Nanowire-Based Electrochemical Biosensors Review

533
Review
Nanowire-Based Electrochemical Biosensors
Adam K. Wanekaya, Wilfred Chen, Nosang V. Myung,* Ashok Mulchandani*
Department of Chemical and Environmental Engineering and Center for Nanoscale Science and Engineering, University of
California, Riverside, CA 92521, USA
*e-mail: [email protected]; [email protected]
Received: October 27, 2005
Accepted: January 17, 2006
Abstract
We review recent advances in biosensors based on one-dimensional (1-D) nanostructure field-effect transistors (FET).
Specifically, we address the fabrication, functionalization, assembly/alignment and sensing applications of FET based
on carbon nanotubes, silicon nanowires and conducting polymer nanowires. The advantages and disadvantages of
various fabrication, functionalization, and assembling procedures of these nanosensors are reviewed and discussed.
We evaluate how they have been used for detection of various biological molecules and how such devices have
enabled the achievement of high sensitivity and selectivity with low detection limits. Finally, we conclude by
highlighting some of the challenges researchers face in the 1-D nanostructures research arena and also predict the
direction toward which future research in this area might be directed.
Keywords: Nanosensors, Biosensors, Field effect transistors (FETs), Carbon nanotubes, Conducting polymer
nanowires, Silicon nanowires, Metallic nanowires, One-dimensional nanostructures, Assembly, Magnetic alignment,
Functionalization
DOI: 10.1002/elan.200503449
1. Introduction
One dimensional (1-D) nanostructures such as nanowires,
nanotubes, nanobelts and nanosprings have become the
focus of intensive research due to their unique properties
and their potential for fabrication into high density nanoscale devices including sensors, electronics, and optoelectronics. Further, 1-D nanostructures can be used for both
efficient transport of electrons and optical excitation, and
these two factors make them critical to the function and
integration of nanoscale devices. In fact, 1-D systems are the
smallest dimension structures that can be used for efficient
transport of electrons and are thus critical to the function
and integration of these nanoscale devices. Because of their
high surface-to-volume ratio and tunable electron transport
properties due to quantum confinement effect, their electrical properties are strongly influenced by minor perturbations (Fig. 1). Compared to 2-D thin films where binding to
the surface leads to depletion or accumulation of charge
carriers only on the surface of a planar device (Fig. 1A), the
charge accumulation or depletion in the 1-D nanostructure
takes place in the “bulk” of the structure (Fig. 1B) thus
giving rise to large changes in the electrical properties that
potentially enables the detection of a single molecule. 1-D
nanostructures thus avoid the reduction in signal intensities
that are inherent in 2-D thin films as a result lateral current
shunting. This property of the 1-D nanostructures provides a
sensing modality for label-free and direct electrical readout
when the nanostructure is used as a semiconducting channel
of a chemiresistor or field-effect transistor [1]. Such labelElectroanalysis 18, 2006, No. 6, 533 – 550
free and direct detection is particularly desirable for rapid
and real-time monitoring of receptor – ligand interaction
with a receptor-modified nanostructure, particularly when
the receptor is a biomolecule such as antibody, DNA, and
proteins. This is critical for clinical diagnosis and biowarfare
agents detection applications. Additionally, the sizes of
biological macromolecules, such as proteins and nucleic
acids are comparable to nanoscale building blocks. Therefore, any interaction between such molecules should induce
significant changes in the electrical properties of 1-D
nanostructures. Further, 1-D nanostructures offer new
capabilities not available in larger scale devices (for
example, study of single molecule properties).
This review summarizes recent advances in biosensors
based on 1-D nanostructures. Fabrication methods of 1-D
nanostructures are reviewed in Section 2, followed by the
assembly and functionalization of the 1-D nanostructures in
Sections 3, 4 and 5. In Section 6, some significant applications of 1-D nanostructures based sensors are discussed. In
Section 7, the possible future directions of nanosensors
based on 1-D nanostructures are suggested.
2. Fabrication of 1-D Nanostructures
A good method for generating 1-D nanostructures should
enable simultaneous control of the dimensions, properties,
and morphology. In general, 1-D nanostructures are synthesized by promoting the crystallization of solid-state structures along one direction by various mechanisms including:
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Fig. 1. The major advantage of 1-D nanostructures (B) over 2-D
thin film (A). Binding to 1-D nanowire leads to depletion or
accumulation in the “bulk” of the nanowire as opposed to only the
surface in 2-D thin-film case.
– use of templates with 1-D morphologies to direct the
formation of 1-D nanostructures
– use of the intrinsically anisotropic crystallographic structure of a solid to achieve 1-D growth
– use of a liquid/solid interface to reduce the symmetry of a
seed
– use of appropriate capping agents to kinetically control
the growth rates of various facets of a seed.
The objective of this Section is to briefly describe methods
used to fabricate 1-D nanostructures such as silicon nanowires (SiNWs), carbon nanotubes (CNTs), and conducting
polymer nanowires (CP NWs).
a graphite target held in a controlled atmosphere oven at
temperatures near 1200 8C is vaporized by a laser and the
vapors condensed over a water-cooled target. To produce
SWNTs, the graphite target is doped with a catalyst [5].
Both the arc-discharge and the laser ablation techniques
produce a limited volume of sample in relation to the size of
the carbon source (the anode in arc-discharge and the target
in laser ablation) and require subsequent purification steps
to separate the tubes from undesirable byproducts. These
limitations have motivated the development of gas-phase
techniques, such as chemical vapor deposition (CVD), in
which nanotubes are formed by the decomposition of a
hydrocarbon or carbon monoxide gas. The gas-phase
techniques are amenable to continuous processes since the
carbon source is continually replaced by flowing gas. In
addition, the purity of the as-produced nanotubes can be
relatively high, minimizing subsequent purification steps.
Nikolaev et al. described the gas-phase growth of SWNTs
with carbon monoxide as the carbon source [6]. They
reported that the highest yields of SWNTs occurred at the
high temperature and pressure (1200 8C, 10 atm). Smalley
and his co-workers have refined the process to produce large
quantities of SWNTs with increased purity. Other gas-phase
techniques utilize hydrocarbon gases as the carbon source
for production of both single and multi-walled carbon
nanotubes [15 – 18].
2.2. Silicon Nanowires (SiNWs)
2.1. Carbon Nanotubes (CNTs)
Carbon nanotubes, first observed in 1991 [2], occur as multiwalled nanotubes (MWNTs) and single-walled nanotubes
(SWNTs) [3]. Primary methods for CNTs synthesis include
arc-discharge [2, 4], laser ablation [5], gas-phase catalytic
growth from carbon monoxide [6], and chemical vapor
deposition (CVD) from hydrocarbons [7 – 9]. Because
impurities in the form of catalyst particles, amorphous
carbon, and nontubular fullerenes are also produced during
CNTs synthesis, subsequent purification steps are required
to separate the tubes. The gas-phase processes tend to
produce nanotubes with fewer impurities and are more
amenable to large-scale processing.
