] Caruso F and Sukhorukov G 2003 Multilayer Thin Films 331[28] Fendler J H 1996 Chem. Mater. 8 1616[29] Terrill R H et al 1995 J. Am. Chem. Soc. 117 12537[30] Hostetler M J et al 1998 Langmuir 14 17[31] Johnson S R, Evans S D and Brydson R 1998 Langmuir

14 6639[32] Chen S and Murray R W 1999 Langmuir 15 682[33] Buining P A, Humbel B M, Philipse A P and Verkleij A J

1997Langmuir 13 3921[34] Porter L A J, Ji D, Westcott S L, Graupe M,

Czernuszewicz R S, Halas N J and Lee T R 1998Langmuir 14 7378

[35] Yonezawa T, Yasui K and Kimizuka N 2001 Langmuir 17 271[36] Tzhayik O, Sawant P, Efrima S, Kovalev E and Klug J T X

2002 Langmuir 18 3364[37] Demers L M, Mirkin C A, Mucic R C, Reynolds R A I,

Letsinger R L, Elghanian R and Viswanadham G 2000Anal. Chem. 72 5535

[38] Alivisatos A P, Johnsson K P, Peng X, Wislon T E,Loweth C J, Bruchez M P Jr and Schultz P G 1996 Nature382 609

[39] Storhoff J J, Mucic R C and Mirkin C A 1997 J. Cluster Sci.8 179

[40] Hayat M A 1989 Colloidal Gold, Principles, Methods andApplications (New York: Academic)

[41] Esumi K, Hosoya T, Suzuki A and Torigoe K 2000 Langmuir16 2978

[42] Wilson R 2003 Chem. Commun. 1 108[43] Hone D C, Haines A H and Russell D A 2003 Langmuir

19 7141[44] Nolting B, Yu J-J, Liu G-y, Cho S-J, Kauzlarich S and

Gervay-Hague J 2003 Langmuir 19 6465[45] Burkett S L and Mann S 1996 Chem. Commun. 3 321[46] Rautaray D, Kumar A, Reddy S, Sainkar S R and Sastry M

2002 Cryst. Growth Des. 2 197[47] Bhattacharya S and Srivastava A 2003 Langmuir 19 4439[48] Gole A, Dash C, Soman C, Sainkar S R, Rao M and Sastry M

2001 Bioconj. Chem. 12 684[49] Collier C P, Saykally R J, Shiang J J, Henrichs S E and

Heath J R 1997 Science 277 1978[50] Hostetler M J, Zhong C-J, Yen B K H, Anderegg J,

Gross S M, Evans N D, Porter M and Murray R W 1998J. Am. Chem. Soc. 120 9396

[51] Ely T O, Amiens C, Chaudret B, Snoeck E, Verelst M,Respaud M and Broto J-M 1999 Chem. Mater. 11 526

[52] Kim J H, Kim J, Kim C K and Yoon C S 2007 Colloids Surf.A 293 101

[53] Tang H, Luo Z, Pan M, Jiang S P and Liu Z 2005 J. Chem.Res. 7 449

[54] Ye H, Scott R W J and Crooks R M 2004 Langmuir20 2915

[55] Chen S and Sommers J M 2001 J. Phys. Chem. B105 8816

[56] Jouet R J, Warren A D, Rosenberg D M, Bellitto V J, Park Kand Zachariah M R 2005 Chem. Mater. 17 2987

[57] Kyung-Won P, Dae-Seob H and Yung-Eun S 2006 J. PowerSource 163 82

[58] Lim S K, Ban K S, Kim Y-H, Kim C K, Yoon C S and Jin S2006 Appl. Phys. Lett. 88 163102/1

[59] Luo J, Wang L, Mott D, Njoki P N, Kariuki N, Zhong C-Jand He T 2006 J. Mater. Chem. 16 1665

[60] Roy D and Fendler J 2004 Adv. Mater. 16 479[61] Penn S G, Hey L and Natan M J 2003 Curr. Opin. Chem.

