REVIEW

DOI: 10.1002/adma.200602043

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

Source Drain
There is an explosive interest in 1D nanostructured materials for bio-
SiO2
logical sensors. Among these nanometer-scale materials, single-walled Gate

carbon nanotubes (SWNTs) offer the advantages of possible biocom-

patibility, size compatibility, and sensitivity towards minute electrical perturbations. In particu-
lar, because of these inherent qualities, changes in SWNT conductivity have been explored in
order 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, DNA
hybridization, and enzymatic reactions involving glucose are summarized. Examples of
complementary techniques, such as microscopy and spectroscopy, are covered as well.

1. Introduction electronic devices, therefore, eventually integrate biology and

The interplay between nanomaterials and biological sys-
tems forms an emerging research field of broad importance.[1]
In particular, novel biosensors based on nanomaterials have
received considerable attention.[2] The integration of 1D
nanomaterials, such as nanowires, into electrical devices offers
substantial advantages for the detection of biological species,
and has significant advantages over conventional optical bio-
detection methods.[3] The first advantage is related to size
compatibility: electronic circuits in which the component parts
are 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 are
directly detected by electronic nanocircuits. Nanowire-based
electronics into a common platform suitable for electronic
control 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 the
charge 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 a
convenient interface with micrometer-scale circuitry. More-
over, their all-carbon composition provides a natural match to
organic molecules. Thus, among different nanomaterials, car-
bon nanotubes have a great potential for biosensing applica-
tions.

–
[*] Prof. A. Star, B. L. Allen, Dr. P. D. Kichambare 1.1. Field-Effect-Transistor-Based Inorganic Nanowire
Department of Chemistry Biosensors
University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: astar@pitt.edu One promising approach for the direct electrical detection
[**] A.S. would like to thank his co-workers from Nanomix Inc. cited in of biomolecules uses nanowires configured as field-effect
this article for their contribution to the research. transistors (FETs). These sensors offer several advantages for

Adv. Mater. 2007, 19, 1439–1451 © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1439
 B. L. Allen et al./Carbon Nanotube FET-Based Biosensors
REVIEW

the detection of biological species. Firstly, nanowires form the

conducting 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), where
the conducting channel is buried in the bulk material in which
the depletion layer is formed.[5] Finally, all of the electrical
current flows through the nanometer-scale cross section of the
nanowires. All these remarkable characteristics lead to a FET
device configuration that is extremely sensitive to minute
variations in the surrounding environment. FETs readily
change 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 recent
review,[6] have demonstrated the use of silicon nanowire FETs
for 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] Nanowires
have the potential for very high detection sensitivity through
the depletion or accumulation of charge carriers, caused by
the binding of charged biomolecules at the surface. This sur-
face binding can affect the entire cross-sectional conduction
Figure 1. Concept of nanowire-based detection of single viruses. Left:
pathway of the nanostructures.
Schematic illustration showing two nanowire devices, 1 and 2, in which
Lieber’s group was also able to push the sensitivity of sili- the nanowires are modified with different antibody receptors. Specific
con nanowires and demonstrate their ability for detecting sin- binding of a single virus to the receptors on nanowire 2 produces a con-
gle viruses.[11] Particularly, they used bifunctional molecules ductance change. Right: Characteristics of the surface charge of the virus
to attach antibodies specific to Influenza A for electrochemi- only in nanowire 2. When the virus unbinds from the surface the conduc-
tance returns to the baseline value. Reproduced with permission from
cal detection on an individual nanotube device with Si3N4 pas- [11]. Copyright 2004 The National Academy of Sciences.
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). 1.2. Carbon Nanotube FETs
Although silicon nanowires have been the most popular
choice for biosensors,[12] other 1D structures have also been Since their discovery by Iijima over a decade ago,[14] experi-
used. Curreli et al. have employed indium oxide (In2O3) mentation with carbon nanotubes has grown considerably.[15]
nanowires for biological detection.[13] By treating the nano- Subsequently, several experiments have been undertaken to
wire with a phosphonic acid solution, they were able to study the physical and electrical properties of carbon nano-
further immobilize single-stranded DNA in a nanoelectronic tubes on both the individual and the macroscopic scale.[16] It is
DNA assay. known that the properties of carbon nanotubes depend
strongly on physical properties, such as their diameter, their

Alexander Star was born in Almaty, Kazakhstan, in 1971. He immigrated to Israel in 1991, where
he received a B.S. degree in chemistry in 1994 and a Ph.D. in supramolecular chemistry (with
Prof. 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 University
of 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 carbon
nanotubes. 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.