The arc-discharge technique generally involves the use of
two high purity graphite rods as the anode and cathode. The
rods are brought together under a helium atmosphere and a
voltage is applied until a stable arc is achieved. The exact
process variables depend on the size of the graphite rods. As
the anode is consumed, a constant gap between the anode
and cathode is maintained by adjusting the position of the
anode. The material deposits on the cathode to form a
buildup consisting of an outside shell of fused material and a
softer fibrous core containing nanotubes and other carbon
particles. To create SWNTs, the electrodes are doped with a
small amount of catalyst particles [3, 4, 10 – 12].
Initially used for the production of fullerenes, laser
ablation technique has, over the years, been improved to
allow the production of SWNTs [5, 13, 14]. In this technique,
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The first reported synthesis of SiNWs by thermal evaporation was by Yu et al., who sublimed a hot-pressed Si
powder target mixed with Fe at 1200 8C in flowing Ar gas at a
pressure of ca. 100 Torr [19]. Using this simple method, they
obtained SiNWs with a diameter of ca. 15 nm and length
varying from a few tens to hundreds of microns.
The vapor – liquid – solid (VLS) method, involves the use
of liquid – metal solvents with low solubility for Si and other
elemental semiconductor materials. This method has been
very successful in producing SiNWs in large quantities and
at low temperatures [20]. The vapor – liquid – solid (VLS)
method is the most successful in generating large quantities
of nanowires with single crystalline structures. Originally
developed in 1964 for single crystals growth [21] the VLS
method has since been used to synthesize various inorganic
nanowires and nanorods [22 – 32]. In this VLS process, a
metal, such as gold, that forms a low temperature eutectic
phase with silicon is used as the catalyst for nanowire
growth. A Si gas source (silane or silicon tetrachloride) is
passed over the metal catalyst, which is heated to a
temperature greater than the eutectic temperature. The Si
gas source decomposes on the surface of the catalyst, and Si
diffuses into the metal, forming an alloy. Upon reaching
supersaturation, SiNWs are precipitated and the liquid alloy
drop remains on the nanowire as it grows in length. The
diameter of the SiNWs is controlled by the initial size of the
metal catalyst [33] and, to some extent, the growth
conditions [24, 34]. Porous alumina membranes have
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recently been used as an alternative to control nanowire
diameter in the VLS process [35, 36]. Defect-free SiNWs
with diameters in the range of 4 – 5 nm and lengths of several
microns were synthesized using a supercritical fluid solution-phase approach wherein alkanethiol-coated Au nanocrystals (2.5 nm in diameter) were used as seeds to direct the
one-dimensional crystallization of Si in a solvent heated and
pressurized above its critical point [37]. The reaction
pressure controlled the orientation of the nanowires.
Another method that has been used to synthesize high
purity SiNWs is the laser ablation technique. In this method
high purity, crystalline nanowires were obtained in high
yields [38] with diameters ranging from 3 to 43 nm and
lengths extending up to a few hundred microns. The
diameters of the nanowires synthesized using laser ablation
change with the ambient gas used during the process [39].
Thus, nanowires with different diameters have been synthesized in the presence of He, forming gas (95% Ar þ 5% H2),
and N2. Laser ablation has been combined with the VLS
method with good results to synthesize semiconductor
nanowires [40]. In this process, laser ablation generated
the nanometric catalyst clusters that then defined the size of
the Si/Ge nanowires produced by the VLS growth. The use
of targets of Si mixed with SiO2 enhanced the formation and
growth of SiNWs obtained by laser ablation [41, 42]. SiO2
plays a more important role than the metal in the laser
ablation synthesis of SiNWs.
Thermal methods have been applied to the synthesis of
SiNWs. For example, thermal evaporation of a mixture of Si
and SiO2 yielded SiNWs that consisted of a polycrystalline Si
core with a high density of defects and a silicon oxide shell
[43]. Highly oriented, long SiNWs have been obtained in
large yields on flat silicon substrates by the thermal
evaporation of SiO [44]. SiNWs have also been synthesized
by the thermal evaporation of SiO powders without any
metal catalyst [45]. These have been grown from particles
and the growth mechanism examined. The substrate temperature is crucial for controlling the diameter of the
nanowires, as well as the morphologies resulting from
thermal evaporation of SiO powders mixed with 0 – 1% Fe
[46]. Ultrafine SiNWs of diameters between 1 and 5 nm,
sheathed with a SiO2 outer layer of 10 – 20 nm, were
synthesized by oxide-assisted growth via the disproportionation of thermally evaporated SiO using a zeolite template
[47]. The zeolite restricted the growth of the nanowires
laterally and supplied the oxide to form the outer sheath.
2.3. Conducting Polymer Nanowires (CP NWs)
Among the methods that have been used to fabricate
conducting polymers on the nanometer scale are electrochemical dip-pen lithography, mechanical stretching [48],
electrospinning [49, 50] and template-directed electrochemical synthesis [51].
Dip-pen nanolithography (DPN) is a scanning probe
nanopatterning technique in which an AFM tip is used to
deliver molecules to a surface via a solvent meniscus which
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naturally forms in the ambient atmosphere. Doped polyaniline and polypyrrole lines down to 310 nm and 290 nm
widths, respectively, were formed using ionically charged
conducting polymers as the “ink” for writing on oppositely
charged substrates. Electrostatic interactions between the
water-soluble ink materials and charged substrates provided
a significant driving force for the generation of stable DPN
patterns on the silicon substrates [52]. Similarly, writing of
poly 3,4-ethylenedioxythiophene down to 30 nm by polymerization of 3,4-ethylenedioxythiophene at the AFM tip/
substrate was achieved [53].
In the mechanical stretching procedure, conducting
polymer nanowires are fabricated by electrochemical polymerization of the corresponding monomer onto a sharp
scanning tunneling microscope (STM) tip that is held at a
small distance (between 20 – 100 nm) from an electrode
followed by the reduction of the diameter of the deposited
polymer by stretching by moving the STM tip. Highly
conductive polyaniline wire with diameter of about 20 nm
has been reported using this method [48].
Conducting polymers as nanofibers have also been
fabricated by electrospinning. This method uses a microfabricated scanned tip as an electrospinning source. The tip
is dipped in a polymer solution to gather a droplet as a
source material. A voltage applied to the tip causes the
formation of a Taylor cone, and at sufficiently high voltages,
a polymer jet is extracted from the droplet. By moving the
source relative to a surface, acting as a counter-electrode,
oriented nanofibers can be deposited and integrated with
microfabricated surface structures. In addition to the uniform fiber deposition, the scanning tip electrospinning
source can produce self-assembled composite fibers of
micro-and nanoparticles aligned in a polymeric fiber [54 –
56].
Like other one-dimensional nanostructures, 1-D conducting polymer nanostructures can be synthesized by templatedirected methods. Porous anodic alumina oxide (AAO),
track-etched porous polymer membranes, and mica are the
three types of templates that are commonly used and
electrochemical deposition is usually the technique of
choice. Electrochemical deposition is accomplished by
coating one face of the template with an inert conducting
film (e.g. gold and platinum) and using this inert conducting
film as the anode. The polymer is then electrochemically
synthesized within the pores of the membrane. The length of
the nanowires is determined by the current density and
deposition time. Chemical template synthesis can be
similarly accomplished by simply immersing the membrane
into a solution of the desired monomer and its oxidizing
agent. The diameter of nanowire is determined by the pore
diameter of template. Figure 2 depicts a schematic of the
template-based synthesis process. Conducting polymers
show preferential deposition along the walls of the polycarbonate membrane resulting in nanotubule structures due
to solvophobic interactions. These tubules close up as the
deposition time is increased and eventually results in
nanowires [57, 58]. Following nanowires electrodeposition,
the conducting film used for electrochemical polymeriza-
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tion and the template are then subsequently dissolved using
appropriate acids or bases. Organic solvents may be used to
dissolve polymer templates. It has been shown that template-directed conducting polymer nanotubes and nanowires have higher electronic conductivities than bulk
samples of the same material. Furthermore, the mechanism
of electronic conduction in these template-directed nanostructures can be varied at will by changing their diameter
[59].
