Advanced Review

Nanotechnology for implantable

sensors: carbon nanotubes and
graphene in medicine
Evan K. Wujcik and Chelsea N. Monty∗

Implantable sensors utilizing nanotechnology are at the forefront of diagnostic,

medical monitoring, and biological technologies. These sensors are often equipped
with nanostructured carbon allotropes, such as graphene or carbon nanotubes
(CNTs), because of their unique and often enhanced properties over forms of bulk
carbon, such as diamond or graphite. Because of these properties, the fundamental
and applied research of these carbon nanomaterials have become some of the
most cited topics in scientific literature in the past decades. The age of carbon
nanomaterials is simply budding, however, and is expected to have a major impact
in many areas. These areas include electronics, photonics, plasmonics, energy
capture (including batteries, fuel cells, and photovoltaics), and—the emphasis of
this review—biosensors and sensor technologies. The following review will discuss
future prospects of the two most commonly used carbon allotropes in implantable
sensors for nanomedicine and nanobiotechnology, CNTs and graphene. Sufficient
further reading and resources have been provided for more in-depth and specific
reading that is outside the scope of this general review. © 2013 Wiley Periodicals, Inc.

How to cite this article:

WIREs Nanomed Nanobiotechnol 2013, 5:233–249. doi: 10.1002/wnan.1213

INTRODUCTION graphene, was first theorized in 1947 to better

understand the band structure of graphite.7,8 How-
S ince the discovery of buckminsterfullerenes (nano-
C60 , buckyballs) by Kroto et al. in 1985,1 both
the synthesis and material properties of nanostruc-
ever, since its intentional isolation by Geim and
Novoselov in 20049 it has become one of the sci-
entific community’s main focuses. Other nanostruc-
tured carbon allotropes have been of great interest
tured carbon allotropes include, but are certainly
to many fields of both basic science and engineering.
not limited to, double-walled CNTs (DWCNTs),10
Carbon nanomaterials have been highly cited over
graphenated CNTs,11,12 nanobuds,13,14 graphene
the past decades and are of interest to a number of
nanoribbons,15–17 graphene nanoplatelets,18,19 car-
areas of human activity including both fundamental
bon foam,20,21 nanodiamonds,22 and many variations
research—electronics, photonics, and plasmonics—
of fullerenes (nano-C20 ,23 nano-C70 ,24 etc.). The list
and applied research and engineering—energy cap-
goes on, and one day may include the theorized
ture and storage (including batteries, fuel cells, and
sp-sp2 −graphyne25 or sp-sp3 -yne-diamond,26 which,
photovoltaics), catalysis, corrosion prevention, and
because of containing double and triple bonds, may
sensors.2–5 Following the mainstreaming of carbon
exhibit nearly massless electrons and have the poten-
nanotubes (CNTs) by Iijima in 1991,6 further inves-
tial to surpass graphene’s interesting electrical proper-
tigations into various morphologies have been con-
ties. The appeal of these carbon-based nanostructures
ducted, resulting in a number of newly discovered
is due to their unique and often enhanced electri-
nanostructured carbon allotropes. One of which,
cal, optical, and mechanical properties, as well as
∗
their high aspect ratio (over bulk carbon allotropes).
Correspondence to: cm78@uakron.edu
These properties can be ascribed to the sp2 -hybridized
Monty Research Laboratory, Department of Chemical and
Biomolecular Engineering, The University of Akron, Akron, bonds,27,28 quantum-size effects,29,30 extreme aspect
OH, USA ratios, in zero, one, and two dimensions, and

