carbon nanotube cnttft based biosensors

8/17/2019 Carbon Nanotube CNTTFT Based Biosensors

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DOI: 10.1002/adma.200602043

Carbon Nanotube

Field-Effect-Transistor-Based Biosensors**By Brett Lee Allen , Padmakar D. Kichambare ,and Alexander Star *

1. IntroductionThe interplay between nanomaterials and biological sys-

tems forms an emerging research field of broad importance. [1]

In particular, novel biosensors based on nanomaterials havereceived considerable attention. [2] The integration of 1Dnanomaterials, such as nanowires, into electrical devices offerssubstantial advantages for the detection of biological species,and has significant advantages over conventional optical bio-detection methods. [3] The first advantage is related to sizecompatibility: electronic circuits in which the component partsare comparable in size to biological entities ensure appropri-ate size compatibility between the detector and the biological

analyte. The second advantage to developing nanomaterial-based electronic detection is that most biological processes in-volve electrostatic interactions and charge transfer, which aredirectly detected by electronic nanocircuits. Nanowire-based

electronic devices, therefore, eventually integrate biology andelectronics into a common platform suitable for electroniccontrol and biological sensing as well as bioelectronically driv-en nanoassembly. [4]

This biocompatibility and size compatibility is seen espe-cially with carbon nanotubes. In the case of single-walled car-bon nanotubes (SWNTs) every atom is on the surface and ex-posed to the environment and, thus, even small changes in thecharge environment can cause drastic changes to their electri-cal properties. In addition to their diameters being compar-able to the size of single molecules (e.g., DNA is 1 nm in size),SWNTs are several micrometers long, thereby providing aconvenient interface with micrometer-scale circuitry. More-

over, their all-carbon composition provides a natural match toorganic molecules. Thus, among different nanomaterials, car-bon nanotubes have a great potential for biosensing applica-tions.

1.1. Field-Effect-Transistor-Based Inorganic NanowireBiosensors

One promising approach for the direct electrical detectionof biomolecules uses nanowires configured as field-effecttransistors (FETs). These sensors offer several advantages for

Adv. Mater. 2007, 19 , 1439–1451 © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 143

–[*] Prof. A. Star, B. L. Allen, Dr. P. D. KichambareDepartment of ChemistryUniversity of PittsburghPittsburgh, PA 15260 (USA)E-mail: [email protected]

[**] A.S. would like to thank his co-workers from Nanomix Inc. cited inthis article for their contribution to the research.

There is an explosive interest in 1D nanostructured materials for bio-logical sensors. Among these nanometer-scale materials, single-walledcarbon nanotubes (SWNTs) offer the advantages of possible biocompatibility, size compatibility, and sensitivity towards minute electrical perturbations. In particu-lar, because of these inherent qualities, changes in SWNT conductivity have been explored inorder to study the interaction of biomolecules with SWNTs. This Review discusses these interac-tions, with a focus on carbon nanotube field-effect transistors (NTFETs). Recent examples of applications of NTFET devices for detection of proteins, antibody–antigen assays, DNAhybridization, and enzymatic reactions involving glucose are summarized. Examples of complementary techniques, such as microscopy and spectroscopy, are covered as well.

Source Drain

SiO 2

Gate

+


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the detection of biological species. Firstly, nanowires form theconducting channel in a transistor configuration. Secondly,the nanowires are typically located on the surface of the sup-porting substrate and are in direct contact with the environ-ment. This device geometry contrasts the traditional metal ox-ide semiconductor field-effect transistors (MOSFETs), wherethe conducting channel is buried in the bulk material in whichthe depletion layer is formed. [5] Finally, all of the electricalcurrent flows through the nanometer-scale cross section of thenanowires. All these remarkable characteristics lead to a FETdevice configuration that is extremely sensitive to minutevariations in the surrounding environment. FETs readilychange their conductance upon binding of charged target bio-molecules to receptors linked to the device’s surfaces. For ex-ample, the studies by Lieber’s group, summarized in a recentreview, [6] have demonstrated the use of silicon nanowire FETsfor detecting proteins, [7] DNA hybrids, [8] and cancer mark-ers. [9] This biodetection approach may allow, in principle, se-

lective detection at the single-particle level.[10]

Nanowireshave the potential for very high detection sensitivity throughthe depletion or accumulation of charge carriers, caused bythe binding of charged biomolecules at the surface. This sur-face binding can affect the entire cross-sectional conductionpathway of the nanostructures.