Direct electrochemical synthesis of large arrays of uniform and oriented nanowires of conducting polymers with a
diameter of less than 100 nm on a variety of substances such
as Pt, Si, Au and carbon without using a supporting template
was recently reported [60]. A three-step electrochemical
deposition procedure was utilized. In the first step, a large
current density was used to create the nucleation sites on the
substrate. The initial stage is followed by continued
polymerization with reduced current density.
Other researchers have used DNA as templates in the
fabrication of CP NWs. For example, He and co-workers
[61] synthesized polyaniline nanowires by stretching, aligning and immobilizing double-stranded l-DNA on a thermally oxidized Si chip by the molecular combing method
[62, 63]. Then the DNA templates were incubated in
protonated aniline monomer solution to emulsify and
organize the aniline monomers along the DNA chains.
Finally, the aligned aniline monomers were polymerized
enzymatically by adding horseradish peroxidase (HRP) and
H2O2 successively to form polyaniline/DNA nanowires.
Simmel and co-workers also synthesized polyaniline nanowires templated by DNA [64]. They found that DNA
templating worked best for polyaniline formed by oxidative
polymerization of aniline with ammonium persulfate, both
in solution and on templates immobilized on a chip.
However, immobilization of these structures between contact electrodes was compromised by extensive protein
adsorption to the surface. A photo-oxidation method using
ruthenium tris(bipyridinium) complexes as a photo-oxidant
resulted in less uniform polyaniline/DNA structures than
the other methods.
2.3.1. Individually Addressable Single Conducting Polymer
Nanowires
Although several examples of uses of the above methods of
synthesis and fabrication of 1-D nanostructures have been
reported, their full-scale development, particularly in highdensity arrays, have been limited for the following reasons
[65 – 67]:
– the harsh conditions, i.e. highly concentrated sodium
hydroxide or phosphoric acid and organic solvent,
respectively, required to dissolve alumina and polycarbonate templates in the template-synthesized conducting
polymer nanowires might not be suitable for many
biological applications.
– functionalization/modification for incorporation of specific sensing capabilities can only be performed as
postsynthesis and in many cases post-assembly.
– nanodevice fabrication requires complex postsynthesis
assembly using sophisticated manipulating tools.
In an attempt to address the above challenges, we recently
reported a facile technique for synthesis of high aspect ratio
(100 nm wide by up to 13 mm long), dendrite-free, single and
multiple individually addressable conducting polymer
nanowires by electrodeposition within nanochannels between two electrodes on the surface of silicon wafers [68, 69].
Figure 3 shows a cross section of the silicon wafer. The
deposition and growth of the nanowires were based on wellknown electrochemical oxidative polymerization, starting
with monomers and dopants. The procedure is a single-step
deposition process for each nanowire, and multiple-nanowire arrays of different materials can be deposited on the
same wafer sequentially. Polypyrrole (PPY) and polyaniline
(PANI) were used as models for demonstration.
Figure 4A shows the SEM image of a 100 nm wide and
3 mm long electrochemically grown PANI nanowire. The
nanowire is continuous, well-confined, and nondendrite,
spanning the entire length and making contact between the
two electrodes. Similarly, the ability to make individually
addressable nanowires in high density was demonstrated by
Fig. 2. Schematic of template-based synthesis of conducting polymer nanowires.
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Fig. 3. Schematic of e-beam lithographically patterned electrolyte channels with defined channel dimensions, showing cross-sectional
details.
making two 200 nm wide by 2.5 mm long PPY nanowires
separated by 6 mm sequentially as shown in Figure 4B.
A complementary approach to the one reported above,
based on conducting polymer nanojunctions formed by
bridging two electrodes separated with a gap of 1 – 100 nm
with polymer, was reported by Tao and co-workers [70]. The
process is started with an array of electrode (Au or other
materials) pairs, 1 – 100 nm apart, fabricated on an oxidized
Si chip using either optical lithography or electron beam
lithography (Fig. 5a). The gap between the Au electrodes is
then reduced down to ca. 1 nm by first electrochemically
depositing Au onto the electrodes (Fig. 5b). This causes an
increase in the current flowing across the gap, due to
quantum tunneling effect (Fig. 5c). Because the tunneling
current is extremely sensitive to the gap width, the width can
be controlled using the tunneling current as a feedback
signal. Subsequently, taking advantage of the reversibility of
the electrochemical process, Au atoms are etched away from
the electrodes to enlarge the gap to the desired dimensions.
Once the nanoelectrodes separated with nm-scale gaps are
fabricated, the gaps are bridged with conducting polymers
(e.g., polyaniline and polypyrrole) to form nanojunctions by
cycling the potential of the nanoelectrodes in a solution
containing monomer (Fig. 6). The potential cycling converts
the monomers into polymers and deposited the polymers
into the gap. A controlled amount of polymer is deposited in
the gap by controlling the cycling time. Unlike the nanowires produced using preformed channels, the length to
width ratio of the nanojunction is not well controlled and the
aspect ratio is small. However, since the conductance path
defined by the separation between the electrodes is small,
this nanojunction approach is particularly suitable for
polymers that are poorly conductive under physiological
conditions, or polymers that lose much of their conductivity
upon attachment of receptor groups.
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3. Assembly/Alignment of 1-D Nanostructures
Although considerable progress has been made in the
synthesis of 1-D nanostructured materials, device fabrication is hindered by the lack of efficient processes that can
assemble the materials with the desired connectivity into
useful architectures and practical functional devices. Controlled assembly of nanostructures is necessary to realize
any meaningful applications. A good nanoscale assembly
technique should be affordable, fast, defect tolerant and
compatible with a variety of materials in various dimensions.
In fact, the key to the future success of nanotechnology will
depend on the availability of facile techniques for assembly
and alignment. Various methods have been utilized in the
assembly/alignment of 1-D nanostructures including magnetic, electric, fluid based and lithographic techniques.
3.1. Magnetic Alignment
The magnetic properties of template fabricated nanowires
made from ferromagnetic elements such as Co or Ni are
dominated by shape anisotropy due to their large aspect
ratios. After a nanowire has been magnetized, its magnetization remains along the wireNs axis with only two possible
orientations, like a magnetic dipole. Magnetic nanowires
exhibit interesting behavior when placed in fluid suspensions. Their large magnetic shape anisotropy and high
remnant magnetization make suspended nanowires highly
orientable and easily manipulated in small external magnetic fields. This property can be used to control the
interwire dipolar forces and hence obtain ordered structures. Additionally, the nanowires can be functionalized,
and this influences how they interact with the environment.