Volume 5, May/June 2013 © 2013 Wiley Periodicals, Inc. 233

 Advanced Review
Examples of fullerenes
C60 C540 C70
Carbon nanotubes
1991
Fullerenes
1985
FIGURE 1 | Illustration showing a timeline of some of the structures of nanostructured carbon allotropes. (Reprinted with permission from Ref 26.
Copyright 2010 Nature Publishing Group, a division of Macmillan Publishers Limited; Reprinted with permission from Ref 31. Copyright 2006 Free
Software Foundation)
exclusive structure of carbon allotropes as seen in
Figure 1.
Recently, carbon nanomaterial allotropes have
been some of the most studied nanomaterials in the
scientific community, and their toxicity—which can
differ from bulk allotropes—has been a continuing
debate among the scientific community.32,33 At
the nanoscale, there are a few key factors that
influence toxicity—namely the surface area/mass ratio,
retention time within the body/tissue (or in contact
with the cell), and the reactivity of the compound(s)
making up the material.34 Although many studies are
currently underway to determine the ongoing debate
surrounding the biocompatibility of the growing
number of nanostructured materials,34,35 many have
been found to be both cytocompatible and nontoxic
for many purposes under specific conditions.36–40
Zhang et al.116 shows that graphene oxide (GO)
can be used for cancer-targeted drug delivery and/or
photothermal therapy in vivo, utilizing vascular
marker targeting. Liao et al.137 showed that the
blood compatibility and cytotoxicity of GO and
graphene sheets (GS) greatly depend on the sizes
and oxygen content of the graphene-based materials,
finding that smaller GO showed higher hemolytic
activity over larger GO and GS. However, GS
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Many undiscovered
allotropes, for example,
sp-sp2-graphyne
20??
Graphene
2004
...or sp-sp3-yne-diamond
20??
functionalized with chitosan seemed to eliminate the
hemolytic activity. CNT toxicity has also been two
sided,34 showing that unrefined CNTs exhibit some
degree of toxicity, which is predominately due to
the presence of transition metal catalysts. Exposure
to pristine CNTs, however, has been shown to
cause minimal cytotoxicity at higher concentrations.
Also, chemically functionalized CNTs—enhanced for
drug delivery—have not demonstrated any toxicity
to date. It should also be noted that aggregation
phenomena—which can alter the toxicity of a
material—is a common issue in the biocompatibility
debate. Despite these inconsistencies in reports,
the versatility and utility of carbon nanomaterials
make them promising candidates for a number of
applications in nanomedicine and bionanotechnology,
including bioelectronics,41–43 cellular scaffolds,44–46
and biosensors.47–56
In this review, present and prospective
implantable sensors incorporating nanostructured car-
bon allotropes shall be discussed. This topic will
be enumerated via literature surveys supplying brief
histories and backgrounds of the allotropes of nanos-
tructured carbon (CNTs, graphene, and other—less
commonly discussed—allotropes) and applications of
each, in relation to implantable sensor technologies.
© 2013 Wiley Periodicals, Inc. Volume 5, May/June 2013
 WIREs Nanomedicine and Nanobiotechnology
We will then describe various applications with
an in-depth look at the implantable sensors from
the viewpoints of nanomedicine, materials science,
nanobiotechnology, and sensor design, both present
and future.
CARBON NANOTUBES
CNTs are believed to be conceptualized as early
as 1889 in a patent57 suggesting the use of such
carbon filaments in Edison’s recently presented light
bulb.58 Actual nanostructured carbon tubes are
thought to be first isolated as early as 1952 by
the Soviets.59 In the 39-year period between this
time (1952) and the mainstreaming of CNTs by
Iijima (1991), a number of publications mention
their use,60–62 but do not receive considerable
attention. Throughout this time, the ever-increasing
resolution of transmission electron microscopy
allowed carbon—and many other—nanostructures
to become more easily characterizable and, hence,
more popular amongst the scientific and engineering
communities. There are a number of reviews,
books, and articles discussing the fabrication and
purification of CNTs—including chemical vapor
deposition (CVD), arc discharge, laser ablation, or
high-pressure carbon monoxide disproportionation
methods—therefore, these topics will not be covered
in this review.63–66 CNTs have a number of properties
making them auspicious for in vitro and in vivo
sensing, such as their ability to enter cells, their ability
to be modified to avoid toxicity issues, and their
intrinsic optical and electronic properties—which
are easily tuned and felicitous for biological and
life science applications. In the next two sections,
implantable sensing applications of multiwalled CNTs
(MWNTs) and single-walled CNTs (SWNTs) will be
discussed separately.
MWNT Applications for Implantable
Sensors
MWNTs are thought to be first isolated and identified
in 1952 in the Soviet publication Russian Journal
of Physical Chemistry A59 (seen in Figure 2(a));
however, the discovery of MWNTs is commonly
attributed to Iijima6 in 1991.58,67 In any respect,
Iijima’s mainstreaming of nanostructured carbon
inspired many researchers to investigate the uses
of this unique allotrope since its reintroduction.
MWNTs can be thought of as a number of
different diameter SWNTs coaxially arranged, with
an intertube separation (0.34–0.35 nm) similar to
that of the interplane separation in graphite.64 This
Volume 5, May/June 2013 © 2013 Wiley Periodicals, Inc.
Nanotechnology for implantable sensors
(a) (b) Carbon nanotube
Pnc. 7
× 20,000
C C
C C
Graphene sheet
C C C C
FIGURE 2 | (a) Early (1952) transmission electron micrographs of
Soviet carbon nanotubes (CNTs). No scale bar is provided; however, on
the basis of the magnification, one may calculate the diameters of
nanotubes to be about 50 nm. (b) An illustration of the sp 2 -hybridized
bonds of graphene and CNTs—where it can be seen that the distorted
electron clouds of the CNTs make them more electrochemically active.
(Reprinted with permission from Ref 59. Copyright 1952 Pleiades
Publishing, Ltd.; Reprinted with permission from Ref 63. Copyright 2007
WILEY-VCH Verlag GmbH & Co.)
configuration is commonly referred to as the ‘Russian
nesting doll’ or ‘matryoshka’ model, as the CNTs
are nested within one another. MWNTs—being a
very electrically conductive and electronically stable
fullerene of carbon—have a great potential for
implantable biosensors, but show promise in a
number of areas, including enhanced neural growth
substrates,68–70 liquid and vapor sensing,71,72 and
even nanodynamite.73,74
MWNTs have shown great promise in orthope-
dic implant systems, for their scaffolding abilities as
well as monitoring bone growth via electrochemical
sensing techniques.75–78 Greater osteoblast differenti-
ation has been shown previously using a MWNT-Ti
composite, in comparison to titanium (Ti) alone.79
For this application, the MWNTs can be grown,
via cobalt-catalyzed CVD, in the nanopores of the
anodized-Ti implant prior to surgery.75 This method
allows for a strong electrical contact between metallic-
Ti and the MWNTs.77 To verify its use as a new bone
growth electrochemical sensor, Sirivisoot and Web-
ster tested its osteoblast differentiation redox reaction
sensing ability. The cyclic voltammograms (CVs) seen
in Figure 3(a) show the response of the Ti, anodized-
Ti, and MWNT-Ti electrodes (with a working area of
1 cm2 ) to an electrolyte solution of the extracellular
matrix secreted by osteoblasts after 21 days of culture.
Here, it can be seen that the highly conductive surface
of the MWNTs enhances the electroactivity, because
of increased surface area, in a mimicked orthopedic
implant environment. Figure 3(b) shows the calcium
deposition assay (Figure 3(b)—inset) and correspond-
ing CV plots at different time periods, illustrating
235
 Advanced Review wires.wiley.com/nanomed