Lieber’s group was also able to push the sensitivity of sili-con nanowires and demonstrate their ability for detecting sin-gle viruses. [11] Particularly, they used bifunctional moleculesto attach antibodies specific to Influenza A for electrochemi-cal detection on an individual nanotube device with Si 3N4 pas-sivated nickel contacts. As with other cases, conductance ver-sus time was plotted and indicated a charge-transfer

interaction between the antibodies and the virus (Fig. 1).Although silicon nanowires have been the most popular

choice for biosensors, [12] other 1D structures have also beenused. Curreli et al. have employed indium oxide (In 2O3)nanowires for biological detection. [13] By treating the nano-wire with a phosphonic acid solution, they were able tofurther immobilize single-stranded DNA in a nanoelectronicDNA assay.

1.2. Carbon Nanotube FETs

Since their discovery by Iijima over a decade ago, [14] experi-mentation with carbon nanotubes has grown considerably. [15]

Subsequently, several experiments have been undertaken tostudy the physical and electrical properties of carbon nano-tubes on both the individual and the macroscopic scale. [16] It isknown that the properties of carbon nanotubes dependstrongly on physical properties, such as their diameter, their

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B. L. Allen et al. /Carbon Nanotube FET-Based Biosensors

440 www.advmat.de © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2007, 19 , 1439–1451

Alexander Star was born in Almaty, Kazakhstan, in 1971. He immigrated to Israel in 1991, wherehe received a B.S. degree in chemistry in 1994 and a Ph.D. in supramolecular chemistry (withProf. Benzion Fuchs) from Tel Aviv University in 2000. He then spent two years as a postdoctor-al associate in Prof. J. Fraser Stoddart’s California NanoSystems Institute group at the Universityof California, Los Angeles. After his postdoctoral studies he was employed as Senior Scientist at Nanomix, Inc. for three years, working on the development of sensor applications of carbonnanotubes. He has been an Assistant Professor of Chemistry at University of Pittsburgh since 2005. His research interests are in areas of molecular recognition at the nanoscale and nanotech-nology-enabled molecular sensing.

Figure 1. Concept of nanowire-based detection of single viruses. Left:Schematic illustration showing two nanowire devices, 1 and 2, in whichthe nanowires are modified with different antibody receptors. Specificbinding of a single virus to the receptors on nanowire 2 produces a con-ductance change. Right: Characteristics of the surface charge of the virusonly in nanowire 2. When the virus unbinds from the surface the conduc-tance returns to the baseline value. Reproduced with permission from[11]. Copyright 2004 The National Academy of Sciences.


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length, the presence of residual catalyst, and chirality. For ex-ample, carbon nanotubes can be either single-walled or multi-walled with varying intrinsic bandgaps and helicities. [17] In ad-dition, single-walled nanotubes can be either metallicconductors or semiconductors, based on the chirality of thestructure. [18] Semiconducting SWNTs can be used to fabricateFET devices, which can operate at room temperature and inambient conditions. [19] It has also been shown that semicon-ducting SWNTs exhibit significant conductance changes in re-sponse to the physisorption of different gases. [20] Therefore,SWNT-based nanosensors can be fabricated based on a FETlayout, where the solid-state gate is replaced by adsorbed mol-ecules that modulate the nanotube conductance. [20] There aretwo classical types of device design regarding single-walledcarbon nanotube field-effect transistors (NTFETs, Fig. 2).The first design uses a single carbon nanotube to act as anelectron channel between the source and the drain elec-trodes. [19] The second type of structure involves a network of

carbon nanotubes serving as a collective channel between thesource and drain. [21,22] The analyte–nanotube interaction mayhave one of two effects. The first effect involves charge trans-fer from analyte molecules to the carbon nanotubes. In thesecond type of mechanism, the analyte acts as a scattering po-tential across the carbon nanotube. It is possible to distinguishbetween the two mechanisms by taking transistor measure-

ments. [22a] If a charge transfer occurs, the threshold voltagewill become either more positive (electron withdrawing) ormore negative (electron donating). In addition, a scatteringmechanism may be observed from an overall drop in conduc-tance. This is because of the scattering effect induced by thetarget analyte [22a] absorbed on the sidewalls of SWNT. The ex-act mechanism of NTFET detection is still a subject of debate:In the carbon nanotube sensors mentioned below, chemicalsensing experiments have been conducted with devices inwhich nanotubes and nanotube–metal contacts were directlyexposed to the environment. The sensing could be dominatedby the interaction of molecules with metal contacts or the con-tact interfaces. Adsorbed molecules would modify the metalwork functions, and thereby the Schottky barrier. [23] Heinzeet al. [24] have assigned the effect of oxygen exposure not todoping nanotubes but to changing the work function of theexposed portion of the metal electrodes. The mechanism of detection of other molecules is still controversial. [25]

1.3. Scope of the Review

Up to date, sensor applications of carbon nanotubes havebeen summarized and discussed in several excellent review ar-ticles, [26] which primarily focused on carbon nanotube based

electrochemical sensors. In this Review,we will cover recent advances in detec-tion of biological species in a variety of manners using carbon nanotubes, withemphasis on NTFET devices, and dis-cuss how these measurements relate to

spectroscopic and microscopic evidencefor molecular interactions betweenSWNTs and biomolecules. [27] We shallcover applications of carbon nanotubesfor the detection of biomolecules suchas proteins, carbohydrates, and DNA.In particular, we discuss several recentexamples of NTFET use for detectionof antibody–antigen interactions, DNAhybridization, and enzyme reactions(Table 1). We then conclude with possi-ble directions for advancement in nano-tube biosensor technology.