1440 www.advmat.de © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2007, 19, 1439–1451
B. L. Allen et al./Carbon Nanotube FET-Based Biosensors

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 metallic
conductors or semiconductors, based on the chirality of the
structure.[18] Semiconducting SWNTs can be used to fabricate
FET devices, which can operate at room temperature and in
ambient 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 FET
layout, where the solid-state gate is replaced by adsorbed mol-
ecules that modulate the nanotube conductance.[20] There are
two classical types of device design regarding single-walled
carbon nanotube field-effect transistors (NTFETs, Fig. 2).
The first design uses a single carbon nanotube to act as an
electron 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 the
source and drain.[21,22] The analyte–nanotube interaction may
have one of two effects. The first effect involves charge trans-
fer from analyte molecules to the carbon nanotubes. In the
second type of mechanism, the analyte acts as a scattering po-
tential across the carbon nanotube. It is possible to distinguish
between the two mechanisms by taking transistor measure-
a) c)
S D
SiO2
Si Back Gate
VSD VG
15 µm
b) d)
i 4
3
GSD (µS)
REVIEW
ments.[22a] If a charge transfer occurs, the threshold voltage
will become either more positive (electron withdrawing) or
more negative (electron donating). In addition, a scattering
mechanism may be observed from an overall drop in conduc-
tance. This is because of the scattering effect induced by the
target 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, chemical
sensing experiments have been conducted with devices in
which nanotubes and nanotube–metal contacts were directly
exposed to the environment. The sensing could be dominated
by the interaction of molecules with metal contacts or the con-
tact interfaces. Adsorbed molecules would modify the metal
work functions, and thereby the Schottky barrier.[23] Heinze
et al.[24] have assigned the effect of oxygen exposure not to
doping nanotubes but to changing the work function of the
exposed 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 have
been 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, with
emphasis on NTFET devices, and dis-
cuss how these measurements relate to
spectroscopic and microscopic evidence
for molecular interactions between
SWNTs and biomolecules.[27] We shall
cover applications of carbon nanotubes
for the detection of biomolecules such
as proteins, carbohydrates, and DNA.
In particular, we discuss several recent
examples of NTFET use for detection
p-type of antibody–antigen interactions, DNA
iii hybridization, and enzyme reactions

2 (Table 1). We then conclude with possi-

4.5 µm ii ble directions for advancement in nano-
iv tube biosensor technology.
1 v
0
-10 -5 0 5 10 2. Protein Detection Using
VG (V) Carbon Nanotubes
Figure 2. a) Schematic representation of a nanotube field-effect transistor (NTFET) device with a The majority of research towards bio-
semiconducting SWNT (black) contacted by two Ti/Au electrodes (light brown), representing the
source (S) and the drain (D), and a Si back gate (green), separated by a SiO2 insulating layer (dark sensing involves the interactions of pro-
brown) in a transistor-configured circuit. b) Atomic force microscopy image of a typical NTFET de- teins with carbon nanotubes. Several
vice with individual SWNTs connecting the S and D electrodes. c) Scanning electron microscopy examples will be demonstrated in this
image of a typical NTFET device consisting of a random array of carbon nanotubes. d) Typical section, including some general mecha-
NTFET transfer characteristic; dependence of the source–drain conductance (GSD) on the gate volt-
age (VG). i) Maximum conductance, ii) modulation, iii) transconductance, iv) hysteresis, and
nisms, conductivity measurements
v) threshold voltage. based on interactions, antibody–antigen