We recently demonstrated the assembly of segmented
nanowires between ferromagnetic electrodes by integrating
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Fig. 5. Fabrication of nanoelectrode arrays. a) Scanning electron
microscopy image of an array of Au electrode pairs on an oxidized
Si chip. The inset shows a pair of electrodes (a big and a small
one) separated with a gap of a few nm. b) The gap between the
electrodes in each pair decreases as one electrochemically
deposits atoms onto the electrodes, and the process is monitored
by the current across the gap. c) When the gap is reduced to a few
nm, electron tunneling takes place between the electrodes. The
tunneling current increases in discrete steps, reflecting the discrete
nature of atoms.
Fig. 4. A) SEM image of a 100 nm wide by 3 mm long PANI
nanowire [68]. B) SEM image of two 200 nm wide by 2.5 mm long
PPY nanowires separated by 10 mm, deposited one at a time [68].
ferromagnetic ends on segmented Ni/Bi/Ni (Fig. 7A) and
Ni/Au/Ni (Fig. 7B) nanowires and high density arrays of Ni/
Au/Ni nanowires (Fig. 7C) [71]. The assembly, alignment
and manipulation of the nanowires were achieved by using
the magnetic interaction between the nanowires and the
ferromagnetic electrodes. Further, we demonstrated how
magnetic field can be used to manipulate the directionality
of the nanowires (Fig. 8).
Crone and coworkers reported a method of manipulating
nonmagnetic metal nanowires, specifically CuSn alloy
nanowires, by capping them with nickel ends and using an
applied magnetic field to orient and align them between two
nickel electrodes [72]. We recently extended that principle
to the alignment of MWNTs [73]. Magnetic capped MWNTs
were thermally fabricated by evaporating nickel on top of a
vertical array of CVD grown MWNTs on silicon. Magnetic
interactions between the magnets on the nanotubes and the
ferromagnetic electrodes aligned and directed the placement of the nanotubes (Fig. 9).
Fig. 6. A) Polyaniline (PANI) and poly(acrylic acid) (PAA) nanojunction sensor. B) SEM image of PANI-PAA films deposited on gold
pads with 20 – 60 nm gaps [70].
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Fig. 7. Alignment of A) a single Ni/Bi/Ni nanowire on nickel
lines, B) an optical image of a single Ni/Au/Ni nanowire between
solder-plated nickel electrodes, and C) high-density arrays of Ni/
Au/Ni [71].
Other researchers have assembled Ni nanowires into long
chains using magnetic fields [74, 75]. The suspended nanowires showed a tendency to aggregate in a random manner
in the absence of an applied magnetic field, whereas
application of an external field of less than 10 Gauss
restrained the aggregation and aligned the suspended
nanowires, resulting in head-to-tail nanowires chains. This
phenomenon has recently been applied in the manipulation
and precise positioning of mammalian cells [76]. In this
technique, the cells were bound to Ni nanowires and
subjected to low magnetic fields, resulting in 1-D chains of
cells through the manipulation of the wiresN dipolar
interactions.
Tao and co-workers demonstrated a magnetic-fieldassisted method to assemble an array of electrically wired
conducting polymer junctions [77]. An aqueous solution
containing conducting polymer coated Au/Ni/Au metallic
bars was introduced onto an array of parallel microelectrodes on a silicon chip. In the presence of a magnetic field, the
polymer coated magnetic bars are aligned perpendicular to
the microelectrodes, thus enabling metal/polymer/metal
junctions between the two microelectrodes. Others have
also reported the surface functionalization of Ni nanowires
with porphyrin molecules and their subsequent magnetic
field-assisted alignment [78].
3.2. Electric Field Alignment
Fig. 8. Magnetically aligned Ni/Au/Ni nanowires at A) 458, B)
908, and C) 1358 with respect to the ferromagnetic lines [71].
Fig. 9. SEM image of a MWNT aligned across Ni electrodes on
Si [73].
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When an electric field is applied to a nanowire suspension, it
polarizes the nanowires, which forces them to align with
their length oriented parallel to the direction of the electric
field. The alignment quality is dependent on many factors,
including the field strength and thermal energy. Additionally, the length of the nanostructures has also been found to
be a factor because of its dependence on the anisotropy in
electric polarizability [79, 80].
Electric field-assisted assembly has been used to align
individual Au nanowires from colloidal suspensions onto
electrodes [79, 81]. Nanowires are electrically polarized and
aligned with electrodes by alternating the electrical field
through manipulating voltage and frequency. Carbon nanotubes have also been aligned with an alternating current
electric field [82]. The influence of electric field type on the
assembly of carbon nanotubes was studied recently [83]. The
dc electric field resulted in a lower number of aligned
nanotubes across the electrodes. However, an ac electric
field proved to be more effective in the alignment of CNTs.
This procedure also straightened the entangled CNTs at
high frequencies [84]. Using the ac electric field procedure, a
self assembled monolayer (SAM) of NH2(CH2)11SH was
first allowed to form on a gold surface. The Au substrate was
then immersed in an ethanol solution containing SWNTs
that were modified at both ends with carboxyl groups. The
assembly of the SWNTs was obtained through the electrostatic interactions between the positively charged amino
groups on the gold surface and the negatively charged
carboxyl groups at the ends of the SWNTs. Application of dc
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electric field on the two gold substrate electrodes induced
the alignment of SWNTs along the electric field. Silicon
nanowires (SiNWs) have also been aligned by the application of an electric field [85].
3.3. Lithography
Heath and coworkers demonstrated the fabrication of metal
and semiconductor nanowires of controllable dimensions
and ultrahigh density using lithographic techniques by
transferring prefabricated nanowires from templates to
other surfaces [86]. However, it is still difficult to apply this
scheme beyond the fabrication of grids of identical metal or
silicon nanowires.
motivated by the recent activities in biological applications
of novel solid-state nanomaterials. The unique physical
properties of molecular-scale or nanoscale materials, when
utilized in conjunction with the remarkable biomolecular
recognition capabilities, could lead to miniature biological
electronic devices, including probes and sensors. The interface between biological molecules and nanomaterials is
therefore critical to such applications. Like in planar
materials, functionalization in 1-D nanostructures can
generally be divided into covalent and noncovalent functionalization. However, covalent sidewall functionalization
of nanotubes from sp2 to sp3 structure is both difficult and
results in loss of conjugation. In this Section, we discuss the
functionalization of CNTs, SiNWs and metallic nanowires.
4.1. Covalent Functionalization with Biomolecules
3.4. Langmuir – Blodgett Techniques
The Langmuir – Blodgett (LB) technique has been extensively used in the preparation of monolayers for molecular
electronics and more recently to create nanocrystal monolayers with tunable properties [87]. The application of LB
techniques has been extended to the assembly of 1-D
nanostructures with large aspect ratios [88] and assembly of
SiNWs [89] and silver nanowires [90] have been demonstrated. The procedure starts with dispersing the nanowire
suspensions on the water surface of a Langmuir – Blodgett
trough using surfactants. The interaction between the
surfactants and the nanowires causes the nanowires to float
on the water surface and to align themselves parallel to the
trough barriers, forming a closely packed monolayer which
then can be transferred to planar substrates. LB is thus the
best method for aligning 1-D nanostructures with a large
aspect ratio over a wide area. However, difficulties in
providing electrical contacts to individual nanowires and the
lack of geometric versatility are challenges that need to be
addressed.
