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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 biological sensors. Among these nanometer-scale materials, single-walled
carbon nanotubes (SWNTs) offer the advantages of possible biocompatibility, size compatibility, and sensitivity towards minute electrical perturbations. In particular, 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 interactions, 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.
SiO2

Gate

1. Introduction
The interplay between nanomaterials and biological systems 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 biodetection 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 appropriate size compatibility between the detector and the biological
analyte. The second advantage to developing nanomaterialbased electronic detection is that most biological processes involve electrostatic interactions and charge transfer, which are
directly detected by electronic nanocircuits. Nanowire-based


[*] Prof. A. Star, B. L. Allen, Dr. P. D. Kichambare
Department of Chemistry
University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: astar@pitt.edu
[**] A.S. would like to thank his co-workers from Nanomix Inc. cited in
this article for their contribution to the research.

Adv. Mater. 2007, 19, 1439–1451

electronic devices, therefore, eventually integrate biology and
electronics into a common platform suitable for electronic
control and biological sensing as well as bioelectronically driven nanoassembly.[4]
This biocompatibility and size compatibility is seen especially with carbon nanotubes. In the case of single-walled carbon nanotubes (SWNTs) every atom is on the surface and exposed to the environment and, thus, even small changes in the
charge environment can cause drastic changes to their electrical properties. In addition to their diameters being comparable 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. Moreover, their all-carbon composition provides a natural match to
organic molecules. Thus, among different nanomaterials, carbon nanotubes have a great potential for biosensing applications.

1.1. Field-Effect-Transistor-Based Inorganic Nanowire
Biosensors
One promising approach for the direct electrical detection
of biomolecules uses nanowires configured as field-effect
transistors (FETs). These sensors offer several advantages for

© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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

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 supporting substrate and are in direct contact with the environment. This device geometry contrasts the traditional metal oxide 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 biomolecules to receptors linked to the device’s surfaces. For example, 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 markers.[9] This biodetection approach may allow, in principle, selective 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 surface binding can affect the entire cross-sectional conduction
pathway of the nanostructures.
Lieber’s group was also able to push the sensitivity of silicon nanowires and demonstrate their ability for detecting single viruses.[11] Particularly, they used bifunctional molecules
to attach antibodies specific to Influenza A for electrochemical detection on an individual nanotube device with Si3N4 passivated nickel contacts. As with other cases, conductance versus 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 been
used. Curreli et al. have employed indium oxide (In2O3)
nanowires for biological detection.[13] By treating the nanowire with a phosphonic acid solution, they were able to
further immobilize single-stranded DNA in a nanoelectronic
DNA assay.

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

1.2. Carbon Nanotube FETs
Since their discovery by Iijima over a decade ago,[14] experimentation with carbon nanotubes has grown considerably.[15]
Subsequently, several experiments have been undertaken to
study the physical and electrical properties of carbon nanotubes on both the individual and the macroscopic scale.[16] It is
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 postdoctoral 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 nanotechnology-enabled molecular sensing.

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

a)

D
SiO2
Si Back Gate
VSD

b)

VG
d)

i

4
GSD (µS)

3
4.5 µm

2

ii

1
0
-10

1.3. Scope of the Review

Up to date, sensor applications of carbon nanotubes have
been summarized and discussed in several excellent review articles,[26] which primarily focused on carbon nanotube based
electrochemical sensors. In this Review,
we will cover recent advances in detection of biological species in a variety of
manners using carbon nanotubes, with
emphasis on NTFET devices, and discuss how these measurements relate to
spectroscopic and microscopic evidence
for molecular interactions between
SWNTs and biomolecules.[27] We shall
15 µm
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
hybridization, and enzyme reactions
iii
(Table 1). We then conclude with possible directions for advancement in nanoiv
tube biosensor technology.

c)

S

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 conductance. This is because of the scattering effect induced by the
target analyte[22a] absorbed on the sidewalls of SWNT. The exact 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 contact 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]

v

-5

0
5
VG (V)