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REVIEW
Table 1. Biomolecular interactions with SWNTs.
Technique
Proteins Enzymes
Nonspecific binding
to SWNTs [31,32]
Microscopy/ Fluorescence glucose
Spectroscopy detection [45]
Electrochemistry
NT electrodes Glucose
detection [26]
Protein detection
[29,38,39]
NTFET Antibody-antigen assays Glucose
[40-43] detection [44]
interactions, and enzymatic glucose detection. All of these
interactions are listed and explained in detail to develop an
understanding of the applications of carbon nanotubes as pro-
tein sensors.
2.1. Molecular Interactions Between Carbon Nanotubes and
Protein Molecules
A variety of proteins can strongly bind to the nanotube ex-
terior surface via nonspecific adsorption. Proteins such as
streptavidin 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 the
widely recognized hydrophobic interactions. It is quite possi-
ble that the observed substantial protein adsorption is, at least
in 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., histidine
and tryptophan) in the polypeptide chains of the proteins can
contribute to the observed affinity of the peptides to carbon
nanotubes.[30]
The interaction between carbon nanotubes and protein
molecules 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 the
surface of a carbon nanotube without any preference. Bala-
voine et al. found that the protein streptavidin binds strongly
to the sidewalls of a carbon nanotube in a helical fashion dur-
ing incubation.[28]
Other groups have witnessed other interactions between
proteins and carbon nanotubes as well. Kam and Dai dis-
cussed the phenomenon of nonspecific binding in a study to
use carbon nanotubes as protein intercellular transporters.[31]
They found that imparting hydrophilicity was insufficient to
block this type of binding (Fig. 3). Haddon’s group also found
nonspecific binding to dominate, as tendrils from an osteo-
1442 www.advmat.de © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
B. L. Allen et al./Carbon Nanotube FET-Based Biosensors
Application
Sugars DNA
SWNTs solubilization/ SWNTs solubilization/
wrapping [47,48] wrapping [55,56]
DNA hybridization
[57,58]
DNA hybridization
[52,53]
Detection of enzymatic degradation DNA hybridization
of starch [49] [61,62]
Figure 3. Atomic force microscopy images of various SWNT samples de-
posited on SiO2 substrates. a) Oxidized SWNT prior to conjugation with
proteins, and after conjugation to 1 lM 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.
blastic cell stretched out to make a bridge between the cell
and the carbon nanotubes.[32]
This does not mean, however, that the attachment of pro-
teins to carbon nanotubes cannot be orchestrated. In most
cases, carbon nanotubes can be adapted to specifically bind
protein to the sidewalls. There are many reports that demon-
strate the ability to chemically functionalize nanotubes for
this 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 attachment
involve covalent and noncovalent modification to achieve the
desired results. In terms of covalent attachment, the carbon
nanotubes 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 electronic
properties of SWNTs. Noncovalent modifications,[35] on the
other hand, not only improve the solubility of SWNTs in
water but also constitute nondestructive processes, preserving
the primary structures of the SWNTs along with their unique
mechanical and electronic properties.
Generally, there are two main schemes to noncovalent
functionalization of carbon nanotubes. The first involves bi-
Adv. Mater. 2007, 19, 1439–1451
B. L. Allen et al./Carbon Nanotube FET-Based Biosensors

REVIEW
functional molecules that exhibit p–p a)
stacking on the sidewalls of the carbon
nanotubes. A pyrene moiety, commonly
used for graphite functionalization, is c)
typically employed for noncovalent 2.8
functionalization, and referred to as a
“sticky label”.[36] 2.4
The other type of noncovalent func-