2. Protein Detection UsingCarbon Nanotubes

The majority of research towards bio-sensing involves the interactions of pro-teins with carbon nanotubes. Severalexamples will be demonstrated in thissection, including some general mecha-nisms, conductivity measurementsbased on interactions, antibody–antigen


Adv. Mater. 2007, 19 , 1439–1451 © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advmat.de 1441

15 µ m

V G (V)

G S D

( µ S )

i

ii

iii

viv

p-type4

3

2

1

0-10 -5 0 5 10

S DSiO 2

V SD

Si Back Gate

V G

4.5 µ m

a) c)

b) d)

Figure 2. a) Schematic representation of a nanotube field-effect transistor (NTFET) device with asemiconducting SWNT (black) contacted by two Ti/Au electrodes (light brown), representing thesource (S) and the drain (D), and a Si back gate (green), separated by a SiO 2 insulating layer (darkbrown) in a transistor-configured circuit. b) Atomic force microscopy image of a typical NTFET de-vice with individual SWNTs connecting the S and D electrodes. c) Scanning electron microscopyimage of a typical NTFET device consisting of a random array of carbon nanotubes. d) TypicalNTFET transfer characteristic; dependence of the source–drain conductance ( G SD) on the gate volt-age (V G). i) Maximum conductance, ii) modulation, iii) transconductance, iv) hysteresis, andv) threshold voltage.


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interactions, and enzymatic glucose detection. All of these

interactions are listed and explained in detail to develop anunderstanding of the applications of carbon nanotubes as pro-tein sensors.

2.1. Molecular Interactions Between Carbon Nanotubes andProtein Molecules

A variety of proteins can strongly bind to the nanotube ex-terior surface via nonspecific adsorption. Proteins such asstreptavidin and HupR crystallize in a helical fashion, result-ing in ordered arrays of proteins on the nanotube surface. [28]

Mechanistically, the nonspecific adsorption of proteins onto

the nanotube surface may be more complicated than thewidely recognized hydrophobic interactions. It is quite possi-ble that the observed substantial protein adsorption is, at leastin part, associated with the amino affinity of carbon nano-tubes, as was demonstrated recently by monitoring the con-ductance change in a carbon nanotube. [29] Also, intermolecu-lar interactions involving aromatic amino acids (i.e., histidineand tryptophan) in the polypeptide chains of the proteins cancontribute to the observed affinity of the peptides to carbonnanotubes. [30]

The interaction between carbon nanotubes and proteinmolecules can primarily be described as nonspecific. To elabo-rate on this, several groups have looked into protein–nano-tube interactions and found that proteins will adsorb onto thesurface of a carbon nanotube without any preference. Bala-voine et al. found that the protein streptavidin binds stronglyto the sidewalls of a carbon nanotube in a helical fashion dur-ing incubation. [28]

Other groups have witnessed other interactions betweenproteins and carbon nanotubes as well. Kam and Dai dis-cussed the phenomenon of nonspecific binding in a study touse carbon nanotubes as protein intercellular transporters. [31]

They found that imparting hydrophilicity was insufficient toblock this type of binding (Fig. 3). Haddon’s group also foundnonspecific binding to dominate, as tendrils from an osteo-

blastic cell stretched out to make a bridge between the celland the carbon nanotubes. [32]

This does not mean, however, that the attachment of pro-teins to carbon nanotubes cannot be orchestrated. In mostcases, carbon nanotubes can be adapted to specifically bindprotein to the sidewalls. There are many reports that demon-strate the ability to chemically functionalize nanotubes forthis purpose. Such chemistry is readily transferable to numer-ous applications, ranging from sensors to electronic de-vices. [33]

The two generalized approaches to this kind of attachmentinvolve covalent and noncovalent modification to achieve thedesired results. In terms of covalent attachment, the carbonnanotubes are oxidized to have free carboxyl groups that un-dergo coupling with amino groups in proteins. [31] While cova-lent modifications [34] are often effective at introducing func-tionality, they impair the desirable mechanical and electronicproperties of SWNTs. Noncovalent modifications, [35] on theother hand, not only improve the solubility of SWNTs inwater but also constitute nondestructive processes, preservingthe primary structures of the SWNTs along with their uniquemechanical and electronic properties.

