Overview
Carbon nanotubes towards
medicinal biochips
Alexander O. Tarakanov,1∗ Larisa B. Goncharova2 and Yury
A. Tarakanov3
This overview focuses on the recent advances in carbon nanotube (CNT)-based
biochips and tries to clarify their potential for modern molecular medicine.  2009
John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2010 2 1–10
C arbon nanotubes (CNTs) exhibit a unique com-
bination of biological and physical properties.1–3
These properties make CNT-based devices, especially
CNT field-effect transistors (FETs),3,4 promising as a
novel platform for chemical sensors,5 biosensors,6–8
and biochips.9–11 The last ones seem to be especially
promising for clinical diagnostics.12 Namely, biochips
permit the analysis of DNA, proteins, and other bio-
logical and chemical molecules in a massively parallel
format.13 They represent a multidisciplinary devel-
opment unifying molecular biology, chemical and
electronics engineering.14 The emerging technologies
of CNT biochips in medicine might provide further
advantages relative to traditional biochip platforms
including the cost and speed of medical tests.12,15,16
Accordingly, our overview focuses on the recent
advances in CNT-based biochips and tries to clar-
ify their medicinal potential including lab-on-chips
for molecular diagnostics,17,18 drug screening,19 and
also novel strategies in molecular medicine.20–22
BIOCHIPS, MICROARRAYS,
AND BIOSENSORS
Biochip (biological microchip) can be considered
as a biological equivalent for computer microchip
or even a microchip that is able to interact with
biomolecules.22 Instead of performing of millions
of mathematical operations, biochip is intended for
carrying out thousands of biological interactions per
∗ Correspondence to: tar@iias.spb.su
1
St Petersburg Institute for Informatics and Automation, Russian
Academy of Sciences, St. Petersburg, 199178, Russia
2
City Diagnostic Center (Virology), St Petersburg, 193167, Russia
3 Departmentof Applied Physics, Chalmers University of Technol-
ogy, Gothenburg, SE-41296, Sweden
DOI: 10.1002/wnan.069
Vo lu me 2, Jan u ary /Febru ary 2010  2009 Jo h n Wiley & So n s, In c.
minute, that is thousands times faster in comparison
with existing technologies. Biochips appeared as a
result of application of the ideas of miniaturization,
integration and parallel processing of information
from microelectronics, where they were born, to
biological processes.
The main advantage of biochips over conven-
tional analytical devices is the possibility of massive
parallel analysis. Biochips are smaller than conven-
tional testing systems and highly economical in the
use of specimen and reagents. The development of
DNA chips was one of the fastest growing areas in
DNA/RNA analysis.23 Different names for the chips
such as DNA/RNA chips, biochips, genechips, biosen-
sors, or DNA arrays appeared.24 Although major
progress has been achieved in the manufacturing and
application of DNA microchips, DNA is not the only
biological entity that can be arrayed or spotted onto
the surface of biochip matrix. The possibility to con-
figure arrays of proteins is a real fact now, but their
construction is vastly more complicated than creating
DNA chips.
Main component of any DNA or protein biochip
is a microarray where the biochemical reactions take
place (that is why ‘microarray’ is also used as a syn-
onym for ‘biochip’). This principle can be illustrated
in Figure 1 by a hand-made prototype of protein
microarray for the detection and quantitative evalua-
tion of microalbuminuria (mAU) in preclinical diag-
nosis of renal failure (nephropathy) in patients with
diabetes mellitus. Human serum albumin (HSA) and
target urine samples of diabetic patients and healthy
persons were immobilized as microarray onto approx-
imately 15 × 15-mm nitrocellulose matrix. The stan-
dard enzyme linked immunosorbent assay procedure
was adapted to microarray format and the reactions
were visualized by peroxidase-labeled HSA-binding
fragment of recombinant G-protein.25 Such microar-
ray allowed carrying out a simultaneous screening
1
 Overview
FIGURE 1 | Example of microarray prototype for visual detection of
microalbuminuria (mAU). The 56 urine samples have been spotted
manually onto 15 × 15-mm nitrocellulose matrix. The borded spot
(upper left corner) represents high level of blackness typical for mAU,
because of the increased concentration of albumin.
analysis of 56 urine samples to detect patients with
mAU visually (Figure 1) or automatically, using a
computer (Figure 2). This simple example of a primi-
tive microarray prototype with label-dependent detec-
tion method, nevertheless, can help to clarify further
advantages of biochips, especially label-free electro-
chemical biosensors.
Generally, a biochip is known as plastic, glass, or
silicon wafer that may rapidly detect chemical agents
from biological material.26 However, optical biochip
readers (e.g., microscopes) remain expensive and not
portable.27,28 Although such DNA chips have played
an important role in the human genome project,29 a
biochip system that electronically detects biomolecules
seems more promising. Electronics-based methods
are advantageous in that they allow further miniatur-
izaion. The intensity of the electrical current indicates
not only the presence (or absence) of the analyte in the
sample, as it is in the case of optical systems, but also
concentration of the tested substance. So, recent con-
cepts of both DNA and protein chips use individually
addressable microelectrodes or optical fibers.10
It is also worth noting that genomics approaches
have limitations in finding out an accurate mechanism
of human disease processes and in treating human
diseases. For this reason, proteomics approaches are
gaining favor as an important area of research. Com-
paring with DNA-based microarrays, however, it is
more difficult to minimize and highly integrate a
protein-based microarray for higher sensitivity. For
example, a grid-like pattern for DNA oligonucleotides
2  2009 Jo h n Wiley & So n s, In c.
www.wiley.com/wires/nanomed
can be formed on a substrate surface by photolithog-
raphy, but it is very difficult to form a grid pattern
for an antibody (which is a large protein having about
1400 amino acids) to a high density for accurate diag-
nosis of diseases. Another limitation is the possibility
of arranging a protein with a high resolution with-
out denaturing its tertiary structure.30,31 Apparently,
these problems might be solved by a new generation
of electrochemical nanobiosensors.