I (µA)
(∝A)
∝A)
tionalization involves the use of a poly- 2.0

(∝
mer addition.[35] Dai’s group employed b) Source Liquid Gate Drain
a polymer scheme to achieve protein (S) (D)
1.6
binding.[37] The functionalization of the
carbon nanotubes was performed by co- 1.2
adsorption of the surfactant Triton and SWNT -0.4 -0.2 0 0.2 0.4
channel Vliquid (V)
poly(ethylene glycol). By using this
method, they were able to examine the
resistance to nonspecific binding while
Back Gate
also using a “director” for specific pro-
tein attachment. 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 (Vsd) 10 mV. Red trace:
2.2. Conductivity Measurements of measurement in phosphate buffer before streptavidin addition. Black trace: identical conditions, to
measure the uncertainty in the threshold voltage. Green trace: measurement after 10 h of incuba-
Carbon Nanotube–Protein Interactions
tion with streptavidin, Arrows indicate the threshold voltages for the three curves. Reproduced with
permission from [29]. Copyright 2004 The American Chemical Society.
Interactions of carbon nanotubes
with proteins have been explored by
NTFET devices.[29] In the NTFET device, the ability to mea- The protein adsorption on NTFETs leads to appreciable
sure the electronic properties of the nanotube allowed for changes in the electrical conductance of the devices that can be
identification of the electronic state of the immobilization exploited for label-free detection of biomolecules with a high
substrate. In this experiment two types of measurements of potential for miniaturization. For example, Dai and co-work-
the individual nanotube device transfer characteristics were ers[38] used a sensor design consisting of an array of four
performed. In the first measurement, referred to as the sub- NTFET sensors on SiO2/Si chips. Each NTFET comprised a
strate–gate transfer characteristics, the current through the network of multiple SWNTs connected roughly in parallel
drain contact (at fixed source–drain bias) was monitored across two closely spaced bridging metal electrodes. Three
while a variable gate voltage was applied through a metallic types of devices with different surface functional groups were
gate buried underneath the SiO2 substrate. In the second prepared for the investigation of the biosensing. The first type
measurement, referred to as the liquid–gate transfer charac- (type 1) consisted of unmodified as-made devices. The second
teristic, the device was immersed in a buffer solution and a type (type 2) of devices were fabricated with methoxy(po-
variable gate voltage was applied through a platinum elec- ly(ethylene glycol))thiol (mPEG-SH) self-assembled mono-
trode. The current was passed through the drain contact and layers (SAMs) formed on, and only on, the metal contact elec-
a silver reference electrode in the solution. After 10 h, the trodes for passivation, and the third type (type 3) of devices
devices were rinsed with distilled water and blown dry, and were fabricated with mPEG-SH SAMs on the metal contacts
the substrate–gate transfer characteristics of the dried de- and a Tween 20 coating on the carbon nanotubes. The electrical
vices were measured. conductance of these devices upon the addition of various pro-
These results were discussed in terms of a simple model in tein molecules was monitored. Device type 1 showed signifi-
which adsorbed streptavidin coats the SWNT (Fig. 4). The cant conductance changes with protein adsorption, while de-
gradual shift in the threshold voltage is assumed to result from vice type 2, with an mPEG-SH SAM on the metal electrodes,
the slow accumulation of a full monolayer of adsorbed pro- did not give any conductance change except in the case of the
tein. This coverage-dependent threshold shift is analogous to protein avidin. It was reported that the metal/nanotube inter-
the concentration-dependent shift observed when such de- face or contact region is highly susceptible to modulation by ad-
vices are exposed to aqueous ammonia.[19i] The protein ad- sorbed species. The modulation of the metal work function can
sorbate equilibrates over several hours so that only the full alter the Schottky barrier of the metal/nanotube interface, thus
monolayer can be conclusively determined. The results sup- leading to a significant change in the nature of contacts and
port the proposal that conductance changes are the result of consequently a change in the conductance of the devices.
charge injection or field effects caused by proteins adsorbed In situ detection of a small number of proteins via directly
solely along the lengths of the nanotubes. measuring the electron transport properties of a single SWNT

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

has been reported by Nagahara and co-workers.[39] The cyto-
chrome C (cytc) adsorption onto individual NTFETs has been
detected via the changes in the electron transport properties
of the transistors. The adsorption of cytc induces a decrease in
the conductance of the NTFET devices, corresponding to a
few tens of molecules.
2.3. NTFET Detection of Antibody–Antigen Interactions
Specific sensitivity can be achieved by employing recognition
layers that induce chemical reactions and modify the transfer
characteristics. In this two-layer architecture carbon nanotubes
function as extremely sensitive transducers, while recognition
layers provide chemical selectivity and prevent nonspecific
binding, which is common for complex biological samples.
Following this design, nanotubes have been functionalized
to 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 a
bioreceptor molecule with a high degree of control and speci-
ficity. Star et al.[40] have fabricated NTFET devices sensitive
to streptavidin by using individual biotin-functionalized car-
bon nanotube arrays bridging two microelectrodes (source
and drain, Fig. 5a). The SWNT in the NTFET device was
coated with a mixture of two polymers: poly(ethylene imine)
(PEI) and poly(ethylene glycol) (PEG). The former provided
amino 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

a) b) H H
Streptavidin Drain N
S O
Source N
Biotin H H
biotin-N-hydroxy- H H
succinimide ester N
S O
O O N
H H
O N O
DMF
+ RT
NH2 HN O
Gate
H OH
O n
Polymer N N
N PEI PEG
N
H x y H x y

c)

biotin
PEI / PEG d) 1
NT
w/ streptavidin
0.8
biotin
PEI / PEG
NT
Current (µA)