3.5. Biomolecule Mediated Self-Assembly
Braun and his co-worker reported the DNA mediated self
assembly of FETs based on CNTs [91]. In this approach, a
SWNTwas localized at a desired address on a DNA scaffold
molecule, using homologous recombination by the RecA
protein from E. Coli. DNA metallization led to the
formation of wires that contacted the SWNT. Similarly,
the ability of peptides to assemble SWNTs has also been
demonstrated [92, 93].
Covalent functionalization is a chemical process in which a
strong bond is formed between the 1-D nanostructured
material and the biological molecule or its linkers. In many
cases, some previous chemical modification of the surface is
necessary to create active groups that are necessary for the
binding of biomolecules. The most commonly used method
for the covalent binding of biomolecules onto 1-D nanostructures is through the diimide-activated amidation of
carboxylic acid terminated nanostructures. Alternatively, it
is possible to covalently functionalize amine-terminated 1D nanostructures with biomolecules.
4.1.1. Carbon Nanotubes
One of the most powerful methods that is particularly
suitable for the preparation of soluble CNTs is the 1,3dipolar cycloaddition of azomethine ylides [94]. In this
method, a suspension of pristine carbon nanotubes in
dimethylformamide (DMF) is reacted with N-substituted
glycine and an aldehyde (Scheme 1).
Bioactive peptides can be covalently linked to SWNTs
through a stable bond by the fragment condensation of fully
protected peptides (Scheme 2a) [95]. Using this chemistry,
SWNTs with azomethine ylides groups, produced using the
Scheme 1 described above, can be coupled to a peptide
(BM-COOH) by reacting the N-terminal and side-chain
protected peptide that has been activated with O-(7-azaN-hydroxybenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
4. Functionalization of 1-D Nanostructures
Functionalization is an important aspect of the chemistry of
1-D nanostructured materials as chemical modification is
often necessary for their functionality and biocompatibility.
1-D nanostructure functionalization with biomolecules is
Electroanalysis 18, 2006, No. 6, 533 – 550
Scheme 1. General scheme for the 1,3-dipolar cycloaddition of
azomethine ylides CNTs [94].
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Scheme 2. Covalent funtionalization of CNTs with biomolecules. BM: biomolecule; DIEA: diisopropylethylamine; DMF: dimethylformamide; EDC: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; HATU: O-(7-aza-N-hydroxybenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; NHS: N-hydroxysuccinimide; SMCC: succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate;
TFA: trifluoroacetic acid.
hexafluorophosphate (HATU) and diisopropylethylamine
(DIEA) in dimethylformamide (DMF). The peptide-derivatized CNT can then be isolated and the protecting groups
subsequently removed by treating the conjugate with
trifluoroacetic acid (TFA) as illustrated in Scheme 2a.
The most commonly used method for the covalent binding
of proteins onto CNTs utilizes the diimide-activated amidation of carboxylic acid-functionalized CNTs (Scheme 2b
and 2c) [96 – 99]. Similarly, it is possible to link amineterminated DNA to carboxylic acid functionalized CNTs
using the diimide chemistry [95, 96]. Alternatively, it is
possible to covalently functionalize amine-terminated
CNTs with DNA via the heterobifunctional cross-linker
succinimidyl
4-(N-maleimidomethyl)cyclohexane-1-carboxylate, (SMCC) (Scheme 2d) [100]. In this procedure,
purified SWNTs are oxidized to form carboxylic acid groups
at the ends and sidewalls. These are reacted with thionyl
chloride and then ethylenediamine to produce amineterminated sites. The amines are then reacted with SMCC,
leaving the surface terminated with maleimide groups.
Finally, thiol-terminated DNA is reacted with these groups
to produce DNA-modified SWNTs.
Carbon nanotubes have also been covalently functionalized by bovine serum albumin (BSA) proteins via diimideactivated amidation as demonstrated by Sun and co-workers
[101] and by reaction of the oxidized carboxyl group by
amine terminated DNA [102, 103].
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4.1.2. Silicon Nanowires
The most commonly used method for the modification of
the SiNW surface is silanization. Before surface modification, the surface of the SiNWs is treated with water-vapor
plasma. The plasma treatment cleans the nanowire surface
and generates a hydrophilic surface by hydroxyl-terminating the silicon oxide surface. The hydroxide layer is then
activated with an organosilane, which introduces reactive
groups. A desired biomolecule may then be covalently
attached by a variety of methods as illustrated in Scheme 3.
In the first case the SiNWs are reacted with 3-(trimethoxysilyl)propyl aldehyde resulting in aldehyde terminated
surfaces. The modified nanowires are then reacted with the
biomolecule in sodium cyanoborane resulting in a covalent
linkage of the biomolecule to the SiNW (Scheme 3b) [104 –
106]. Alternatively, the SiNWs are reacted with 3-mercaptopropyltrimethoxysilane by gas- phase reaction in Ar
followed by the immobilization of biolomolecules that are
modified with acrylic phosphoramide. This technique was
used for the functionalization of SiNWs with DNA probes
modified with acrylic phosphoramide at the 5N-end [107].
The use of photochemical hydrosilation to functionalize
free standing SiNWs with DNA without an intervening
oxide was recently demonstrated [108]. In this procedure
hydrogen terminated SiNWs are covalently linked to 10-NBoc-Amino-dec-1-ene through ultraviolet (UV) initiated
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Scheme 3. Covalent functionalization of SiNWs with biomolecules. BM: biomolecule; SMCC: succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate; TFA: trifluoroacetic acid.
reaction (Scheme 3a) [109]. Removal of the t-Boc protecting group leaves primary amines covalently linked to the
SiNW surface. Thiol-terminated DNA is then covalently
linked to the amines with the help of the heterobifunctional
linker, SMCC.
Martin and co-workers have demonstrated the differential functionalization of silica nanotubes with two distinct
kinds of silane molecules on the inner and outer surfaces of
the nanotubes [110] by first modifying the inner surfaces of
the nanotubes with the first silane when it is still embedded
within the pores of the template membrane. This silane
attaches to the inner nanotube surfaces because the outer
surfaces are in contact with the pore wall and are thus
masked. The template was then dissolved to liberate the
nanotubes, which unmasked the outer nanotube surfaces
and the nanotubes were then exposed to a second silane to
attach this silane to only the outer nanotube surfaces.
Antibodies or other biological material can then be attached
to the silane functionalized surface.
Although covalent modification of 1-D nanostructures is
very robust, it has the disadvantage of impairing the physical
properties of 1-D nanostructures in most cases. Many
covalent functionalization protocols require a multistep
procedure and often concentrated acids and strong oxidizers
are used for the modification of the surfaces prior to
attachment of the biological molecules.
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4.2. Noncovalent Functionalization of 1-D Nanostructures
with Biomolecules
In contrast to covalent functionalization, noncovalent
functionalization can immobilize molecules on the 1-D
nanostructures without destroying their geometric and
electronic structures. Noncovalent interactions are of critical importance in many biological systems, including the
complex tertiary structure of proteins and the hydrogen
bonding network that holds together complementary
strands of DNA. Hydrophobic and hydrophilic interactions
are involved in passive adsorption of proteins to surfaces.
