Polypyrrole-based conducting polymers and interactions with biological tissues.
ABSTRACT Polypyrrole (PPy) is a conjugated polymer that displays particular electronic properties including conductivity. In biomedical applications, it is usually electrochemically generated with the incorporation of any anionic species including also negatively charged biological macromolecules such as proteins and polysaccharides to give composite materials. In biomedical research, it has mainly been assessed for its role as a reporting interface in biosensors. However, there is an increasing literature on the application of PPy as a potentially electrically addressable tissue/cell support substrate. Here, we review studies that have considered such PPy based conducting polymers in direct contact with biological tissues and conclude that due to its versatile functional properties, it could contribute to a new generation of biomaterials.
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ABSTRACT: Conjugated polymer actuators have potential use in implantable neural interface devices for modulating the position of electrode sites within brain tissue or guiding insertion of neural probes along curved trajectories. The actuation of polypyrrole (PPy) doped with dodecylbenzenesulfonate (DBS) is characterized to ascertain whether it can be employed in the cerebral environment. Microfabricated bilayer beams are electrochemically cycled at either 22 or 37 °C in aqueous NaDBS or in artificial cerebrospinal fluid (aCSF). Nearly all the ions in aCSF are exchanged into the PPy-the cations Na(+) , K(+) , Mg(2+) , Ca(2+) , as well as the anion PO4 (3-) ; Cl(-) is not present. Nevertheless, deflections in aCSF are comparable to those in NaDBS and they are monotonic with oxidation level: strain increases upon reduction, with no reversal of motion despite the mixture of ionic charges and valences being exchanged. Actuation depends on temperature. Upon warming, the cyclic voltammograms show additional peaks and an increase of 70% in the consumed charge. Bending is, however, much less affected: strain increases somewhat (6%-13%) but remains monotonic, and deflections shift (up to 20%). These results show how the actuation environment must be taken into account, and demonstrate proof of concept for actuated implantable neural interfaces.Advanced Healthcare Materials 02/2014;
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ABSTRACT: Graphical abstract Figure optionsDownload full-size imageDownload high-quality image (67 K)Download as PowerPoint slideActa biomaterialia 01/2014; · 5.09 Impact Factor
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ABSTRACT: Conjugated polymers due to their reversible transition between the redox states are potentially able to immobilise and release ionic species. In this study, we have successfully developed a conducting polymer system based on poly(3,4-ethylenedioxythiophene) (PEDOT) for electrically triggered, local delivery of an ionic form of ibuprofen (IBU), a non-steroidal anti-inflammatory, and analgesic drug. It was shown that by changing the electropolymerisation conditions, the polymer matrix of specified IBU content can be synthesised. The electrochemical synthesis has been optimised to obtain the conducting matrix with the highest possible drug content. The process of electrically stimulated drug release has been extensively studied in terms of the dynamics of the controlled IBU release under varying conditions. The maximum concentration of the released IBU, 0.66 (±0.10) mM, was observed at the applied potential E = −0.5 V (vs. Ag/AgCl). It was demonstrated that the immobilisation-release procedure can be repeated several times making the PEDOT matrix promising materials for controlled drug release systems applied e.g. in neuroprosthetics.Journal of Materials Science 08/2014; 49(16). · 2.16 Impact Factor
Polypyrrole-based conducting polymers
and interactions with biological tissues
D. D. Ateh1,2,*, H. A. Navsaria2and P. Vadgama1
1IRC in Biomedical Materials, Queen Mary University of London, London E14NS, UK
2Centre for Cutaneous Research, Institute of Cell and Molecular Sciences,
Barts and The London School of Medicine and Dentistry, Queen Mary
University of London, London E1 2AT, UK
Polypyrrole (PPy) is a conjugated polymer that displays particular electronic properties
including conductivity. In biomedical applications, it is usually electrochemically generated
with the incorporation of any anionic species including also negatively charged biological
macromolecules such as proteins and polysaccharides to give composite materials. In
biomedical research, it has mainly been assessed for its role as a reporting interface in
biosensors. However, there is an increasing literature on the application of PPy as a
potentially electrically addressable tissue/cell support substrate. Here, we review studies
that have considered such PPy based conducting polymers in direct contact with biological
tissues and conclude that due to its versatile functional properties, it could contribute to a
new generation of biomaterials.