0.6
Ti/Au
Source &
Drain 0.4
electrodes w/ streptavidin
0.2

0
-10 -5 0 5 10
1.2 µm Gate Voltage (V)

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.

1444 www.advmat.de © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2007, 19, 1439–1451
B. L. Allen et al./Carbon Nanotube FET-Based Biosensors
nanoparticles (10 nm). Light dots represent gold nanoparti-
cles and indicate the presence of streptavidin bound to the
biotinylated 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 reveal
the specific binding of streptavidin, which occurs only at the
biotinylated interface.
The mechanism of the biodetection was explained in terms
of the effect of the electron doping of the carbon nanotube
channel 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 mAbs
antibody (a prototype target of the autoimmune response in
patients with systematic lupus erythematosus and mixed con-
nective tissue disease) to human auto antigen U1 A.
More recently, Li et al.[42] studied the complementary detec-
tion of prostate-specific antigen by using a network of SWNTs
as a FET. They found the sensitivity to be comparable to metal
oxide 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 this
type of detection is shown in Figure 6.[42] The interaction is
thought to be a charge-transfer mechanism as well. They
showed a prostate-specific antibody in the act of capturing a
specific antigen and measured the electronic interaction. Func-
tionalization of the SWNTs uses a p–p stacking method with a
pyrene moiety. Passivation of the electrodes, however, was not
mentioned in terms of the sensing mechanism.
Aside from protein interactions with SWNTs, some groups
have researched the possibility of functionalizing them with
more complex structures, such as aptamers or single-stranded
DNA (ssDNA). Lee and co-workers[43] suggested the use of ap-
Figure 6. a) Schematic illustration of a nanosensor. Prostate-specific
antigen antibodies (PSA-ABs) are anchored to the NW/SWNT surface
and function as specific recognition groups for PSA binding. b) Reaction
sequence for the modification of the SWNT. i) deposition of 1-pyrenebu-
tanoic acid succinimidyl ester, ii) PSA–AB incubation. Reproduced with
permission from [42]. Copyright 2005 The American Chemical Society.
Adv. Mater. 2007, 19, 1439–1451 © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
REVIEW
tamers for recognition of biomolecules, instead of antibodies.
Aptamers are classified as artificial oligonucleotides that are
capable of a wide range of detection of specific biomolecules,
based upon the aptamer configuration. The other attractive ap-
peal to an aptamer approach is that they are less costly and are
capable of reversible denaturation, meaning that the biosensor
can be reused continuously. As in this case, they measured cur-
rent over a period of 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 other
glucose sensors, electrochemical glucose detection is based on
enzymatic 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 individual
semiconducting SWNTs as a versatile biosensor has been
demonstrated by Dekker and co-workers.[44] The redox en-
zyme glucose oxidase (GOx) that catalyzes the oxidation of
b-D-glucose (C6H12O6) to D-glucono-1,5-lactone (C6H10O6)
has been studied. The redox enzymes go through a catalytic
reaction cycle, where groups in the enzyme temporarily
change their charge state and conformational changes occur
in the enzyme, that can be detected by using NTFET devices.
In addition to pH sensitivity, GOx-coated semiconducting
SWNTs appeared to be sensitive to glucose, the substrate of
GOx. Figure 7 exhibits real-time measurements, where the
conductance of a GOx-coated semiconducting SWNT in milli-
Q water has been recorded in the liquid. No significant change
in conductance was observed as a result of water addition (red
arrow in Fig. 7). When 0.1 M glucose in milli-Q water was added
to the liquid (blue arrow), however, the conductance of the
tube 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 bare
semiconducting SWNT. These measurements clearly indicate
that the GOx activity is responsible for the measured increase
in 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 optical
sensor for long-term glucose sensing. They proposed a design
for in vivo applications. By observing fluorescent emission
after 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 the
reaction of carbon nanotubes with hydrogen peroxide. Song
et al.[46] studied the reaction of hydrogen peroxide with
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 B. L. Allen et al./Carbon Nanotube FET-Based Biosensors
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3.1. NTFET Detection of Carbohydrates