4.2.1. Carbon Nanotubes
Matsui and co-workers developed a method to functionalize
CNTs with avidin only at the ends of nanotubes using Au
nanocrystals as protective masks on the sidewalls of the
nanotubes [111]. While the Au nanocrystal-masked nanotubes adsorbed avidin on their entire surfaces, the chemical
etching of the Au nanocrystal masks removed avidin
molecules only from the sidewalls leaving avidin at the
nanotube ends bound. The chemical etching process did not
denature avidin, and the nanotube ends could recognize and
immobilize onto the self-assembled monolayers of complimentary biotin (Scheme 4).
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Scheme 4. Procedure to immobilize proteins at the ends of nanotubes using Au nanocrystals as protective masks. Step 1) Thiolation of
the nanotube sidewalls. Step 2) Au nanocrystal coating as a mask on the sidewall of the nanotube. Step 3) Incubation of sulforhodaminelabeled avidin in the nanotube solution. Step 4) Chemical etching of the Au nanocrystals on the sidewalls . Step 5) Immobilization of
biotin [111].
As means to prevent protein binding, Dai and co-workers
reported the functionalization of SWNTs by coadsorption of
a surfactant and poly(ethylene glycol) [112]. This was found
to be effective in resisting nonspecific adsorption of
streptavidin. Specific binding of streptavidin onto SWNTs
was achieved by co-functionalization of nanotubes with
biotin and protein-resistant polymers. Polyethylene oxide
(PEO) chains have also been used to overcome nonspecific
binding on nanotubes. For example, nonspecific binding of
proteins on the nanotubes was overcome by immobilization
of PEO chains [113]. Other non covalent protein immobilization techniques demonstrated by the Dai group involved
the bifunctional molecule, 1-pyrenebutanoic acid succinimidyl ester irreversibly adsorbed onto the SWNTs prior to
being reacted with a desired protein [114].
4.2.2. Silicon Nanowires
Lieber and co-workers used non covalent affinity immobilization to functionalize SiNWs with peptide nucleic acid
(PNA) [115]. In this procedure, SiNWs were incubated in a
pyridine solution containing biotinyl p-nitrophenyl ester
and 4-(dimethylamino)pyridine. The SiNWs were then
exposed to avidin and finally linked with biotinylated
PNA probes.
4.2.3. Metallic Nanowires
Mallouk and co-workers demonstrated that DNA-functionalized nanowires could be used as building blocks of surface
assemblies [116]. Single-strand DNA (ssDNA) was modiElectroanalysis 18, 2006, No. 6, 533 – 550
fied with a thiol at the position 5N and tetramethyl rhodamine at the position 3’. The ssDNA was reacted with gold
nanowires and the ssDNA coated nanowires were then
allowed to hybridize with ssDNA coated gold surfaces.
Optical micrographs showed that the gold surface functionalized with the complementary ssDNA strand had four
times as many gold nanowires attached to its surface as did
surfaces functionalized with noncomplementary DNA.
Biological functionalization has also been extended to
segmented nanostructures. Because the different metallic
segments have distinct surface chemistry, it is possible to
achieve spatially selective functionalization along the nanowire length [117]. Figure 10 shows the selective functionalization of an Au/Pt/Au nanowire, based on the differential
reactivity of Pt and Au towards thiols and isocyanides. A
butaneisonitrile monolayer on the Au /Pt/Au wire surface is
replaced by a SAM of 2-mercaptoethylamine (MEA) only
on Au, and not on Pt. The MEA-bearing gold portion of the
nanowires can be tagged with a fluorescent indicator
molecule to image the spatially localized SAMs along the
length of the nanowires.
In another example, nickel-gold nanowires were differentially functionalized by palmitic acid and hexa(ethylene
glycol) terminated long chain thiol [118]. Gold surfaces were
functionalized with alkanethiols with terminal hexa(ethylene glycol) groups (EG6), while nickel surfaces were
functionalized with palmitic acid. When exposed to a
fluorescently tagged protein, hydrophobic nickel wires
exhibited bright fluorescence while EG6-terminated gold
wires did not, indicating that the protein did not adhere to
the EG6-functionalized nanowires. Nickel-gold nanowires
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Fig. 10. Top: Successive derivatization of Au/Pt/Au nanowires with butaneisonitrile and MEA. To make the MEA-bearing ends
distinguishable by fluorescence microscopy, the MEA molecules were coupled with rhodamine B isothiocyanate. Bottom: a) bright field
optical micrograph and b) fluorescence micrograph of derivatized Au/Pt/Au nanowires (1000 magnification) [117].
presenting distinct segments of alkyl and EG6 surfaces were
also exposed to the fluorescent protein. Fluorescence was
only observed on the nickel segment of these wires,
demonstrating that proteins selectively adsorbed to one
portion of these multicomponent nanostructures.
5. Functionalization of CP NWs
Most of the research in the functionalization of conducting
polymers has been based on thin-films. However the same
techniques should also be applicable in the functionalization
of conducting polymer nanowires. Various functional
groups can be immobilized within the conducting polymers
(CP) matrix inducing specific properties in the polymer.
This process offers attractive possibilities to develop materials that show behaviors resulting from the combination of
properties due to CPs and those due to the functional
groups. The functionalization of conducting polymers can be
carried out in three ways: before, during, and after the
polymerization process. The fourth procedure is an entrapment technique where the target material is immobilized
during electrochemical polymerization processes.
The first technique involves covalently linking a specific
group to the starting monomer and subsequently preparing
the functionalized polymer. For example the hydrogen
attached to the nitrogen on the pyrrole molecule can be
easily substituted with a specific group. This method can be
adopted only if the specific group is stable during the
polymerization.
In the second route, some of the specific anions can be
electrostatically incorporated simultaneously during the
Electroanalysis 18, 2006, No. 6, 533 – 550
electropolymerization. In this way, the functionalization is
obtained if the doping anion is irreversibly captured in the
polymer matrix. The incorporation of anionic complexing
ligands to the conducting polymers comes under this
category. For example, Wang and co-workers reported the
incorporation of polypyrrole nanowires with CNTs using a
template-directed electrochemical synthetic route [119].
PPy was electrodeposited in the pores of a host membrane in
the presence of shortened and carboxylated CNT dopants
that served as charge balancing counterions. The electron
flow within these composite nanowires was enhanced by the
CNTs. Using a similar procedure the same group demonstrated a one-step preparation route of amperometric
enzyme electrodes based on incorporating a CNT dopant
and glucose oxidase (GOx) enzyme within an electropolymerized polypyrrole film [120]. The CNT dopant retained its
electrocatalytic activity to impart high sensitivity upon
entrapment within the PPy network. Such simultaneous
incorporation of CNT and GOx thus imparts biocatalytic
and electrocatalytic properties onto amperometric transducers and represents a simple and effective route for
preparing enzyme electrodes.
The third procedure is the postpolymerization functionalization method. In this case, the functionalization is
performed after the polymerization. An appropriate functional group in a polymer is allowed to covalently bind to
another functional group of a specific molecule. This
approach requires the electrosynthesis of CPs possessing
reactive entities used as anchoring points to graft the
functional groups. A good example is the postpolymerization functionalization of poly(N-substituted pyrrole) film
[121].