Generally, there are two main schemes to noncovalentfunctionalization of carbon nanotubes. The first involves bi-

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Table 1. Biomolecular interactions with SWNTs.

Technique Application

Proteins Enzymes Sugars DNA

Nonspecific bindingto SWNTs [31,32]

SWNTs solubilization/wrapping [47,48]

SWNTs solubilization/wrapping [55,56]

Microscopy/Spectroscopy

Fluorescence glucosedetection [45]

DNA hybridization[57,58]

ElectrochemistryNT electrodes Glucose

detection [26]DNA hybridization

[52,53]

NTFET

Protein detection[29,38,39]

Antibody-antigen assays[40-43]

Glucosedetection [44]

Detection of enzymatic degradationof starch [49]

DNA hybridization[61,62]

Figure 3. Atomic force microscopy images of various SWNT samples de-posited on SiO 2 substrates. a) Oxidized SWNTprior to conjugation withproteins, and after conjugation to 1 l M of b) Alexa-Fluor 488 bovine ser-um albumine (BSA), c) Alexa-Fluor 488 spA, and d) Alexa-Fluor 488 cy-tochrome C. The scale bar is 100 nm. Reproduced with permission from[31]. Copyright 2005 The American Chemical Society.


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functional molecules that exhibit p –pstacking on the sidewalls of the carbonnanotubes. A pyrene moiety, commonlyused for graphite functionalization, istypically employed for noncovalentfunctionalization, and referred to as a“sticky label”. [36]

The other type of noncovalent func-tionalization involves the use of a poly-mer addition. [35] Dai’s group employeda polymer scheme to achieve proteinbinding. [37] The functionalization of thecarbon nanotubes was performed by co-adsorption of the surfactant Triton andpoly(ethylene glycol). By using thismethod, they were able to examine theresistance to nonspecific binding whilealso using a “director” for specific pro-

tein attachment.

2.2. Conductivity Measurements of Carbon Nanotube–Protein Interactions

Interactions of carbon nanotubeswith proteins have been explored byNTFET devices. [29] In the NTFET device, the ability to mea-sure the electronic properties of the nanotube allowed foridentification of the electronic state of the immobilizationsubstrate. In this experiment two types of measurements of the individual nanotube device transfer characteristics were

performed. In the first measurement, referred to as the sub-strate–gate transfer characteristics, the current through thedrain contact (at fixed source–drain bias) was monitoredwhile a variable gate voltage was applied through a metallicgate buried underneath the SiO 2 substrate. In the secondmeasurement, referred to as the liquid–gate transfer charac-teristic, the device was immersed in a buffer solution and avariable gate voltage was applied through a platinum elec-trode. The current was passed through the drain contact anda silver reference electrode in the solution. After 10 h, thedevices were rinsed with distilled water and blown dry, andthe substrate–gate transfer characteristics of the dried de-vices were measured.

These results were discussed in terms of a simple model inwhich adsorbed streptavidin coats the SWNT (Fig. 4). Thegradual shift in the threshold voltage is assumed to result fromthe slow accumulation of a full monolayer of adsorbed pro-tein. This coverage-dependent threshold shift is analogous tothe concentration-dependent shift observed when such de-vices are exposed to aqueous ammonia. [19i] The protein ad-sorbate equilibrates over several hours so that only the fullmonolayer can be conclusively determined. The results sup-port the proposal that conductance changes are the result of charge injection or field effects caused by proteins adsorbedsolely along the lengths of the nanotubes.

The protein adsorption on NTFETs leads to appreciablechanges in the electrical conductance of the devices that can beexploited for label-free detection of biomolecules with a highpotential for miniaturization. For example, Dai and co-work-ers [38] used a sensor design consisting of an array of four

NTFET sensors on SiO 2/Si chips. Each NTFET comprised anetwork of multiple SWNTs connected roughly in parallelacross two closely spaced bridging metal electrodes. Threetypes of devices with different surface functional groups wereprepared for the investigation of the biosensing. The first type(type 1) consisted of unmodified as-made devices. The secondtype (type 2) of devices were fabricated with methoxy(po-ly(ethylene glycol))thiol (mPEG-SH) self-assembled mono-layers (SAMs) formed on, and only on, the metal contact elec-trodes for passivation, and the third type (type 3) of deviceswere fabricated with mPEG-SH SAMs on the metal contactsanda Tween 20 coating on thecarbonnanotubes. The electricalconductance of these devices upon the addition of various pro-tein molecules was monitored. Device type 1 showed signifi-cant conductance changes with protein adsorption, while de-vice type 2, with an mPEG-SH SAM on the metal electrodes,did not give any conductance change except in the case of theprotein avidin. It was reported that the metal/nanotube inter-face or contact region is highlysusceptibleto modulation by ad-sorbed species. The modulation of the metal work function canalter the Schottky barrier of the metal/nanotube interface, thusleading to a significant change in the nature of contacts andconsequentlya change in theconductance of thedevices.