Keywords: biomaterials; conducting polymers; polypyrrole; tissue; cells
Through new combined knowledge of molecular biology
and the biophysical correlates of material surface
properties (Kasemo 1998; Castner & Ratner 2002;
Tiefenauer & Ros 2002), local interactions between
cells and their immediate microenvironments are
increasingly better understood and recapitulated for
the design of practical biomaterials (Discher et al. 2005;
Liu & Chen 2005; Stevens & George 2005). Tissue
engineering (Langer & Vacanti 1993) is probably one of
the most likely avenues for exploitation of such new
generation materials along with other niche areas such
as neuroprosthetics, biosensors and drug delivery.
In tissue engineering, especially with regard to
bioreactors for optimal tissue growth in artificial
constructs prior to implantation, the majority of cell-
supporting scaffolds currently used are porous and
degradable polymers (Seal et al. 2001). Such structures
may be fabricated from natural materials, such as
collagen or fibrin or synthetic polymers such as
polyglycolide or polylactide. However, such scaffolds
(or substrates) and their associated bio-functionality
are now known to be important in tissue growth and
guidance beyond any mesoscopic organization. For
example, their topography (Curtis & Wilkinson 1997),
mechanics (Wong et al. 2004) and incorporated
controlled release growth factors and signal molecules
(Saltzman & Olbricht 2002) can have profound effects
on cell behaviour.
Tailoring specific material properties, bulk as well as
surface, could provide novel solutions for tissue-
engineered systems including controlled cell assembly
(micro and nanopatterned surfaces), drug release
(degradable polymers), tissue release (thermorespon-
sive polymers) and integrated biosensing (electroactive
polymers). In addition, such materials provide a plat-
form for the study of the fundamental underpinning
science relating to tissue-material surface interactions.
It is in recognition of these special requirements that
researchers have engaged unique classes of materials for
trial use in biological applications. Conducting poly-
mers such as polypyrrole (PPy) offer a new class of
material in this regard. This review presents research
where PPy is in contact with biological tissue and
outlines current achievements with an assessment of
2. POLYPYRROLE-BASED CONDUCTING
2.1. Conducting polymers
Letheby in 1862 first reported the anodic oxidation of
aniline in dilute sulphuric acid, yielding an insoluble
blue–black shiny powdered deposit on a platinum
electrode. Further experiments led Goppelsroeder in
1876 to establish that oligomers were formed by the
J. R. Soc. Interface (2006) 3, 741–752
Published online 22 June 2006
*Author for correspondence (firstname.lastname@example.org).
Received 4 April 2006
Accepted 2 June 2006
q 2006 The Royal Society
oxidation of aniline (Heinze 1989). Natta et al. (1958)
synthesized polyacetylene and Dall’olio et al. (1968)
discovered yet another compound, PPy, at the time
called pyrrole black. However, it was not until 1977
that Shirakawa and his co-workers wrote their seminal
paper showing that halogen doping of polyacetylene
dramatically increased its conductivity (to around
103s mK1in the case of I-doped trans-polyacetylene).
The major breakthrough with regard to the routine
synthesis of conducting polymers, however, was
achieved by Diaz and co-workers (Diaz & Kanazawa
1979; Kanazawa et al. 1979; Diaz 1981) when they
reported the formation of a highly conductive, stable
and manageable PPy film under controlled electro-
chemical conditions. Since then, in the context of cell-
material studies, PPy has mainly been produced by
electrochemical reaction. However, along with chemical
synthesis, other polymerization methods have involved
photochemistry, metathesis, concentrated emulsion,
inclusion, solid-state, plasma, pyrolysis and soluble
precursor polymer preparation (Kumar & Sharma
There are currently over 25 reported conducting
polymer systems (Skotheim 1986) with the common-
ality that they have a conjugated structure of alternat-
ing carbon–carbon double bonds (figure 1). It is this
peculiar structure that confers electronic properties,
notably, low-energy optical transitions and ionization
potentials as well as high-electron affinities. The most
important aspect of a conjugated polymer from an
electrochemical view is its ability to act as an electronic
conductor. This property is further controlled by redox
switching at specific potentials accompanied by the
movement of dopant ions into or out of the material
depending on net polymer charge.
Chemically synthesized conjugated polymers are
initially insulators (i.e. in a neutral state) and it is
only through oxidation (p-doping) and less frequently
reduction (n-doping) by chemical or electrochemical
means, that the necessary mobile charge carriers for
conductivity are formed. In the case of PPy for
instance, the backbone is neutral in the reduced state
and positively charged in the oxidized state. Therefore,
to maintain electroneutrality, some counterion is
required to diffuse into the polymer during charging
and out during neutralization. The oxidation process
may also be accompanied by significant change in
polymer volume upon ingress of the mobile anionic
species, a characteristic exploited in actuator appli-
cations (Otero & Sansinena 1995). Overoxidation of
conducting polymers, notably PPy, where the polymer
is held above the standard oxidative potential, leads to
loss of conductivity and de-doping (Gao et al. 1994;
Farrington & Slater 1997; Shiigi et al. 2002).