Biol. 7 609[62] Ashkenasy G, Cahen D, Cohen R, Shanzer A and Vilan A

2002 Acc. Chem. Res. 35 121

7184

Chemical sensors based on molecularly modified metallic nanoparticles

[63] Adams D M et al 2003 J. Phys. Chem. B 107 6668[64] Jana N R, Gearheart L and Murphy C J 2001 Langmuir

17 6782[65] Chen S, Ingrma R S, Hostetler M J, Pietron J J, Murray R W,

Schaaff T G, Khoury J T, Alvarez M M and Whetten R L1998 Science 280 2098

[66] Sau T K and Murphy C J 2004 J. Am. Chem. Soc. 126 8648[67] Murphy C J, Sau T K, Gole A M, Orendorff C J, Gao J,

Gou L, Hunyadi S E and Li T J 2005 J. Phys. Chem. B109 13857

[68] Lisiecki I 2005 J. Phys. Chem. B 109 12231[69] Kurdak C, Kim J, Kuo A, Lucido J J, Farina L A, Bai X,

Rowe M P and Matzger A 2005 Appl. Phys. Lett.86 073506/1

[70] Boal A, Ilhan F, Derouchey J E, Thurn-Albrecht T,Russell T P and Rotello V 2000 Nature 404 746

[71] Jin J, Iyoda T, Cao C, Song Y, Jiang L, Li T J and Zhu D B2001 Angew. Chem. Int. Edn. 40 2135

[72] Liu J, Mendoza S, Roman E, Lynn M J, Xu R and Kaifer A E1999 J. Am. Chem. Soc. 121 4304

[73] Patil V, Mayya K S, Pradhan S D and Satry M J 1997 J. Am.Chem. Soc. 119 9281

[74] Caruso F, Caruso R A and Mohwald H 1998 Science282 1111

[75] Naka K, Itoh H and Chujo Y 2003 Langmuir 19 5496[76] Shenton W, Davies S A and Mann S 1999 Adv. Mater. 11 449[77] Elghanian R, Storhoff J J, Mucic R C, Letsinger R L and

Mirkin C A 1997 Science 277 1078[78] Gopel W 1996 Microelectron. Eng. 32 75[79] Gopel W 1997 Mikrochim. Acta 125 179[80] Zhu S S, Carroll P J and Swager T M 1996 J. Am. Chem. Soc.

118 8713[81] Rickert J, Weiss T and Gopel W 1996 Sensors Actuators B

31 45[82] Schierbaum K D 1994 Sensors Actuators B 18 71[83] Lahav M, Shipway A N and Willner I 1999 J. Chem. Soc.

Perkin Trans. 2 9 1925[84] Lahav M, Shipway A N, Willner I, Nielsen M B and

Stoddart J F 2000 J. Electroanal. Chem. 482 217[85] Shipway A N, Lahav M, Blonder R and Willner I 1999 Chem.

Mater. 11 13[86] Lahav M, Gabai R, Shipway A N and Willner I 1999 Chem.

Commun. 19 1937[87] Labande A and Astruc D 2000 Chem. Commun. 12 1007[88] Boal A K and Rotello V M 1999 J. Am. Chem. Soc. 121 4914[89] Israel L B, Kariuki N N, Han L, Maye M M, Luo J and

Zhong C-J 2001 J. Electroanal. Chem. 517 69[90] Raj C R, Okajima T and Ohsaka T 2003 J. Electroanal.

Chem. 543 127[91] Obare S O, Hollowell R E and Murphy C J 2002 Langmuir

18 10407[92] Kim Y, Johnson R C and Hupp J T 2001 Nano Lett. 1 165[93] Lyon L A, Musick M D and Natan M J 1998 Anal. Chem.

70 5177[94] Lyon L A, Pena D J and 1999 J. Phys. Chem. B 103 5826[95] He L, Musick M D, Nicewarner S R, Salinas F G,

Benkovic S J, Natan M J and Keating C D 2000 J. Am.Chem. Soc. 122 9071

[96] Wang R, Tombelli S, Minunni M, Spiriti M M and Mascini M2004 Biosens. Bioelectron. 20 967

[97] Giakoumaki E, Minunni M, Tombelli S, Tothill I E,Mascini M, Bogani P and Buiatti M 2003 Biosens.Bioelectron. 19 337

[98] Haes A J and Van Duyne R P 2002 J. Am. Chem. Soc.124 10596

[99] Liu X, Sun Y, Song D, Zhang Q, Tian Y and Zhang H 2006Talanta 68 1026

[100] Joseph Y, Guse B, Yasuda A and Vossmeyer T 2004 SensorsActuators B 98 188

[101] Joseph Y et al 2003 J. Phys. Chem. B 2003 7406[102] Zheng W, Maye M M, Leibowitz F L and Zhong C-J 2000

Anal. Chem. 72 2190

[103] Leduc P R et al 2007 Nature Nanotech. 2 3[104] Dhawan S 2006 Expert Rev. Mol. Diagn. 6 749[105] St. Pierre T G et al 2005 J. Physique. 17 122[106] Aslan K, Lakowicz J R and Geddes C D 2005 Curr. Opin.

