JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE REVIEW ARTICLE

J Tissue Eng Regen Med 2011;5: e17–e35.

Published online 10 January 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/term.383

Application of conductive polymers, scaffolds and

electrical stimulation for nerve tissue engineering
Laleh Ghasemi-Mobarakeh1 , Molamma P Prabhakaran2∗ , Mohammad Morshed3 ,
Mohammad Hossein Nasr-Esfahani4 , Hossein Baharvand5 , Sahar Kiani5 , Salem S Al-Deyab6
and Seeram Ramakrishna2,6∗
1 Islamic
Azad University, Najafabad Branch, Isfahan, Iran
2 HealthCare & Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of
Singapore, 2 Engineering Drive 3, Singapore 117576
3 Department of Textile Engineering, Isfahan University of Technology, Isfahan, Iran
4 Department of Cell and Molecular Biology, Royan Institute for Animal Biotechnology, Isfahan, Iran
5 Department of Stem Cells and Developmental Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
6 Department of Chemistry, Faculty of Science, King Saud University, Riyadh, Saudi Arabia

Abstract
Among the numerous attempts to integrate tissue engineering concepts into strategies to repair
nearly all parts of the body, neuronal repair stands out. This is partially due to the complexity of the
nervous anatomical system, its functioning and the inefficiency of conventional repair approaches,
which are based on single components of either biomaterials or cells alone. Electrical stimulation
has been shown to enhance the nerve regeneration process and this consequently makes the use
of electrically conductive polymers very attractive for the construction of scaffolds for nerve tissue
engineering. In this review, by taking into consideration the electrical properties of nerve cells and
the effect of electrical stimulation on nerve cells, we discuss the most commonly utilized conductive
polymers, polypyrrole (PPy) and polyaniline (PANI), along with their design and modifications,
thus making them suitable scaffolds for nerve tissue engineering. Other electrospun, composite,
conductive scaffolds, such as PANI/gelatin and PPy/poly(ε-caprolactone), with or without electrical
stimulation, are also discussed. Different procedures of electrical stimulation which have been used
in tissue engineering, with examples on their specific applications in tissue engineering, are also
discussed. Copyright  2011 John Wiley & Sons, Ltd.

Received 5 March 2010; Accepted 12 October 2010

Keywords tissue engineering; electrical stimulation; conductive polymers; nanofibres; nerve cells;
modification