Biosensor is a functional hybrid system,
generally combining two basic components connected
in series: a biomolecular recognition system and a
physicochemical transducer.32,33 The recognition sys-
tem is often called the bioreceptor (Figure 3). The
biosensor is usually constructed by attaching a bio-
logically sensitive material to a suitable transducing
system. The transduction unit can be electrochemical,
optical, piezoelectric, magnetic, or calorimetric. The
recognition layer can be constructed using enzymes,
antibodies, cells, tissues, nucleic acids, peptide nucleic
acids, and aptamers.34,35 Aptamers are artificial (syn-
thetic) oligonucleotides that can be generated to recog-
nize amino acids, drugs, proteins, and other molecules
with high specificity.36
Electrochemical biosensors can provide sensi-
tive, selective, reliable, rapid, simple and low-cost
on-field detection, thus having superior properties
over other existing measurement systems.34 Electro-
chemical detection approaches are falling into two
basic categories: labeled (label-dependent) and label-
free detection systems. The former relies on a redox-
active signal from a reporter molecule or a label, which
changes upon the interaction of the target protein.
The label-free electrochemical detection of proteins
pays particular emphasis to those that exploit intrinsic
redox-active amino acids.34 Electrochemical measure-
ment protocols are also suitable for mass fabrication
of biochips. Therefore, a microarray of electrochemi-
cal biosensors can be considered as the key component
of a modern biochip (Figure 4).
CNT TRANSISTORS AND BIOCHIPS
The above example of medical diagnostic (Figures 1
and 2) demonstrates the common label-dependent
principle of biosensing where label molecules such
as enzymes are linked to antibodies or antigens or
receptors in order to carry detectable species to the
sensor.33 Such label can also be nanoparticle (NP)
and CNT. An NP is a microscopic particle with at
least one dimension less than 100 nm, which plays
an important role in the area of biosensing.27,28 The
application of gold NPs instead of fluorescence dyes
and enzyme-conjugation is usual in biochips.11,37
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 WIREs Nanomedicine and Nanobiotechnology Carbon nanotubes

FIGURE 2 | Example of computer detection

of microalbuminuria (mAU) using microarray
prototype. The borded spots have been
detected as the samples with mAU, while the
numerical concentrations of albumine have
been computed in the right-hand table,
according to the blackness of the spots.

A CNT is a hollow cylinder made of wrapped sheets
of carbon atoms.1,6,38 CNTs can be also used for
optical detection and biomedical imaging.38,39 Such
label-dependent detection principle leads to several
additional difficulties in preparing and processing
of microarrays since an appropriate device (e.g.,
microscope) is necessary for the detection of the
obtained results. An effective alternative to indirect
label-dependent detection methods is the direct
label-free electronic detection of biomolecules, using
CNTs.40,41 FET devices with CNT conducting
channels (CNT-FET) have been developed and used
for biosensing and biodetection.6 Such CNT-FET can
be used as a label-free biosensor (Figure 3) with a

Ligand

Bioreceptor
Source Drain
Linker
CNT
Au Cr, Ti, etc.

SiO2

Si back gate

FIGURE 3 | Electrochemical scheme of

label-free biosensor based on carbon nanotube
V2 Gate voltage
field-effect transistor. The electrical current through
the channel CNT is altered upon binding the Current
ligand–receptor (because of the charge of the V1
ligand) and can be detected, e.g., by the change of
radio frequency (RF) signal. Source-drain voltage

Vo lu me 2, Jan u ary /Febru ary 2010  2009 Jo h n Wiley & So n s, In c. 3

 Overview
FIGURE 4 | Scheme of biochip Microfluidics/actuators
(‘lab-on-chip’) based on microarray of
carbon nanotube field-effect transistor
(CNT-FET) biosensors. The samples are
spotted automatically using a
microfluidics/actuators block (upper
left). This block is controlled by a
microchip (bottom right block, just a Detection
schematic photo). The target
biomolecules are detected using a
microarray of CNT-FET biosensors
(upper right block), which is connected !
to the same microchip. This microchip
also provides human-friendly
representation of the obtained results
using an output indication (and/or Output indicators
diagnostics at bottom left block).
clear change of the CNT conductance in response to
the ligand binding event. CNT-FETs are promising
for electronic detection of biomolecules in solution.42
However, the physical mechanism of sensing remains
controversial. Previously suggested mechanisms are
electrostatic gating, changes in gate coupling, carrier
mobility changes, and so called Schottky barrier
effects.43 The authors argue that each mechanism has
its characteristic effect on the liquid gate potential
dependence of the device conductance. For exam-
ple, there have been fabricated label-free protein
biosensors based on aptamer-modified CNT-FETs
for the detection of immunoglobulin E (IgE).35 The
introduction of target IgE at various concentrations
caused a sharp decrease in the source–drain current,
whereas a gradual saturation was observed at lower
concentrations. The authors suggest that the aptamer-
modified CNT-FETs are promising candidates for
the development of label-free protein biosensors.
They also arrayed 26 CNT-FET devices on the chip.