There has been a large effort focusing on the
development of conducting polymers for practical
applications. Thus, these materials have been investi-
gated for rechargeable batteries, electrochromic dis-
plays, information memory, anti-static materials,
anti-corrosives, electrocatalysis, sensors, electromecha-
nical devices, infra-red polarizers and radar (Stenger-
Smith 1998). Biomedical applications have also been
considered including biosensors (Lillie et al. 2001;
Gerard et al. 2002) and as of late cell growth substrates.
The later application is made more appealing by the
possibility of dopant substitution with biologically
functional macromolecules such as proteins, polysac-
charides and even whole living cells, during the
polymerization process (Adejolu & Wallace 1996).
Furthermore, with recent evidence uncovering import-
ant physiological roles for in vivo electric fields as
created by cell layers in order to provide wound healing
or developmental cues for instance (Martindale 2004),
conducting polymers may offer new advantages as
Certainly, in past experiments, small electrical
currents have been shown to stimulate tissue responses
such as bone re-growth and wound healing (Lindsey
et al. 1987; Kohavi et al. 1992; Kloth & McCulloch 1996;
Reger et al. 1999). These were achieved using metallic
electrodes inherently incompatible with biological
tissues. With organic conducting polymers, the possi-
bility for a more intimate relationship with biological
systems exists (Kane-Maguire & Wallace 2001). In
particular, certain tissues such as those of the nervous
system (Velasco 2000) or skeletal and smooth muscle
(Grandjean et al. 1996) may be particularly susceptible
to modulation via electrical stimulation. With these
possibilities in mind, PPy has become by far the most
studied conducting polymer and is therefore the focus of
PPy is generally synthesized by chemical or electro-
chemical means. Chemical synthesis is used when large
quantities of material are required and involves mixing
a strong oxidizing agent (typically FeCl3) with a
monomer solution (Armes 1987; Duchet et al. 1998).
Electrochemical synthesis is preferred for research
purposes due to the simplicity of the technique, control
over material thickness, geometry and location, the
facility for doping during synthesis, the wide choice of
available dopant ions and the generation of good
quality films (Kumar & Sharma 1998; Inzelt et al.
2000). It leads to the development of adherent surface
conformal deposits i.e. thin solid films, from the bulk
solution phase of monomer units. The electrodeposition
on the positively polarized working electrode proceeds
Figure 1. Examples of conducting polymer structures. The
conjugated structure consisting of an alternating carbon–
carbon double bond is common to all conducting polymers.
742 PPy with biological tissuesD. D. Ateh and others
J. R. Soc. Interface (2006)
via a condensation reaction between the monomer units
of the five-membered heterocycle pyrrole (figure 2).
Concomitantly, negatively charged counterions must
be present in solution to maintain charge balance
within the polymer since positive charges are developed
along the PPy backbone. This latter process is referred
to as doping and the choice of counterion, including
biomolecules, affects formed polymer properties.
The growth of the PPy depends on its electrical
characteristics; if it was non-conducting, its growth
would be self-limiting, producing very thin films as in
the case of polyphenol and its derivatives (Eddy et al.
1995). By contrast, PPy growth is virtually unlimited
due to inherent conductivity and therefore charge
connectivity to the subjacent anode. There are a
large number of experimental formulations for the
Figure 2. Electropolymerizaion mechanism of polypyrrole. Monomer units are adsorbed onto the surface of the working electrode
resulting in one-electron oxidation to form a pyrrole cation radical. These cations then couple with themselves, with other cations
or with neutral monomers from solution. In each case, this leads to the formation of a dimer dication, which undergoes a double
deprotonation to give a neutral molecule. These more stable dimer radicals have a lower oxidation potential compared with the
monomer units and chain growth then occurs by preferential coupling between the dimers and monomers (Skotheim 1986).
Anion (AK) is required to maintain electroneutrality.
PPy with biological tissuesD. D. Ateh and others 743
J. R. Soc. Interface (2006)
preparation of PPy each of which significantly modify
the phenomenological properties of the polymer.