1. Introduction consequences and its recovery is difficult. Moreover,

The nervous system plays a central and complex role in
human biological processes interacting in physiological
processes, such as cognition and individual cell func-
tion. Damage to the nerve may impose tremendous
*Correspondence to: Molamma P Prabhakaran or Seeram
Ramakrishna, Health Care and Energy Materials Labora-
tory, Nanoscience and Nanotechnology Initiative, Faculty of
Engineering, National University of Singapore, 2 Engineering
Drive 3, Singapore 117576. E-mail: nnimpp@nus.edu.sg or
seeram@nus.edu.sg
Copyright  2011 John Wiley & Sons, Ltd.
malfunctions in other parts of the body might also occur
because mature neurons do not undergo cell division
(Huang et al., 2006). Neurodegenerative disorders of the
spinal cord and brain after injury, stroke or multiple
sclerosis have increased over the past few years (Prab-
hakaran et al., 2009). Peripheral nerve lesions are also
common, with serious injuries affecting 2.8% of trauma
patients annually, leading to lifelong disability (Ciardelli
and Chiono, 2006). In the USA, 360 000 people suffer
from upper extremity paralytic syndromes on an annual
basis and approximately 253 000 people in the USA live
with the after-effects of spinal cord injury. Moreover, each
e18
year this number grows by an estimated 11 000 people
in the USA (Willerth and Sakiyama-Elbert, 2007) and
in Europe more than 300 000 cases of peripheral nerve
injury are reported annually (Ciardelli and Chiono, 2006;
Bueno and Shah, 2008).
Numerous strategies have been applied for the repair
of peripheral nerve lesions, with the common goals of
directing the regenerating nerve fibres into the proper
distal endoneural tubes and improving the prospects of
axonal regeneration and functional recovery (Schmidt
et al., 1997). Implantation of autografts, allografts and
xenografts, providing grafts from the patient, cadavers
and animals, respectively, are a few strategies applied in
this field. But the loss of function at the donor nerve graft
site and mismatch of damaged nerve and graft dimensions
are major disadvantages of using autograft nerve repair
system (Schmidt et al., 1997; Schmidt and Leach, 2003).
On the other hand, allogenic and xenogeneic tissues have
the advantages of their availability, along with the benefit
of not requiring harvesting from patients. However, their
disadvantages include disease transmission and problems
of immunogenicity (Schmidt and Leach, 2003).
Tissue engineering provides a new medical therapy as
an alternative to conventional transplantation methods,
which regulates the cell behaviour and tissue progres-
sion through the development and design of synthetic
extracellular matrix (ECM) analogues of novel bioma-
terials to support three-dimensional (3D) cell culture
and tissue regeneration (Yang et al., 2004a; Subrama-
nian et al., 2009). The fundamental approach in neural
tissue engineering involves the fabrication of polymeric
scaffolds seeded with nerve cells to produce a 3D func-
tional tissue suitable for implantation (Yang et al., 2004).
Historically, tissue-engineering strategies have been used
in an effort to develop therapies for peripheral nerve
and spinal cord injury, combining biomaterials, cell ther-
apy and drug delivery approaches (Li and Hoffman-Kim,
2008). Successful nerve regeneration requires tissue-
engineered scaffolds that provide not only mechanical
support for growing neurites and prevention of ingrowth
of fibrous scar tissue, but also biological signals to direct
the axonal growth cone to the distal stump (Huang et al.,
2006). Recently, a synthetic nerve guidance channel has
provided surgeons with an interesting option to bridge
severed nerves instead of conventional methods includ-
ing autografts, allografts and xenografts (Zhang et al.,
2007), and numerous efforts have been devoted towards
the development of synthetic guidance conduits for the
repair of peripheral nerve defects (Hadlock et al.,2000;
Kijima et al., 2009; Rooney et al., 2008a; Ellis and Chaud-
huri, 2008; Jiang et al., 2008; Rooney et al., 2008; Patel
et al., 2009; Houchin-Ray et al., 2009; Park et al., 2007).
Nerve guidance channels are biomaterials-based devices
that are designed to be transplanted for nerve repair,
experimentally studied as a possible alternative to nerve
grafts. Nerve guidance channels aim to provide a conduit
through which regenerating axons can grow and con-
nect to their appropriate targets (Li and Hoffman-Kim,
2008). An appropriate synthetic material for fabricating
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
nerve guidance channels must readily shape to a con-
duit with the desired dimensions, must be sterilizable,
tear-resistant, easy to handle and suture, biodegradable,
and should maintain its shape and resist collapse dur-
ing implantation over the course of nerve regeneration
(Blacher et al., 2003). The physical, chemical and electri-
cal properties of synthetic conduit affect the outcome of
nerve regeneration. The inherent nature of neurons is to
transmit electrochemical signals throughout the nervous
system and, as a result, they are highly influenced by
electrical stimuli (Yu et al., 2008b). Previous studies have
shown that electrical stimulation is an effective cue in
stimulating either the proliferation or differentiation of
various cell types (Zhang et al., 2007; McCaig and Zhao,
1997; Sun et al., 2006; Ciombor and Aaron, 1993; Aaron
and Ciombor, 1993; Goldman and Pollack, 1996; Dust
and Bawornluck, 2006; Shi et al., 2008; Zhao et al.,1996,
1999; Yaoita et al.,1990; Guimarda et al., 2007; Rivers
et al., 2002; Jeong et al., 2008; Whitehead et al., 2007;
Ateh et al., 2006; Schmidt et al., 2003; Valentini et al.,
1992). In this review we discuss the electrical properties of
nerve cells, the most commonly utilized conductive poly-
mers, namely polypyrrole (PPy) and polyaniline (PANI),
the principle of electrical stimulation and the application
of electrical stimulation through conductive scaffolds to
nerve cells. A brief evaluation of the methods of electrical
stimulation, electrospinning of conductive polymers and
modifications carried out to conductive scaffolds, thus
making them suitable substrates for tissue engineering,
are also discussed.
2. Electrical properties of nerve cells
Recent interest in electrical stimulation arises from a
growing knowledge of the electrical properties of tissues
and cells (Snyder-Mackler, 1987). Living cells employ
many of the properties of electrical systems. For example,
they generate electromotive force, maintain a required
difference in potential, increase or decrease the difference
in potential as necessary, use varying resistances in series
or parallel, switch current on and off, control current
flow, rectify current flow and store charge, which is
even more crucial (Kitchen, 2002). An electrical voltage
exists across the plasma membrane, while the inside
of the cell remains more negative than the outside.
By convention, the potential outside the cell is called
zero; therefore, the typical value of the membrane
potential is −60 to −100 mV (Matthews, 2003). This
potential difference is maintained at a steady level when
excitable cells are inactive and is called the resting
potential (Paul, 1975). Regarding the electrical properties
of cells, electrical signals strongly affect cell behaviour,
affecting ion influx across the cell membrane, altering the
membrane potential and conditioning the intracellular
signal transduction pathways (Mattioli-Belmonte et al.,
2003). The transition of information from one place to
another in the nervous system takes place along the axon.
It is known that the activity in axons is accompanied by
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Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering
Figure 1. Various stages (resting state, depolarization and
repolarization) of nerve cells during electrical stimulation
electrical changes in and around them and the specific
electrical event that occurs is called the action potential,
which is an active response generated by the neuron that
appears on an oscilloscope as a brief (∼1 ms) change from
negative to positive in the transmembrane potential. The
action potential represents transient changes in the resting
membrane potential. One way to elicit an action potential
is to pass an electrical current across the membrane of the
neuron. Several steps are involved during this process,
the first being a stimulus received by the dendrite of a
nerve cell. This causes the Na+ channels to open and,
if the opening is sufficient to drive the interior potential
from −70 mV to −55 mV, it reaches the action threshold.
In this step, more Na+ channels are opened and the
Na+ influx drives the interior of the cell membrane up
to about +30 mV. The process at this point is called
depolarization. Further, the Na+ channels close and the
K+ channels are opened, and since the K+ channels
are much slower to open, the depolarization process
is completed. The membrane begins to repolarize back
towards its resting potential as the K+ channels open. The
repolarization typically overshoots the resting potential to
about −90 mV, when it is termed hyperpolarization and
prevents the neuron from receiving another stimulus,
or at least raises the threshold for a new stimulus.
Hyperpolarization also assists in preventing any stimulus
that has already been sent up an axon from triggering
another action potential in the opposite direction. In other
words, hyperpolarization assures that the signal is always
proceeding in one direction. After hyperpolarization, the
Na+ /K+ pump eventually brings the membrane back to
its resting state of −70 mV (Kandel, 2000).
Typically, the membrane must be depolarized by
about 10–20 mV in order to trigger an action potential.
Figure 1 shows a schematic illustration of the resting
state, depolarization, action potential and repolarization
of nerve cells. As can be observed in this figure, in response
to the appropriate stimulus, the cell membrane of a nerve
cell goes through a sequence of depolarization from its
resting state, followed by repolarization to that resting
state. In the sequence, it actually reverses its normal
Copyright  2011 John Wiley & Sons, Ltd.
e19
polarity for a brief period before re-establishing the resting
potential.
3. Electrical stimulation and its effects
An action potential can be elicited artificially by changing
the electrical potential of a nerve cell by inducing an
electrical charge to the cells, and the process is termed
‘electrical stimulation’ (Kitchen, 2002). A variety of
cellular responses to electric stimulation of different cell
types, including fibroblasts, osteoblasts, myoblasts, chick
embryo dorsal root ganglia and neural crest cells, have
been reported (Schmidt et al., 1997; Kimura et al., 1998;
Wong et al., 1994; Li et al., 2006; Bidez et al., 2006;
Wood et al., 2006). The proposition related to electrical
stimulation is based on the fact that bioelectricity present
in the human body plays an integral role in maintaining
normal biological functions, such as signalling of the
nervous system, muscle contraction and wound healing
(Shi et al., 2008). McCaig et al. (1997) reported the
generation of electrical fields during major cellular
events such as cell division, development and migration.
They also found that the presence of a steady weak
direct current (DC) electrical field in some biological
systems affects cellular activities such as cell division,
differentiation, migration and the extension of motile
processes (Zhao et al., 1999). Endogenous electric fields
in the form of voltage gradients have been observed to
polarize the nervous system along the rostral–caudal
axis (5–18 mV/mm) and to direct nerve growth (Li
and Hoffman-Kim, 2008). Initial studies investigating the
effect of electrical stimulation on neurons were performed
on Xenopus neurons after exposing them to a steady direct
current field. Extracellular electric fields (0.1–10 V/cm)
applied in solution reversibly influenced the direction of
neurite growth and increased the neurite initiation and
length in Xenopus (Li and Hoffman-Kim, 2008). Applied
electrical fields have been shown to influence the rate and
orientation of neurite outgrowth from cultured neurons
in vitro (Valentini et al., 1992). For example, applied
electric fields influenced the extension and direction of
neurite outgrowth from neurons cultured in vitro and
pulsed electromagnetic fields stimulated sciatic nerve
regeneration in vivo (Wang et al., 2004). Borgens (1999)
demonstrated that 7 days of electric field imposed within
a damaged adult guinea-pig spinal cord can both induce
the regeneration of axons and guide their growth into the
ends of a hollow silicone rubber tube inserted into the
dorsal half of the cord. Borgens (1999) concluded that this
was due to production of a DC voltage gradient within the
injured spinal cord, with the cathode located within the
experimental tubes. Electrical stimulation has been shown
to influence the differentiation of stem cells. Yamada et al.
(2007) showed that mild electrical stimulation strongly
influences embryonic stem cells to assume a neuronal
fate. Although the resulting neuronal cells showed no
sign of specific terminal differentiation in culture, they
showed potential to differentiate into various types of
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e20
neurons in vivo, and contributed to the injured spinal
cord as neuronal cells. The induction of calcium ion influx
is significant in this differentiation system.
Several theories have been suggested to explain the
effect of electric stimulation on nerve regeneration.
Patel et al. (1982) suggested three possible ways by
which electrical stimulation could act directly on a
neuron, including the redistribution of cytoplasmic
materials, the activation of growth-controlling transport
processes across the plasma membrane due to change
in cell membrane potential, and the electrophoretic
accumulation of surface molecules responsible for neurite
growth or cell–substratum adhesion. Changes in ionic
currents around the growing fibre tips induced by electric
fields have been suggested by Freeman et al. (1985) as one
possible mechanism through which electrical stimulation
can affect nerve cells. Sisken et al. (1989) suggested
that electrical stimulation affects protein synthesis in
transected sciatic nerve segments and stimulates neurite
outgrowth in vitro. Kimura et al. (1998) postulated that
gene expression for nerve growth factor (NGF) is
electrically activated for rat neuronal pheochromocytoma
cells (PC12 cells) by alternative potential, while Kotwal
et al. (2001) showed that fibronectin adsorption increased
with immediate electrical stimulation and explained
enhanced neurite extension on electrically stimulated PPy
films.
3.1. Method of electrical stimulation
in the tissue engineering context
Electrical stimulation is a relatively simple, flexible and
feasible method carried out for both in vivo and in vitro
two-dimensional (2D) and 3D cultured cells (Sun et al.,
2006). The behaviour of an excitable cell such as nerve
cells can be modified by application of electrical current
through two external electrodes. The current passing
between the electrodes can cause depolarization of the
membrane (Paul, 1975). Surface electrodes, usually made
of silver plates, available in different sizes in the range
0.5–1.0 cm in diameter, are commonly used for clinical
applications. Gold and platinum electrodes have also been
used for electrical stimulation procedures (Kimura, 2001).
Some researchers applied voltage to conductive materials,
considering it as one of the electrodes, where another
electrode was used separately as anode or cathode. For
example, Schmidt and co-workers (1997) utilized PPy
film as the anode and a gold wire as the cathode for
the electrical stimulation of PC12 cells. In other cases,
voltage was applied between two electrodes through
conductive scaffolds seeded with cells (Shi et al., 2007,
2008; Ghasemi-Mobarakeh et al., 2009).
Shi et al. (2007) studied the effect of electrical
stimulation in culture media and did not detect any
measurable variations in pH or temperature during the
period of cell culture. Moreover, no biologically significant
ionic current was observed in the electrical cell culture
system. To avoid cultures from potentially toxic electrode
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
products, agar-gelled salt bridges have also been applied
for connecting the metal electrodes within the culture
medium, where one end of a salt bridge is connected to a
scaffold placed in the culture medium, and the other end
of the salt bridge is placed in a beaker of electrodes, along
with their relevant salt (e.g. Ag/AgCl) and the electrodes
in each beaker are attached to a DC power supply (Mccaig
et al., 2005).
Salt bridges are prepared from flexible plastic tubing
filled with 2% agarose in PBS. This provides a conducting
pathway for applied current and prevents electrolysis
products from contaminating the chamber by providing a
pathway for current transfer from each media reservoir to
the Ag–AgCl electrode (Tandon et al.,2009).
The amplitude of the stimulus is also very important and
a direct relationship exists between stimulus amplitude
and response amplitude within a small range, which is
quite enough to induce the depolarization of nerve cells
(Paul, 1975). If the amplitude of the electrical stimulus
is too weak to produce a threshold depolarization, an
action potential will not take place. If the applied
current depolarizes the membrane to threshold, an action
potential will result.
Steady DC voltage has been applied in many previous
studies for electrical stimulation, mainly due to the
existence of DC electrical gradients of voltage within
tissues (endogenous electrical fields) (Mccaig et al.,
2005). Wood et al. (2006) investigated the influence of
brief DC electric stimulation on neurite outgrowth and
outgrowth rates after application. Their results showed
that the presence of a 25 V/m electrical field for 10 min
increased overall neurite outgrowth over controls for
up to 48 h after stimulation. In the literature, both
electrical field and current have been reported to be
effective in modulating cell behaviour. There are a few
reports indicating more effectiveness of DC electrical
fields than DC currents in electrical stimulation. Shi
et al. (2007) applied both electrical field (100 mV/mm)
and current (2.5–250 µA/mm) for electrical stimulation
and concluded that a wide range of surface current
density (2.5–250 µA/mm) had no significant effect on
cell adhesion or cell viability, while a constant electrical
field of 100 mV/mm upregulated the mitochondrial
activity of human cutaneous fibroblasts and enhanced
their adhesion. Their results showed that electrical field
plays a more substantial role than electrical current in
modulating the activity of cells cultured on conductive
polymeric scaffolds compared to the non-stimulated
cell cultures. However, these researchers did not rule
out the importance of current as potential gradient
reaches a certain critical level. Some studies also showed
that, on exposure to an electrical field (<100 mV/mm),
stimulative effects on cell migration and cell growth occur.
Many cell types respond to an applied electric field by a
perpendicular orientation. The mechanism is not very
clear but the asymmetric redistribution of charged cell
surface receptors might be effective (Zhao et al., 1996).
Electrical field plays an important role in certain processes
that regulate the axis of cell division, and in the presence
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Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering e21