10

Figure 2. a) Schematic representation of a nanotube field-effect transistor (NTFET) device with a
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
brown) in a transistor-configured circuit. b) Atomic force microscopy image of a typical NTFET device with individual SWNTs connecting the S and D electrodes. c) Scanning electron microscopy
image of a typical NTFET device consisting of a random array of carbon nanotubes. d) Typical
NTFET transfer characteristic; dependence of the source–drain conductance (GSD) on the gate voltage (VG). i) Maximum conductance, ii) modulation, iii) transconductance, iv) hysteresis, and
v) threshold voltage.

Adv. Mater. 2007, 19, 1439–1451

REVIEW

length, the presence of residual catalyst, and chirality. For example, carbon nanotubes can be either single-walled or multiwalled with varying intrinsic bandgaps and helicities.[17] In addition, 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 semiconducting SWNTs exhibit significant conductance changes in response 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 molecules 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 electrodes.[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 transfer from analyte molecules to the carbon nanotubes. In the
second type of mechanism, the analyte acts as a scattering potential across the carbon nanotube. It is possible to distinguish
between the two mechanisms by taking transistor measure-

2. Protein Detection Using
Carbon Nanotubes
The majority of research towards biosensing involves the interactions of proteins with carbon nanotubes. Several
examples will be demonstrated in this
section, including some general mechanisms,
conductivity
measurements
based on interactions, antibody–antigen

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Table 1. Biomolecular interactions with SWNTs.
Technique

Application
Proteins

Enzymes

Sugars

DNA

SWNTs solubilization/
wrapping [47,48]
Fluorescence glucose
detection [45]

SWNTs solubilization/
wrapping [55,56]
DNA hybridization
[57,58]

Glucose
detection [26]

DNA hybridization
[52,53]

Nonspecific binding
to SWNTs [31,32]
Microscopy/
Spectroscopy
Electrochemistry
NT electrodes

NTFET

Protein detection
[29,38,39]
Antibody-antigen assays
[40-43]

Glucose
detection [44]

Detection of enzymatic degradation
of starch [49]

DNA hybridization
[61,62]

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 protein sensors.

2.1. Molecular Interactions Between Carbon Nanotubes and
Protein Molecules
A variety of proteins can strongly bind to the nanotube exterior surface via nonspecific adsorption. Proteins such as
streptavidin and HupR crystallize in a helical fashion, resulting 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 possible that the observed substantial protein adsorption is, at least
in part, associated with the amino affinity of carbon nanotubes, as was demonstrated recently by monitoring the conductance change in a carbon nanotube.[29] Also, intermolecular 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 elaborate on this, several groups have looked into protein–nanotube interactions and found that proteins will adsorb onto the
surface of a carbon nanotube without any preference. Balavoine et al. found that the protein streptavidin binds strongly
to the sidewalls of a carbon nanotube in a helical fashion during incubation.[28]
Other groups have witnessed other interactions between
proteins and carbon nanotubes as well. Kam and Dai discussed 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-

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Figure 3. Atomic force microscopy images of various SWNT samples deposited on SiO2 substrates. a) Oxidized SWNT prior to conjugation with
proteins, and after conjugation to 1 lM of b) Alexa-Fluor 488 bovine serum albumine (BSA), c) Alexa-Fluor 488 spA, and d) Alexa-Fluor 488 cytochrome 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 proteins 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 demonstrate the ability to chemically functionalize nanotubes for
this purpose. Such chemistry is readily transferable to numerous applications, ranging from sensors to electronic devices.[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 undergo coupling with amino groups in proteins.[31] While covalent modifications[34] are often effective at introducing functionality, 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-

© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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

2.2. Conductivity Measurements of
Carbon Nanotube–Protein Interactions

REVIEW

a)

c)
2.8
2.4

b)

Source
(S)

Liquid Gate

2.0

1.6
1.2
-0.4

SWNT
channel

-0.2

0

0.2

0.4

Vliquid (V)