Generally, electrochemical polymerization is under-
taken at potentials above C600 mV versus a Ag/AgCl
reference. The morphology of the resulting film depends
in particular on the nature of the supporting electro-
lyte, the crystallographic structure of the underlying
anode, the kinetics of the process (related to the
electrode material), the potential used for deposition,
the nature of the dopant and the concentration of the
original monomer solution. Temperature and pH also
have an effect on the ensuing film. Figure 3 shows
examples of how different surface topographies are
generated when the counterion and synthesis duration
For formed films, conductivity arises from electronic
transfer along the conjugated p-molecular orbital
backbone coupled with the motion of charge carriers
in the material. Upon oxidation, an electron is removed
from the p-system of the backbone producing a cation
and a local distortion due to a change in geometry every
four pyrrole units. This radical cation coupled with the
local deformation constitutes a polaron. Upon further
oxidation, at higher charging levels, pairs of polarons
combine to form bipolarons as these are energetically
more favourable. Bipolarons are able to migrate along
the conjugated polymer chain and provide the main
charge transport mechanism within the conducting
polymer (Heinze 1989; Inzelt et al. 2000). Final
conductivity reflects the charge transfer between the
dopant and the polymer segment, charge carrier
mobility within the conjugated segments of a single
polymer chain and charge transfer (or ‘hopping’)
between individual chains (Bhattacharya et al. 1996).
Essentially, it has been postulated that it is the least
efficient of any of these mechanisms under any given
condition of say temperature and pH that determines
the final conductivity of the material at a macroscopic
level. Research is still continuing with the aim of
reaching a fuller, more detailed understanding of charge
storage and transport mechanisms in conjugated
polymers (Papathanassiou et al. 2005).
3. TISSUE AND CELL INTERACTIONS
Since the early nineties, PPy has been substantially
studied as a cell growth substrate within in vitro culture
models. Furthermore, the effects of implantation in vivo
have also been studied using animal models. These PPy
films have usually been electrodeposited on an under-
lying electrode surface (e.g. indium tin oxide or gold)
with simultaneous incorporation of inert counterions or
biologically active molecules ready for cell culture or to
be peeled off prior to use. These studies could be
broadly divided into two categories, those that inves-
tigate interactions with tissue for PPy used after
synthesis with specific loadings or conditions and
those that additionally exploit conducting properties
as a means of influencing cellular outcomes.
3.2. Unstimulated polypyrrole
The preferential maintenance of secretory function for
chromaffin cells, neuroendocrine cells that secrete
neurotransmitters, cultured on PPy modified indium
tin oxide compared to the unmodified substrate was
demonstrated by Aoki et al. (1995, 1996). Their
research and that of others suggested early on that
advantages over traditional electrode surfaces may be
gained through such modifications. In other constructs,
such as the commercially available PPy-coated woven
polyester fabrics known as Contex, the response of
various cell types has been studied (Jakubiec et al.
1998). Four different grades of increasing conductivity
were compared with uncoated polyester fabrics and
polydimethylsiloxane. Overall, it was found that for
fabrics of highest conductivity, fibroblast and endo-
thelial cell viability was impaired, polymorphonuclear
cell activation increased and macrophage IL-6
expression reduced. Optimal responses were found
for PPy-coated polyester fabrics of intermediate
Figure 3. Scanning electron microscopy images of polypyrrole
(PPy) surface topography generated for different counterions
and electropolymerization durations (a–b) PPy/chloride,
(c–d) PPy/polyvinyl sulphate, (e–f) PPy/dermatan and
(g–h) PPy/collagen. The shorter times produced thin films
(left column) with none or little surface features whereas at
extended times, thicker films with distinct topography are
seen (right column). More instances of counterion controlled
topography may be found in the literature (Skotheim 1986).
744PPy with biological tissuesD. D. Ateh and others
J. R. Soc. Interface (2006)
conductivity and the authors, though not yet fully
understanding the reason for this, speculated that local
release of cations from PPy, which presumably varies
between their compositions, affects cell behaviour due
to modification of ionic transport across the neighbour-
ing cell membrane. Similarly coated polyester fabrics
have been shown to elicit less or comparable cellular
reactive responses including inflammation as well as
acid and alkaline phosphatase levels when implanted
subcutaneously in rats over 3–90 days and compared
with their uncoated counterparts (Jiang et al. 2002).
Garner et al. (1999a) studied human umbilical vein
endothelial cells on PPy-heparin films. They chose the
counterion heparin, as it is a component of the
extracellular matrix of blood vessels as well as having
anticoagulant properties. They established that the
conditions for synthesis as well as polymer redox state
led to variations in the level of surface exposed heparin.