Table 1. Electrical stimulation conditions applied by various research groups

Conductive scaffolds DC/AC current; potential Duration Cells Reference

PANI/PG DC: 100 mV 1h C17.2 Ghasemi-Mobarakeh

et al., 2009
PANI/PLACL DC: 0–200 mA 2 days NIH-3T3 fibroblasts Jeong et al., 2008
PPy DC: 100 mV 2h PC12 Schmidt et al., 1997
PLGA coated DC: 10 mV/cm 2h PC12 Lee et al., 2009a
with PPy
PPy/PLLA DC: 100 mV/mm 2, 24 h Fibroblasts Shi et al., 2007
PDLLA/CL DC: 0, 2, 8 and 20 µA/mm – PC12 Zhang et al., 2007
coated with
PPy
PPy AC: 50 µA at 0.05, 5 and – VSMC Rowlands et al., 2008
500 Hz
PPy/PLLA DC: 50 mV/mm 24 h Fibroblasts Shi et al., 2008
ITO AC: 100 mV (100 Hz) 30 min/day (3 days) PC12 Kimura et al., 1998
PLLA/CNT AC: 10 mA (10 Hz) 6 h/day Osteoblasts Supronowicz et al.,
2002
PCL/PPy DC: 10 V 4 h/day DRG Xie et al.,2009
PPy Biphasic 100 µs pulses of 8 h/day Cochlear neural explants Thompson et al., 2010
±1 mA/cm2 at 250 Hz
PLAAP Electric potential of 0.1 V 1 h/day PC12 Huang et al., 2008
(1 Hz)
PPy/chitosan DC: 100 mV 4h Schwann cells Huang et al, 2010

PANI, polyaniline; PG, PCL/gelatin; PDLLA/CL, poly(D,L-lactide-co-ε-caprolactone); PLLA, poly(L-lactic acid)l PLGA, poly(D,L-lactide-
co-glycolide); CNT, carbon nanotubes; PLACL, poly(L-lactide-co-ε-caprolactone); ITO, indium–tin oxide; PLAAP, copolymer of
hydroxyl-capped poly(L-lactide) (PLA) and carboxyl-capped aniline pentamer (AP); PC12, rat neuronal phaeochromocytoma cells;
PPy, polypyrrole; VSMC, vascular smooth muscle cells; DRG, dorsal root ganglia; C17.2, mouse neuronal cerebellum stem cells;
PC12, rat neuronal phaeochromocytoma cells.

of electrical field cell divisions occurred in vivo (Zhao
et al., 1999).
However, electrical stimulation in the form of a
pulsed electromagnetic field has also been applied in
tissue engineering as well as in clinical settings, as
an alternative treatment to promote wound healing,
reduce chronic pain and headaches, to treat diseases
such as Parkinson’s disease and to enhance nerve
regeneration (Shi et al., 2008). In vivo studies carried
out by Sisken et al. (1989) showed that stimulation of rat
sciatic nerves with pulsed electromagnetic fields (PEMFs)
for as short a time as 1 h/day for 3 days increased
nerve regeneration rates. Various conditions have been
described in the literature for electrical stimulation for
tissue engineering applications. Table 1 gives a summary
of various conditions of electrical stimulation which have
been applied by various researchers.
4. Electrically conducting materials
in nerve tissue engineering
for cell growth and tissue repair and allow precise
external control over the level and duration of stimulation
(Skotheim and Reynolds, 2007). These materials show
good capacity to support and modulate the growth of
various cells, such as nerve cells and bone cells, and are
widely used in biological systems (Zhang et al., 2010).
The importance of conductive polymeric composites is
based on the hypothesis that such composites can be used
to host the growth of cells, so that electrical stimulation
can be applied directly to the cells through the composite,
proved to be beneficial in many regenerative medicine
strategies, including neural and cardiac tissue engineering
(Bettinger et al., 2009). Conductive polymers show great
promise in biomedicine and are stimulus-responsive
polymers that can be synthesized to form composites
that could serve as ‘smart’ biomaterials (Skotheim
and Reynolds, 2007). Unlike exogenous electromagnetic
fields, electrical stimulation through such polymers would
be predominantly focused to the area around the polymer,
allowing spatial control of stimulation (Schmidt et al.,
1997).