Similar microarrays of CNT-FET biosensors might
be the key component of a fully automated and
computerized biochip as a prospective ‘lab-on-chip’
(Figure 4).
Therefore, the biochip can be seen as a step
from single to multianalyte and microarray detection
format.23 The CNT-FET biosensor (Figure 3) can be
seen as a next step from indirect label-dependent
to direct label-free detection and from optical to
electronic detection. In its own turn, the electronic
detection system allows direct connection between
CNT-FET microarray of biosensors and a computer
microchip (Figure 4, right) or even an integration
of the both in one chip. It is worth noting that
the combination of biosensor with microfluidics and
actuators on a biochip (Figure 4, top) has already led
to total microanalysis system.10
4  2009 Jo h n Wiley & So n s, In c.
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Biological Microarray of CNT-FET
buffer etc. biosensors
Samples
Results
Microchip analyser/controller
TOWARDS MEDICINAL
NANOBIOCHIPS
The scale-down of biochips from the microscale
to nanoscale will benefit over current technologies
in further miniaturization, automation, reduction in
the analyzing time as well as better sensitivity.23
For example, the automation can minimize prob-
lems caused as a result of contamination as well as
human error in medical diagnostics. The challenge for
nanobiochips remains that of appropriate miniatur-
ization and integration.34 This will further enhance
multianalyte capability of current biochips in simulta-
neous determination of pathogens, biowarfare agents,
proteins, etc.44–47 Nanobiochips might also be a novel
screening platform for molecular medicine, including
G-protein coupled receptors (GPCRs) and their role
in neuroinflammations.21,48,49 Consider several fields
of modern medicine where prospective nanobiochips
might be useful.
Molecular and Point-of-Care Diagnostics
Molecular diagnostics in the coming years will con-
tinue to be of critical importance to public health
worldwide.17 Several label-dependent approaches,
including NPs and CNTs, are clinically relevant.8,50,51
They enable the diagnosis at single cell and molecular
level and some of these can be incorporated in the
current molecular diagnostic tools such as biochips.
Nanobiochips extend the limits of current molecu-
lar diagnostics and enable point-of-care diagnostics
(POCD) as well as the development of personalized
medicine. Most important current applications are
foreseen in the areas of biomarker research, cancer
diagnosis, and detection of infectious microorgan-
isms as well as on-site monitoring of food and
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 WIREs Nanomedicine and Nanobiotechnology
water.52 There are several commercially available
biosensing tools for home use such as monitoring
of glucose levels for diabetic patients.34,53 Most com-
mercially available POCDs are based on immunochro-
matographic membrane strips (immunostrips). In
their own turn, most immunostrips have nanomolar
level sensitivity, whereas CNT-based biosensors go
down to picomolar concentrations.54–56 NP-enhanced
immunostrips also increase essentially the sensitiv-
ity of biosensors for clinical samples.57,58 Future
developments of nanobiochips for POCD enable
the clinician to make the diagnosis directly at the
bedside.
DNA Chips and Genetic Screening
DNA chips rapidly decrease laboratory turnaround
times so that results can be available within 2–6 h
compared to perhaps 24 h.12 They used as ‘genomic
sensors’ that might revolutionize clinical diagnostics
through their ability to simultaneously investigate
thousands of potential pathogens in order to make
a diagnosis.52 For example, microarrays can be used
for the robust and accurate diagnosis of pathogens
in clinical diagnostics.12,37,47 However, questions
remain regarding their sensitivity and reliability as
well as cost and speed. Apparently, these problems
can be overcome by CNT-based biochips.16 Genetic
screening is another bright horizon for biochip
analysis.13 In genetic screening applications, DNA
samples are examined to identify single-nucleotide
changes, deletions, and other minor sequence variants
in genes that underlie genetic and infectious diseases.
Recent successes in benchmarking microarrays by
the US Food and Drug Administration suggest broad
applications for assessing the safety of food, drugs,
vaccines, medical devices, and other products of con-
sumer interest including genetic modified products.59
A related use of ‘bacto-chips’ would be in clinical
settings, to establish the identity of organisms in
patients admitted to hospitals with systemic bacterial
infections. Population-based screening also holds
great promise for identifying disease carriers, thereby
reducing the incidence of genetic disease.13 There is
also progress in electric DNA chips, for both indirect
detection of labeled molecules and direct analysis of
label-free nucleic acids in respect to detection of such
pathogens as anthrax, etc.23
Protein Chips
Protein chips can also detect hazardous biological
agents including toxins and pathogens.45,46,60 CNT-
based protein biochips can also be used for the
simultaneous detection of several neurotransmitters
Vo lu me 2, Jan u ary /Febru ary 2010  2009 Jo h n Wiley & So n s, In c.