and their Enzymatic Degradation

It has been reported[47] that SWNTs can

be made water-soluble by wrapping in amy-
lose (linear component of starch). These
SWNT solutions are stable for weeks pro-
vided nobody spits on them. Indeed, addi-
tion of saliva, which contains a-amylase,
precipitate the nanotubes as the enzyme
breaks amylose down into smaller carbohy-
drate fragments, finally resulting in the for-
mation of glucose. The enzymatic degrada-
tion of starch has been recently monitored
electronically by using NTFETs.[49] The ex-
perimental setup used for this study is dis-
played in Figure 8 as an individual nano-
tube array device. NTFET devices display
Figure 7. Left: Real time electronic response of an NTFET sensor to glucose, the substrate of transconductance and source-drain cur-
GOx. The conductance of a semiconducting SWNT with immobilized GOx is measured as a rent–voltage characteristics, typical of the
function of time in 5 lL milli-Q water. The conductance of the GOx-coated SWNT is observed
to increase upon addition of glucose to the liquid. Insets: a) the same measurement on a sec-
p-type device behavior. The device charac-
ond device, where the conductance was a factor of 10 lower; b) the same measurement on a teristics, i.e., the source-drain current ISD as
semiconducting SWNT without GOx. No conductance increase is observed in this case. Repro- a function of the gate voltage VG, were
duced with permission from [44]. Copyright 2003 The American Chemical Society. Right: Sche- measured to evaluate the effect of starch
matic of GOx immobilized on SWNT for electronic glucose detection.
deposition and the subsequent enzymatic
degradation of the starch layer on the car-
bon nanotubes.
SWNTs encased in sodium dodecyl sulfate (SDS). By using The deposition of starch onto the FET was achieved by
Raman spectroscopy, they were able to characterize some of soaking the silicon wafer in a 5 % aqueous starch solution,
the reactions taking place. The group found that the nano- and the device characteristics were found to be shifted by ap-
tubes were able to recover by increasing the pH, by decom- proximately 2 V towards more negative gate voltages. The di-
posing hydrogen peroxide, and by dialytically removing it. rection of the shift equates with electron doping of the nano-
They also suggested possible enzyme-assisted molecular rec- tube channel by the polysaccharide. Quantitatively similar
ognition applications of biological species whose enzyme-cat- doping effects have been observed when carbon nanotube
alyzed products include hydrogen peroxide. FET devices were exposed to NH3,[19i] amines,[50] PEI,[51] and
proteins.[29] After the enzyme-catalyzed reaction had been
performed on the starch-functionalized devices and washing
3. Carbohydrate Detection Using Carbon with buffer, the ISD versus VG characteristic was found to
Nanotubes have recovered almost completely to the trace recorded be-
fore the starch deposition (Fig. 8). This observation indicates
Previously, it has been shown that polysaccharides such as that during the enzyme-catalyzed reaction nearly all the
starch, gum Arabic, and the b-1,3-glucans, curdlan and schizo- starch deposits on the surface of the nanotube device are hy-
phyllan, will solubilize SWNTs in water.[47] It has been pro- drolyzed to glucose, which is washed off by the buffer prior to
posed that at least some of these polymers achieve this by the electronic measurements.
wrapping themselves around SWNTs in a helical fashion. So-
lubilization of SWNTs with cyclodextrins (CD), which are
macrocyclic polysaccharides, has been investigated re-
cently.[47] The observed aqueous solubility of SWNTs with 4. DNA Detection by Using Carbon Nanotubes
c-CD is unlikely the result of encapsulation, because the inner
cavity dimensions of this CD are far too small to allow it to To date, there are several reports on the electrochemical de-
thread onto even the smallest-diameter SWNTs. More re- tection of DNA hybridization by using carbon nanotube elec-
cently, however, it has been shown[48] that g-CD has 12 trodes.[26] For example, Li et al.[52] were able to covalently link
a-1,4-linked D-glucopyranose residues and is therefore large DNA onto the tips of carbon nanotube arrays for electro-
enough to be able to thread onto SWNTs, and does so in chemical DNA detection. Other groups have focused on the
water; not only solubilizing the nanotubes but also permitting covalent functionalization aspect of carbon nanotubes by
some partial separations according to their diameters. DNA or other nucleic acids of this type, as well.[53,54]