Electrically conductive polymers have attracted much

interest in the last 20 years because they simultaneously
display the physical and chemical properties of organic
polymers and the electrical characteristics of metals
(Chronakis et al., 2006) and are very attractive materials
for the construction of nerve guidance channels. The
use of conductive polymers would allow one to locally
deliver electrical stimulus, provide a physical template
Copyright  2011 John Wiley & Sons, Ltd.
4.1. Conducting polymers
Polymers with loosely held electrons in their backbones
are often referred as conducting polymers. Each atom
along the backbone is involved in a π bond, which is
much weaker than the σ bonds that hold the atoms in
the polymer chain together, and they characteristically
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e22
have a conjugated backbone with a high degree of π -
orbital overlap (Breads and Silbey, 1991). Through a
process known as ‘doping’, the neutral polymer chain can
be oxidized or reduced to become either positively or
negatively charged (Wong et al., 1994). It is well known
that conducting polymers in general are not conductive
without doping, and doping of π -conjugated polymers
results in a highly conducting state of the polymer. The
doping process includes charge transfer from dopant
molecules to polymer chains within an overall neutral
system, and in this process charge carriers, polarons and
bipolarons, are introduced into the conjugated chain.
The doping process can be influenced by factors such
as polaron length, chain length, charge transfer to
adjacent molecules and conjugation length (Breads and
Silbey, 1991). Different dopants have been used for the
protonation of conductive polymers. For example, strong
inorganic hydrochloric acid (HCl), organic and aromatic
acids containing different aromatic substitution, such as p-
toluene sulphonic acid (PTSA), dodecylbenzenesulphonic
acid (DBSA), organic and aliphatic acids having a
long hydrocarbon chain, such as lauric acid (LA) and
amphiphilic dopants that belong to the family of sulphonic
acids have been used as dopants for PANI. The properties
of doped conductive polymers depend on the type
and molecular size of the dopant (Sinha et al., 2009;
Reena et al., 2009). Liu et al. (1994) showed that the
surface energies of the doped conducting polymers vary
greatly, depending on the choice of the dopants and
doping level. For example, surface energies and polarities
of the HCl-doped PANI increase with increasing HCl
concentration in the doping solution. Sinha et al. (2009)
also showed that the solubility of doped PANI depends
on the molecular size of the dopant, and with increase
in the dopant chain length the solubility increases. Jang
et al. (2004) synthesized organic solvent-soluble PPy by
using functional dopants (such as naphthalene sulphonic
acid sodium salt, dodecylbenzenesulphonic acid sodium
salt, butyl naphthalene sulphonic acid sodium salt and
di-2-ethylhexyl sulphosuccinic acid sodium salt). Liu
et al. (2008a) doped PPy with different naphthalene
mono/disulphonic acids by in situ doping polymerization,
and investigated the thermal stability of PPy doped
by different dopants. Their results showed that the
thermal stability of PPy was greatly affected by the type
and concentration of the dopant. PPy doped with non-
biologically active dopants, such as tosylate, have been
characterized for biological interactions as they can trigger
cellular responses in biological applications. However,
the incorporation of more biologically active dopants
has shown greater promise and can be used to modify
PPy-based hybrid material for biomedical applications
(Guimarda et al., 2007; Skotheim and Reynolds, 2007).
Although dopants that are relevant to biomedical
applications, such as hyaluronic acid, can be used to
develop PPy-based hybrid material, the choice of dopants
is limited to the size and charge (negative) of molecules
(Sanchvi et al., 2005).
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
The biggest limitation of conductive polymers for in vivo
applications is their inherent inability to degrade, which
may induce chronic inflammation and require surgical
removal (Huang et al., 2007). To address the drawbacks of
existing conductive polymers, attempts to blend them with
suitable biodegradable polymers have been carried out.
Rivers et al. (2002) synthesized biodegradable conductive
polymer from conducting oligomers of pyrrole and thio-
phene that were connected together via degradable ester
linkages. Ester linkages can be cleaved by enzymes in vivo
and the resultant polymer had the unique properties
of being both electrically conducting and biodegradable
(Rivers et al., 2002). Studies by Shi et al. (2004) also
introduced the biodegradation property to conductive
polymers by blending them with suitable degradable poly-
mers. On the other hand, Huang et al. (2007) fabricated
a novel electroactive biodegradable composite contain-
ing polylactide as the biodegradable segment and the
low molecular weight aniline pentamer as electroactive
segment. A novel block copolymer of polyglycolide and
aniline pentamer that is electro-active and degradable was
also synthesized by Ding and co-workers (2007). Zhang
et al. (2010) synthesized a novel, electricallyconductive
and biodegradable polyphosphazene polymer contain-
ing aniline pentamer with glycine ethyl ester as side
chains and evaluated its biocompatibility using Schwann
cells. Their results showed that the polymer exhibited no
cytotoxicity, indicating suitability of this polymer as a scaf-
fold material for peripheral nerve regeneration or other
biomedical devices that require electroactivity. Huang
et al. (2008) synthesized a multiblock copolymer (PLAAP)
through condensation polymerization of hydroxyl-capped
poly(L-lactide) (PLA) and carboxyl-capped aniline pen-
tamer (AP) with excellent electroactivity and biodegrad-
ability, suitable for tissue engineering application.
PPy and PANI remain the most extensively studied
conductive polymers for tissue engineering purposes to
date, and hence emphasis is given to these polymers in
this review, in terms of their biocompatibility for tissue-
engineering applications and especially for nerve tissue
engineering.
4.1.1. Polypyrrole
Polypyrrole (PPy) is a conductive synthetic polymer that
has numerous applications in drug delivery and nerve
regeneration and it has also been used in biosensors
and coatings for neural probes (Sanchvi et al., 2005).
Figure 2 shows the chemical structure of PPy before
and after doping. The high degree of conjugation in the
molecular backbone of PPy makes it very rigid, insoluble
and poorly processable. It is therefore very difficult to be
used alone as a structural material and must be optimized
and transformed into a mechanically manageable and
processable form (Shi et al., 2004).
Wong et al. (1994) synthesized optically transparent
PPy thin films and studied them for mammalian cell
culture. In vitro studies demonstrated that PPy thin films
supported endothelial cell attachment and growth. Wang
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Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering
Figure 2. Chemical structure of PPy: (A) before doping; (B) after
doping
et al. (2004) showed that PPy has good biocompatibility
with rat peripheral nerve tissue and showed it to be
a suitable substrate for bridging the peripheral nerve
gap. They reported that PPy extraction solution showed
no evidence of acute and subacute toxicity, pyretogens,
haemolysis, allergens and mutagenesis, and the migration
of Schwann cells and the neurite extension from dorsal
root ganglia on the surface of PPy membrane-coated glass
were found to be better than those on bare glass (Wang
et al., 2004). Williams and Doherty (1994) investigated
the biocompatibility of PPy in vitro and in vivo using
mouse fibroblast (L929) and neuroblastoma cells. Their
results demonstrated that PPy is cytocompatible and
in vivo experiments showed that there was only a
minimal tissue response after 4 weeks in situ. Jiang
et al. (2002) coated polyester fabrics with PPy and
investigated the in vivo biocompatibility and biostability
of PPy-coated polyester fabrics. Their results showed
in vivo biocompatibility of the PPy-coated and non-
coated polyester fabrics. In vitro enhancement of nerve
cell axonal extension has been reported using PPy with
application of either constant current or constant voltage
(Rivers et al., 2002). Chen et al. (2000) fabricated PPy
tube as nerve guide for sciatic nerve regeneration. Their
results showed light contraction of the gastrocnemius
muscles and little ulceration, proving the biocompatibility
of PPy. George et al(2009) also fabricated conductive
PPy tubes using the electrodeposition of PPy onto
wire templates and subsequent separation from the
template after electrochemical reduction. Conduits made
of this material did not show any acute or active
chronic inflammatory infiltrate, or tissue damage in
the surrounding tissues, for at least 8 weeks of in vivo
implantation as sciatic nerve guides. Olayo et al. (2008)
synthesized semiconductor biomaterials of iodine-doped
PPy and PPy-polyethylene glycol. Their results showed
good compatibility of these materials after implantation
into the transectioned spinal cord tissue, indicating the
suitability of the materials for repairing spinal cord
damage.
To date, PPy has been reported to support cell adhesion
and growth of a number of different cell types, which
makes it a potential candidate for tissue engineering
(Garner et al., 1999a, 1999b; Song et al., 2006; Stauffer
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e23
Figure 3. PANI: (A) reduced; (B) oxidized; and (C) half-oxidized
forms
Figure 4. Chemical structure of PANI: (A) before doping;
(B) after doping
et al., 2006; Gomez et al., 2007b; Castano et al., 2004;
Seal et al., 2001; Evans, 2001; Ateh et al., 2006b).
4.1.2. Polyaniline
PANI is the oxidative polymeric product of aniline under
acidic conditions and is commonly known as aniline black
(Nalwa, 1997). Depending on the oxidation level, PANI
can be synthesized in various insulating forms, such as
the fully reduced leucoemeraldine base, half-oxidized
emeraldine base (PANI-emeraldine base) and the fully
oxidized pernigraniline base. PANI emeraldine base is the
most stable and widely investigated form of PANI (León,
2001). Figure 3 shows the reduced, oxidized and half-
oxidized forms of PANI, while Figure 4 shows the chemical
structure of PANI emeraldine base (the most important
form of PANI) before and after doping (MacDiarmid and
Epstein, 1994).
The exploration of PANI for tissue-engineering applica-
tions has progressed more slowly than the development
of PPy for similar applications. However, recently there
has been more evidence of the ability of PANI and PANI
variants to support cell growth (Mattioli-Belmonte et al.,
2003).
Wang et al. (1999) investigated the in vivo tissue
response to PANI and found no characteristic features
resulting from tissue incompatibility after PANI implan-
tation. Studies have assessed the in vivo response to
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e24
implants of different oxidation states of PANI. In gen-
eral, no significant inflammation at the implant site and
no signs of abnormality of muscle and adipose tissues
in the vicinity of the implants were observed (Guimarda
et al., 2007). Kamalesh et al. (2000) also investigated the
biocompatibility of PANI in different states and found that
these polymers are sufficiently biocompatible to be used
for biomedical applications. Bidez et al. (2006) investi-
gated the adhesion and proliferation properties of H9c2
cardiac myoblasts on a conductive PANI substrate. Both
the non-conductive emeraldine base and the conduc-
tive salt forms of PANI were found to be biocompatible
and to support cell attachment and proliferation. The
demonstration of the biocompatibility of PANI in vivo has
sparked much interest in tissue-engineering applications
(Guimarda et al., 2007).
4.2. Other conducting polymers
Although PPy and PANI remain the most extensively stud-
ied conductive polymers for tissue-engineering purposes
to date, the use of a few other conductive polymers, such
as polythiophene, for tissue engineering application has
also been investigated (Guimarda et al., 2007).
4.2.1. Poly (3, 4-ethylenedioxythiophene)
Poly (3,4-ethylenedioxythiophene) (PEDOT) is consid-
ered the most successful polythiophene derivative, with
interesting properties. Valle et al. (2007) investigated
the interaction of PEDOT films with epithelial cells and
showed the biocompatibility of PEDOT with epithelial