Carbon nanotubes
like dopamine, catecholamine, serotonin.9,61,62 For
example, a multiwalled CNT has been synthesized and
used for sensitive dopamine detection.61 Dopamine
and serotonin are important neurotransmitters that
interact in the brain. While dopamine is easily
detected with electrochemical sensors, the detection
of serotonin is more difficult because reactive species
formed after oxidation can absorb to the electrode,
reducing sensitivity. The CNT-modified electrodes
not only increase the sensitivity and reduce fouling
but also allow monitoring dopamine and serotonin
changes simultaneously.62 These studies show that
CNT-coated microelectrodes can be used with fast
scanning techniques and are advantageous for in vivo
measurements of neurotransmitters. Thus, protein
biochips can be used for drug screening based on the
detection of drug effect on neurotransmitter release.19
Such CNT-based biochips might be useful in early
diagnostics of several neuroinflammatory diseases,
including Alzheimer’s disease. 63,64
GPCR Dimerization and Drug Discovery
GPCRs are found on the surface of all cells of multicel-
lular organisms. They are major mediators of intercel-
lular communication and act as cell surface receptors
responsible for the transduction of endogenous signals
(hormones, neurotransmitters, chemokines, odorants,
tastants) into a cellular response.65 GPCRs form one
of the largest superfamilies of cell surface receptors
and the largest class of cell surface receptors in mam-
malian genomes.66 In human, the estimated number of
GPCRs is about 1000, where about 300–400 mediate
the effects of endogenous ligands, with the remain-
der being sensory receptors.67,68 This corresponds to
about 5% of the total number of human genes.69
GPCRs represent the most widely targeted pharma-
cological protein class.70 Drugs that either directly or
indirectly modulate GPCR function have proved to
be effective therapeutics for the treatment of many
disease states, and as many as 50% of marketed
drugs target GPCRs.71 These represent around 25%
of the 100 top-selling drugs worldwide.72,73 However,
the only GPCRs for which three-dimensional struc-
tures have been solved to date are bovine rhodopsin
and human adrenergic receptor.74,75 Recent data also
suggest that GPCR dimerization might have serious
impact on molecular medicine, including Parkin-
son’s disease.20,21,76–81 Development of new tools
such as nanobiochips should facilitate significant
progress in our understanding of the nature of GPCR
dimers and their multiple functions, and also pro-
vide new strategies for the development of novel drug
therapies.82–86
5
 Overview
Membrane Nanodiscs
A number of recent studies continue to support the
existence of GPCR dimers but appear to give con-
flicting results.87–90 However, rigorous analysis of
the role of dimers in G-protein activation has pre-
viously not been possible because of the inability to
physically isolate and characterize the function of a
monomeric GPCR embedded in its plasma membrane
milieu rather than in detergent micelle. Recent results
suggest that a monomeric receptor in a lipid bilayer is
the minimal function unit necessary for signaling, and
that the cooperativity of agonist binding is because
of G-protein association with a receptor monomer
and not because of receptor oligomerization.91 Mem-
brane nanodiscs can provide distinct advantages over
detergents and liposomes, to observe and compare
the function of GPCR in nanodiscs containing one
and two GPCR molecules.92 Nanodiscs are nanome-
ter scale planar membrane of controlled size that are
rendered soluble in aqueous solution via an encircling
amphipathic membrane scaffold protein ‘belt’.93 Inte-
gral membrane proteins can be self-assembled into the
nanodiscs bilayer with defined stoichiometry which
allows an unprecedented opportunity to investigate
the nature of the oligomerization state of a GPCR and
its coupling to heterotrimeric G-proteins. A number
of recent advances in fluorescence correlation spec-
troscopy (FCS), such as total internal reflection-FCS
and the use of nanostructures like NPs and CNTs,
could further increase the axial resolution of these
measurements. For example, FCS can be used to
perform subcellular quantitative pharmacology, with
particular reference to GPCRs.94 These results have
important implications for GPCRs and their cross-talk
in signaling pathways.
Implantable Biochips and Drug Delivery
There is an old dream on implanting sensors and other
devices that interface with the body’s biochemistry
to treat diseases such as diabetes and even predict
coming ailments.95 Although there might be several
safety concerns with respect to the in vivo use of
NPs and CNTs, studies are in place to determine
the nature and extent of their chemical reactivity,
toxicity, and biocompatibility.38,51 For example,
CNTs can inhibit human embryonic kidney cell
growth by inducing cell apoptosis and decreasing
cellular adhesion ability.96 On the other hand, the
treatment of CNTs could reduce the viability of
primary osteoblasts and inhibit the mineralization of
osteoblasts in a dose-dependent manner.97 In addition,
CNTs are expected to be used as local drug delivery
systems and/or scaffolds to promote and guide bone
6  2009 Jo h n Wiley & So n s, In c.
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tissue regeneration.2 Nanotubes, including the natural
ones (e.g., tunneling nanotubes) and CNTs, can be
used for a physical transport of biochemical cargoes,
including drugs.1 In addition, some nanosubstances
(such as fullerenes) could be potential drugs for
the future.51 An approach has been even proposed
for the development of ‘nanorobots’ with sensors
for medical target identification and drug delivery.98
Of course, further study on the molecular mechanisms
of such effects is needed for future safe applications of
CNTs and the design of biocompatible nanomaterials,
including biochip implants.
CONCLUSION
Recent results suggest that a growing number of
aptamers and label-free nanobiosensors will soon
be used for the diagnosis and therapeutic follow-
up of diseases.34 Our overview also proposes that
CNT-FET-based biosensors are most promising for
medicinal biochips. Their main advantage is elec-
tronic detection that allows their direct integration
with a computer chip. Also CNT-FET modified with
aptamers can be utilized for both DNA and protein
chips. It is also worth noting that CNT-FETs are drag-
ging much attention for their extremely high operation
speed which enables them to work at frequencies in
radio frequency (RF) range.4 This feature may lead
to a prospective implementation of RF biosensors,99
and CNT-FET biochips in telemedicine as a rapidly
developing application of clinical medicine where the
results of screening should be transferred via RF (e.g.,
from battlefield or spaceship). In addition, a small
pattern or material change in an RF microstrip causes
large changes in RF characteristics,99 when compared
to other than CNT materials (e.g., inorganic semicon-
ductors and conducting polymers). On the other hand,
CNT-based nanoelectromechanical systems (NEMS)
have been discussed theoretically and demonstrated
experimentally,3,4 including lipid bilayers bioNEMS
that mimic a cell membrane.100 Integrated carbon
nanopipettes with nanoscale dimensions have also
been developed that can probe cells with minimal
intrusion, inject fluids into the cells, and concur-
rently carry out electrical measurements.101 Such
universality and integrity of CNTs and, thus, further
miniaturization, automation, and high throughput of
prospective nanobiochips make them very promising
for medicinal applications.