0.1
(b)
0.8
(a) 0.05
0.6 800 mV/s (MWNT-Ti)

0.4 400 mV/s (MWNT-Ti)

0

Current (mA) / mm2

Current (mA) / cm2

0.2

0 −0.05

−0.2 3
2.482
800 mV/s (anodized-Ti)

Calcium deposition
400 mV/s (anodized-Ti)
−0.1 2.5 *

−0.4 2

(μg/cm2)
1.597
1.481
1.5
−0.6 400 mV/s (Ti)
800 mV/s (Ti) −0.15 7 days 1
0.5
−0.8 14 days
0
−350 −300 −250 −200 −150 −100 −50 0 21 days 7 Days 14 Days 21 Days
Potential (mV) versus Ag/AgCl −0.2
−350 −300 −250 −200 −150 −100 −50 0
Potential (mV) versus Ag/AgCl (scan rate = 300 mV/s)

FIGURE 3 | Cyclic voltammograms showing (a) the redox reaction peaks produced by titanium (Ti), anodized-Ti, and multiwalled carbon
nanotube-Ti (MWNT-Ti) electrodes and (b) how the MWNT-Ti electrode redox peaks correspond to the calcium deposition (inset shows calcium
deposition assay results). (Reprinted with permission from Ref 76. Copyright 2008 IOP Publishing Ltd.)

the sensing of new bone growth over time. Here, we semiconducting. Here, the chiral indices (n, m) used to
predict that using the MWNT-Ti electrode to sense describe the roll-up vector denote the number of lat-
osteoblast extracellular components may improve the tice vectors (a1 and a2 ) along two directions in a sheet
diagnosis of in vivo orthopedic implant success or of graphene. The zigzag (n, 0) and armchair (n, n) con-
failure, leading to improved clinical efficacy. figurations are a few common CNT representations.
SWNTs also exhibit a distinctive resonance-enhanced
Raman spectrum—which is very stable because of
SWNT Applications for Implantable Sensors the sp2 carbon lattice—that can be used for detec-
SWNTs were first isolated and identified indepen- tion and imaging in vivo.64 These resonance bands
dently by two groups in Japan80 and in the United show no quenching or bleaching, even under extreme
States81 in 1993, while trying to synthesize MWNTs laser powers, and can be easily distinguished from the
filled with transition metals.58 The optical properties background of biological species (autofluorescence).64
of semiconducting SWNTs make them advantageous SWNTs also have distorted electron clouds, which
for biolabeling, imaging, and sensing in biological tis- make them more electrochemically active—in refer-
sues, as they absorb and emit in the near-infrared ence to graphene, as shown in Figure 2(b). All of
(NIR) region—where biological tissues are highly the aforementioned properties make them propitious
transparent and the background cellular autofluores- for the sensitive biosensing and imaging of multiple
cence is low.64 This NIR emission changes instantly analytes simultaneously.
upon the binding of a target analyte and is much A remarkable area in which SWNTs have
more stable than many common fluorophores, such shown great promise as implantable sensors is the
as dye molecules or semiconducting quantum dots.64 imaging and detection of single molecules by: (1) their
It should also be noted that the emission wavelength intrinsic bright NIR fluorescence, (2) the fact that the
differs based on the diameter—which can be varied bandgap structure is sensitive to their local dielectric
from nanometers to micrometers—and chirality of the environment, and (3) the quenching capability of
SWNT—which can be rolled up in a number of ways the CNTs. The Strano Research Group at MIT
to make them either metallic or semiconducting.64 shows a mechanism in which DNA wrapped around
Based on the chiral vector (Ch , also called the roll- a SWNT transitions from a B to Z confirmation
up or translational vector), which can be seen in (DNA polymorphism)—because of the presence of
Figure 4, a CNT (n, m) is metallic if n = m or if divalent metal cations—causing a red shift in the
n − m is a multiple of 3; otherwise, the nanotube is bandgap fluorescence82 (shown in Figure 5(a) and