1446 www.advmat.de © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2007, 19, 1439–1451
B. L. Allen et al./Carbon Nanotube FET-Based Biosensors

REVIEW
a) OH DNA–SWNT interactions in water originate from the nucleic
acid–base p–p stacking on the nanotube surface, resulting in a
AMG HO
HO
O
Glucose hydrophilic sugar–phosphate backbone pointing to the exteri-
HO OH
or, thereby achieving solubility in water. Similarly to carbohy-
drates (e.g., amylose), the mode of interaction may be helical
Source Starch Drain wrapping or simple surface adsorption (Fig. 9). The charge
differences among the DNA–SWNT conjugates, which are as-
sociated with the negatively charged phosphate groups of
DNA and the different electronic properties of SWNTs, have
allowed postproduction preparation of samples enriched in
SiO2 metallic and semiconducting SWNTs.[56] Work done by Stra-
no’s group looks into DNA polymorphism on nanotubes.[57]
Gate They found that the conformational rearrangement of a bio-
molecule could be transduced directly by a SWNT system. In
a second study, this group looked at DNA–SWNTs used as a
b)
photobleaching-resistant marker, which remained functional
in live cells for up to three months.[58] On the other hand, Staii
et al.[59] incorporated single-stranded DNA into a FET device
for detection of a range of vaporous odors. Some of the vapors
that 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-
c) 1.2

0.8 Bare
ISD / µA

0.6
0.4 After
AMG
After
0.2
Starch
0
-10 -5 0 5 10
VG / V
Figure 8. a) NTFET device for electronic monitoring of the enzymatic
degradation 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 solution
of starch. The starch has been stained with RuO4 vapor. c) NTFET device
characteristics in the form of ISD–VG curves measured from +10 to –10 V
gate 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.

4.1. Noncovalent Interactions between Carbon Nanotubes
and 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
Figure 9. Binding model of a (10,0) carbon nanotube wrapped by a
poly(T) sequence. The right-handed helical structure shown here is one
of several binding structures found, including left-handed helices and lin-
early adsorbed structures. In all cases, the bases (red) orient to stack
with 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.

Adv. Mater. 2007, 19, 1439–1451 © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advmat.de 1447
 B. L. Allen et al./Carbon Nanotube FET-Based Biosensors
REVIEW

fer, which allows electronic detection using NTFET devices. a)

However, the exact mechanism of the nanoelectronic detec-
tion still remains unclear. The selective attachment of DNA
Pt
molecules on various segments of the NTFET device can al-
low, in principle, to investigate the sensing mechanism of the
MCH
nanotube biosensor. DNA molecules attached to the nano-
tube will mostly influence FET characteristics by electron de- +10 mV
pletion in the channel, whereas chemical attachment to metal
electrodes will influence only the metal/nanotube interface,
that is, the Schottky barrier. Therefore, by correlating the Au
sensing results to the attachment mode, one can obtain infor-
mation about the mechanism of NTFET biosensing. Thiolated ssDNA (Probe)
NTFET devices have been used for DNA detection. DNA Complementary ssDNA (Target)
hybridization was studied on the surface at the gate of
NTFETs.[60] As a result, the conductance in SWNTs was b) 1.04
changed through the gate insulators. In this work, 5′ end-ami- 5 µL
L PBS 100 nM
1.02
no modified peptide nucleic acid (PNA) oligonucleotides
were covalently immobilized onto the NTFET back-gate Au 1
mismatched
surfaces. PNA mimicked the behavior of DNA and hybridized 0.98