In situ detection of a small number of proteins via directlymeasuring the electron transport properties of a single SWNT



Back Gate

Source(S)

Drain(D)

Liquid Gate

SWNTchannel

1.2

2.0

2.4

2.8

0.4-0.2-0.4

V liquid (V)

1.6

I ( ∝ A )

0 0.21.2

2.0

2.4

2.8

0.4-0.2-0.4

V liquid (V)

1.6

I ( A )

0 0.21.2

2.0

2.4

2.8

0.4-0.2-0.4

V liquid (V)

1.6

I

( A )

0 0.2

a)

b)

c)

Figure 4. a) Size comparison between a carbon nanotube and a streptavidin molecule. b) Detec-tion in a liquid with NTFET devices by using either the back gate or liquid gate configuration.c) Current vs. gate voltage for the nanotube device. Source–drain voltage ( V sd ) 10 mV. Red trace:measurement in phosphate buffer before streptavidin addition. Black trace: identical conditions, tomeasure the uncertainty in the threshold voltage. Green trace: measurement after 10 h of incuba-tion with streptavidin, Arrows indicate the threshold voltages for the three curves. Reproduced withpermission from [29]. Copyright 2004 The American Chemical Society.


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has been reported by Nagahara and co-workers. [39] The cyto-chrome C (cytc) adsorption onto individual NTFETs has beendetected via the changes in the electron transport propertiesof the transistors. The adsorption of cytc induces a decrease inthe conductance of the NTFET devices, corresponding to afew tens of molecules.

2.3. NTFET Detection of Antibody–Antigen Interactions

Specific sensitivity can be achieved by employingrecognitionlayers that induce chemical reactions and modify the transfercharacteristics. In this two-layer architecture carbon nanotubesfunction as extremely sensitive transducers, while recognitionlayers provide chemical selectivity and prevent nonspecificbinding, which is commonforcomplex biological samples.

Following this design, nanotubes have been functionalizedto be biocompatible and to be capable of recognizing proteins.This functionalization has involved noncovalent binding be-tween a bifunctional molecule and a nanotube to anchor abioreceptor molecule with a high degree of control and speci-ficity. Star et al. [40] have fabricated NTFET devices sensitiveto streptavidin by using individual biotin-functionalized car-bon nanotube arrays bridging two microelectrodes (sourceand drain, Fig. 5a). The SWNT in the NTFET device wascoated with a mixture of two polymers: poly(ethylene imine)(PEI) and poly(ethylene glycol) (PEG). The former providedamino groups for the coupling of biotin-N-hydroxy-succinimi-dyl ester (Fig. 5b) and the latter prevented the nonspecific ad-sorption of proteins on the functionalized carbon nanotube.Figure 5c shows an atomic force microscopy (AFM) image of the device after its exposure to streptavidin labeled with gold

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1.2 µ m

biotinPEI / PEG

NTw/ streptavidin

Ti/AuSource &

Drainelectrodes

c)

NO O

O O

SNH

H

N

H

H

O

DMF

RT

NH

N

NH2H O OH

x xNH

N

HN O

SNH

HN

H

H

O

y

n

yPEI PEG

+

biotin-N-hydroxy-succinimide ester

b)

d)

a)

SourceDrain

Gate

Streptavidin

Biotin

Polymer

0

0.2

0.4

0.6

0.8

1

-10 -5 0 5 10

biotinPEI / PEG

NT

w/ streptavidin

Gate Voltage (V)

C u r r e n

t ( µ A )

Figure 5. a) Schematic illustration of an NTFET coated with a biotinylated polymer layer for specific streptavidin binding. b) Biotinylation reaction of the polymer layer (poly(ethylene imine)/poly(ethylene glycol) (PEI/PEG)) on the sidewall of the SWNT. c) Atomic force microscopy image of the poly-mer-coated and biotinylated NTFET device after exposure to streptavidin labeled with gold nanoparticles (10 nm in diameter). d) The source-drain cur-rent dependence on the gate voltage of the NTFET device based on SWNT functionalized with biotin in the absence and presence of streptavidin.DMF: dimethylformamide. RT: room temperature. Reproduced with permission from [40]. Copyright 2003 The American Chemical Society.


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nanoparticles (10 nm). Light dots represent gold nanoparti-cles and indicate the presence of streptavidin bound to thebiotinylated carbon nanotube. The source-drain current de-pendence on the gate voltage of the NTFET shows a signifi-cant change upon the streptavidin binding to the biotin-func-tionalized carbon nanotube (Fig. 5d). The experiments revealthe specific binding of streptavidin, which occurs only at thebiotinylated interface.