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The fourth way involves entrapment of target molecules
within conducting polymers. This route involves the application of an appropriate potential to the working electrode
soaked a solution containing the target molecule, the
monomer and dopant. However, in some cases, physical
entrapment and steric, hindrances may drastically reduce
the catalytic activity and flexibility of some immobilized
biomolecules such as enzymes as observed in polymer films
[122, 123]. On the other hand, an advantage of this method is
that entrapment of the molecules occurs without any
chemical reaction that could affect their activity. For
example we recently entrapped biological molecules within
conducting polymer nanowires using a procedure that is
safe, fast and convenient [124]. In this process, avidin was
entrapped during the electrochemical polymerization of
polypyrrole in a single step protocol within a 100 nm-wide
channel connecting 2 electrodes resulting in avidin-functionalized CP NW of controlled dimensions and high aspect
ratio. Similarly, Mallouk and co-workers reported the
fabrication of gold-capped, protein-modified polypyrrole
nanowires using a porous aluminum oxide template [125].
Fig. 11. Conductance-versus-time data recorded for the simultaneous detection of PSA, CEA and mucin-1 on p-type siliconnanowire array in which NW1, NW2 and NW3 were functionalized with mAbs for PSA, CEA and mucin-1, respectively. The
solutions were delivered to the nanowire array sequentially as
follows: 1) 0.9 ng/mL PSA, 2) 1.4 pg/mL PSA, 3) 0.2 ng/mL CEA,
4) 2 pg/mL CEA, 5) 0.5 ng/mL mucin-1, 6) 5 pg/mL mucin-1.
Buffer solutions were injected following each protein solution at
points indicated by black arrows [105].
6. Applications of 1-D Nanostructures in Biosensing
6.1. Protein Detection
1-D nanostructured materials have been used in the
detection of various protein molecules. An excellent
example is in the detection of cancer marker proteins.
Cancer marker proteins are molecules occurring in blood or
tissue that are associated with cancer and whose measurement or identification is useful in patient diagnosis or
clinical management. Recent studies have indicated that 1D nanostructures are very capable of sensitive and selective
real-rime detection of these markers. For example, Lieber
and co-workers have reported a highly sensitive and multiplexed detection of cancer marker proteins using Si NWs
[105]. Modification of the arrays with cancer marker antibodies allowed real-time multiplexed detection of free
protein specific antigen (f-PSA), PSA-a-antichymotrypsin
(PSA-ACT) complex, carcinoembryonic antigen (CEA)
and mucin-1 with good signal-to-noise ratios down to a 50- to
100-fg/mL level (Fig. 11). High selectivity and sensitivity to
concentrations down to 0.9 pg/mL of the targeted cancer
markers was achieved in undiluted serum samples. The
incorporation of PSA antibody functionalized p- and n-type
nanowires in a single sensor chip enabled discrimination of
possible electrical cross-talk and/or false-positive signals in
the detection of PSA by correlating the response versus time
from the two types of device elements (Fig. 12). Real and
selective binding events showed complementary responses
in the p- and n-type devices. The magnitudes of the
conductance changes in the two devices were nearly the
same and consistent with the concentration-dependent
conductance measurements.
Complementary responses in the p- and n-type devices
were also recently demonstrated by Zhou [126] (Fig. 13). In2
Electroanalysis 18, 2006, No. 6, 533 – 550
Fig. 12. Complementary sensing of PSA using p-type (NW1) and
n-type (NW2) silicon-nanowire devices in the same array. The
vertical solid lines correspond to times at which PSA solutions of
1) 0.9 ng/mL, 2) 0.9 ng/mL, 3) 9 pg/mL, 4) 0.9 pg/mL, and 5) 5 ng/
mL were connected to the microfluidic channel [105].
O3 NW and SWNT mat surfaces were functionalized with
PSA antibody. Subsequent electronic detection of PSA
revealed enhanced conduction for In2O3 nanowire devices
and suppressed conduction for SWNT devices upon PSA
exposure, with sensitivity down to 5 ng/mL.
1-D- nanostructures have also been used for the detection
of other proteins. For example, biotin-functionalized SiNWs
have been utilized for the label-free detection of streptavidin and monoclonal antibiotin (m-antibiotin down to 10 pM
(Fig. 14) [127]. The use of SiNW FET devices was recently
extended to the detection of small molecules. For example,
the detection of small molecules inhibitors of ATP binding
to Abelson protein (Abl) was achieved by covalently linking
it to SiNWs [104]. Abl is a tyrosine-protein kinase whose
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Fig. 13. Current recorded over time for an individual In2O3 NW
device (a) and a SWNT mat device (b) when sequentially exposed
to buffer, BSA, and PSA. Insets: SEM images of respective
devices [126].
constitutive activity is responsible for chronic myelogenous
leukemia. Gruner and co-workers have used nanoscale field
effect transistor devices with carbon nanotubes as the
conducting channel to detect biotin-streptavidin binding
[128]. A polymer coating layer was employed to avoid
nonspecific binding, with attachment of biotin to the layer
for specific molecular recognition. Biotin-streptavidin binding was detected electrically by changes in the FET device
characteristics.
Chen et al. reported the specific detection of human
autoantigen U1A down to 1 nM using mAbs functionalized
SWNTs [129] (Fig. 15). U1A is a prototype of the autoimmune response in patients with systemic lupus erythematosus and mixed connective tissue disease. An investigation into the mechanisms of electrical sensing of protein
adsorption on carbon nanotubes devices revealed that
electrical effects occurring at the metal-nanotube contacts
due to protein adsorption constituted a more significant
contribution to the electrical biosensing signal than adsorption on the nanotube [130].
6.2. Nucleic Acids Detection
Si NWs have also been used for the direct detection of DNA.
In the first case, the surfaces of the Si NW devices were
modified with peptide nucleic acid (PNA) receptors, and the
identification of fully complementary versus mismatched
DNAwas carried out to at least the tens of femtomolar range
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Fig. 14. Real-time detection of protein binding. A) Schematic
illustrating a biotin-modified Si NW (left) and subsequent binding
of streptavidin to the Si NW surface (right). The Si NW and
streptavidin are drawn approximately to scale. B) Plot of
conductance versus time for a biotin-modified Si NW, where
Region 1 corresponds to buffer solution, Region 2 corresponds to
the addition of 250 nM streptavidin, and Region 3 corresponds to
pure buffer solution. C) Conductance versus time for an
unmodified Si NW; Regions 1 and 2 are the same as in (B). D)
Conductance versus time for a biotin-modified Si NW, where
Region 1 corresponds to buffer solution and Region 2 to the
addition of a 250 nM streptavidin solution that was preincubated
with 4 equivalents d-biotin. E) Conductance versus time for a
biotin-modified Si NW, where Region 1 corresponds to buffer
solution, Region 2 corresponds to the addition of 25 pM
streptavidin, and Region 3 corresponds to pure buffer solution.
Arrows mark the points when solutions were changed [127].
[115]. In the second case, single stranded (ss) probe DNA
was covalently immobilized on the Si nanowires for
detection of up to 25 pM of label-free complimentary
(target) ss-DNA in sample solutions [107].
