Biomed Microdevices (2009) 11:495–501
DOI 10.1007/s10544-008-9255-7
Engineered neuronal circuits shaped and interfaced
with carbon nanotube microelectrode arrays
M. Shein & A. Greenbaum & T. Gabay & R. Sorkin &
M. David-Pur & E. Ben-Jacob & Y. Hanein
Published online: 8 December 2008
# Springer Science + Business Media, LLC 2008
Abstract Standard micro-fabrication techniques which
were originally developed to fabricate semi-conducting
electronic devices were inadvertently found to be adequate
for bio-chip fabrication suited for applications such as
stimulation and recording from neurons in-vitro as well as
in-vivo. However, cell adhesion to conventional micro-
chips is poor and chemical treatments are needed to
facilitate the interaction between the device surface and
the cells. Here we present novel carbon nanotube-based
electrode arrays composed of cell-alluring carbon nanotube
(CNT) islands. These play a double role of anchoring
neurons directly and only onto the electrode sites (with
no need for chemical treatments) and facilitating high
fidelity electrical interfacing–recording and stimulation.
This method presents an important step towards building
nano-based neurochips of precisely engineered networks.
These neurochips can provide unique platform for studying
the activity patterns of ordered networks as well as for
testing the effects of network damage and methods of
network repair.
Keywords Carbon nanotubes . Electrodes . Stimulation .
Circuit . Neurochip
M. Shein : A. Greenbaum : T. Gabay : R. Sorkin : M. David-Pur :
Y. Hanein (*)
School of Electrical Engineering, Tel-Aviv University,
Tel-Aviv 69978, Israel
e-mail: hanein@eng.tau.ac.il
E. Ben-Jacob
School of Physics and Astronomy, Tel-Aviv University,
Tel-Aviv 69978, Israel
1 Introduction
Recent studies have suggested the great potential of high-
density, carbon nanotube (CNT) coated surfaces as an
interfacing material with neural systems (Bekyarova et al.
2005; Gabay et al. 2007; Gabay et al. 2005; Hu et al. 2004;
Lovat et al. 2005; Mattson et al. 2000; Mazzatenta et al.
2007; Sorkin et al. 2006; Zhang et al. 2005). Foremost,
CNT surfaces act as an extremely efficient biocompatible
substrate on which neurons adhere and proliferate. The
pioneering work of Mattson et al. demonstrated that neu-
rons can attach and grow on chemically modified CNT
coated surfaces. Later studies confirmed that pristine CNT
surfaces support cell adhesion and viability even without
any surface modification (Gabay et al. 2005). Subsequent
studies revealed that CNT coated surfaces can facilitate cell
patterning, network engineering (Gabay et al. 2005), guided
neurite growth (Zhang et al. 2005) and even boost neuronal
electrical activity (Lovat et al. 2005). These findings
complement a wealth of experimental results with other
nano-patterned surfaces, suggesting a strong cellular sensi-
tivity to nano scale topographical patterns (Craighead et al.
2001; Dowell-Mesfin et al. 2004).
The fact that, in addition to being biocompatible (Hu et
al. 2004; Webster et al. 2004), CNTs are also electrically
conducting and can be seamlessly integrated into micro-
fabricated devices opens up new and exciting prospects in
the realm of neurochips (Breckenridge et al. 1995; Grattarola
and Martinoia 1993; Jimbo and Kawana 1992; Nguyen-Vu
et al. 2007; Stenger et al. 2001; Wheeler et al. 1999; Yu et
al. 2007). Indeed, previous studies, carried out in our group
and by others, have demonstrated that CNT decorated
micro electrodes are very promising as electro-chemical
electrodes for neuronal recording and stimulation applica-
tions (Gabay et al. 2007; Wang et al. 2006).
496
Here we demonstrate, for the first time, a direct,
unmediated electrical interfacing between pristine CNT
micro-electrode array (CNT-MEA) and cultured neurons.
The CNT coatings function as an adhesive, high specific
capacitance interface material. Unlike conventional elec-
trode materials, the islands of the CNT coatings are cell-
alluring—the neurons and glia cells have high affinity for
selective attachment to the islands. Hence the CNT elec-
trodes automatically control the cells and the network
arrangement in addition to facilitating electrical interfacing.