cells. Luo et al. (2008) synthesized PEDOT films and
investigated their biocompatibility by seeding NIH3T3
fibroblasts on PEDOT films, and carried out subcuta-
neous implantation of PEDOT films by in vivo study. Their
results showed that PEDOT films exhibit very low intrinsic
cytotoxicity and that their inflammatory response upon
implantation was good, making them ideal for biosensing
and bioengineering applications. Bolin et al. (2009) fab-
ricated electrospun poly(ethylene terephthalate) (PET)
nanofibres and coated PET nanofibres with PEDOT doped
with tosylate, using the vapour phase polymerization
method. Their results showed excellent adhesion and
proliferation of neuronal cells on PEDOT-coated PET
nanofibres.
Modification of conventional platinum, gold or iridium
oxide electrodes with conducting polymer coatings has
the potential to significantly improve the long-term per-
formance of neural implants, including cochlear implants,
vision prostheses, neural regeneration devices and neu-
ral recording electrodes (Green et al., 2009). Implantable
electrodes can be used for the treatment of different
disabilities and neurological disorders and can be used
either to electrically elicit neural impulses or to record
neuron signalling (Asplund et al., 2009). Asplund et al.
(2009) coated platinum electrodes with PEDOT and
investigated the biocompatibility of resultant electrode.
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
L929 fibroblasts and human neuroblastoma SH-SY5Y cell
lines were used for in vitro cell culture study and fur-
ther in vivo study was carried out using polymer-coated
implants in rodent cortex. Their results indicated that plat-
inum electrodes coated with PEDOT were non-cytotoxic
and showed no marked differences in immunological
response in cortical tissue compared to pure platinum
controls. Green et al. (2009) used anionically modified
laminin peptides, such as DEDEDYFQRYLI and DCDP-
GYIGSR, to dope PEDOT electrodeposited on platinum
electrodes and assessed the bioactivity of incorporated
peptides and their effect upon nerve cell growth (PC12
cells). Their results demonstrated that large peptide
dopants produced softer PEDOT films with a minimal
decrease in electrochemical stability, compared to con-
ventional dopants, and longer neurite outgrowth was
observed on PEDOT films doped with synthetic anionic
laminin peptides than that on PEDOT films doped
with conventional paratoluene sulphonate dopant. Per-
amo et al. (2008) investigated a method to chemically
deposit PEDOT on acellularized muscle tissue constructs.
Their results revealed that in situ polymerization occurs
throughout the tissue, converting it into an extensive
acellular, non-antigenic substrate which will be crucial
for in vivo experiments related to nerve repair and bioar-
tificial prostheses.
The interactions between neural cells and PEDOT for
the development of electrically conductive biomaterials
intended for direct and functional contact with electrically
active tissues, such as the nervous system, heart and
skeletal muscle, was also studied by Richardson-Burns
et al. (2007). They polymerized PEDOT around living cells
and described a neural cell-templated conducting polymer
coating for microelectrodes and a hybrid conducting
polymer–live neural cell electrode.
4.2.2. Carbon nanotubes
Carbon nanotubes (CNTs) are another group of conduct-
ing polymers incorporated into non-conducting polymers
to provide structural reinforcement and impart novel
properties, such as electrical conductivity, into the scaf-
folds and to direct cell growth (Harrison and Anthony,
2007).
Some studies have indicated that carbon nanotubes
are cytotoxic, while others have shown nanotubes to
be excellent substrates for cellular growth (Harrison
and Anthony, 2007). A closer look at the published
literature on this issue reveals the resultant positive
or negative reports on cytotoxicity to be due to the
manner in which CNTs have been used in the experiments
by different researchers. CNTs are shown to be toxic
to cells when used as a suspension in cell culture
media in any given experiment, while they appear to
be non-toxic if immobilized to a matrix or to a culture
dish (Hussain et al., 2009). Potential cytotoxic effects
associated with carbon nanotubes may be mitigated
by chemically functionalizing their surfaces (Harrison
and Anthony, 2007). Chemically functionalized CNTs
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Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering
have been used successfully as potential devices to
improve neural signal transfer while supporting dendrite
elongation and cell adhesion. These results strongly
suggest that the growth of neuronal circuits on a
CNT grid is accompanied by a significant increase
in network activity. The increase in the efficacy of
neural signal transmission may be related to the
specific properties of CNT materials, such as the
high electrical conductivity controlling the neuronal
extracellular–molecular interactions (Lovat et al., 2005;
Hu et al., 2004, 2005; Mattson et al., 2000). In fact,
CNTs represent a scaffold composed of small fibres or
tubes that have diameters similar to those of neural
processes such as dendrites (Lovat et al., 2005). Interest
in carbon nanofibres has also been growing exponentially
due to their unique electrical, mechanical and surface
properties. Webster et al. (2004) developed a carbon
nanofibre-reinforced polycarbonate urethane composite
in an attempt to determine the possibility of using carbon
nanofibres as either neural or orthopaedic prosthetic
devices. Their results showed that this composite supports
neural cell function and has the ability to tailor electrical
properties for polyurethane composites containing carbon
nanofibres and represent acceptable parameters for
further investigation of carbon nanofibres as a neural
probe. However, there are several limitations to the
application of carbon nanotubes being non-degradable
(Harrison and Anthony, 2007).
4.3. Piezoelectric polymeric materials
In addition to conductive polymers, piezoelectric poly-
meric materials have also been considered in tissue-
engineering applications. Piezoelectric polymeric materi-
als generate transient surface charges by tiny mechanical
deformations of the material under minute mechanical
strain and do not require additional energy sources or
electrodes (Schmidt et al., 1997; Valentini et al., 1992).
Poly(vinylidenefluoride) (PVDF) is a synthetic, semi-
crystalline polymer with piezoelectric properties that
generate transient surface charges due to their unique
molecular structure (Valentini et al., 1992). Tschoeke
et al. (2008) fabricated a textile scaffold composed of
PVDF which was integrated into the wall of vascular
composite graft to provide sufficient mechanical sup-
port. A two-step moulding technique was carried out
to integrate a PVDF mesh in the wall of a fibrin-based
vascular graft seeded with carotid myofibroblasts. Cell
growth and tissue development within the fibrin gel
matrix surrounding the PVDF fibres was excellent, and
the tissue structure demonstrated much similarity to
the native tissue. Yang et al. (2010) demonstrated that
the epithelial–mesenchymal interaction of salivary tissue
could be mediated using PVDF membrane in a serum-free
condition. Their result demonstrated that it is possible
to establish a serum-free system that is competent in
facilitating epithelial–mesenchymal interaction of sali-
vary tissue and facilitated by PVDF, the submandibular
Copyright  2011 John Wiley & Sons, Ltd.
e25
gland recombinant was able to sprout new branches with-
out serum (Yang et al., 2010). Lu et al. (2003) designed
a PVDF surface coated with galactose-tethered pluronic
polymer and investigated the efficacy of attachment of
rat hepatocytes on PVDF membrane. Their results showed
the potential of galactose-immobilized PVDF membrane
as a suitable substrate for hepatocyte culture. Young
et al. (2008) fabricated microporous PVDF membranes for
nerve tissue engineering by immobilizing L-lysine cova-
lently on the surface of PVDF membrane. PC12 cells
cultured on L-lysine/PVDF membranes showed good cell
adhesion and proliferation on L-lysine/PVDF membranes,
suggesting its usefulness in the development of strategies
to promote the regrowth and regeneration of nervous
tissue. Previous studies showed that neurite extension
is significantly enhanced on piezoelectric materials such
as PVDF and are comparable to those obtained using
electrically conducting polymers (Schmidt and Leach,
2003). Aebischer et al. (1987) fabricated piezoelectric
nerve guidance channels using PVDF and evaluated
it in a transected mouse sciatic nerve model. Their
results showed that piezoelectric nerve guidance channels
enhance peripheral nerve regeneration and provide a tool
to investigate the influence of electrical activity on nerve
regeneration. In yet another study, Fine et al. (1991)
synthesized tubular nerve guidance using a vinylidene-
fluoride–trifluoroethylene copolymer synthesized by a
melt–erosion process. Piezoelectrically active vinylidene-
fluoride–trifluoroethylene copolymer tubes were found
to significantly enhance the nerve regeneration process.
Enhanced neurite outgrowth has been attributed to the
presence of their surface charges and transient charge
generation (Schmidt et al., 1997; Aebischer et al., 1987).
The use of intrinsically charged piezoelectric polymers
as tissue culture substrates provide a means of expos-
ing cells directly to local time-varying charges, such as
those produced by elements of ECM (Valentini et al.,
1992).
Conductive polymers, however, exhibit many advan-
tages over piezoelectric materials. Compared to piezo-
electric materials, conductive polymers generate elec-
trical signals by electron transfer between different
polymer chains and allow external control over the
level and duration of stimulation, which is beneficial
for biomedical applications. Moreover, conducting poly-
mers are inexpensive, easy to synthesize, versatile and
their properties can be readily modulated by a wide
range of molecules that can be entrapped and do
not require extensive processing to render them elec-
troactive (Dust and Bawornluck, 2006; Rivers et al.,
2002). Although piezoelectric materials such as PVDF
can aid in localized stimulation, the external control
over stimulation is limited. The possibility that electri-
cal stimulation can be externally controlled and pre-
cisely regulated with electrically conducting polymers,
along with the flexibility of synthesizing electrically con-
ducting polymers, offer many advantages of conductive
polymers compared to piezoelectric materials (Schmidt
et al.,1997).
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e26
Figure 5. Different modification methods for conducting polymers
5. Modification of conductive
polymers for tissue-engineering
applications
Although conducting polymers offer many advantages
over other materials because of their electrical properties,
opportunities to further optimize these materials when
targeting tissue engineering application remains a
challenge (Guimarda et al., 2007). In the field of
biomaterials the design of bioactive surfaces is of
particular interest, since biological systems interact with
biomaterials via the interface and a variety of surface
modification and immobilization methods have been
developed to create surfaces having bioactive ligands
to interact with biomolecules and cells (Cen et al.,
2002). Several attempts have been made to combine the
conductivity and biocompatibility of conducting polymers,
such as doping by biological dopants, incorporation
of bioactive molecules for increasing cell adhesion
and proliferation, patterning of conductive scaffolds for
improvement of their surface topography and surface
modification of conducting polymeric materials with
biological moieties (Cen et al., 2002; Lee et al., 2006;
Song et al., 2006; Stauffer and Cui, 2006; Gomez et al.,
2007). Figure 5 summarizes the different modification
methods that have been carried out for the modification
of conductive biomaterials.
5.1. Modification of conductive polymers
with bioactive molecules
At present, ECM molecules are mainly chosen as dopants
under the premise that the resulting polymer will have a
higher binding affinity for cell adhesion molecules (Gelmi
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
et al., 2010). By selecting bioactive molecules as dopants,
the polymers can be modified for specific functionality
through the incorporation of proteins, peptides or ECM
components (Gilmore et al., 2009). Doping of conductive
polymers using bioactive molecules such as heparin,