Chem. Biol. 9 538[107] Maier J 2000 Sensors Actuators B 65 199[108] Pejcic B and De Marco R 2006 Electrochim. Acta 51 6217[109] Hernandez-Santos D, Gonzalez-Garcia M B and Garcia A C

2002 Electroanalysis 14 1225[110] Shipway A N, Katz E and Willner I 2000 Chem. Phys. Chem

1 18[111] Shipway A N and Willner I 2001 Chem. Commun. 20 2035[112] Shipway A N, Lahav M and Willner I 2000 Adv. Mater.

12 993[113] Ozsoz M, Erdem A, Kerman K, Ozkan D, Tugrul B,

Topcuoglu N, Ekren H and Taylan M 2003 Anal. Chem.75 2181

[114] Baca A J, Zhou F, Wang J, Hu J, Li J, Wang J andChikneyana Z S 2004 Electroanalysis 16 73

[115] Huang E, Zhou F and Deng L 2000 Langmuir 16 3272[116] Wang J, Li J, Baca A J, Hu J, Zhou F, Yan W and Pang D W

2003 Anal. Chem. 75 3941[117] Wang J, Xu D and Polsky R 2002 J. Am. Chem. Soc. 124 4208[118] Bard A J F, Faulkner L R 2001 Electrochemical Methods:

Fundamentals and Applications (New York: Wiley)[119] Wang J, Liu G and Merkoci A 2003 J. Am. Chem. Soc.

125 3214[120] Hotate K 2006 Japan. J. Appl. Phys. 45 6616 Part 1[121] Feng M Q and Kim D-H 2006 Sensors Actuators A 128 37[122] Swim C, Vanderbeek R, Emge D and Wong A 2006 Overview

of chem-bio sensing Proc. SPIE 6218 621802/1[123] Wolfbeis O S 2005 J. Mater. Chem. 15 2657[124] Shirshov Y M, Svechnikov S V, Kiyanovskii A P,

Ushenin Y V, Venger E F, Samoylov A V and Merker R1998 Sensors Actuators A 68 384

[125] Bussetti G, Corradini C, Goletti C, Chiaradia P, Russo M,Paolesse R, Di Natale C, D’Amico A and Valli L 2005Phys. Status Solidi b 242 2714

[126] Puyol M, Villuendas F, Dominguez C, Cadarso V, Llobera A,Salinas I, Garces I and Alonso J 2005 Absorbance-BasedIntegrated Optical Sensors (Berlin: Springer)

[127] Wiki M and Kunz R E 2000 Opt. Lett. 25 463[128] Riza N A, Sheikh M and Perez F 2007 Opt. Commun.

269 24[129] Caglar P, Tuncel S A, Malcik N, Landers J P and

Ferrance J P 2006 Anal. Bioanal. Chem. 386 1303[130] Frankamp B L, Uzun O, Ilhan F, Boal A K and Rotello V M

2002 J. Am. Chem. Soc. 124 892[131] Cho J and Caruso F 2005 Chem. Mater. 17 4547[132] Lin S-Y, Liu S-W, Lin C-M and Chen C-H 2002 Anal. Chem.

74 330[133] Pavlov V, Xiao Y, Shlyahovsky B and Willner I 2004 J. Am.

Chem. Soc. 126 11768[134] Reynolds R A I, Mirkin C A and Letsinger R L 2000 Pure

Appl. Chem. 72 229[135] Thanh N T K and Rosenzweig Z 2002 Anal. Chem. 74 1624[136] Kato N and Caruso F 2005 J. Phys. Chem. B 109 19604[137] Trau D, Yang W, Seydack M, Caruso F, Yu N-T and

Renneberg R 2002 Anal. Chem. 74 5480[138] Zhao X, Tapec-Dytioco R and Tan W 2003 J. Am. Chem. Soc.

125 11474[139] Maxwell D J, Taylor J R and Nie S 2002 J. Am. Chem. Soc.

124 9606[140] Dubertret B, Calame M and Libchaber A J 2001 Nat.