However, it is worth highlighting that all
of these technologies are far from a routine in
clinical use. For example, several available images
clearly show that actual CNT-FETs (but not their
schemes) are still curved and irregular and, thus, too
Vo lu me 2, Jan u ary /Febru ary 2010
 WIREs Nanomedicine and Nanobiotechnology
far from a controlled growth (i.e., reproducibility
of their parameters).6,35,42 The physical mechanism
underlying sensing by CNT-FETs remains also con-
troversial, which hampers full exploitation of these
promising nanosensors.42 Also, the CNTs’ toxicity
debate continues to unfold.38 Therefore, a lot of
experimental work is still necessary to demonstrate
feasibility of CNTs in medicinal biochips. Further
investigations of the molecular mechanisms of their
NOTES
Y. T. acknowledges the support of the European Commission (EC) through the FP6 research project NanoRF
(contract number FP6-2005-028158). This publication reflects the views of the authors and not necessarily
those of the EC. The EC is not liable for any use that may be made of the information contained herein.
REFERENCES
1. Goncharova LB, Tarakanov AO. Nanotubes at neu-
ral and immune synapses. Curr Med Chem 2008,
15:210–218.
2. Saito N, Usui Y, Aoki K, Narita N, Shimizu M, et al.
Carbon nanotubes for biomaterials in contact with
bone. Curr Med Chem 2008, 15:523–527.
3. Tarakanov YA, Kinaret JM. A carbon nanotube field
effect transistor with a suspended nanotube gate.
Nano Lett 2007, 7:2291–2294.
4. Svensson J, Tarakanov YA, Lee DS, Kinaret JM, Park
YW, et al. A carbon nanotube gated carbon nanotube
transistor with 5 ps gate delay. Nanotechnology 2008,
19:325201.
5. Huang XJ, Choi YK. Chemical sensors based on
nanostructured materials. Sens Actuators, A 2007,
122:659–671.
6. Gruner G. Carbon nanotube transistors for biosens-
ing applications. Anal Bioanal Chem 2006,
384:322–335.
7. Kirgoz UA, Timur S, Odaci D, Perez B, Alegret
S, et al. Carbon nanotube composite as novel plat-
form for microbial biosensor. Electroanalysis 2007,
19:893–898.
8. Pumera M, Sánchez S, Ichinose I, Tang J. Electro-
chemical nanobiosensors. Sens Actuators, A 2007,
123:1195–1205.
9. Pumera M, Merkoçi A, Alegret S. Carbon nan-
otube detectors for microchip: comparative study
of single-wall and multiwall carbon nanotube, and
graphite powder films on glassy carbon, gold, and
platinum electrode surfaces. Electrophoresis 2007,
28:1274–1280.
Vo lu me 2, Jan u ary /Febru ary 2010  2009 Jo h n Wiley & So n s, In c.
Carbon nanotubes
effects on biological complexes (molecules, cells, tis-
sues) in vitro and in vivo are needed in order to
provide a better understanding of the impact of CNTs
on biological systems and important information for
future safe applications and the design of biocom-
patible nanomaterials. In general, medical applica-
tions of nanotechnology are growing but a number
of outstanding issues need to be resolved before
nanomedicine moves from the lab to the bedside.102
10. Scheller FW. From biosensor to biochip. FEBS Lett
2007, 274:5451.
11. Wang YF, Zhang YQ, Jiang XD. The application
of nanoparticles in biochips. Recent Pat Biotechnol
2008, 2:55–59.
12. Wong CW, Heng CLW, Yee LW, Soh SWL, Kartasas-
mita CB, et al. Optimization and clinical validation of
a pathogen detection microarray. Genome Biol 2007,
8:R93.
13. Stears RL, Martinsky T, Schena M. Trends in microar-
ray analysis. Nat Med 2003, 9:140–145.
14. Khanna VK. Existing and emerging detection tech-
nologies for DNA finger printing, sequencing, bio-
and analytical chips: a multidisciplinary development
unifying molecular biology, chemical and electronics
engineering. Biotechnol Adv 2007, 25:85–98.
15. Chen B, Parker G, Han J, Meyyappan M, Cassell AM.
Heterogeneous single-walled carbon nanotube cata-
lyst discovery and optimization. Chem Mater 2002,
14:1891–1896.
16. Koehne JE, Chen H, Cassell AM, Ye Q, Han J,
et al. Miniaturized multiplex label-free electronic chip
for rapid nucleic acid analysis based on carbon
nanotube nanoelectrode arrays. Clin Chem 2004,
50:1886–1893.
17. Fortina P, Surrey S, Kricka LJ. Molecular diagnostics:
hurdles for clinical implementation. Trends Mol Med
2002, 8:264–266.
18. Borini S, Staiano M, Rocchia M, Rossi AM, Rossi
M, et al. Advanced nanotechnological approaches
for designing protein-based ‘lab-on-chips’ sensors on
porous silicon wafer. Recent Pat DNA Gene Seq
2007, 1:1–7.