236 © 2013 Wiley Periodicals, Inc. Volume 5, May/June 2013

 WIREs Nanomedicine and Nanobiotechnology Nanotechnology for implantable sensors

a1
a2 ir
cha
arm
( n ,n )

Ch = na1 + ma2 (n,0) zigzag

FIGURE 4 | Graphic illustrating the possible 0D (buckyballs), 1D (carbon nanotubes, CNTs), and 3D (graphite) structures that can be made from
graphene (2D), as well as the chiral vectors of both the zigzag and armchair single-walled CNT rolling patterns. The CNT in the figure is of the zigzag
configuration, with the indices n = 8 and m = 0 (8, 0). (Reprinted with permission from Ref 8. Copyright 2007 Nature Publishing Group)

(b)). This NIR photoluminescence depends on the
bandgap energy, which is sensitive to the local
dielectric environment of the SWNT. Through
changing confirmations, the DNA modulates this
local environment, and the transition is prevalent in
blood, living mammalian cells, and tissues. A similar
sensing technique has also been developed by Heller
et al.,83 where a SWNT-based DNA conjugation is
used to detect active alkylating drugs and reactive
oxygen species. Here, the unique intensity- and
shift-dependent fluorescence emission responses of
two semiconducting SWNTs [(6, 5) and (7, 5)]
are correlated to the detection of several species
simultaneously. Using this technique, a number of
analytes/processes were detected within and out of
live 3T3 cells, including guanine alkylation with
mechlorethamine, H2 O2 adsorption, single oxygen
interaction with wrapped DNA, and hydroxyl radical
damage to the wrapped DNA. This label-free sensor
was the first of its kind capable of genotoxin
discrimination.
This technique has also been applied to a
blood glucose sensor for point-of-care constant
monitoring of blood glucose concentration.85 Here,
the SWNT NIR fluorophores were functionalized with
phenoxy-derivatized dextran—a glucose mimic—and
then aggregated by adding concanavalin A (Con
A) at a pH of 7.4. This aggregation results in an
altered photoluminescence from the nonaggregated
SWNTs (because of energy transfer effects), and
when glucose is present the competitive binding
of the Con A and glucose causes the aggregates
to dissociate—making the detection prevalent. This
demonstrated the first solution-phase-affinity glucose
sensor incorporating SWNT photoluminescence.
SWNT fluorescence in vivo sensor studies have
been conducted to examine the pharmacological
effects of the sequential delivery of dexamethasone
(DX) followed by vascular endothelial growth
factor (VEGF) on the immune response and
localized vascular network formation around a
hydrogel-coated, microcapillary implant.86 Here, we
have shown that the subcutaneously implanted
device’s local environment immune response was
lowered—based on the therapeutic index and vascular
density—when the DX and VEGF were, respectfully,

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 Advanced Review wires.wiley.com/nanomed

(a) (b)
1.255

1.252 Mg2+
CO2+
Peak energy (eV) 1.249

1.246
1
0.9
1.243 Hg2+ Ca2+
0.8
I

0.7
1.240 0.6
1.23 1.24 1.25
Energy (eV)
1.237
0.001 1 1000 1,000,000
Concentration (μM)

(c)

FIGURE 5 | (a) Graph showing the concentration-dependent fluorescence responses of the DNA-encapsulated (6, 5) single-walled carbon
nanotube (SWNT) to divalent chloride counterions and (b) an illustration on DNA undergoing a conformational transition from the B form (top) to the
Z form (bottom) on a SWNT. (c) The mechanism by which a SWNT acts as a molecular beacon nanoquencher. (Reprinted with permission from Ref 82.
Copyright 2006 American Association for the Advancement of Science; Reprinted with permission from Ref 84. Copyright 2008 American Chemical
Society)

delivered sequentially rather than simultaneously or
not at all. The authors demonstrated—in a computer-
aided manufacturing tissue model—that a hydrogel-
coated, microdialysis capillary was suitable for
implantation of a SWNT-based fluorescence sensor, as
well as SWNT fluorescence detection through tissue.
Tan and coworkers have also shown quench-
ing using a self-assembled SWNT/oligonucleotide
complex.84 Here, a single-fluorophore-labeled oli-
gonucleotide is used as a molecular beacon biosensor.
This oligonucleotide’s hairpin structure allows the
SWNT to act as a ‘nanoscaffold’ for the oligonu-
cleotide and a ‘nanoquencher’ for the fluorophore
(shown in Figure 5(c)), allowing the detection of the
corresponding oligonucleotide strand. Through com-
petitive binding, the presence of the corresponding
strand would pull the oligonucleotide off the SWNT
and the fluorophore would stay intact, acting as the
corresponding strand’s detection mechanism.
SWNTs also have distinct Raman spectroscopy
bands around 150–300, 1590–1600, and 2600 cm−1 ,
which do not overlap with the excitation wavelength,
and unlike the NIR fluorescence of SWNTs, the
Raman scattering is present in both the metallic and
semiconducting chiralities. The radial breathing mode
(RBM) vibration (150–300 cm−1 ) is due to an out-of-
plane phonon mode in which the carbon atoms vibrate
in a radial movement. This RBM vibration can be used
to characterize the chirality of the SWNT.87,88 This
value is also inversely proportional to the SWNT
diameter,89 making it important in determining
the electronic type and size of the nanotube.
This band has a low intensity and is normally
not used for intracellular Raman spectroscopy;
however, the G-band (1590–1600 cm−1 )—a feature
of the tangential stretching of carbon atoms in the
SWNT—is widely used in vivo with high sensitivity
and intensity.90 Similar to the NIR fluorescence,
the RBM band of SWNTs is sensitive to both
the bundling and the local dielectric environment
of the nanotubes, whereas the G-band—in contrast
to the NIR fluorescence—is largely insensitive to
varying diameters, bundling confirmations, and
the local dielectric environment.64 Utilizing SWNT