They then showed that the PPy-heparin composite
supported the growth of endothelial cells with a
reduction in the normal amount of heparin required
as a medium supplement. Since cells did not grow on
PPy-nitrate, this was attributed to the presence of
heparin with attachment shown to be vitronectin
dependent (Garner et al. 1999b). The work of Collier
et al. (2000) considered composites of PPy and the
ubiquitous glycosaminoglycan, hyaluronic acid (HA).
They showed HA retained affinity properties on the
surface of the formed polymer using biotinylated HA
binding protein. In vitro compatibility studies using
PC-12 cells (cell line derived from a transplantable rat
phaechromocytoma that serves as a model for primary
neuronal cells) confirmed that the PPy-HA composites
supported cell attachment and viability. In vivo inves-
tigation using implantation in rat subcutaneous
pouches for two and six weeks demonstrated various
tissue responses (figure 4). It was found that compared
with a PPy-polystyrene sulphate control implant, there
was a statistically significant increase in vasculariza-
tion around the HA containing polymer. In tissue, HA
is a known angiogenesis promoter important during
wound healing for instance; this study suggests it
retains this ability whilst incorporated in PPy films.
Others have showed good PC-12 growth and blood
compatibility when PPy surfaces have been functiona-
lized with HA and sulphated HA (Cen et al. 2004).
Neural recording microelectrodes have been coated
with PPy doped with fibronectin and laminin fragments
(Cui et al. 2001). In the study, preferential binding was
reported for glial cells on films incorporating fibronectin
fragments whereas neuroblastoma cells favoured films
CDPGYIGSR (p31) amino acid sequence. It was
found that the coatings did not interfere with record-
ings when measurements were made in guinea pig
cerebellum. PPy films incorporating another laminin
sequence, RNIAEIIKDI (p20), and those incorporating
both p20 and p31 were found to generate increased
neuron densities in culture compared with polystyrene
sulphonate loaded films (Stauffer & Cui 2006). Micro-
patterns produced through covalent attachment of
polylysine and/or laminin to PPy-polyglutamic acid
composites showed that neuron adhesion and neurite
extension could be controlled in terms of spatial
arrangement on these substrates (Song et al. 2006).
These studies demonstrate that biomolecules pertinent
to nervous system cell adhesion, migration and
proliferation may be used in the provision of PPy-
based neuroprosthetics since they enhance cell-material
interactions. George et al. (2005) considered the
response of rat cortical tissue both in vitro and in vivo
to PPy formed under varying dopant compositions and
electrodeposition temperatures (figure 5). They did not
incorporate biomolecules, but nevertheless reported
favourable responses compared to Teflon implants in
terms of macrophage activity, gliosis and neuronal
integration after implantation, although they presented
pilot studies of PPy incorporating nerve growth factor
(NGF), which suggested increased neural integration.
Figure 4. In vivo tissue response to polypyrrole-hyaluronic
acid (PPy/HA) bilayer films. (a) Polypyrrole-polystyrene
sulphonate (PPy/PSS) films and (b) PPy/HA bilayer films
were implanted into subcutaneous pouches in rats. Tissue
surrounding the material was harvested after two weeks,
fixed, imbedded and stained with hematoxylin and eosin. The
heavy black lines in both images are the PPy/PSS and
PPy/HA bilayer films. Blood vessels are denoted by arrows.
Scale bar, 100 mm (both images are at the same magni-
fication). This figure shows that HA retains its angiogenesis
properties whilst incorporated in PPy since more blood
vessels were seen around this implant compared to the
PPy/PSS control. Reprinted from Collier et al. (2000) with
permission from John Wiley & Sons, Inc.
PPy with biological tissuesD. D. Ateh and others 745
J. R. Soc. Interface (2006)
They thought that improvements for the PPy neuro-
prosthetics compared with the inert Teflon were due to
less physical integration and higher inflammatory
responses in the latter whereas PPy presents a more
favourable surface chemistry.