Back Gate

Figure 4. a) Size comparison between a carbon nanotube and a streptavidin molecule. b) Detection 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:
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 incubation 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 measure the electronic properties of the nanotube allowed for
identification of the electronic state of the immobilization
substrate. In this experiment two types of measurements of
the individual nanotube device transfer characteristics were
performed. In the first measurement, referred to as the substrate–gate transfer characteristics, the current through the
drain contact (at fixed source–drain bias) was monitored
while a variable gate voltage was applied through a metallic
gate buried underneath the SiO2 substrate. In the second
measurement, referred to as the liquid–gate transfer characteristic, the device was immersed in a buffer solution and a
variable gate voltage was applied through a platinum electrode. The current was passed through the drain contact and
a silver reference electrode in the solution. After 10 h, the
devices were rinsed with distilled water and blown dry, and
the substrate–gate transfer characteristics of the dried devices were measured.
These results were discussed in terms of a simple model in
which adsorbed streptavidin coats the SWNT (Fig. 4). The
gradual shift in the threshold voltage is assumed to result from
the slow accumulation of a full monolayer of adsorbed protein. This coverage-dependent threshold shift is analogous to
the concentration-dependent shift observed when such devices are exposed to aqueous ammonia.[19i] The protein adsorbate equilibrates over several hours so that only the full
monolayer can be conclusively determined. The results support the proposal that conductance changes are the result of
charge injection or field effects caused by proteins adsorbed
solely along the lengths of the nanotubes.

Adv. Mater. 2007, 19, 1439–1451

Drain
(D)

I (µA)
(∝
(∝A)
∝A)

functional molecules that exhibit p–p
stacking on the sidewalls of the carbon
nanotubes. A pyrene moiety, commonly
used for graphite functionalization, is
typically employed for noncovalent
functionalization, and referred to as a
“sticky label”.[36]
The other type of noncovalent functionalization involves the use of a polymer addition.[35] Dai’s group employed
a polymer scheme to achieve protein
binding.[37] The functionalization of the
carbon nanotubes was performed by coadsorption of the surfactant Triton and
poly(ethylene glycol). By using this
method, they were able to examine the
resistance to nonspecific binding while
also using a “director” for specific protein attachment.

The protein adsorption on NTFETs leads to appreciable
changes in the electrical conductance of the devices that can be
exploited for label-free detection of biomolecules with a high
potential for miniaturization. For example, Dai and co-workers[38] used a sensor design consisting of an array of four
NTFET sensors on SiO2/Si chips. Each NTFET comprised a
network of multiple SWNTs connected roughly in parallel
across two closely spaced bridging metal electrodes. Three
types of devices with different surface functional groups were
prepared for the investigation of the biosensing. The first type
(type 1) consisted of unmodified as-made devices. The second
type (type 2) of devices were fabricated with methoxy(poly(ethylene glycol))thiol (mPEG-SH) self-assembled monolayers (SAMs) formed on, and only on, the metal contact electrodes for passivation, and the third type (type 3) of devices
were fabricated with mPEG-SH SAMs on the metal contacts
and a Tween 20 coating on the carbon nanotubes. The electrical
conductance of these devices upon the addition of various protein molecules was monitored. Device type 1 showed significant conductance changes with protein adsorption, while device type 2, with an mPEG-SH SAM on the metal electrodes,
did not give any conductance change except in the case of the
protein avidin. It was reported that the metal/nanotube interface or contact region is highly susceptible to modulation by adsorbed species. The modulation of the metal work function can
alter the Schottky barrier of the metal/nanotube interface, thus
leading to a significant change in the nature of contacts and
consequently a change in the conductance of the devices.
In situ detection of a small number of proteins via directly
measuring the electron transport properties of a single SWNT

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

has been reported by Nagahara and co-workers.[39] The cytochrome 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.