6.3. Virus Detection
Viruses are among the most important causes of human
disease and are of increasing concern as possible agents of
biowarfare and bioterrorism. Lieber and co-worker have
used SiNWs for real-time electrical detection of single virus
particles with high selectivity (Fig. 16) [106]. Measurements
made with SiNWs functionalized with antibodies specific to
influenza A virus showed the detection of influenza A virus
but not paramyxovirus or adenovirus. Further, they demonstrated selective detection of multiple viruses in parallel
with SiNWs functionalized with antibodies specific for
influenza virus or adenovirus.
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Fig. 16. Selective detection of single viruses. A) Conductance vs.
time data recorded simultaneously from two silicon nanowires
elements, top and bottom plots, within a single device array after
introduction of an influenza A solution. (Inset) Frequency of
single virus events as a function of virus solution concentration. B)
Conductance changes associated with single influenza A virus
binding/unbinding as a function of solution pH [106].
Fig. 15. Specific detection of mAbs binding to a recombinant
human autoantigen. A) Scheme for specific recognition of 10E3
mAb with a nanotube device coated with a U1A antigen-Tween
conjugate. B) Conductance vs. time curve of a device shows
specific response to 1 nM 10E3 while rejecting polyclonal IgG at
a much greater concentration of 1 mM (Inset) [129].
6.4. Glucose and Other Biologically Relevant Molecules
Direct real-time detection of glucose was achieved by using
glucose oxidase (GOx) modified-SWNTs in a FET device
through the monitoring of the change in the conductance
upon the binding of the glucose to the enzyme [131]. On the
other hand, Tao and co-workers used a conducting polymer
nanojunction sensor for the detection of glucose [70]. GOx
was entrapped into polyaniline by the electrochemical
polymerization procedure. Upon exposure to glucose, the
GOx catalyzed the oxidation of glucose. The reduced form
of GOx was regenerated via re-oxidation by O2 in solution,
which produces H2O2. The H2O2 then oxidized polyaniline,
thus triggering an increase in the polyaniline conductivity.
The increase in polyaniline conductivity constituted the
analytical signal. Due to the small size of the nanojunction
sensor, the GOx was regenerated naturally without the need
of redox mediators. Therefore, responses were very fast
(< 200 ms) and a minimal amount of oxygen was consumed.
We recently demonstrated the ability to fabricate avidin
functionalized CP NWs in predefined nanochannels with inElectroanalysis 18, 2006, No. 6, 533 – 550
built electrical contacts in a one-step procedure [124]. We
thus eliminated the complex issue of assembly/alignment of
the CP NW as our device was already in a functional sensor
circuit. Further, we were able individually address each
nanostructured sensing element with the desired bioreceptor [124]. When challenged with biotin-DNA (20 mer oligo)
conjugate, the resistance of the avidin-functionalized polypyrrole nanowire increased as a function of concentration,
while a control nanowire without embedded avidin showed
no response (Fig. 17). These results demonstrated the utility
of the biomolecule-functionalized CP nanowires for labelfree biosensing. As low as 1 nM of biotin-DNA was detected
in a few seconds. The one-step incorporation of functional
biological molecules into the CP nanowire during its
synthesis within built-in electrical contacts is the major
advantage of the new fabrication method over the reported
silicon nanowire and carbon nanotube biosensors that
require postsynthesis functionalization alignment and positioning.
7. Conclusions and Future Perspectives
This review has addressed recent advances in biosensors
based on 1-D nanostructures including their fabrication,
assembly, functionalization and applications. So far, the
most commonly used 1-D nanostructures in biosensing have
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Fig. 17. Electrical responses of an unmodified nanowire (A) to
100 nM biotin-DNA (single stranded) and avidin-embedded
polypyrrole (200 nm) nanowires to 1 nM (B) and 100 nM (C)
biotin-DNA. The responses were recorded on two separate
polypyrrole-avidin nanowires. Polypyrrole nanowire containing
entrapped avidin were grown using 25 nM pyrrole in 10 mM NaCl
and of avidin [124].
been silicon nanowires (SiNWs) and carbon nanotubes
(CNTs). The success of SiNWs is partly due to the fact that
they are always semiconducting and are very compatible
with the conventional Si-based technology. CNTs have also
been very successful in 1D-biosensing. SiNWs and CNTs are
very robust materials based on their tensile strength and
YoungNs Modulus values. However, unlike SiNWs, CNTs
exhibit semiconducting or metallic conductivities depending on their chirality and they normally require further
purification. The existence of both metallic and semiconducting CNTs could be very advantageous. For example,
both active devices (like transistors) and interconnects can
be made out of semiconducting and metallic CNTs, respectively. One major disadvantage shared by both SiNWs and
CNTs is that fact that they require harsh conditions for
synthesis. This means that any biofunctionalization has to be
done after their synthesis. The same applies to the alignment
of these structures to form functional devices.
On the other hand, conducting polymer nanowires (CP
NWs) are newcomers into the 1-D chemical sensing and
biosensing arena. The advantages of CP NWs include the
fact that they can be easily synthesized by benign reagents at
ambient conditions through well known chemical and
electrochemical procedures. Their conductivities can be
modulated up to 15 orders of magnitude by changing the
dopant and monomer/dopant ratios. They can be functionalized before, during and after synthesis. Also the one-step
incorporation of functional biological molecules into the CP
nanowire during its synthesis within built-in electrical
contacts is a major advantage over SiNWs and CNTs
devices that require postsynthesis functionalization alignment and positioning. However, the major disadvantage of
CP NWs is that they are mechanically weak and are likely to
break easily.
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Even though there has been tremendous advancement in
fabrication techniques of 1-D nanostructures, there are still
difficulties associated with the fabrication of these nanostructures with well-controlled and consistent dimensions,
morphology, phase purity, and chemical composition. Finding practical routes to large quantities of 1-D nanostructures
from a diversified range of raw materials, rapidly and at
reasonable cost, is still a big challenge. Likewise, the
assembly and alignment of 1-D nanostructures is one area
that needs improvement. Generalized assembly techniques
that go well beyond current capabilities must be developed
if 1-D nanostructures are to have widespread technological
applications. While several novel sensing concepts based on
1-D nanostructures have been reported, incorporating these
materials into routine functional integrated devices remains
a challenge. Advances in capabilities of assembling larger
and more complex nanowire arrays and integrating them
with nanoscale electronics may lead to advanced applications in clinical, food safety, environmental, military and
other areas.
1-D nanostructures and most of the applications derived
from these materials are still in an early stage of development. Hence, several issues including their chemical/thermal/mechanical stability need to be addressed before these
materials can be utilized to their full potential. This is of
crucial importance because 1-D nanostructures are known
to be less thermally and mechanically stable than their bulk
cousins.
Environmental and health questions have been raised,
especially regarding CNTs. The studies reported by Lam
provided a first insight into the in vivo toxicity of a specific
type of manufactured SWNTs [132]. While the contamination caused during manufacture and/or application of some
1-D nanostructures is a major concern, it should not be
difficult to devise environmentally friendly protocols similar
to those regulating manufacture and use of other chemical,
biological and other materials. In spite of the numerous
challenges, 1-D nanostructured materials offer unlimited
research opportunities.
8. Acknowledgement
We acknowledge the support of this work by grants H9400304-2-0404 from DOD/DARPA/DMEA, BES-0529330 from
the NSF, and GR-83237501 from the U.S. EPA.
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