dextran sulphate, hyaluronic acid, chitosan, collagen,
growth factors, oligodeoxyguanylic acids and ATP are
being carried out for the modification of conductive
polymers (Ateh et al., 2006; Stauffer and Cui, 2006;
View et al., 2008; Richardson et al., 2007). However,
the doping of biomolecules has some limitations, such as
low loading and decrease in conductivity, and for induced
release cases, with polymer reduction the supply becomes
limited and the release occurs faster (Gomez and Schmidt,
2007b). Gelmi et al. (2010) and Gilmore et al. (2009) also
showed that doping with a bioactive polymer could cause
an inverse effect on the physical properties, such as surface
roughness of the final composite material, depending
on the kind of doping molecules. To overcome these
limitations, surface immobilizations of macromolecules
have been explored by a few researchers. Immobilization
of biomolecules into conductive scaffolds can be achieved
via methods such as adsorption, entrapment and covalent
binding (Cen et al., 2002). To modify a surface by
covalent modification, a reactive group must be present
on the polymer, which is not always the case in many
polymers (e.g. PPy; Cen et al., 2004). Lee et al. (2006)
synthesized carboxylic acid-functionalized conductive PPy
and further grafted RGD on the surface of PPy scaffold.
Human umbilical vascular endothelial cells cultured on
PPy-RGD scaffolds demonstrated improved attachment
and proliferations. Cen et al. (2002, 2004) fabricated an
electroactive PPy surface functionalized with biologically
active hyaluronic acid for the development of new
tissue-engineering strategies, such as wound healing
and angiogenesis, and further investigated the in vitro
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Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering
bioactivity of functionalized PPy film using PC12 cells.
Their results showed that cell attachment on a hyaluronic
acid functionalized PPy film surface was significantly
enhanced in the presence of nerve growth factor. Li
et al. (2004) immobilized heparin on the surface of PPy
film covalently via poly(ethylene glycol) methacrylate
graft copolymerization. The immobilization of heparin
on the PPy surface had a significant effect on the
selective adsorption of plasma proteins, albumin and
fibrinogen and consequently the formation of thrombus.
Functionalized PPy with heparin has the highest ratio of
albumin:fibrinogen adsorption, the lowest level of plasma
adsorption and the lowest amount of thrombus formation,
which increased the blood compatibility of PPy film.
Sanchvi et al. (2005) used phage display to select
peptides that specifically bind to PPy and which can
subsequently be used to modify the surface of PPy. The
use of selected peptides for PPy by phage display can
be extended to encompass a variety of therapies and
devices, such as PPy-based drug delivery vehicles, nerve
guidance channel conduits and coatings for neural probes.
Selection of peptides using phage display thus represents
a simple alternative to methods based on electrostatic
and hydrophobic interactions between two moieties to
achieve adsorptive modification of surfaces.
Addition of bioactive factors to conducting polymers
is considered a major strategy in improving cell–tissue
interactions (Green et al., 2008). Electrically conductive
and biologically active scaffolds are desirable for
enhancing the adhesion, proliferation and differentiation
of various cell types, including neurons. The incorporation
of bioactive molecules such as neuroactive molecules
into conductive scaffolds has also been applied for
modification of conductive scaffolds (Lee et al., 2009a).
Kim et al. (2007) incorporated nerve growth factor (NGF)
as a co-dopant in the electrochemical deposition of PPy
and PEDOT. An in vitro study using nerve cells showed
that the incorporation of NGF can modify the biological
interactions of the conductive polymers. However, direct
covalent attachment of moieties to the backbone of a
conducting polymer usually has an adverse effect on the
electrical properties of the polymer (Thompson et al.,
2010). Lee et al. (2009a) developed copolymers of N-
hydroxyl succinimidyl ester pyrrole (PPy-NSE) and further
modified it, using immobilization of NGF molecules on
PPy-NSE films. Immobilized NGF on PPy copolymer
was studied under physiological conditions and with
the application of an external electrical potential. Their
results showed that PC12 cells extended neurites similar
to cells cultured in NGF-containing medium. Application
of an external electrical potential to NGF-immobilized
PPy films did not cause any significant release of NGF or
reduce their neurotrophic activity. Such novel scaffolds,
providing electroconductive and neurotrophic activities,
has potential for neural applications, such as tissue
engineering and biosensor applications. Thompson et al.
(2010) incorporated neurotrophin-3 (NT-3) and brain-
derived neurotrophic factor (BDNF) into PPy during
electrosynthesis and evaluated neurite outgrowth from
Copyright  2011 John Wiley & Sons, Ltd.
e27
cochlear neural explants grown on PPy containing NT-
3 and BDNF. Neurite outgrowth from explants grown
on polymers containing both NT-3 and BDNF showed
significant improvement over PPy doped specifically
with NT-3, due to the synergistic effect of the two
neurotrophins. Lee et al. (2006a) synthesized carboxy-
endcapped polypyrrole (PPy-α-COOH), composed of
a polypyrrole (PPy) surface modified with pyrrole-α-
carboxylic acid, and further grafted it with the cell-
adhesive Arg–Gly–Asp (RGD) motif. Human umbilical
vein endothelial cells (HUVECs) cultured on RGD-
modified PPy-α-COOH demonstrated significantly higher
adhesion and spreading on the RGD-modified PPy-α-
COOH than negative PPy-α-COOH without RGD motif
and unmodified PPy. Cullen et al. (2008) fabricated
small diameter (<400 µm) fibres consisting of a blend of
electrically conductive PANI and PPy and carried out bio-
adhesive surface modification using either poly-L-lysine
(PLL) alone or PLL combined with collagen type I.
5.2. Modification of conductive materials
with biopolymers
Fabrication of hybrid material has also been investigated
as a method for modifying the properties of conductive
polymers. The biocompatibility of electroactive polymers
is commonly improved by blending them with natu-
ral polymers (Huang et al., 2007). For example, Khor
et al. (1995) prepared a chitosan–PPy hybrid biomaterial
by chemical polymerization of pyrrole in the presence
of 2% chitosan solution in aqueous acetic acid under
anhydrous conditions. However, no cell culture experi-
ments were carried out by these researchers, although
the chitosan–PPy hybrid appeared a promising material
for tissue-engineering applications. Collagen–PPy hybrid
material prepared by the chemical polymerization of pyr-
role, using FeCl3 as initiator, was also carried out by
these researchers in the presence of soluble collagen
(Li and Khor, 1994). Huang et al. (2010) fabricated a
PPy–chitosan membrane, seeded Schwann cells on the
scaffolds and showed that the PPy–chitosan membranes
supported cell adhesion and proliferation, indicating its
biocompatibility. We carried out the electrospinning of a
blend of poly(ε-caprolactone) (PCL), gelatin and PANI to
obtain conductive nanofibrous scaffolds for nerve tissue
engineering. This scaffold had the advantages of utiliz-
ing both a synthetic polymer where the PCL domain
provides mechanical strength and a natural polymer
(gelatin) that supported cell adhesion and proliferations.
Moreover, the incorporated PANI made the nanofibrous
scaffold a conductive material suitable for the electri-
cal stimulation required for enhanced nerve regeneration
(Ghasemi-Mobarakeh et al., 2009). On the other hand, Li
et al. (2006) blended PANI and gelatin, fabricated scaf-
folds and investigated the attachment and proliferation
of H9c2 cardiac myoblasts on PANI–gelatin scaffolds.
Their results showed that the incorporation of PANI into
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e28
Figure 6. Morphology of (A) PG and (B) PANI/PG (15:85) nanofibrous scaffolds
gelatin has the advantages of inducing electrical conduc-
tivity to the scaffolds with improved cell attachment and
proliferation due to the presence of gelatin.
Akkouch et al. (2010) incorporated fibronectin and
bovine serum albumin into PPy through water-in-
oil emulsion polymerization to create bio-activated
conductive PPy nanoparticles. Conductive biodegradable
membranes were prepared by blending bioactive PPy
nanoparticles with poly(L-lactide) and showed the ability
of these membranes to modulate cell adhesion and
proliferation due to the presence of the bioactive proteins
on their surfaces.
5.3. Topographical modification of conductive
scaffolds
The topographical features of a scaffold have a significant
effect in tissue engineering and it has been demon-
strated that the surface roughness of scaffolds affects
cell behaviour, including cell attachment, proliferation
and differentiation (Chen et al., 2007; Naji and Harmand,
1990; Meyer et al., 1993; Steele et al., 1993; Chu et al.,
1999; Xu et al., 2004b). Moreover, the topographical fea-
tures are described to have a positive effect on axonal
orientation, where the physical guidance of axons is a vital
component of nerve repair. Song et al. (2006) fabricated
wide PPy microchannels using electron-beam (e-beam)
lithography and electropolymerization, and further devel-
oped a method for directing the axonal guidance to a
desired location in the PPy supporting matrix. Gomez
et al. (2007) also synthesized PPy microchannels electro-
chemically to fabricate electroconductive, topographical
substrates for neural interfacing and found that PPy
microchannels facilitated axonal establishment of rat
embryonic hippocampal neurons.
6. Electrospun conductive polymers
for nerve tissue engineering
Scaffolds suitable for tissue engineering should mimic the
structural and biological function of native ECM as much
as possible (Ma et al., 2005; Ashammakhi et al., 2008; Ma,
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
2004; Smith and Ma, 2004). Collagen is a major natural
ECM component and has a fibrous structure with fibre
bundles varying in diameter (50–500 nm) (Ma et al.,
2005; Ashammakhi et al., 2008; Ma, 2004; Smith and Ma,
2004). Nanoscale dimensions have been shown by various
researchers to influence cell behaviour. Cells attach and
organize around fibres with diameters smaller than that
of the cells (Ma et al., 2005). Nanoscale features have the
potential to improve the specificity and accuracy of the
materials for a number of neural engineering applications,
ranging from neural probes to guidance channels for nerve
regeneration (Seidlits et al., 2008). Nanofibrous scaffolds
having fibres in the nanometer scale can therefore serve
as a potential substrate for cell attachment, function
and proliferation rather than the traditional scaffolds
(Ma et al., 2005; Ashammakhi et al., 2008; Ma, 2004;
Smith and Ma, 2004). Polymeric nanofibres can be
processed by a number of techniques, such as drawing,
template synthesis, phase separation, self-assembly and
electrospinning (Ashammakhi et al., 2008; Smith and
Ma, 2004). Electrospinning is one of the most important
techniques to fabricate nanofibres. An attractive feature of
electrospinning is the simplicity and inexpensive nature of
the set-up (Seidlits et al., 2008). The structure and surface
morphologies of electrospun nanofibres can be controlled
by adjusting various parameters during electrospinning,
such as the solution properties, applied voltage and
spinning conditions (Ramakrishna and Fujihara, 2000;
Pham et al., 2006). During the electrospinning process, a
strong electrostatic field is applied to a polymer solution
and, when the electric forces overcome the surface
tension of the solution, a charged jet of solution is
ejected towards the collecting material screen, where a
continuous stretch of nanofibres is obtained (Zong et al.,
2002; Zeng et al., 2003; Yarin et al., 2001). Electrospun
nanofibrous scaffolds of PCL, PCL–gelatin, poly(L-lactic
acid), PCL–collagen, PCL–chitosan, poly(lactic acid-co-
glycolic acid) have been used for nerve tissue engineering
(Yang et al., 2004; Xu et al., 2004; Bini et al., 2006;
Schnell et al., 2007; Yang et al., 2005; Murugan and
Ramakrishna, 2007; Lee et al., 2009c). To take advantage
of the nanofibrous structures together with the electrical
stimulations in tissue engineering, conductive nanofibrous
scaffolds were applied for nerve tissue engineering.
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Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering e29