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 between a bifunctional molecule and a nanotube to anchor a
bioreceptor molecule with a high degree of control and specificity. Star et al.[40] have fabricated NTFET devices sensitive
to streptavidin by using individual biotin-functionalized carbon 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-succinimidyl ester (Fig. 5b) and the latter prevented the nonspecific adsorption 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)

2.3. NTFET Detection of Antibody–Antigen Interactions

Streptavidin

Drain

H H
N
S

O
N
H H

Source
Biotin

biotin-N-hydroxysuccinimide ester

O

O
N

O

DMF

O

RT

+

HN
H

Polymer
N
H

O
N
H H

NH2

Gate

H H
N

S

N
y

x

O n

PEI

O

OH
N
H

PEG

N
x

y

c)

biotin
PEI / PEG
NT
w/ streptavidin

1

d)

Current (µA)

0.8

Ti/Au
Source &
Drain
electrodes

biotin
PEI / PEG
NT

0.6
0.4

w/ streptavidin

0.2
0
-10
1.2 µm

-5

0
Gate Voltage (V)

5

10

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 polymer-coated and biotinylated NTFET device after exposure to streptavidin labeled with gold nanoparticles (10 nm in diameter). d) The source-drain current 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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B. L. Allen et al./Carbon Nanotube FET-Based Biosensors

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-pyrenebutanoic acid succinimidyl ester, ii) PSA–AB incubation. Reproduced with
permission from [42]. Copyright 2005 The American Chemical Society.

Adv. Mater. 2007, 19, 1439–1451

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 appeal 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 current over a period of time after chemical induction.

REVIEW

nanoparticles (10 nm). Light dots represent gold nanoparticles and indicate the presence of streptavidin bound to the
biotinylated carbon nanotube. The source-drain current dependence on the gate voltage of the NTFET shows a significant change upon the streptavidin binding to the biotin-functionalized 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 molecules. Dai and co-workers[41] have also analyzed specific antigen–antibody interactions using NTFET devices. In particular, 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 connective tissue disease) to human auto antigen U1 A.
More recently, Li et al.[42] studied the complementary detection 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 bifunctional 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. Functionalization 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-

2.4. Application of FETs for Glucose Detection
The diagnosis and management of diabetes mellitus requires a tight monitoring of blood glucose levels. Electrochemical detection of glucose using carbon nanotube electrodes is already an exploding field.[26] Similar to other
glucose sensors, electrochemical glucose detection is based on
enzymatic glucose oxidation and subsequent hydrogen peroxide detection on the carbon nanotube electrodes. Many examples of such sensor design have been summarized in recent reviews.[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 enzyme 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 milliQ 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 Figure 7, a similar 10 % conductance change was observed for another 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 immobilized. 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 nanodevices as feasible enzymatic-activity sensors.
In addition to electronic detection, Strano and co-workers[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 indicating 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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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 amylose (linear component of starch). These
SWNT solutions are stable for weeks provided nobody spits on them. Indeed, addition of saliva, which contains a-amylase,
precipitate the nanotubes as the enzyme
breaks amylose down into smaller carbohydrate fragments, finally resulting in the formation of glucose. The enzymatic degradation of starch has been recently monitored
electronically by using NTFETs.[49] The experimental setup used for this study is displayed in Figure 8 as an individual nanotube 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 curGOx. 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
p-type device behavior. The device characto increase upon addition of glucose to the liquid. Insets: a) the same measurement on a secteristics, i.e., the source-drain current ISD as
ond device, where the conductance was a factor of 10 lower; b) the same measurement on a
semiconducting SWNT without GOx. No conductance increase is observed in this case. Reproa function of the gate voltage VG, were
duced with permission from [44]. Copyright 2003 The American Chemical Society. Right: Schemeasured 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 carbon 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 nanoand the device characteristics were found to be shifted by aptubes were able to recover by increasing the pH, by decomproximately 2 V towards more negative gate voltages. The diposing hydrogen peroxide, and by dialytically removing it.
rection of the shift equates with electron doping of the nanoThey also suggested possible enzyme-assisted molecular rectube channel by the polysaccharide. Quantitatively similar
ognition applications of biological species whose enzyme-catdoping 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
have recovered almost completely to the trace recorded beNanotubes
fore the starch deposition (Fig. 8). This observation indicates
that during the enzyme-catalyzed reaction nearly all the
Previously, it has been shown that polysaccharides such as
starch deposits on the surface of the nanotube device are hystarch, gum Arabic, and the b-1,3-glucans, curdlan and schizodrolyzed to glucose, which is washed off by the buffer prior to
phyllan, will solubilize SWNTs in water.[47] It has been prothe electronic measurements.
posed that at least some of these polymers achieve this by
wrapping themselves around SWNTs in a helical fashion. Solubilization of SWNTs with cyclodextrins (CD), which are
macrocyclic polysaccharides, has been investigated re4. DNA Detection by Using Carbon Nanotubes
cently.[47] The observed aqueous solubility of SWNTs with
c-CD is unlikely the result of encapsulation, because the inner
To date, there are several reports on the electrochemical decavity dimensions of this CD are far too small to allow it to
tection of DNA hybridization by using carbon nanotube electhread onto even the smallest-diameter SWNTs. More retrodes.[26] For example, Li et al.[52] were able to covalently link
cently, however, it has been shown[48] that g-CD has 12
DNA onto the tips of carbon nanotube arrays for electroa-1,4-linked D-glucopyranose residues and is therefore large
chemical DNA detection. Other groups have focused on the
enough to be able to thread onto SWNTs, and does so in
covalent functionalization aspect of carbon nanotubes by
water; not only solubilizing the nanotubes but also permitting
DNA or other nucleic acids of this type, as well.[53,54]
some partial separations according to their diameters.