Biotechnol. 19 365[141] Du Y, Qi B, Yang X and Wang E 2006 J. Phys. Chem. B

110 21662[142] Kretschmann E 1971 Z. fuer Phys. 241 313[143] Flatgen G, Krischer K, Pettinger B, Doblhofer K, Junkes H

and Ertl G 1995Science 269 668[144] Hanken D G, Jordan C E, Frey B L and Corn R M 1998

Surface plasmon resonance measurements of ultrathin

7185

H Haick

organic films at electrode surfaces ElectroanalyticalChemistry ed A J Bard (ed) (New York: Dekker)

[145] Yong-Jun L, Oslonovitch J, Mazouz N, Plenge F, Krischer Kand Ertl G 2001Science 291 2395

[146] Nelson B P, Grimsrud T E, Liles M R, Goodman R M andCorn R M 2001Anal. Chem. 73 1

[147] Goodrich T T, Lee H J and Corn R M 2004J. Am. Chem. Soc.126 4086

[148] Shumaker-Parry J S, Aebersold R and Campbell C T2004Anal. Chem. 76 2071

[149] Wang R, Minunni M, Tombelli S and Mascini M2004Biosens. Bioelectron. 20 598

[150] Wang Z, Wilkop T and Cheng Q 2005 Langmuir 21 10292[151] Lee H J, Wark A W, Li Y and Corn R M 2005 Anal. Chem.

77 7832[152] Lee H J, Wark A W and Corn R M 2006 Langmuir 22 5241[153] Adam P, Dostalek J and Homola J 2006 Sensors Actuators B

B113 774[154] Homola J, Yee S S and Gauglitz G 1999 Sensors Actuators B

54 3[155] Lehn J M 1995 Supramolecular Chemistry: Concepts and

Perspectives (New York: VCH)[156] Xu H and Kall M 2002 Sensors Actuators B 87 244[157] Elghanian R, Storhoff J J, Mucic R C, Letsinger R L and

Mirkin C A 1997 Science 277 1078[158] Lazarides A A and Schatz G C 2000J. Chem. Phys. 112 2987[159] Bauer G, Pittner F and Schalkhammer T 1999Microchim.

Acta 131 107[160] Himmelhaus M and Takei H 2000 Sensors Actuators B 63 24[161] Okamoto T, Yamaguchi I and Kobayashi T 2000 Opt. Lett. 25

372[162] Hutter E, Fendler J H and Roy D 2001 J. Phys. Chem. B

105 11159[163] Lee C-Y, Canavan H E, Gamble L J and Castner D G 2005

Langmuir 21 5134[164] Goodrich T T, Lee H J and Corn R M 2004 J. Am. Chem. Soc.

126 4086[165] Goodrich T T, Lee H J and Corn R M 2004 Anal. Chem.

76 6173[166] Nilsson P, Persson B, Larsson A, Uhlen M and Nygren P-A

1997 J. Mol. Recognit. 10 7[167] Kai E, Sawata S, Ikebukuro K, Iida T, Honda T and Karube I

1999 Anal. Chem. 71 796[168] Yao D, Kim J, Yu F, Nielsen P E, Sinner E-K and Knoll W

2005 Biophys. J. 88 2745[169] Tao N J, Boussaad S, Huang W L, Arechabaleta R A and

D’Agnese J 1999 Rev. Sci. Instrum. 70 4656[170] Rich R L and Myszka D G 2000 Curr. Opin. Biotechnol.

11 54[171] Wang S, Boussaad S and Tao N J 2000 Anal. Chem.

72 4003[172] Kurita R, Yokota Y, Sato Y, Mizutani F and Niwa O 2006

Anal. Chem. 78 5525[173] Nie S and Emory S R 1997 Science 275 1102[174] Xu H 1999 Phys. Rev. Lett. 83 4357[175] Grate J W, Martin S J and White R M 1993 Anal. Chem. 65

940A[176] Sauerbrey G 1959 Z. Phys. 155 206[177] Daniel B 1991 Applications of the QCM to Electrochemistry

(New York: Dekker)[178] Ward M D and Buttry D A 1990 Science 249 1000[179] Yang C-Y, Li C-L and Lu C J 2006 Analy. Chim. Acta

565 17[180] Luo J, Kariuki N, Han L, Maye M M, Moussa L W,

Kowaleski S R, Kirk F L, Hepel M and Zhong C-J 2002J. Phys. Chem. B 106 9313

[181] Kurosawa S, Park J-W, Aizawa H, Wakida S-I, Tao H andIshihara K 2006 Biosens. Bioelectron. 22 473

[182] Zhao H Q, Lin L, Li J R, Tang J A, Duan M X and Jiang L2001 J. Nanopart. Res. 3 321