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 WIREs Nanomedicine and Nanobiotechnology
applications, much work has been done in the
area of ex vivo Raman spectroscopy to examine
SWNT retention—along with the long-term fate—and
biolabeling possibilities in different tissue medias.91–95
SWNTs have a number of other useful properties
making them suitable for many applications, such as
implantable SWNT bone strain sensors, which have
recently been developed for the real-time monitoring
of musculoskeletal conditions, to aid in rehabilitation
and advanced orthopedic operations.96 These flexible
sensors consist of SWNTs arranged in a single-
walled carbon nanonet design. Here, as the bone
endures higher microstresses, an increased resistance
is seen. SWNTs have also been applied to implantable
electrochemical glucose sensors (Box 1).97,98 Claussen
et al. have fabricated a biocompatible amperometric
glucose biosensor using SWNTs coated in platinum
(Pt) nanospheres. The enzyme glucose oxidase (GOx )
was then immobilized onto the SWNT/Pt nanosphere
composite to allow for selective and sensitive in situ
detection of glucose.
Neuronal interfacing is yet another area in
which SWNTs have become of interest for the
monitoring and stimulation of neurons, as well as
potential neuroprosthetic devices.46,99,100 Ben-Jacob
and Hanein have fabricated SWNT-coated Ti-nitride
electrodes for interfacing with neuronal systems, and
have shown that these electrodes exhibit the high
surface area needed for cells to adhere and grow, and
the ability to stimulate and record neural activity.
The usefulness of CNT applications to both
medicine and the general life sciences is undebatable.
However, many have a long road to travel before
becoming accepted as viable diagnosis and treatment
options. Much work has yet to be done regarding the
long-term fate and effects of these nanomaterials in
both our bodies and our ecosystem.
BOX 1
SWNTs VERSUS MWNTs: ELECTRONIC
PROPERTIES (SUMMARIZED FROM REF
101)
The electronic band structure of a SWNT can
be described by considering the bonding of
the carbon atoms arranged in a hexagonal
lattice. As the unit cell of graphene has two
carbon atoms, an even number of electrons
are contained in the basic nanotube structure,
which can be metallic or semiconducting.
Researchers have predicted that the relationship
between the coefficients of the translational
vector Ch = na1 + ma2 , which connects two
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Nanotechnology for implantable sensors
crystallographically equivalent sites, determines
the conducting properties. When 2n + m is an
integer multiple of three, the CNT exhibits metal-
lic behavior, while nonmetallic/semiconducting
behavior, with a bandgap for conduction, is
obtained in all other cases.
As MWNTs are composed of several coaxial
SWNTs it might be expected that they are not
strictly one-dimensional conductors; however, a
pseudo-gap was observed. It was also deter-
mined that the current flow only occurs through
the outer most nanotube cylinder. [. . .] While this
mutual interaction between the adjacent coaxial
cylinders might be very small, it cannot be com-
pletely neglected. This allows MWNTs to have a
richer band structure in contrast to SWNTs and
comparable to graphite (where the interplane
coupling is ∼10 meV). Intertube coupling (which
depends inversely with the MWNT diameter) can
also significantly affect the band structure. For
instance, in a DWCNT, one metallic and the other
semiconducting low-energy properties charac-
teristic of metallic tubes predominate, whereas if
both the constituent tubes are metallic, a much
more complicated situation in terms of band
crossings can arise.
GRAPHENE
Since its intentional isolation in 2004 by Geim and
Novoselov, graphene has captured the interest of
both scientists and the public alike, because of its
unique optoelectronic and physical properties, as well
as being ‘the mother of all graphitic forms.8 ’ This
concept is illustrated in Figure 4, through showing
the pathway in which 2D graphene can be wrapped,
rolled, or stacked into 0D (buckyballs), 1D (CNTs), or
3D (graphite) dimensionalities. Its enhanced electronic
properties are due to graphene’s sp2 -hybridized bonds
and exceptional electronic-quality crystals, making
charge carrier mobility and extraction extremely effi-
cient. Graphene has also displayed unmatched and
very interesting material properties, such as trans-
parent wetting of certain substrates (copper, gold,
and silicon) because of its extreme thinness and band
structure102 (displayed in Figure 6). The ability to tune
the surface morphology of a substrate without chang-
ing its wettability could have implications in the design
of conducting, conformal, and impermeable surface
coatings.102 This study and graphene’s ‘superomni-
phobicity’, however, have recently been challenged by
researchers at the Massachusetts Institute of Tech-
nology (MIT) who found that there is a significant
239
 Advanced Review
77.4
(a)
80
Contact angle (°)
70
60
50
32.6 33.2
40
30
20
No graphene Graphene (single layer)
FIGURE 6 | Contact angle bar graphs illustrating (a) graphene’s wetting transparency and (b) how its wetting transparency diminishes (becoming
more similar to bulk graphite) as additional graphene layers are added. (Reprinted with permission from Ref 102. Copyright 2012 Nature Publishing
Group, a division of Macmillan Publishers Limited)
breakdown of this phenomenon on superhydropho-
bic and superhydrophilic substrates.103 There are a
number of reviews, books, and articles discussing the
fabrication and purification of graphene and GO—in-
cluding a number of schemes for chemical or mechan-
ical exfoliation—therefore, these topics will not be
covered in this review.104–106 Although graphene—a-
long with GO and its reduced form—has been found
to be both biocompatible under specific conditions and
able to be interfaced with biological molecules38–40 (as
illustrated in Figure 7(a)), their toxicity is a continu-
ing debate among the scientific community. Although
isolated graphene is relatively new to applications, its
characteristics have the potential to lead to enhanced