7
 Overview
19. Cui HF, Ye JS, Chen Y, Chong SC, Sheu FS.
Microelectrode array biochip: tool for in vitro drug
screening based on the detection of a drug effect on
dopamine release from PC12 cells. Anal Chem 2006,
78:6347–6355.
20. Fuxe K, Canals M, Torvinen M, Marcellino D,
Terasmaa A, et al. Intramembrane receptor-receptor
interactions: a novel principle in molecular medicine.
J Neural Transm 2007, 114:49–75.
21. Fuxe KG, Tarakanov AO, Goncharova LB, Agnati
LF. A new road to neuroinflammation in Parkinson’s
disease? Brain Res Rev 2008, 58:453–458.
22. Goncharova LB, Jacques Y, Martin-Vide C,
Tarakanov AO, Timmis JI. Biomolecular immune-
computer: theoretical basis and experimental simula-
tor. Lect Notes Comput Sci 2005, 3627:72–85.
23. Gabig-Ciminska M. Developing nucleic acid-based
electrical detection systems. Microb Cell Fact 2006,
5:9–16.
24. Gabid M, Wegrzyn G. An introduction to DNA chips:
principles, technology, applications and analysis. Acta
Biochim Pol 2001, 48:615–622.
25. Gupalova T, Orlova S, Palagnuk V, Volchek N,
Kusmina M, et al. Usage of recombinant receptor pro-
teins in clinical diagnosis. Folia Vet 1997, 41:81–83.
26. Ramsey M. DNA chips: state-of-the-art. Nat Biotech-
nol 1998, 16:40–44.
27. Wang J. Nanoparticle-based electrochemical DNA
detection. Anal Chim Acta 2003, 500:247–257.
28. Lee YEK, Kopelman R. Optical nanoparticle sensors
for quantitative intracellular imaging. Wiley Interdis-
cip Rev Nanomed Nanobiotechnol 2009, 1:98–110.
29. Venter JC, Adams MD, Myers EW, Li PW, Mural
RJ, et al. The sequence of the human genome. Science
2001, 291:1304–1351.
30. Bernard A, Michel B, Delamarche E. Microsaic
immunoassays. Anal Chem 2001, 73:8–12.
31. Katzman S. Chip-based mosaic immunoassays. Anal
Chem 2001, 73:14A.
32. Thevenot DR, Toth K, Durst RA, Wilson GS. Elec-
trochemical biosensors: recommended definitions and
classification. Biosens Bioelectron 2001, 16:121–131.
33. Schöning MJ, Poghossian A. Recent advances in bio-
logically sensitive field-effect transistors (BioFETs).
Analyst 2002, 127:1137–1151.
34. Vestergaard M, Kerman K, Tamiya E. An overview
of label-free electrochemical protein sensors. Sensors
2007, 7:3442–3458.
35. Maehashi K, Katsura T, Kerman K, Takamura Y,
Matsumoto K, et al. Label-free protein biosensor
based on aptamer-modified carbon nanotube field-
effect transistors. Anal Chem 2007, 79:782–787.
36. O’Sullivan CK. Aptasensors—the future of biosens-
ing? Anal Bioanal Chem 2002, 372:44–48.
8  2009 Jo h n Wiley & So n s, In c.
www.wiley.com/wires/nanomed
37. Wang D, Urisman A, Liu YT, Springer M, Ksiazek
TG, et al. Viral discovery and sequence recovery using
DNA microarrays. PLoS Biol 2003, 1:257–260.
38. Rey DA, Batt CA, Miller JC. Carbon nanotubes
in biomedical applications. Nanotech Law Business
2006, 3:263–292.
39. Bottini M, Fabio C, Tautz L, Rosato N, Berga-
maschi A, et al. Adsorption of streptavidin onto
single-walled carbon nanotubes: application in flu-
orescent supramolecular nanoassemblies. J Nanosci
Nanotechnol 2006, 6:3693–3698.
40. Williams KA, Veenhuizen PTM, de la Torre B, Eritja
R, Dekker C. Carbon nanotubes with DNA recogni-
tion. Nature 2002, 420:761.
41. Lee JO, Wiertz FGM, Heering HA, Dekker C.
Enzyme-coated carbon nanotubes as single-molecule
biosensors. Nano Lett 2003, 3:727–730.
42. Heller I, Janssens AM, Mannik J, Minot ED, Lemay
SG, et al. Identifying the mechanism of biosensing
with carbon nanotube transistors. Nano Lett 2008,
8:591–595.
43. Freitag M, Tsang JC, Bol A, Yuan D, Liu J, et al.
Imaging of the Schottky barriers and charge deple-
tion in carbon nanotube transistors. Nano Lett 2007,
7:2037–2042.
44. Rowe-Taitt CA, Golden JP, Feldstein MJ, Cras JJ,
Hoffman KE, et al. Array biosensor for detection of
biohazards. Biosens Bioelectron 2000, 14:785–794.
45. Tsai HC, Doong RA. Simultaneous determination
of pH, urea, acetylcholine and heavy metals using
array-based enzymatic optical biosensor. Biosens
Bioelectron 2005, 20:1796–1804.
46. Moreno-Bondi MC, Taitt CR, Shriver-Lake LC, Ligler
FS. Multiplexed measurement of serum antibodies
using an array biosensor. Biosens Bioelectron 2006,
21:1880–1886.
47. Liu Q, Bai Y, Ge Q, Zhou S, Wen T, et al. Microarray-
in-a-tube for detection of multiple viruses. Clin Chem
2007, 53:188–194.