2 Experimental
2.1 Cell culturing
Dissociated cortical cultures were prepared as follows:
The entire cortices of (E18) Sprague Dawley rat embryos
were finely removed. The cortical tissue was digested
with 0.065% trypsin (Biological Industries, Kibbutz
Beit Haemek, Israel, Cat. No. 03-046-1) in phosphate
buffered saline (PBS) (Biological Industries, Kibbutz
Beit Haemek, Israel, Cat. No. 02-023-1) for 15 minutes,
followed by mechanical dissociation by trituration. Cells
were re-suspended in a modified essential medium with
Eagle’s salts (Biological Industries, Kibbutz Beit Haemek,
Israel, Cat. No. 01-025-1), 5% horse serum (Biological
Industries, Kibbutz Beit Haemek, Israel, Cat. No. 04-
004-1), 5 mg/ml gentamycin (Biological Industries,
Kibbutz Beit Haemek, Israel, Cat. No. 03-035-1), 50 μM
glutamine (Biological Industries, Kibbutz Beit Haemek,
Israel, Cat. No. 03-020-1) and 0.02 mM glucose (BDH, Cat.
No. 101174Y), and plated onto the CNT patterned sub-
strates at a density of 700 cells/mm2. To promote the long-
term survivability of the cells on the CNT islands it was
crucial to use a “feeder” colony of cells. To do so, a PDL-
coated (Sigma, Cat. No. p7889) thin disk of poly-
dimethylsiloxane (PDMS) was placed around the CNT
patterned area. The surrounding feeder culture on the disk
covered approximately 75% of the total neuro-chip area
and did not directly contact the CNT patterned culture.
The cultures were maintained at 37°C with 5% CO2 and
95% humidity. The growth medium was partially replaced
every 3–4 days.
2.2 Chemical inhibition
Control inhabitation tests were carried out to validate the
biological nature of the electrical signals measured. Inhibition
of electrical activity in the neuronal network was performed
by applying both a-amino-3-hydroxy-5-methylisoxazole-4-
propionic acid (AMPA) and N-methyl d-aspartate (NMDA)
receptor antagonists (20 μM 6-cyano-7-nitroquinoxaline-2,
Biomed Microdevices (2009) 11:495–501
3-dione (CNQX) (Sigma, Cat. No. C239) and 100 μM (2R)-
amino-5-phosphonovaleric acid (APV) (Sigma, Cat. No.
A5282)) to the medium.
2.3 Electron microscopy
Scanning electron microscopy observations were preformed
as follows: samples were fixated for 30 min (37°C) in PBS
with 2.5% glutaraldehyde (Fluka, Cat. No. 49629) and 4%
sucrose. The fixed samples were then dehydrated by rinsing
for 5 min in increasing concentrations of ethanol (25%,
50% and 75%), keeping the sample covered with each of
the ethanol solutions, followed by 10 min rinses with 96%
and 100% ethanol solutions. Finally, the dehydrated
samples were critical-point dried using a Balzers Union
critical-point drier and chrome coated (6 nm layer, Emiteck
K575X, SEM coating unit). The samples were examined
using a JEOL 6700F high resolution scanning electron
microscope (HRSEM).
2.4 Immunostaining
Immunostaining for glial cells and synapses was performed
using the following procedure: samples were washed in
PBS and fixed with 4% PFA (Paraformaldehyde), 4%
sucrose solution for 20 min. Next, they were perforated and
blocked with 0.25% triton X-100 (Sigma, Cat. No. T8787)
with 10% NGS (normal goat serum)(Biological Industries,
Kibbutz Beit Haemek, Israel, Cat. No. 04-009-1) in PBS for
20 min followed by an additional block using PBS solution
with 10% NGS for another 20 min. Samples were then
washed with 1% NGS in PBS solution and incubated with
primary antibodies in a solution containing 1% NGS in
PBS overnight at 4°C. To detect glial cells, mouse anti-glial
fibrillary acidic protein (GFAP) monoclonal antibody,
diluted 1:400 (Biotest, Cat. No. MAB3402), was used.
Synapses were immunostained using rabbit anti-synapsin I
polyclonal antibody, diluted 1:300 (Biotest, Cat. No.
AB1543). After incubation, the samples were washed three
times with PBS and incubated for 1 h (in the dark) with the
secondary antibodies: Alexa fluor 488 goat anti-mouse IgG,
diluted 1:800 (molecular probes, Cat. No. A-11029) for
detection of GFAP, and Alexa fluor 546 goat anti-rabbit
IgG, diluted 1:600 (molecular probes, Cat. No. A-11035)
for detection of synapsyn-I. Finally, samples were mounted
using a mounting medium (Sigma, Cat. No. G0918) and
covered with a cover slip. The mounting medium was
dried overnight at 4°C before fluorescence measurements.
Confocal laser scanning microscope images were obtained
using LSM 510 META NLO (Zeiss). LEXT OLS3100
(Olympus) confocal microscope was used to construct
three-dimensional images of neuronal networks on the
neurochips.