The mechanism of the biodetection was explained in termsof the effect of the electron doping of the carbon nanotubechannel upon the binding of the charged streptavidin mole-cules. Dai and co-workers [41] have also analyzed specific anti-gen–antibody interactions using NTFET devices. In particu-lar, they have studied the affinity binding of 10E3 mAbsantibody (a prototype target of the autoimmune response inpatients with systematic lupus erythematosus and mixed con-nective tissue disease) to human auto antigen U1A.

More recently, Li et al. [42] studied the complementary detec-

tion of prostate-specific antigen by using a network of SWNTsas a FET. They found the sensitivity to be comparable to metaloxide nanowires. The limit of detection was ca. 500 pg mL –1,or 14 pM, at a signal-to-noise ratio of 2. A schematic of the bi-functional molecular interaction they incorporated for thistype of detection is shown in Figure 6. [42] The interaction isthought to be a charge-transfer mechanism as well. Theyshowed a prostate-specific antibody in the act of capturing aspecific antigen and measured the electronic interaction. Func-tionalization of the SWNTs uses a p –p stacking method with apyrene moiety. Passivation of the electrodes, however, was notmentioned in terms of the sensing mechanism.

Aside from protein interactions with SWNTs, some groups

have researched the possibility of functionalizing them withmore complex structures, such as aptamers or single-strandedDNA(ssDNA). Lee and co-workers [43] suggestedthe useof ap-

tamers for recognition of biomolecules, instead of antibodies.Aptamers are classified as artificial oligonucleotides that arecapable of a wide range of detection of specific biomolecules,basedupon the aptamer configuration. Theotherattractive ap-peal to an aptamer approach is that they are less costly and arecapable of reversible denaturation, meaning that the biosensorcan be reused continuously. As in this case, they measured cur-rent over a periodof time after chemical induction.

2.4. Application of FETs for Glucose Detection

The diagnosis and management of diabetes mellitus re-quires a tight monitoring of blood glucose levels. Electro-chemical detection of glucose using carbon nanotube elec-trodes is already an exploding field. [26] Similar to otherglucose sensors, electrochemical glucose detection is based onenzymatic glucose oxidation and subsequent hydrogen perox-

ide detection on the carbon nanotube electrodes. Many exam-ples of such sensor design have been summarized in recent re-views. [26] The use of NTFETs consisting of individualsemiconducting SWNTs as a versatile biosensor has beendemonstrated by Dekker and co-workers. [44] The redox en-zyme glucose oxidase (GOx) that catalyzes the oxidation of b -D-glucose (C 6H 12O6) to D-glucono-1,5-lactone (C 6H 10O 6)has been studied. The redox enzymes go through a catalyticreaction cycle, where groups in the enzyme temporarilychange their charge state and conformational changes occurin the enzyme, that can be detected by using NTFET devices.

In addition to pH sensitivity, GOx-coated semiconductingSWNTs appeared to be sensitive to glucose, the substrate of

GOx. Figure 7 exhibits real-time measurements, where theconductance of a GOx-coated semiconducting SWNT in milli-Q water has been recorded in the liquid. No significant changein conductance was observed as a result of water addition (redarrow in Fig. 7). When 0.1 M glucose in milli-Q water wasaddedto the liquid (blue arrow), however, the conductance of thetube increased by about 10 %. As shown in inset (a) of Fig-ure 7, a similar 10% conductance change was observed for an-other device, which had a lower conductance by a factor of 10.Glucose did not change the conductance of the bare SWNT,but did increase the device conductance after GOx was immo-bilized. Inset (b) of Figure 7 shows a measurement on a baresemiconducting SWNT. These measurements clearly indicatethat the GOx activity is responsible for the measured increasein conductance upon glucose addition, thus rendering such na-nodevices as feasible enzymatic-activity sensors.

In addition to electronic detection, Strano and co-work-ers [45] were able to develop a carbon-nanotube-based opticalsensor for long-term glucose sensing. They proposed a designfor in vivo applications. By observing fluorescent emissionafter excitation, this can then be converted into a signal indi-cating the presence and degree of glucose interaction.

Another group, using Raman spectroscopy, focused on thereaction of carbon nanotubes with hydrogen peroxide. Songet al. [46] studied the reaction of hydrogen peroxide with



Figure 6. a) Schematic illustration of a nanosensor. Prostate-specificantigen antibodies (PSA-ABs) are anchored to the NW/SWNT surfaceand function as specific recognition groups for PSA binding. b) Reactionsequence for the modification of the SWNT. i) deposition of 1-pyrenebu-tanoic acid succinimidyl ester, ii) PSA–AB incubation. Reproduced withpermission from [42]. Copyright 2005 The American Chemical Society.