Mattioli-Belmonte et al. (2003) studied the tissue
and cellular tolerance of non-resorbable and resorbable
materials. While they reported the absence of necrosis
or degeneration around implants inserted subcu-
taneously in rats, the extent of fibrous encapsulation
and the number of surrounding inflammatory cells
reduced in the order, poly(lactide-b-1,5-dioxepan-2-
one-b-L-lactide) ! polyaniline ! polypyrrole !
polyimide for the former response and polyaniline !
polypyrrole ! poly(lactide-b-1,5-dioxepan-2-one-b-L-
lactide) ! polyimide for the latter. They also studied
the in vitro growth of a human keratinocyte cell line on
PPy films and found poor adhesion compared with the
other substrates including the resorbable triblock
polymer based on poly-L-lactide. In another study,
from Mattioli-Belmonte et al. (2005), it was shown that
behaviour of the same keratinocyte cell line was
modulated by redox state and morphology of PPy-
tosylate films with poor growth occurring on oxidized
substrates but none on those that were overoxidized.
They assigned this limited cell growth to surface
tension and irregular roughness in the oxidized films,
with the possibility that tosylate diffusion into the
culture media worsened the outcome on overoxidized
films. Poor proliferation was also reported by Lakard
et al. (2004, 2005) for a rat neuronal cell line on PPy
when compared to other substrates including those that
were electrodeposited (figure 6). Furthermore, Castano
et al. (2004) showed a dependence on film thickness as
controlled by monomer concentration during admicel-
lar polymerization, where a surfactant, monomer and
initiator are used to form the polymer, for the viability
and differentiation of mesenchymal stem cells towards
the osteoblastic phenotype. Thin films prepared from
lower monomer concentrations were excellent for cell
Figure 5. Polypyrrole (PPy) implants. (a) An example of a
typical implant; scale bar, 1 mm (b) two PPy implants placed
in the rat’s cortex; scale bar, 2 mm (c) a histological slice at
six weeks post-implantation with the remnants of the
Polypyrrole implant; scale bar, 200 mm. Favourable responses
for PPy compared to Teflon implants in terms of macrophage
activity, gliosis and neuronal integration were found after
implantation. Reprinted from George et al. (2005) with
permission from Elsevier.
(times of initial cells seeded density)
cell proliferation at 24 h
cell proliferation at 72 h
Figure 6. Neuronal cell line adhesion and proliferation on
different substrates after 8, 24 and 72 h of culture. The
numbers of cells were normalized to initial density of seeded
cells (200 000 cells mlK1) (nZ3 per substrates). The volume
of the cell suspension used is 100 ml. All results are given at G
5%. PEI is polyethyleneimine, PPy is polypyrrole, PPI is
polypropyleneimine andFTO isfluorine-doped tin oxide.This
study illustrates that under some conditions poor interactions
may occur between polypyrrole and cells compared to other
materials. Reprinted from Lakard et al. (2004) with per-
mission from Elsevier.
746 PPy with biological tissuesD. D. Ateh and others
J. R. Soc. Interface (2006)
adhesion and subsequent growth in contrast to thicker
films and those made by the standard chemical
polymerization method i.e. without surfactant. They
thought poor results for increased monomer concen-
trations could be due to toxic leachables or surface
properties that impede cell attachment.
The biocompatibility of PPy prepared from both
chemical and electrochemical means was thoroughly
evaluated by Wang et al. (2004). They carried out a
series of systemic toxicity tests according to ISO 10993
and ASTM F1748-82 standards by applying a solution
of extracts from PPy powder to cell cultures and animal
models. They found that extract solutions did not have
adverse effects on cell cultures or on the animals tested.
In the case of the animal models, this included the
absence of body temperature change, red cell haemo-
lysis, allergic response or mutagenesis. In addition,
good growth of Schawnn cells cultured on electroche-
mically polymerized PPy compared with bare glass
substrates was observed. The report also demonstrated
the novel electrochemical deposition of PPy on the
inner surface of a silicone tube, used to bridge gaps
created in the sciatic nerve of rats. Slightly improved
nerve regeneration with only mild inflammation after
six months was seen compared to uncoated silicone
tubes. Li et al. (2005) showed PC12 cell attachment and
growth to be superior on their porous PPy-tetraethy-
lammonium perchlorate-polyvinyl alcohol composites
compared with tissue culture polystyrene. They
thought this was due to the presence of pores in the
PPy composite, which enhanced signal triggering and
acted as nutrient reservoirs below the cells.
In our studies, we have shown that variously loaded
PPy films including those incorporating proteins are
feasible for producing coherent membranes and are able
to support keratinocyte growth (Ateh et al. 2006).