Figure 7. Morphology of (A) PLLA and (B) PANI/PLLA nanofibrous scaffolds

Table 2. Biocompatibility of conductive nanofibrous scaffolds utilized for tissue engineering applications

Scaffold Cell type Purpose (TE) Reference

PANI/gelatin H9c2 (rat cardiac myoblasts) Cardiac Li et al., 2006

PANI/PG C17.2 (mouse neuronal stem Nerve Ghasemi-Mobarakeh
cells) et al., 2009
PPy/SIBS PC12 (rat neuronal cells) Nerve Liu et al., 2008
PANI/PLCL HDF (human dermal Skin and muscle Jeong et al., 2008
fibroblasts); C2C12 myoblasts
PET/PEDOT SH-SY5Y neuroblastoma cells Nanobiointerface Luo et al., 2008
PDLA/PANI Primary rat muscle cells Muscle McKeon et al., 2010
PCL/PPy Dorsal root ganglia Nerve Xie et al., 2009

TE, tissue engineering; PANI, polyaniline; SIBS, poly(styrene-β-isobutylene-styrene); PET, poly(ethylene terephthalate); PEDOT,
poly(3,4-ethylenedioxythiophene); PPy, polypyrrole; PCL, poly(ε-caprolactone); PLCL, poly(L-lactide-co-ε-caprolactone).

Figure 8. Morphology of nerve cells (×1500 magnification) on PANI/PG nanofibrous scaffolds: (A) without electrical stimulation;
(B) with electrical stimulation. Arrows show neurite extension of neurons