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4.1. Noncovalent Interactions between Carbon Nanotubesand DNA

Nucleic acids, such as ssDNA, short double-stranded DNA,and some total RNA, can disperse SWNTs in water. [55,56]

Molecular modeling has shown [16] that the nonspecific

DNA–SWNT interactions in water originate from the nucleicacid–base p –p stacking on the nanotube surface, resulting in ahydrophilic sugar–phosphate backbone pointing to the exteri-or, thereby achieving solubility in water. Similarly to carbohy-drates (e.g., amylose), the mode of interaction may be helicalwrapping or simple surface adsorption (Fig. 9). The chargedifferences among the DNA–SWNT conjugates, which are as-sociated with the negatively charged phosphate groups of DNA and the different electronic properties of SWNTs, haveallowed postproduction preparation of samples enriched inmetallic and semiconducting SWNTs. [56] Work done by Stra-no’s group looks into DNA polymorphism on nanotubes. [57]

They found that the conformational rearrangement of a bio-molecule could be transduced directly by a SWNT system. Ina second study, this group looked at DNA–SWNTs used as aphotobleaching-resistant marker, which remained functionalin live cells for up to three months. [58] On the other hand, Staiiet al. [59] incorporated single-stranded DNA into a FET device

for detection of a range of vaporous odors. Some of the vaporsthat showed NTFET detection were water, propionic acid, tri-methylamine (TMA), methanol, dimethyl methylphosphonate(DMMP), and dinitrotoluene (DNT).

4.2. NTFET Detection of DNA Hybridization

Generally, most biological processes including DNA hy-bridization involve electrostatic interactions and charge trans-



Source Drain

SiO 2

Gate

O

HOHO

HO

OH

OH

Glucose

Starch

AMG

Bare

AfterAMGAfter

Starch

V G / V

I S D

/ µ

A

1.2

0.8

0.6

0.4

0.2

0

1

-10 -5 0 5 10

a)

b)

c)

Figure 8. a) NTFET device for electronic monitoring of the enzymaticdegradation of starch with amyloglucosidase (AMG) to glucose. b) High-resolution transmission electron microscopy (HRTEM) image of a SWNT

(diameter 2.0 nm) after treatment with a drop of a 1 % aqueous solutionof starch. The starch has been stained with RuO 4 vapor. c) NTFET devicecharacteristics in the form of ISD–V G curves measured from +10 to –10 Vgate voltage with +0.6 V bias voltage before (bare) and after starch de-position, as well as after hydrolysis with AMG. Reproduced with permis-sion from [49]. Copyright 2004 The American Chemical Society.

Figure 9. Binding model of a (10,0) carbon nanotube wrapped by apoly(T) sequence. The right-handed helical structure shown here is oneof several binding structures found, including left-handed helices and lin-early adsorbed structures. In all cases, the bases (red) orient to stackwith the surface of the nanotube, and extend away from the sugar–phos-phate backbone (yellow). Reproduced with permission from [55]. Copy-right 2003 Macmillan Publishers Ltd.


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fer, which allows electronic detection using NTFET devices.However, the exact mechanism of the nanoelectronic detec-tion still remains unclear. The selective attachment of DNAmolecules on various segments of the NTFET device can al-low, in principle, to investigate the sensing mechanism of thenanotube biosensor. DNA molecules attached to the nano-tube will mostly influence FET characteristics by electron de-pletion in the channel, whereas chemical attachment to metalelectrodes will influence only the metal/nanotube interface,that is, the Schottky barrier. Therefore, by correlating thesensing results to the attachment mode, one can obtain infor-mation about the mechanism of NTFET biosensing.

NTFET devices have been used for DNA detection. DNAhybridization was studied on the surface at the gate of NTFETs. [60] As a result, the conductance in SWNTs waschanged through the gate insulators. In this work, 5 ′ end-ami-no modified peptide nucleic acid (PNA) oligonucleotideswere covalently immobilized onto the NTFET back-gate Au

surfaces. PNA mimicked the behavior of DNA and hybridizedwith complementary DNA or RNA sequences, thus enablingPNA chips to be used in biosensors. The electrical propertiesof the NTFET devices were measured at room temperature inair. First, the blank phosphate-buffered saline (PBS) solutionwas introduced into the PDMS-based micro flow chip, reveal-ing that no substantial change in the source-drain current of the NTFET was obtained. The current increased dramatically,while monitoring in real time for about 3 h. This increase inconductance for the p-type NTFET device was consistent withan increase in negative surface charge density associated withbinding of negatively charged oligonucleotides at the surface.DNA hybridization can be detected by measuring the electri-

cal characteristics of NTFETs, and SWNT-based FETs can beemployed for label-free, direct real time electrical detectionof biomolecule binding.