materials that could be applied to many implantable
sensor technologies, which will be discussed in the
following sections.
Graphene Applications for Implantable
Sensors
Many interesting aspects of graphene make it a
promising implantable sensor candidate, as dis-
cussed above. To date, pristine graphene has found
applications to implantable sensor technologies as
a glucose detection system,108,109 neural stimula-
tor and signal recorder,110,111 antigen detection
system,112 chemiresistor,113 and biological molecule
sensor.49,52,114–116 Yao and coworkers111 have shown
the development of a graphene-based microelectrode
for recording neural signals (seen in Figure 8(a)). This
microelectrode has been found to be both biocom-
patible and nontoxic, and had a signal-to-noise-ratio
as high as 30.2 ± 2.45 dB, as seen in Figure 8(b).
For enhancement of biological compatibility, the
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78.8 (b) 90.6
91
88.3
90
Contact angle (°)
89
86.5 86.6
Si 88
85.9 86.2
Au
87
86
85
84
Cu Single 1−2 2−3 4−6 6−9 8−12 10−15
baseline layer layers layers layers layers layers layers
microelectrode was treated with steam plasma by
increasing the hydrophobicity.
GO Applications for Implantable Sensors
GO is very similar to graphene, but differs in struc-
ture slightly (as seen in Figure 7(b)). However, these
structural differences greatly affect its material and
electronic properties.105 As the sp2 -hybridization is
broken up by the presence of tertiary alcohols and
ethers (proposed by Lerf and Klinowski to be 1,2-
ethers, i.e., epoxides),107 the π -bonds—hence the
delocalized electrons—that give graphene its enhanced
electronic properties are diminished in number. This
disrupted π -network can be partially restored by
GO’s reduction, leaving one with what is often
called reduced GO (r-GO), which is also commonly
referred to as chemically reduced GO, and even
graphene—although the structure of r-GO can dif-
fer from pristine graphene significantly. This greatly
depends on the route of reduction, which can be
accomplished via chemical, thermal, and electrochemi-
cal pathways (Box 2).107 GO—whose cytocompatibil-
ity is also up for debate37,117 —has been shown to non-
covalently bind proteins to its surface without disrupt-
ing their structures and, hence, their function.40,107,118
This is done via GO’s unique ability to hydrogen bond
with the likes of water molecules and polypeptide
chains, by way of the oxygen of the epoxides. One
should also note the various functionalization-site
possibilities with regard to GO to develop chemi-
cally modified graphenes. These could include the
carboxylic acid groups on the periphery of the basal
plane and the epoxy groups, as well as many noncova-
lent bindings (via π –π stacking, cation–π , or van der
© 2013 Wiley Periodicals, Inc. Volume 5, May/June 2013
 WIREs Nanomedicine and Nanobiotechnology
(a)
FIGURE 7 | (a) Illustration of the various biofunctionalizations of graphene and graphene oxide (GO). These functionalized graphene biosystems
have the unique properties needed to be used to build up biological platforms, biosensors, and biodevices. (b) The Lerf–Klinowski model of GO
(considered the most widely accepted model) with (top) and without (bottom) the carboxylic acid groups on the periphery of the basal plane.
(Reprinted with permission from Ref 40. Copyright 2011 Elsevier Ltd.; Reprinted with permission from Ref 107. Copyright 2011 The Royal Society of
Chemistry)
BOX 2
BASIC ELECTROCHEMISTRY OF
GRAPHENE (SUMMARIZED FROM REF 52)
The electron transfer (ET) behavior studies
of graphene using cyclic voltammetry of
redox couples, such as [Fe(CN)6 ]3−/4− and
[Ru(NH3 )6 ]3+/2+ , exhibit well-defined redox
peaks. Both anodic and cathodic peak currents
in the CVs are linear with the square root of
the scan rate, which suggest that the redox
processes on graphene-based electrodes are
predominantly diffusion-controlled. The peak-
to-peak potential separations (Ep ) in CVs
for most one-electron-transfer redox couples
are quite low, very close to the ideal value
of 59 mV, for example, 61.5–73 mV (10 mV/s)
for [Fe(CN)6 ]3−/4− and 60–65 mV (100 mV/s) for
[Ru(NH3 )6 ]3+/2+ , and much smaller than that on
glassy carbon (GC). The peak-to-peak potential
separation is related to the ET coefficient,
and a low Ep value indicates a fast ET
for a single-electron electrochemical reaction
on graphene. The apparent ET rate constants
(k0 ) calculated from CVs on graphene and
GC electrodes are 0.18 and 0.055 cm/s for
[Ru(NH3 )6 ]3+/2+ , respectively. This indicates that
the unique electronic structure of graphene,
especially the high density of the electronic states
over a wide energy range, endows graphene
Volume 5, May/June 2013
Nanotechnology for implantable sensors
(b)
with fast ET. The k0 for [Fe(CN)6 ]3−/4− on
graphene and GC were calculated to be 0.49
and 0.029 cm/s, respectively, and the ET rates for
Fe3+/2+ at graphene electrode are several orders
of magnitude higher than that at GC electrodes.
These indicate that the electronic structure and
the surface physicochemistry of graphene are
beneficial for ET.
Waals interactions).107 GO has also shown interesting
interactions with lipid membranes, including alter-
nating (lipid/GO or bio/nonbio) multilayers.119 These
bonding abilities and moiety sites are important in its
application as delivery vehicles, as well as implantable
devices.
GO has been found to have a num-
ber of biosensing applications including fluores-
cent d-glucosamine detection,120 immunosensing,121
endonuclease/methyltransferase activity assays,122
enzyme inhibition and modulation,123,124 delivery
vehicles,36 and mycotoxin detection.125 Silver (Ag)
nanoparticle (NP)-modified GO has also been found
to have enhanced antibacterial activity against
Escherichia coli, over that of both GO and Ag
NPs alone,126 which could have applications in
implantable tissue scaffolds or wound dressings.
Dravid and coworkers123 have developed a GO
enzyme inhibitor for modulation of the activity
of α-chymotrypsin (ChT), a serine protease. This
study has demonstrated all the requirements for a
© 2013 Wiley Periodicals, Inc. 241
 Advanced Review wires.wiley.com/nanomed