Biomed Microdevices (2009) 11:495–501 497

2.5 Electrophysiological recording and stimulation

Extra-cellular recording were conducted utilizing low noise

pre-amplifiers board (B-MEA-1060, amplifier, gain ×1,200
with a band-pass filter of 200 Hz to 5 kHz, by Multi
Channel Systems). The signals collected from the micro-
electrodes were sampled at a 10 kHz sampling rate and
stored on a personal computer equipped with a 128-
channel, 12-bits data acquisition board (MC_Card, Multi
Channel Systems) and a MC_Rack data acquisition
software (Multi Channel Systems—version 3.2.20). Focal
electrical stimulations were applied to individual electrodes
by delivering voltage pulses using a stimulus generator
(STG1008, Multi Channel Systems). All pulses were
biphasic (positive-then-negative) pulses, 500 mV in ampli-
tude, with each phase lasting 400 μs. A stimulation session
was composed of 60 pulses separated by 20 s intervals.

3 Results and discussion

To construct the CNT-MEA we utilized conventional micro-

fabrication techniques combined with standard CNT
chemical vapor deposition (CVD) synthesis method. The
entire fabrication process was described in detail in a
previous publication (Gabay et al. 2007). Briefly, under-
lying TiN lines are used as conducting tracks. These lines
are passivated with sputtered Si3N4 which is later removed
at the regions of the active electrode using a reactive ion
etch step. A thin nickel layer is e-beam evaporated at the
openings. The process is concluded with a CNT thermal
chemical vapor (CVD) deposition growth procedure utilizing
the nickel as a catalyst material. The complete device is
presented in Fig. 1(a).
Substrates with isolated CNT islands of 20 and 80 μm in
diameter were also fabricated in a similar fashion and were
used to test the interaction between the cells and the CNT
surface (Fig. 1(b)). To perform electrical recordings from
cultured networks using CNT-MEA chips, clean silicon
chips were bonded to printed circuit board (PCB) supports
and were adjusted with quartz tubes to contain the
biological medium. In order to validate the electro-chemical
properties of the CNT electrodes cyclic voltammetry (CV)
measurements were conducted (Gabay et al. 2007). The CV
data provided direct evidence for the success of the CNT
growth process in promoting high interface capacitance,
similarly to large scale CNT electrodes (Barisci et al. 2000;
Chen et al. 2002; Li et al. 2002; Liu et al. 1999). The
exceptionally high surface area of the CNT electrodes also
facilitates a high charge injection limit of 2×10−3 C/cm2,
measured by applying a current pulse of 2 mA for 50 ms
on a CNT micro-electrode immersed in PBS (David-Pur
et al. 2008).
Fig. 1 The CNT based neuro-chip (a). The CNT based multi
electrode array is fabricated using standard optical lithography
combined with chemical vapor deposition process to grow the CNTs.
The resulting chip includes passivated interconnecting TiN lines
(bright thin lines) and CNT coated electrodes (dark disks). Electrode
diameter is 80 μm. (b) A high resolution scanning electron
microscope (HRSEM) image of an isolated 20 μm CNT island
revealing the extremely rough morphology of the surface
The nature of the interface between the CNTs and the
cells was first tested by culturing cortical neurons of rats on
isolated CNT islands. Cells were cultured onto the chip
surface and were allowed to adhere and develop for several
days in an incubator. After several days neurons had
aggregated and accumulated at the CNT coated regions,
and the cell density on the CNT-free regions was very low
(Fig. 2). Apparently, the entangled, three-dimensional CNT
matrix provides neurons and glia cells with an appropriate
bed for neurite development and cell adhesion. The propen-
sity of cells to adhere to such surfaces is associated with the
three-dimensional nature of the surface and is discussed in
detail in a separate publication (Sorkin et al. 2008).
The HRSEM images in Fig. 2 clearly show isolated
neuron-like cells positioned directly on the CNT matrix,
forming close contact with the surface. Extensive neurite
branching is also apparent. It should be noted that the
morphology of glia cells on CNT surfaces is conspicuously
498
Fig. 2 Cells cultured on substrates with isolated CNT islands
adhering preferentially onto CNT islands. HRSEM imaging (a, b)
show two islands on the same sample. Both neurons (a) and glia cells
(b) appear to adhere directly on to the CNT surface. Extensive neurite
branching is also apparent (a). The arrangement of cell clusters on the
CNT surface is typified by an underlying glia cell layer and mostly
overlaying neurons with synapses clearly visible under the glia layer.