However, we found that this was strictly dependent on
thorough washing of the films prior to culture so as to
eliminate toxic remnants such as monomers or oligo-
mers from the synthesis step. In addition, we found that
for thicker films which have a rough topography
(figure 3), characteristic of each dopant, cleaning
becomes more difficult presumably due to higher levels
of remnants from the decrease in polymerization
efficiency as films grew. This could help explain poor
cell interactions with PPy for some of the studies
discussed thus far since they did not mention a washing
step for their polymers prior to use. However, it is also
accepted that tissue and cell reactions to PPy-based
conducting polymers are likely to be modulated by a
variety of factors including synthesis conditions and
dopant choice, which affect resulting surface chemi-
stries and topography, as well as the tissue or cell type
considered. Due to the endless combinations possible,
outcomes reported with these factors vary widely in the
3.3. Stimulated polypyrrole
The main attraction of PPy in the role of biomaterial
stems from its electrochemical properties, essentially
the ability to conduct charge coupled with the
polymeric nature. Much work was carried out in the
Late Eighties by Aizawa’s group at the Tokyo Institute
of Technology. They found that electrochemical oxi-
dation of PPy caused a large local pH change along with
incorporation of anions from solution (Shinohara et al.
1989a) and explored the rupture of erythrocyte cell
membranes by an applied potential (Shinohara et al.
1989b). They attributed the pH change to local OHK
transfer between the electrolyte and the PPy film. In
their work with erythrocytes, they found that cell lysis
occurred on PPy-coated electrodes at ca C400 mV
versus Ag/AgCl whereas a potential higher than
C1400 mV was required to do the same on bare
Wong et al. (1994) studied the viability of bovine
aortic endothelial cells on PPy substrates, in some cases
pre-coated with fibronectin, since cell attachment and
spreading were found to be poor on uncoated films.
Further experiments, where cell-seeded films were
switched from oxidized to reduced states by applying
a small negative electrical potential (K0.5 V versus
saturated calomel electrode),
responses within an hour. The reactions involved cell
rounding (where the cell tends to detach from the
substrate) and appeared to be determined by the
electrochemical state of the PPy film. The authors
suggested that this might be due to the local removal of
fibronectin anchors or to mechanical changes in the
reduced film. They further showed that these responses
could be used to exert control over cell cycle progression
since DNA synthesis was reduced to near zero on PPy
in the case of an applied potential compared to over
70% for the control.
Williams & Doherty (1994) demonstrated the
possibility of providing electric fields to neuroblastoma
cells cultured on PPy. The work of Schmidt et al. (1997)
built on these foundations and showed that positive
electrical stimulation of polystyrene sulphonate-loaded
PPy films during the culture of rat PC-12 cells and
primary chicken sciatic nerve explants enhanced
attachment and neurite extension (figure 7). In the
case of PC-12 cells, no significant difference in neurite
extension was recorded for cells grown on tissue culture
polystyrene and unstimulated PPy. For the electrically
stimulated PPy substrate, there was however, a
doubling in median neurite length. They could not
explain the exact mechanism for enhanced neurite
extension in culture, but proposed the electrophoretic
redistribution of molecular components involved in
growth cone formation, favourable protein confor-
mational changes, direct polarization of nerves,
enhanced protein synthesis and field-induced ionic
and molecular gradients in the culture medium as
possible factors. Kotwal & Schmidt (2001) used PC-12
cells to investigate the effect of protein adsorption on
PPy and the subsequent outcome of this on neurite
extension. Their study discovered that electrical
stimulation increased the adsorption of fibronectin
from solution onto the PPy film prior to cell seeding.
They postulated that this was due to fibronectin
adopting a favourable conformation during electrical
stimulation. Upon cell culture on the PPy substrates
after the protein adsorption regimen, they reported
increased neurite extension for electrically driven
PPy with biological tissuesD. D. Ateh and others 747
J. R. Soc. Interface (2006)
fibronectin adsorption compared with the unstimulated
Hodgson et al. (1994, 1996) included NGF among
other bio-components within a PPy-sulphated poly-
saccharide composite and achieved controlled release
by electrical stimulation. Upon reduction of the PPy
backbone at a suitable potential, they registered a
release of NGF and subsequent differentiation of PC-12
cells growing on the polymer surface. More recently,
Wadhwa et al. (2006) showed that the ionic form of the
steroid dexamethasone could be incorporated into PPy
and delivered by cycling the film between fixed
potentials. They found that the delivered drug was as
active as the non-incorporated counterpart in reducing
the number of reactive astrocytes/microglia as well as
in supporting normal neuronal growth and suggested
this could help minimize gliosis around neuropros-
thetics. However, delivery after implantation has yet to
be achieved, and it is possible that the high cycling
potentials required may cause undesired outcomes
within the surrounding tissue. Thus, while there are
numerous examples of PPy-based drug delivery plat-
forms in the literature, in vivo efficacy needs to be
In studies extending beyond macromolecular coun-
terions, Campbell et al. (1999) demonstrated the
possibility of incorporating whole cells into the PPy
matrix. In this study, it was shown possible to grow
PPy films galvanostatically from an aqueous electrolyte
solution of 0.27 M sucrose, 0.1 M pyrrole, 1 g lK1
polyvinyl sulphonate and erythrocytes. Most of the
erythrocytes incorporated were intact disks with strong
red staining suggesting normal haemoglobin content.