with complementary DNA or RNA sequences, thus enabling
PNA chips to be used in biosensors. The electrical properties
of the NTFET devices were measured at room temperature in
air. First, the blank phosphate-buffered saline (PBS) solution
was 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 in
conductance for the p-type NTFET device was consistent with
an increase in negative surface charge density associated with
binding 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 be
employed for label-free, direct real time electrical detection
of biomolecule binding.
A recent paper discusses the interactions with DNA and
NTFETs at various segments. Tang et al.[61] examined the
sensing 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 Schottky
barrier modulation has a more significant role in detection.
They determined that by comparison with optical and other
electrochemical methods, the two-terminal sensors involve
much 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 electrochemical
behavior of the labels, measurements of the direct electron
G/G0
0.96
0.94
0.92
0.90
complementary
0.88
0.86
0.84
0 20 40 60 80 100 120
Time (min)
Figure 10. a) Schematic illustration of a single device during electrical
measurement. 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 lL of complementary and mismatched target oligo solution to
500 lL of buffer. The conductance of a nanotube device functionalized
with thiolated ssDNA exhibits a selective response to the addition of
complementary ssDNA. Reproduced with permission from [61]. Copy-
right 2006 The American Chemical Society.
transfer between SWNTs and DNA molecules pave the way
for label-free DNA detection. To illustrate the practical utility
of 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 reproducibility
means. 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, thus
achieving a drop in conductance. This DNA assay targeted
the H63D polymorphism in the human HFE gene, which is as-
sociated with hereditary hemochromatosis, a common and
easily treated disease of iron metabolism.[63]

1448 www.advmat.de © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2007, 19, 1439–1451
B. L. Allen et al./Carbon Nanotube FET-Based Biosensors

REVIEW
a) 400 lated to the improved fabrication methods of FETs in which
complex arrays consisting of semiconducting SWNTs are cre-
probe_wt
ated. However, there has already been progress to show re-
300
producible device characteristics with biosensor sensitivities
in the picomolar range.[62] The addressability of nanocircuitry
G (µS)

200 elements is particularly important.[64,65] Biomaterials linked to

nanotubes may be used as binding elements for the specific
HFE-H.wt linkage of the nanotube to surface in the form of addressable
100
structures.
The localized nanoscale contacts of SWNTs with biosur-
0 faces will be a major advance in understanding and exploring
-10 -5 0 5 10 the new applications. The use of nanodevices to monitor a
Vg (V) variety of biologically significant reactions is envisioned.[66] In
b) 1000 the future, it should be possible to connect living cells directly
to these nanoelectronic devices to measure the electronic re-
probe_mut
800 sponses of living systems.[66] The combination of the unique
electronic properties of SWNTs and catalytic features of a
biological system could provide new opportunities for carbon
G (µS)

600
nanotubes based bioelectronics.
400 Several research groups are looking into possible in vivo
HFE-H.wt applications of carbon nanotubes for the advancement of
200 nanoscience.[31,67] By examining the compatibility of carbon
nanotubes with the human immune system, we are witnessing
0 the possibilities of drug-delivery systems, cancer therapy, viral
-10 -5 0 5 10 detectors, and glucose sensors. In any case, the possibilities for
medical applications of carbon nanotubes at this point are
c) 0.18 30
seemingly limitless.
Wild Type 25
0.14 Received: September 8, 2006
Mutant Revised: November 17, 2006
Signal, 1-G/G0

20
Published online: April 30, 2007
Signal, mfi

0.1
15

0.06 10

0.02
-0.02
Electronic Optical
Figure 11. Electronic detection of the presence of single nucleotide poly-
morphism (SNP) in synthetic HFE amplicons. a) G–Vg 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–Vg
curves in the experiment with mutant (mut) capture probe. c) Graph
with electronic (1–G/G0) and fluorescent responses in SNP detection as-
says. For electronic response, averages of normalized signals for three
NTNFET devices were calculated. Error bars are equal to one standard
deviation. Reproduced with permission from [62]. Copyright 2006 The
National Academy of Sciences.
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 semiconductor
properties of SWNTs are of special interest as these SWNTs
have been applied to fabricate FETs for biosensing applica-
tions. This area requires further development, particularly re-
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