48. Goncharova LB, Tarakanov AO. Molecular net-
works of brain and immunity. Brain Res Rev 2007,
55:155–166.
49. Agnati LF, Fuxe KG, Goncharova LB, Tarakanov AO.
Receptor mosaics of neural and immune communica-
tion: possible implication for basal ganglia functions.
Brain Res Rev 2008, 58:400–414.
50. Jain KK. Nanotechnology in clinical laboratory diag-
nostics. Clin Chim Acta 2005, 358:37–54.
51. Jain KK. The role of nanobiotechnology in drug dis-
covery. Drug Discov Today 2005, 10:1435–1442.
52. Lee TMH, Hsing IM. DNA-based bioanalytical
microsystems for handheld device applications. Anal
Chim Acta 2006, 556:26–37.
Vo lu me 2, Jan u ary /Febru ary 2010
 WIREs Nanomedicine and Nanobiotechnology
53. Newman J, Turner APF. Home blood glucose biosen-
sors: a commercial perspective. Biosens Bioelectron
2005, 20:2435–2453.
54. Zhao Q, Gan Z, Zhuang Q. Electrochemical sensors
based on carbon nanotubes. Electroanalysis 2002,
14:1609–1613.
55. Kerman K, Nagatani N, Chikae M, Yuhi T, Takamura
Y, et al. Label-free electrochemical immunoassay for
the detection of human chorionic gonadotropin hor-
mone. Anal Chem 2006, 78:5612–5616.
56. Sánchez S, Pumera M, Cabruja E, Fàbregas E. Car-
bon nanotube/polysulfone composite screen-printed
electrochemical enzyme biosensors. Analyst 2007,
132:142.
57. Greenough A, Alexander J, Burgess S, Bytham J, Chet-
cuti PAJ, et al. Health care utilization of premature
born, preschool children related to hospitalization for
RSV infection. Arch Dis Child 2004, 89:673–678.
58. Vestergaard M, Tamiya E. A rapid sample pretreat-
ment protocol: improved sensitivity in the detection of
a low-abundant serum biomarker for prostate cancer.
Anal Sci 2007, 23:1–4.
59. Beaucage SL. Strategies in the preparation of DNA
oligonucleotide arrays for diagnostic applications.
Curr Med Chem 2001, 8:1213–1244.
60. Yacoub-George E, Hell W, Meixner L, Wenninger
F, Bock K, et al. Automated 10-channel capillary
chip immunodetector for biological agents detection.
Biosens Bioelectron 2007, 22:1368–1375.
61. Wu W, Zhu H, Fan L, Liu D, Rennenberg R,
et al. Sensitive dopamine recognition by boronic acid
functionalized multi-walled carbon nanotubes. Chem
Commun 2007, 23:2345–2347.
62. Swamy BEK, Venton BJ. Carbon nanotube-
modified microelectrodes for simultaneous detection
of dopamine and serotonin in vivo. Analyst 2007,
132:876–884.
63. Vestergaard M, Kerman K, Tamiya E. The study
of Alzheimer’s disease biomarkers: current role
and future prospects of nanosensor technology.
NanoBiotechnology 2006, 2:5–16.
64. Vestergaard M, Hamada T, Takagi M. Using model
membranes for the study of amyloid beta: lipid inter-
actions and neurotoxicity. Biotechnol Bioeng 2008,
99:753–763.
65. Zhang Y, DeVries ME, Skolnick J. Structure model-
ing of all identified G protein-coupled receptors in the
human genome. PLoS Comput Biol 2006, 2:88–99.
66. Uings IJ, Farrow SN. Cell receptors and cell signalling.
J Clin Pathol: Mol Pathol 2000, 53:295–299.
67. Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku
S. Identification of G protein-coupled receptor genes
from the human genome sequence. FEBS Lett 2002,
520:97–101.
Vo lu me 2, Jan u ary /Febru ary 2010  2009 Jo h n Wiley & So n s, In c.
Carbon nanotubes
68. Prinster SC, Hague C, Hall RA. Heterodimerization of
G protein-coupled receptors: specificity and functional
significance. Pharmacol Rev 2005, 57:289–298.
69. Collins FS. Finishing the euchromatic sequence of the
human genome. Nature 2004, 431:931–945.
70. Premont RT, Gainetdinov RR. Physiologocal roles
of G protein-coupled receptor kinases and arrestins.
Annu Rev Physiol 2007, 69:511–534.
71. Pierce KL, Premont RT, Lefkowitz RJ. Seven-
transmembrane receptors. Nat Rev Mol Cell Biol
2002, 3:639–650.
72. Flower DR. Modelling G-protein-coupled recep-
tors for drug design. Biochim Biophys Acta 1999,
1422:207–234.
73. Drews J. Drug discovery: a historical perspective.
Science 2000, 287:1960–1963.
74. Allen SJ, Crown SE, Handel TM. Chemokine: recep-
tor structure, interactions, and antagonism. Annu Rev
Immunol 2007, 25:787–820.
75. Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka
TS, Thian FS, et al. Crystal structure of the human β 2
adrenergic G-protein-coupled receptor. Nature 2007,
450:383.
76. Devoino LV, Alperina EL, Gevorgyan MM, Cheido
MA. Involvement of dopamine D1 and D2 receptors
in the rat nucleus accumbens in immunostimulation.
Neurosci Behav Physiol 2007, 37:147–151.