(a) (b) 500 200

Graphene
100
Au line 400
0
PDMS 300

Voltage / uV
Graphene −100
1.485 1.490 1.495 1.500 1.505
200
200 μm
100

−100
Graphene microelectrode
0.0 0.5 1.0 1.5 2.0
Time / s

FIGURE 8 | (a) An optical micrograph of the graphene-based neural microelectrode and (b) extracellular signal with a high signal-to-noise-ratio
(right inset; left inset shows a schematic of the microelectrode). (Reprinted with permission from Ref 111. Copyright 2011 IEEE)

(a) COOH OH COOH COOH (d)

200
Cyclic peptide
Conc of inhibitor (μg/mL)/3.2 μm ChT

OH O PEG like
HOOC COOH
substitution
O O
Aromatic/
150
HO OH Hydrophobic
OH
HOOC Anionic/ Gold nanoparticles
OH
Charged
O 100
COOH Polymeric micelles
COOH OH COOH
Dendrimer
(b) (c) 50
Ferric porphyrin
Carbon nanotube

0
Graphene oxide
Cationic residue
Active pocket
55 60 65 70 75 80 85 90 95 100
% of Inhibition
(e)
O O
1.0 O H2N O
HO HO
ChT +
NH NH
H NO2
N OH
0.8
Normalized activity

O NO2 O
SPNA
0.6

ChT Activity
0.4

0.2

0.0
0 5 10 15 20 25
[GO]/(μm/mL)

FIGURE 9 | (a) Schematics of the functionalization sites of graphene oxide (GO), (b) the structure of α-chymotrypsin (ChT), and (c) the GO/protein
complex. (d) A plot illustrating the degrees of inhibition and relative concentrations of various ChT inhibitors, GO being the most efficient. (e) The
normalized activities of ChT plotted as a function of GO concentration in 5 mM sodium phosphate buffer (pH 7.4) using N -succinyl-L-phenylalanine-p -
nitroanilide as a substrate. (Reprinted with permission from Ref 123. Copyright 2011 American Chemical Society)