This arrangement was validated using confocal fluorescence micros-
copy with glia cells (green) and neuronal synapses (red) specifically
stained (c)
different: unlike the three dimensional structure of the
neurons, isolated glia cells appear to spread as thin carpets
over the CNT surfaces. Additionally, due to the strong
propensity of neuronal cells to aggregate in locally high cell
densities, some CNT islands may be coated with clusters of
glia and neurons containing several tens of cells.
Biomed Microdevices (2009) 11:495–501
To allow an efficient interface between the electrodes
and the cells for recording applications, a most funda-
mental issue is the arrangement of the different cells (i.e.
neurons and glia cells) on these rough surfaces. In fact,
the specific manner by which neurons and glia cells are
arranged on the underlying CNT material is crucial in
determining the properties of the interface. Whether
neurons in the tissue are intimately connected to the
CNTs or adhere to an underlying glial tissue may have a
critical impact on the properties of the interface. A double
layer arrangement (underlying glia cells and overlying
neurons) may hinder surface-specific effects on the neuronal
elements. On the other hand, imposed and unnatural cell
arrangements may negatively affect the activity of the
cultured network.
The true mapping of the arrangement of mixtures of glia
and neuronal cells is revealed using confocal fluorescence
microscopy. Glia cells and synapses were specifically
Fig. 3 Self-assembled neuronal patterned network on a CNT neuro-
chip. After several days of plating, the cells on the CNT neuro-chip
interconnect to form networks with cells aggregates at the CNT
islands and cell-free connections in-between (a, b). Cell plating
density was around 1×10−3 cells/μm2. Images were obtained using a
confocal microscope after fixation and drying
Biomed Microdevices (2009) 11:495–501
labeled and imaged (Fig. 2(c)). The affinity of the glia cells
to the surface is readily seen, as is also the localization of
the synapses at the CNT areas. This extensive formation of
synapses provides further support to the notion that these
CNT islands are a suitable substrate for network develop-
ment. Cross sectional cuts provide direct evidence that
while glia cells do often reside at the interface with the
CNTs, neuronal processes are clearly found in direct
contact with the CNT surfaces. These results demonstrate
that neurons attach either directly to the rough surface or to
an underlying layer of glia cells. Additionally, synapses can
be clearly identified under the glia cell layer. These results
provide a direct indication to the intimate contact between
the CNTs layer and the cells.
While CNT electrodes are indeed very efficient electro-
chemical electrodes as well as excellent substrates for
neuronal culturing, the novelty of the CNT-MEA and its
cardinal advantage, for in-vitro applications, rests in the
unique manner by which neurons and glia cells, at appro-
priate densities, can self-assemble into ordered networks
with pre-designed geometry and topology (Fig. 3). At
specific cell culturing densities (Gabay et al. 2005), neurons
and glia migrate towards the CNT electrodes and form
small interconnected clusters, leaving behind taut bundles
of axons and dendrites to connect neighboring clusters. The
formed networks are highly organized, with geometries
which faithfully follow the pattern of the CNT nodes. The
quality of the network engineering depends on cell density,
Fig. 4 Spontaneous and stimulated electrical activity of neuronal
clusters on CNT electrodes. (a, b) Voltage traces of spontaneous
electrical activity recorded from a CNT electrode. (c) Raster plot of the
spontaneous spiking activity in several CNT electrodes. Activity
patterns are characterized by bursting events; short time windows
(several hundreds of milliseconds) of rapid collective neuronal firing,
which are followed by long intervals (seconds) of sporadic firing. (e)
Activity response to 40 consecutive electrical stimulations of neurons
on a CNT electrode. Each row represents the response of two neurons
499
electrode geometry as well as the overall cell number in
the entire dish. Optimized cell density yields cultured
networks with compact engineered wiring following the
electrode layout (Sorkin et al. 2006). Since the initial cell
density is not entirely uniform on the chip during cell
plating, high cell densities at some areas may result in large
cell clusters extending more than a single CNT island
(Fig. 3(a)).
Once the neurons had self-organized into a connected
circuit, in complete adherence to the electrode layout, the
electrodes were used to directly record electrical activity with
very high fidelity. Extra-cellular electrical activity measure-
ments were taken from neurons on individual 80 μm elec-
trodes after 12 days in vitro (DIV). This activity was
maintained for time periods of up to 60 DIV. To verify that
the activity recordings were of biological nature, we applied
blockers of excitatory synapses. Simultaneous application of
20 μM CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and
100 μM APV (((2R)-amino-5-phosphonovaleric acid) com-
pletely blocked all the electrical activity in the network. This
effect was reversible as the activity was regained following
the wash of the blockers. Due to the relatively large size of
the electrodes, each electrode could record the integrated
activity of a clustered sub-population of several neurons.