77. Cicchetti F, Brownell AL, Williams K, Chen YI, Livni
E, et al. Neuroinflammation of the nigrostriatal path-
way during progressive 6-OHDA dopamine degener-
ation in rats monitored by immunohistochemistry and
PET imaging. Eur J Neurosci 2002, 15:991–998.
78. Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teis-
mann P, et al. The role of glial cells in Parkinson’s
disease. Curr Opin Neurol 2001, 14:483–489.
79. Guyon A, Nahon JL. Multiple actions of the
chemokine stromal cell-derived factor−1α on neu-
ronal activity. J Mol Endocrinol 2007, 38:365–376.
80. Block ML, Zecca L, Hong JS. Microglia-mediated
neurotoxicity: uncovering the molecular mechanisms.
Nat Rev Neurosci 2007, 8:57–59.
81. Devi LA. Heterodimerization of G-protein-coupled
receptors: pharmacology, signaling and trafficking.
Trends Pharmacol Sci 2001, 22:532–537.
82. Milligan G. High-content assays for ligand regulation
of G-protein-coupled receptors. Drug Discov Today
2003, 8:579–585.
83. Milligan G, White JH. Protein-protein interactions at
G-protein-coupled receptors. Trends Pharmacol Sci
2001, 22:513–518.
84. Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT,
et al. Direct protein–protein coupling enables cross-
talk between dopamine D5 and γ -aminobutyric acid
A receptors. Nature 2000, 403:274–280.
9
 Overview
85. Gilchrist A. Modulating G-protein-coupled receptors:
from traditional pharmacology to allosterics. Trends
Pharmacol Sci 2007, 28:431–437.
86. Baker JG, Hill SJ. Multiple GPCR conformations
and signalling pathways: implication for antago-
nist affinity estimates. Trends Pharmacol Sci 2007,
28:375–381.
87. Baneres JL, Parello J. Structure-based analysis of
GPCR function: evidence for a novel pentameric
assembly between the dimeric leukotriene B-4 recep-
tor BLT1 and the G-protein. J Mol Biol 2003,
329:815–829.
88. Pin JP, Kniazeff J, Liu J, Binet V, Goudet C, et al.
Allosteric functioning of dimeric class C G-protein-
coupled receptors. FEBS Lett 2005, 272:2947–2955.
89. Damian M, Martin A, Mesnier D, Pin JP, Banères
JL. Asymmetric conformational changes in a GPCR
dimer controlled by G-proteins. EMBO J 2006,
25:5693–5702.
90. White JF, Grodnitzky J, Louis JM, Trinh LB, Shiloach
J, et al. Dimerization of the class A G protein-
coupled neurotensin receptor NTS1 alters G pro-
tein interaction. Proc Natl Acad Sci USA 2007,
104:12199–12204.
91. Whorton MR, Bokoch MP, Rasmussen SGF, Huang
B, Zare RN, et al. A monomeric G protein-coupled
receptor isolated in a high-density lipoprotein particle
efficiently activates its G protein. Proc Natl Acad Sci
USA 2007, 104:7682–7687.
92. Bayburt TH, Leitz AJ, Xie G, Oprian DD, Sligar SG.
Transducin activation by nanoscale lipid bilayers con-
taining one and two rhodopsins. J Biol Chem 2007,
282:14875–14881.
FURTHER READING
Lassagne B, Tarakanov Y, Kinaret J, Garcia-Sanchez, D, Bachtold A. Coupling mechanics to charge transport
in carbon nanotube mechanical resonators. Science 2009, 325:1107–1110.
Tarakanov AO, Goncharova LB. Cell–cell nanotubes: tunneling through several types of synapses. Commun
Integr Biol 2009, 2:359–361.
10  2009 Jo h n Wiley & So n s, In c.
www.wiley.com/wires/nanomed
93. Bayburt TH, Grinkova YV, Sligar SG. Self-assembly
of discoidal phospholipid bilayer nanoparticles with
membrane scaffold proteins. Nano Lett 2002,
2:853–856.
94. Briddon SJ, Hill S. Pharmacology under the micro-
scope: the use of fluorescence correlation spectroscopy
to determine the properties of ligand-receptor com-
plexes. Trends Pharmacol Sci 2007, 28:637–645.
95. Service RF. Can sensors make a home in the body?
Science 2002, 297:962–963.
96. Cui D, Tian F, Ozkan CS, Wang M, Gao H. Effect
of single wall carbon nanotubes on human HEK293
cells. Toxicol Lett 2005, 155:73–85.
97. Zhang D, Yi C, Zhang J, Chen Y, Yao X, et al. The
effects of carbon nanotubes on the proliferation and
differentiation of primary osteoblasts. Nanotechnol-
ogy 2007, 18:475102.
98. Cavalcanti A, Shirinzadeh B, Freitas RA Jr, Hogg T.
Nanorobot architecture for medical target identifica-
tion. Nanotechnology 2008, 19:0151013.
99. Kim YI, Park TS, Kang JH, Lee MC, Kim JT,
et al. Biosensors for label free detection based on
RF and MEMS technology. Sens Actuators, A 2006,
119:592–599.
100. Artyukhin AB, Shestakov A, Harper J, Bakajin O,
Stroeve P, et al. Functional one-dimensional lipid
bilayers on carbon nanotube templates. J Am Chem
Soc 2005, 127:7538–7542.
101. Schrlau MG, Falls EM, Ziober BL, Bau HH. Car-
bon nanopipettes for cell probes and intracellular
injection. Nanotechnology 2008, 19:015101.
102. Editorial. Nat Nanotechnol 2007, 2:451.
Vo lu me 2, Jan u ary /Febru ary 2010