A recent paper discusses the interactions with DNA andNTFETs at various segments. Tang et al. [61] examined thesensing mechanism between the DNA and SWNTs (Fig. 10).They found that DNA hybridization on gold electrodes, in-stead of SWNT sidewalls, is mainly responsible for the electri-cal conductance change owing to the modulation of the ener-gy level alignment between SWNTs and the gold contact,leading them to believe that for DNA sensing, the Schottkybarrier modulation has a more significant role in detection.They determined that by comparison with optical and otherelectrochemical methods, the two-terminal sensors involvemuch more simplistic chemistry and easier setup.

4.3. SNP Detection Using NTFETs

DNA biosensors based on nucleic acid recognition process-es are rapidly being developed towards the goal of rapid, sim-ple, and inexpensive testing of genetic and infectious diseases.Whereas electrochemical methods rely on the electrochemicalbehavior of the labels, measurements of the direct electron

transfer between SWNTs and DNA molecules pave the wayfor label-free DNA detection. To illustrate the practical utilityof this new nanoelectronic detection method (Fig. 11), an al-lele-specific assay to detect the presence of SNPs using a net-work of carbon nanotubes as NTFETs has been recently de-veloped. [62] This assay shows a statistical reproducibilitymeans. The technique included the ability to differentiate be-tween both mutant (mut) and wild type (wt) alleles. By func-tionalizing the carbon nanotubes with either wt or mut alleles,DNA hybridization matched to the corresponding type, thusachieving a drop in conductance. This DNA assay targetedthe H63D polymorphism in the human HFE gene, which is as-sociated with hereditary hemochromatosis, a common andeasily treated disease of iron metabolism. [63]

REVIEW



Au

+10 mV

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Figure 10. a) Schematic illustration of a single device during electricalmeasurement. Complementary ssDNA oligomers hybridize to thiolated

ssDNA co-immobilized with mercaptohexanol (MCH) on the gold elec-trodes. b) Real-time monitoring of 30 mer DNA hybridization in PBS,pH 7.4. Two liquid cells were used in parallel for simultaneous drop add-ing 5 l L of complementary and mismatched target oligo solution to500 l L of buffer. The conductance of a nanotube device functionalizedwith thiolated ssDNA exhibits a selective response to the addition of complementary ssDNA. Reproduced with permission from [61]. Copy-right 2006 The American Chemical Society.


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5. Conclusion and Outlook

Recent advances in the rapidly developing area of biomole-cule detection using carbon nanotube system have been sum-marized here. SWNTs appear as structurally defined compo-nents for a variety of electronic devices. The semiconductorproperties of SWNTs are of special interest as these SWNTshave been applied to fabricate FETs for biosensing applica-tions. This area requires further development, particularly re-

lated to the improved fabrication methods of FETs in whichcomplex arrays consisting of semiconducting SWNTs are cre-ated. However, there has already been progress to show re-producible device characteristics with biosensor sensitivitiesin the picomolar range. [62] The addressability of nanocircuitryelements is particularly important. [64,65] Biomaterials linked tonanotubes may be used as binding elements for the specificlinkage of the nanotube to surface in the form of addressablestructures.

The localized nanoscale contacts of SWNTs with biosur-faces will be a major advance in understanding and exploringthe new applications. The use of nanodevices to monitor avariety of biologically significant reactions is envisioned. [66] Inthe future, it should be possible to connect living cells directlyto these nanoelectronic devices to measure the electronic re-sponses of living systems. [66] The combination of the uniqueelectronic properties of SWNTs and catalytic features of abiological system could provide new opportunities for carbon

nanotubes based bioelectronics.Several research groups are looking into possible in vivoapplications of carbon nanotubes for the advancement of nanoscience. [31,67] By examining the compatibility of carbonnanotubes with the human immune system, we are witnessingthe possibilities of drug-delivery systems, cancer therapy, viraldetectors, and glucose sensors. In any case, the possibilities formedical applications of carbon nanotubes at this point areseemingly limitless.

Received: September 8, 2006Revised: November 17, 2006

Published online: April 30, 2007

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0

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S i g n a

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b)

c)

Figure 11. Electronic detection of the presence of single nucleotide poly-morphism (SNP) in synthetic HFE amplicons. a) G–V g curves after incu-bation with allele-specific wild-type (wt) capture probe and after challeng-ing the device with wild-type synthetic HFE target (50 nm). b) G–V gcurves in the experiment with mutant (mut) capture probe. c) Graphwith electronic (1–G / G 0) and fluorescent responses in SNP detection as-says. For electronic response, averages of normalized signals for threeNTNFET devices were calculated. Error bars are equal to one standarddeviation. Reproduced with permission from [62]. Copyright 2006 TheNational Academy of Sciences.


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