242 © 2013 Wiley Periodicals, Inc. Volume 5, May/June 2013

 WIREs Nanomedicine and Nanobiotechnology Nanotechnology for implantable sensors

(a) (b)
12 H3C CH3 H3C CH3 H3C CH3
N N N
10

8
Current (μA)

N
CH3 N CH3
CH3 CH3
6 N
25 nM Dopamine H3C CH3
4 H3C CH3 H3C CH3
N N
CH3
0.05 μA

2 N CH3
10s CH
0 IN 3
40 60 80 100 CH3
0 20
Dopamine concentration (μM)

FIGURE 10 | (a) A graph illustrating the amperometric response of the graphene foam (GF) electrode to varying concentrations of dopamine;
insets show an scanning electron micrograph of the GF and a response to a dopamine concentration of 25 nM. (b) Cationic fullerene derivatives that
have shown anti-HIV properties. (Reprinted with permission from Ref 21. Copyright 2012 American Chemical Society; Reprinted with permission from
Ref 127. Copyright 2012 American Chemical Society)

high-efficiency synthetic receptor/inhibitor, namely, Graphene Foam Applications for

(1) strong and compatible binding with the target pro-
tein—in this case, the authors looked at the binding
of ChT, (2) reversible protein–receptor interactions,
and (3) no alteration of the proteins’ native confor-
mation by the receptor/inhibitor material (illustrated
in Figure 9(a)–(c)). GO’s high-efficiency binding can
be seen in Figure 9(d), where a very low concen-
tration of GO—relative to other inhibitors—shows
a much higher percent of inhibition. This high
efficiency is also demonstrated through Figure 9(e),
where activity assays were conducted to assess the
inhibitory potency of the GO using N-succinyl-
l-phenylalanine-p-nitroanilide as a substrate. One
may observe that complete inhibition occurred at
20 μg/mL GO.
OTHER ALLOTROPES OF
NANOSTRUCTURED CARBON IN
IMPLANTABLE DEVICES
Although many forms of nanostructured carbon
already exist, a number of new allotropes are the-
orized and will hopefully one day be discovered, as
discussed earlier. These discoveries will likely—as the
discovery of CNTs and graphene have before—change
the way we think about the correlations between mor-
phology and size, as they pertain to the properties
of a material. In this section, some of the less often
used carbon allotropes—with respect to implantable
sensor systems—will be introduced and some of their
applications will be discussed.
Implantable Sensors
Graphene foam (GF)—a 3D microporous network of
monolayered to few-layered GS templated foam—has
shown some unique properties of its own applicable
to implantable sensor technologies. This includes both
a static and dynamic hydrophobic contact angle in a
GF/water/air system, as well as a superhydrophobic
advancing liquid contact angle—when coated in
Teflon.127 This superhydrophobic property is caused
by the material having a low surface energy
and high roughness—allowing air pockets beneath
the liquid, hence further lowering the surface
energy. In addition to its hydrophobic nature, this
material is also flexible and mechanically robust.
A material such as this could find applications in
self-sterilizing or anticorrosive flexible implants, or
low-friction microfluidic implantable sensors. Chen
and coworkers21 have shown that a GF electrode can
detect dopamine with high sensitivity and selectivity,
and have lowered the detection limit of dopamine
down to a concentration of 25 nM (seen in the inset
of Figure 10(a)). This figure also shows a scanning
electron micrograph of the GF and the average
dose–response curve from three electrodes (error bars
indicate the standard deviations of the three runs).
It can be seen that at a low concentration range, a
linear fitting can be applied. This material could have
a number of implantable sensing applications, with its
high electrode surface area, high charge transfer rate,
efficient mass transport of diffusional redox species,
and the noncovalent interactions (hydrophobic and

Volume 5, May/June 2013 © 2013 Wiley Periodicals, Inc. 243

 Advanced Review
π –π interactions) between biological molecules and
graphene—this promotes ET from the biological
molecules for easy detection.
Fullerenes Applications for Implantable
Sensors
Fullerenes (namely nano-C60 ) have been found to
be highly electrochemically active because of the
formation of sp3 -like anionic centers—which are
thought to lower the energy of the molecule’s sur-
face of distorted sp2 carbons—and the fact that
they have been found to undergo as many as six
one-electron reversible reduction reactions.63 These
lipophilic and relatively inert nanostructures63 have
been modified with a number of inorganic, organic,
and organometallic moieties,128–131 for a number of
applications in medicine, electronics, optoelectron-
ics, and—recently—biosensing.63,132 Some of these
suggested applications include their use as redox
charge transfer mediators,133 monitoring of chemi-
cal and biological species in supported lipid bilayer
membranes,134 antiviral activity,135 and nuclear mag-
netic resonance imaging contrast agents.131 Da Ros
and coworkers136 have also shown anti-HIV prop-
erties of cationic fullerene derivatives (shown in
Figure 10(b)). These patterns of substitutions have
been found to improve the antiviral inhibition against
both HIV-1 and HIV-2 strains.
SUMMARY AND OUTLOOK
A general overview of nanostructured carbon
allotropes used in implantable sensors was provided
in this review, including CNTs, various forms of
graphene, and other carbon nanomaterials. Through
this, the present and potential applications of their
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