However, the major obstacle concerning the electrically
conductive polymers has been the difficulty associated
with the processing of these materials (Pomfret et al.,
2000). To overcome this problem, most researchers have
electrospun conductive polymers by blending conducting
polymers with other spinnable polymers, compromising
the conductivity of the composite fibres (Yu et al., 2008;
Norris et al., 2000; Veluru et al., 2007; Bishop and Gouma,
2005; Desai et al., 2004; Ju et al., 2007; Srivastava
et al., 2007; Liu et al., 2008; McKeon et al., 2010).
Blending of conductive polymers with other polymers
affects the properties of the resultant nanofibres. For
example, previous studies showed that the incorporation
of conductive polymers to other polymeric materials
on electrospinning decreased the fibre diameters of
Copyright  2011 John Wiley & Sons, Ltd.
the resultant nanofibres, mostly due to increasing of
conductivity of the electrospun solution. As mentioned
earlier, we blended PANI with PCL–gelatin solution and
fabricated conductive nanofibrous scaffolds suitable for
nerve tissue engineering. Figure 6 shows the morphology
of PCL–gelatin (PG) and PANI–PG at a ratio of 15:85 w/w
nanofibrous scaffolds fabricated during our study.
Fibre diameter was found to decrease with the
incorporation of PANI in the polymeric blend system,
whereby PG and PANI/PG (15:85) were found to
have fibre diameters of 189 ± 15 nm and 112 ± 8 nm,
respectively, by SEM analysis (Ghasemi-Mobarakeh et al.,
2009). We also fabricated poly(L-lactic acid) (PLLA) and
PLLA/PANI nanofibres and observed a similar trend in
their fibre diameters. Figure 7 shows the SEM images
J Tissue Eng Regen Med 2011;5: e17–e35.
DOI: 10.1002/term
e30
of PLLA and PLLA/PANI nanofibres. Fibre diameter
decreased from 860 ± 110 nm for pure PLLA nanofibres
to 175 ± 55 nm for PLLA/PANI nanofibres.
Li et al. (2006) also showed that the incorporation of
PANI into gelatin solution decreased the fibre diameter
from 803 ± 121 nm for pure gelatin fibres to 61 ± 13 nm
for 60:40 PANI-gelatin blend fibres. In yet another
study, Jeong et al. (2008) showed that by increasing the
volume ratios of PANI in poly(L-lactide-co-ε-caprolactone)
(PLCL) solution, the diameters of resultant nanofibres
decreased from 430 ± 116 nm for pure PLCL to 382 ±
102 nm for PANI/PLCL nanofibres. Table 2 shows the
different conductive nanofibrous scaffolds that have been
fabricated for various tissue-engineering applications.
7. Application of electrical stimulation
in nerve tissue engineering
Published reports on the application of electrical
stimulation for nerve tissue engineering are limited.
In vitro assays conducted by Schmidt et al. (1997)
showed that PC12 cells cultured on PPy films and
subjected to electrical stimulus showed a significant
increase in neurite length (18.14 µm) compared to passive
controls (9.5 µm). Subsequent studies by Schmidt and
colleagues indicated that the longer neurites grown
on PPy were due to increased protein adsorption
from serum-containing medium mediated by electrical
stimulation (Kotwal and Schmidt, 2001). We applied
electrical stimulation to nerve cells through conductive
nanofibrous scaffolds of PANI–PCL–gelatin (PANI–PG)
and found significantly enhanced cell proliferation
and neurite outgrowth compared with non-stimulated
scaffolds (Ghasemi-Mobarakeh et al., 2009). The average
neurite length for nerve cells grown on PANI–PG, with
application of electrical stimulation by DC voltage of
100 mV/mm for 1 h and without electrical stimulation,
was found to be 30 ± 1.1 µm and 22 ± 0.97 µm,
respectively (n = 200), indicating that the application
of electrical stimulus for 1 h to nerve cells cultured
on PANI–PG significantly (p ≤ 0.05) enhanced neurite
outgrowth. Figure 8 demonstrates the effectiveness of
electrical stimulation on neurite length, showing cells
exposed to electrical stimulation for 1 h with extended
neurites, compared to control samples without electrical
stimulation (Ghasemi-Mobarakeh et al., 2009).
Zhang et al(2007) produced poly(D,L-lactide-co-ε-
caprolactone) membrane coated with PPy and the com-
posite scaffolds supported the proliferation and differenti-
ation of PC12 into neuronal phenotypes as well as sciatic
nerve regeneration in rats. Their study demonstrated
that PPy-coated poly(D,L-lactide-co-ε-caprolactone) mem-
branes could successfully be used for electrical stim-
ulation and it enhanced the neurite outgrowth in a
current-dependent fashion. Kimura et al. (1998) applied
alternative potential which generated rectangular pulse
waves to PC12 cells cultured on the ITO electrode. Their
Copyright  2011 John Wiley & Sons, Ltd.
L. Ghasemi-Mobarakeh et al.
results showed that PC12 cells were electrically induced to
extend their neurites on the electrode surface, even in the
absence of nerve growth factor (NGF). They concluded
that electric stimulation induced c-fos expression, which is
essential for cell differentiation, and alternative potential
may stimulate cell differentiation through a protein kinase
C (PKC) cascade. Lee et al. (2009b) produced PPy-coated
electrospun PLGA nanofibres (PPy–PLGA) by nano-thick
deposition of PPy on electrospun PLGA fibres for neural
tissue applications and performed electrical stimulation
of PC12 cells on these cytocompatible electroconduc-
tive nanofibres. In vitro cell culture using PC12 cells and
embryonic hippocampal neurons demonstrated compat-
ible cellular interactions, and the fabricated PPy–PLGA
meshes were found appropriate for neuronal applications.
Their results also showed that the electrical stimula-
tion of PC12 cells on conducting nanofibre scaffolds
improved neurite outgrowth compared to non-stimulated
cells. Xie et al. (2009) fabricated a new type of scaffold
comprised of conductive core-sheath nanofibres prepared
by in situ polymerization of pyrrole on electrospun PCL
or poly(L-lactide) (PLA) nanofibres, to investigate the
synergistic effect of topographic cue and electrical stim-
ulation on axonal regeneration from cultured neuronal
populations. For electrical stimulation, a mat of random
or random–aligned–random nanofibres was fixed to a
custom-built culture plate with silver electrodes connect-
ing the two ends. A constant voltage of 10 V was then
applied across the mat for 4 h/day during cell culture.
The effective direct current (DC) applied to the sample
was estimated to be 250 mA (a value within the range
0.6–400 mA). Their findings indicated that the electrical
stimulation enhanced the rate of neurite extension on both
random and aligned nanofibres. Thompson et al(2010)
also showed that neurite outgrowth from cochlear neural
explants grown on the PPy-containing NT-3 and BDNF
was significantly improved when the polymer containing
both neurotrophins was electrically stimulated. Electrical
stimulation of protein-loaded PPy has a dramatic effect on
auditory nerve survival and growth from cochlear neural
explants. They concluded that electrical stimulation using
clinically acceptable waveforms has a significant effect on
the rate of release of both proteins (NT-3 and BDNF).
Electrical stimulation has also been applied to Schwann
cells cultured on polypyrrole–chitosan membrane (Huang
et al., 2010). Constant potential gradient (100 mV/mm)
was applied to the cells through the membrane for 4 h
and then the cells were incubated for an additional 12, 24
or 36 h. The results showed that electrical stimulation
applied through conductive PPy–chitosan significantly
enhanced the viability of Schwann cells and dramati-
cally enhanced secretion of NGF and brain-derived neu-
rotrophic factor (BDNF) and protein expression. Huang
et al. (2008) carried out electrical stimulation of PC12
cells through conductive film fabricated from a copoly-
mer of PLA and carboxyl-capped aniline pentamer. Their
findings showed that the mean neurite length of PC12
J Tissue Eng Regen Med 2011;5: e17–e35.
DOI: 10.1002/term
Conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering e31

cells on conductive film exposed to electrical stimula-
tion were much higher than TCP exposed to electrical
stimulation and conductive films without stimulation.
Electrical stimulation has also been used for other
cell types. Shi et al. (2007) found the application of
an electrical field to conductive biodegradable PPy–PLA
membranes to be an effective approach to upregulate
the mitochondrial activity of human skin fibroblasts.
These researchers also fabricated a conductive biodegrad-
able composite material made of PPy nanoparticles and
poly(D,L-lactide), applied electrical stimulation after seed-
ing fibroblasts on them and found similar upregula-
tions (Shi et al., 2004). Jeong et al. (2008) fabricated
nanofibrous scaffolds containing PANI and poly(L-lactide-
co-ε-caprolactone) and investigated the behaviour of
human dermal fibroblasts, NIH-3T3 fibroblasts and C2C12
myoblasts on this scaffold. The growth of NIH-3T3
fibroblasts was enhanced by stimulation of various DC
flows. Sun et al. (2006) applied a non-invasive elec-
trical stimulus to regulate the cell adhesion and ori-
entation of bone marrow-derived mesenchymal stem
cells (MSCs) and fibroblasts. Their results showed that
the optimal application of electrical stimulus could
offer a novel engineering technique to regulate the
cell type-dependent cellular shape and orientation that
are known to be involved in cell differentiation and
growth.
8. Conclusion and future remarks
The nervous system responds to electrical fields and the
key component of neural communication is the action
potential generated at the synapse. This implies that for
fabrication of an ideal neural scaffold, introduction of
electrical stimulations through conductive scaffolds could
promote neurite outgrowth and nerve regeneration.
The importance of conductive polymers for the fabrica-
tion of conductive scaffolds and their applications in elec-
trical stimulation are known. Fabrication and modification
of conductive nanofibrous scaffolds by the incorporation
of biological molecules via different methods have been
carried out to improve cell attachment and proliferation
on these conductive scaffolds. Here, we report that elec-
trical stimulation strongly influences nerve regeneration
and describe some in vitro application of electrical stim-
ulation through conductive scaffolds. Although several
in vitro methods have been used for electrical stimula-
tion, clinical application of electrical stimulation using
conductive scaffolds has not been attempted successfully.
Further study is required to fully understand, characterize
and concurrently compare the effects of different condi-
tions of electrical stimulation (intensity and duration) on
neurons. Moreover the mechanisms caused by electrically
stimulated cells need further investigation, and in vivo
electrical stimulation using implanted conductive scaf-
folds must be carried out for deeper understanding and
efficacy evaluations in nerve tissue engineering.

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