This activity was characterized by bursting events; short time
windows (several hundreds of milliseconds long) of rapid
collective neuronal firing, which were followed by long
intervals (seconds) of sporadic firing (Fig. 4(a),(b),(c)). For
(red and blue) to one stimulation (marked by the black line) in an
adjacent electrode. Out of the total 100 stimulations applied to the
stimulated electrode, about half successfully triggered a response.
The activity patterns in the stimulated electrode were marked by the
spiking of single neurons (d) which greatly varied between consecu-
tive stimulations. Nevertheless, repeating activity motifs such as spike-
pairs from different neurons were identified (d, e). Spikes in raster
plots were extracted using a spike sorting and detection algorithm
(Hulata et al. 2002)
500
networks with limited inter-cluster connectivity, bursting
activity was mainly confined to each cluster, and only weak
correlation in activity was observed between clusters
(Fig. 4(c)). All the examined cultures showed similar patterns
of bursting activity (115 electrodes from six cultures).
Interestingly, the collective activity patterns observed in
single CNT electrodes resemble the synchronized bursting
events (SBEs) observed in uniform networks, recorded using
PDL-coated commercial MEA electrodes (Ayali et al. 2004;
Segev et al. 2002; Segev et al. 2003). This implies the
effectiveness of the CNT electrodes in separating the network
into well-defined sub-networks while retaining the hallmark
of large network activity. In this respect, neural networks on
CNT electrodes present an additional hierarchy in the bottom
up approach for studying neuronal network, by enabling the
monitoring of interaction between loosely connected neuro-
nal sub-populations. Preliminary investigations with strong
inter-cluster connectivity show clear inter-cluster signal
correlation and will be reported separately.
Individual CNT electrodes were additionally used to
locally stimulate neurons on these electrodes. Biphasic
voltage pulses were applied between two adjacent CNT
electrodes, triggering a response in an intermediate elec-
trode (Fig. 4(e)). In order to allow easy discrimination
between the spontaneous and evoked activity in the
stimulated electrode, an electrode exhibiting low activity
levels (recording from only two neurons) was selected.
Following a stimulation session, the response activity was
marked by the spiking of the recorded neurons. The
response activity lasted relatively long, about 300 ms. The
exact response pattern (temporal order of the neuron
iring) varied between consecutive stimulations (Fig. 4(e)).
Nevertheless, some activity motifs, which were consistent
over the whole stimulation session, could be identified.
Utilizing a spike sorting algorithm (Hulata et al. 2002) it
was possible to distinguish between the different spikes
according to their distinct sources. An example of such a
separation is shown in Fig. 4(d) and (e), in which a
repeating motif of a large spike followed by a small spike
was identified. The response activities to the stimulation
sessions in addition to the ability to record the spontaneous
activity exemplify the CNT electrode’s capability to bi-
directionally electrically interface neuronal clusters.
4 Conclusions
To conclude, this work presents a new and complete approach
to engineer and interface with electrically viable neuronal
systems. Each micro-electrode in the new scheme is coated by
a layer of several microns of dense and entangled CNTs,
synthesized by a CVD process thus forming a CNT island.
The islands strongly attract and anchor cells to pre-defined
Biomed Microdevices (2009) 11:495–501
locations, and enable the formation of stable sub-networks on
electrically active recording sites. Efficient cell patterning
results with a stable neuronal network even though no
adhesive agents were used. Low electrode impedance
improves the electrochemical interface, and contributes to
high quality recording and efficient stimulating signals.
The electrical viability of the cell cultures on the CNT
substrates, and their long term survivability (up to 2 months),
substantiate the biocompatibility of these surfaces, in agree-
ment with previously reported results. Combined with their
superior electrical performances, it was demonstrated here
that CNT coated electrodes are, in fact, well-suited to assist the
interfacing between electrically active biological cells and
conventional electronic systems. The added advantage of
network patterning provides a unique opportunity to form
consistent, pre-defined networks. The study of signal propa-
gation and the development of patterned networks with a
single cell per electrode are currently underway. We expect
that such CNT based neurochips can provide a valuable
platform for studying network damage (e.g. by mechanical
deletion of connections between islands), and for investigat-
ing network repair (e.g. by adding cells on specific islands).
Acknowledgments The authors thank Inna Brainis for her technical
assistance and Moti-Ben David, Itsik Kalifa, Itay Baruchi and Nadav
Raichman for their assistance and useful discussions. This project was
supported in part by a grant from the Israeli Science Foundation
(1138/04) and by the Tauber Fund at Tel Aviv University.
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