[183] Liu T, Tang J, Han M and Jiang L 2003 Biochem. Biophys.Res. Commun. 304 98

[184] Glynou K, Ioannou P C, Christopoulos T K andSyriopoulou V 2003 Anal. Chem. 75 4155

[185] Sandstroem P, Boncheva M and Kerman B 2003 Langmuir19 7537

[186] Zheng M, Davidson F and Huang X 2003 J. Am. Chem. Soc.125 7790

[187] Patolsky F, Ranjit K T, Lichtenstein A and Willner I 2000Chem. Commun. 12 1025

[188] Zhou X-C, O’Shea S J and Li S F Y 2000 Chem. Commun.11 953

[189] Patolsky F, Lichtenstein A and Willner I 2001J. Am. Chem.Soc. 123 5194

[190] Bodenhofer K, Hierlemann A, Noetzel G, Weimar U andGopel W 1996 Anal. Chem. 68 2210

[191] Cheeke J D N and Wang Z 1999Sensors Actuators B 59 146[192] Schoning M J 2005 Sensors 5 126[193] Zamborini F P, Leopold M C, Hicks J F, Kulesza P J,

Malik M A and Murray R W 2002 J. Am. Chem. Soc.124 8958

[194] Han L, Daniel D R, Maye M M and Zhong C-J 2001 Anal.Chem. 73 4441

[195] Wohltjen H and Snow A W 1998 Anal. Chem. 70 2856[196] Evans S D, Johnson S R, Cheng Y L and Shen T V 2000

J. Mater. Chem. 10 183[197] Krasteva N, Besnard I, Guse B, Bauer R E, Mullen K, Yasuda

A and Vossmeyer T 2002 Nano Lett. 2 551[198] Zhang H-L, Evans S D, Henderson J R, Miles R E and

Shen T-H 2002 Nanotechnology 13 439[199] Krasteva N, Besnard I, Joseph Y, Krustev R, Yasuda A and

Vossmeyer T 2004 Chem. Sens. 20 278[200] Leopold M C, Donkers R L, Georganopoulou D, Fisher M,

Zamborini F P and Murray R W 2003 Faraday Discuss125 63

[201] Vossmeyer T, Guse B, Besnard I, Bauer R E, Mullen K andYasuda A 2002 Adv. Mater. 14 238

[202] Shiigi H, Yamamoto Y and Nagaoka T 2004 Chem. Sens. 20810

[203] Cai C X, Liu B, Mirkin M V, Frank H A and Rusling J F 2002Anal. Chem. 74 114

[204] Grate J W, Nelson D A and Skaggs R 2003 Anal. Chem.75 1868

[205] Joseph Y et al 2004 Faraday Discuss. 125 77[206] Han L et al 2005 Sensors Actuators B 106 431[207] Ingram R S, Hostetler M J, Murray R W, Schaaff T G,

Khoury J, Whetten R L, Bigioni T P, Guthrie D K and FirstP N 1997 J. Am. Chem. Soc. 119 9279

[208] Grigor’ev E I, Vorontsov P S, Zav’yalov S A andChvalun S N 2002 Tech. Phys. Lett. 28 845

[209] Wuelfing W P, Green S J, Pietron J J, Cliffel D E and MurrayR W 2000 J. Am. Chem. Soc. 122 11465

[210] Snow A W and Wohltjen H 1998 Chem. Mater. 10 947[211] Beverly K C, Sampaio J F and Heath J R 2002 J. Phys. Chem.

B 106 2131[212] Leibowitz F L, Zheng W, Maye M M and Zhong C-J 1999

Anal. Chem. 71 5076[213] Doty R C, Yu H, Shih C K and Korgel B A 2001 J. Phys.

Chem. B 105 8291[214] Kruppa W, Ancona M G, Rendell R W, Snow A W, Foos E E

and Bass R 2006 Appl. Phys. Lett. 88 053120[215] Tuller H L 1983 Sensors Actuators 4 679[216] Gopel W and Reinhardt G 1996 Sensors Update 1 47[217] Katz E, Willner I and Wang J 2004 Electroanalysis

16 19[218] Kharitonov A B, Shipway A N and Willner I 1999 Anal.

Chem. 71 5441[219] Kharitonov A B, Shipway A N, Katz E and Willner I 1999

Rev. Anal. Chem. 18 255[220] Franke M E, Koplin T J and Simon U 2006 Small 2 36

7186