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© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Adv. Mater. 2007, 19, 1439–1451

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

AMG

Glucose

O

HO
HO

HO OH

Starch

Source

Drain

SiO2
Gate
b)

DNA–SWNT interactions in water originate from the nucleic
acid–base p–p stacking on the nanotube surface, resulting in a
hydrophilic sugar–phosphate backbone pointing to the exterior, thereby achieving solubility in water. Similarly to carbohydrates (e.g., amylose), the mode of interaction may be helical
wrapping or simple surface adsorption (Fig. 9). The charge
differences among the DNA–SWNT conjugates, which are associated with the negatively charged phosphate groups of
DNA and the different electronic properties of SWNTs, have
allowed postproduction preparation of samples enriched in
metallic and semiconducting SWNTs.[56] Work done by Strano’s group looks into DNA polymorphism on nanotubes.[57]
They found that the conformational rearrangement of a biomolecule could be transduced directly by a SWNT system. In
a second study, this group looked at DNA–SWNTs used as a
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, trimethylamine (TMA), methanol, dimethyl methylphosphonate
(DMMP), and dinitrotoluene (DNT).

REVIEW

OH

a)

4.2. NTFET Detection of DNA Hybridization
Generally, most biological processes including DNA hybridization involve electrostatic interactions and charge trans-

1.2

c)

ISD / µA

1
0.8

Bare

0.6

After
AMG

0.4
0.2

After
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) Highresolution 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 deposition, as well as after hydrolysis with AMG. Reproduced with permission 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

Adv. Mater. 2007, 19, 1439–1451

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 linearly adsorbed structures. In all cases, the bases (red) orient to stack
with the surface of the nanotube, and extend away from the sugar–phosphate backbone (yellow). Reproduced with permission from [55]. Copyright 2003 Macmillan Publishers Ltd.

© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

www.advmat.de

1447

fer, which allows electronic detection using NTFET devices.
However, the exact mechanism of the nanoelectronic detection still remains unclear. The selective attachment of DNA
molecules on various segments of the NTFET device can allow, in principle, to investigate the sensing mechanism of the
nanotube biosensor. DNA molecules attached to the nanotube will mostly influence FET characteristics by electron depletion 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
sensing results to the attachment mode, one can obtain information about the mechanism of NTFET biosensing.
NTFET devices have been used for DNA detection. DNA
hybridization was studied on the surface at the gate of
NTFETs.[60] As a result, the conductance in SWNTs was
changed through the gate insulators. In this work, 5′ end-amino modified peptide nucleic acid (PNA) oligonucleotides
were covalently immobilized onto the NTFET back-gate Au
surfaces. PNA mimicked the behavior of DNA and hybridized
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, revealing 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 electrical 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, instead of SWNT sidewalls, is mainly responsible for the electrical conductance change owing to the modulation of the energy 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 processes are rapidly being developed towards the goal of rapid, simple, and inexpensive testing of genetic and infectious diseases.
Whereas electrochemical methods rely on the electrochemical
behavior of the labels, measurements of the direct electron

1448

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a)

Pt
MCH
+10 mV

Au
Thiolated ssDNA (Probe)
Complementary ssDNA (Target)
b) 1.04

5 µL
L PBS

1.02

100 nM

1

mismatched

0.98

G/G0

REVIEW

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

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 electrodes. b) Real-time monitoring of 30 mer DNA hybridization in PBS,
pH 7.4. Two liquid cells were used in parallel for simultaneous drop adding 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]. Copyright 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 allele-specific assay to detect the presence of SNPs using a network of carbon nanotubes as NTFETs has been recently developed.[62] This assay shows a statistical reproducibility
means. The technique included the ability to differentiate between both mutant (mut) and wild type (wt) alleles. By functionalizing 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 associated with hereditary hemochromatosis, a common and
easily treated disease of iron metabolism.[63]

© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Adv. Mater. 2007, 19, 1439–1451

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

probe_wt
G (µS)

300

200

HFE-H.wt

100

0
-10

-5

0

5

10

5

10

Vg (V)
b) 1000

probe_mut

G (µS)

800
600
400

HFE-H.wt

200
0
-10

-5

0

c) 0.18

30

0.1

15

0.06

10
5

0.02

0
-0.02
Electronic

Optical

-5

Figure 11. Electronic detection of the presence of single nucleotide polymorphism (SNP) in synthetic HFE amplicons. a) G–Vg curves after incubation with allele-specific wild-type (wt) capture probe and after challenging 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 assays. 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 biomolecule detection using carbon nanotube system have been summarized here. SWNTs appear as structurally defined components 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 applications. This area requires further development, particularly re-

Adv. Mater. 2007, 19, 1439–1451

Received: September 8, 2006
Revised: November 17, 2006
Published online: April 30, 2007

20
Signal, mfi

Signal, 1-G/G0

25

Wild Type
Mutant

0.14

REVIEW

lated to the improved fabrication methods of FETs in which
complex arrays consisting of semiconducting SWNTs are created. However, there has already been progress to show reproducible device characteristics with biosensor sensitivities
in the picomolar range.[62] The addressability of nanocircuitry
elements is particularly important.[64,65] Biomaterials linked to
nanotubes may be used as binding elements for the specific
linkage of the nanotube to surface in the form of addressable
structures.
The localized nanoscale contacts of SWNTs with biosurfaces will be a major advance in understanding and exploring
the new applications. The use of nanodevices to monitor a
variety of biologically significant reactions is envisioned.[66] In
the future, it should be possible to connect living cells directly
to these nanoelectronic devices to measure the electronic responses 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
nanotubes based bioelectronics.
Several research groups are looking into possible in vivo
applications of carbon nanotubes for the advancement of
nanoscience.[31,67] By examining the compatibility of carbon
nanotubes with the human immune system, we are witnessing
the possibilities of drug-delivery systems, cancer therapy, viral
detectors, and glucose sensors. In any case, the possibilities for
medical applications of carbon nanotubes at this point are
seemingly limitless.

a) 400


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