A few cells were pale with the presence of inclusion
bodies and this was attributed to haemoglobin loss
either as a result of electroporation or other oxidative
damage during synthesis. It was also found that Rh (D)
antigens on erythrocytes remained intact after
inclusion in PPy and in the presence of antibody, a
resistometric signal (related to changes in electrical
resistance) indicated antigen/antibody binding. This
suggested that erythrocyte-loaded polymers could be
used as the basis of novel blood group immuno-
biosensors. Cui et al. (2003) reported good recordings
of electrical activity with PPy-synthetic peptide coated
electrodes when implanted in guinea pig brain over two
weeks with better nerve cell integration than uncoated
electrodes. When PPy was grown in a hydrogel scaffold
(figure 8) coated on neural electrodes, it was also
possible to make recordings (Kim et al. 2004). We have
recently worked on impedimetric methods, where a
small oscillating voltage is applied and the resulting
current response analysed, to monitor cell behaviour on
PPy-based substrates (Ateh et al. submitted). In fact,
advantages over bare gold were found for the PPy
modification including preferential cell growth and
median length = 8.7 µm
N = 2375
neurite length (µm)
neurite length (µm)
median length = 18 µm
N = 5643
median length = 9.5 µm
N = 4440
median length = 8.2 µm
N = 1356
10 20 30 40 50 60 70 80 90 100
10 20 30 40 50 60 70 80 90 100
Figure 7. (Left) Scanning electron microscopy of a PC-12 cell on polypyrrole (PPy). PC-12 cells were cultured in NGF-
supplemented medium for 48 h on thick disks of PPy, then processed for scanning electron microscopy. Bar Z10 mm. (Right)
Neurite length histograms. Shown are histograms of neurite lengths for cells on PPy (a) with electrical stimulation (S) and (b)
without (NS) potential applied through the PPy film. Histograms for cells on PPy with (c) potential applied through the solution
and on (d) tissue culture polystyrene (TCPS) are also shown. This study demonstrates the potential of electrically stimulating
PPy in order to affect cell behaviour. In this case, enhanced neurite outgrowth has implications in nerve regeneration therapies.
Reprinted from Schmidt et al. (1997) with permission from National Academy of Sciences, USA (Copyright 1997).
Figure 8. Schematic of the cloud-like conducting polymer on
the gold electrode polymerized through the hydrogel matrix.
The flexibility and usefulness of polypyrrole may be further
enhanced with such composites. Reprinted from Kim et al.
(2004) with permission from John Wiley & Sons, Inc.
748PPy with biological tissuesD. D. Ateh and others
J. R. Soc. Interface (2006)
resolution at lower cell numbers presumably due to
better cell-material integration as well as a reduction in
overall impedance due to the increased surface area
generated by the PPy coating.
Researchers at the southeast University of China
have looked at the effect of PPy electrical stimulation in
relation to rat primary keratinocytes cultures (Pu et al.
2001). They electropolymerized PPy films on porous
(120 mm pore size) stainless steel filters and through a
series of experiments, optimized cell culture media
composition and PPy electrical stimulation potential.
The key finding was that under optimal conditions,
including electrical stimulation for 2 h at 100 mV, there
was over a 20% increase in cell viability, as measured by
the MTT assay 3 days later, compared to standard
culture methods. However, the method was unusual as
the keratinocytes were firstly seeded onto tissue culture
plates and after 5–6 h, the PPy films on their stainless
steel supports were placed over the adhered cells.
Therefore, unlike other accounts, the cells were not
directly grown on the conducting polymer. Shi et al.
(2004) developed a conductive biodegradable compo-
site made from polylactide and PPy nanoparticles.
Upon fibroblast culture and the application of a DC
current for 4 days, an up-regulation in growth was also
seen at optimal currents.
To the same extent as any potential biomaterial, the
interactions of PPy with tissue depend on its unique,
intrinsic properties notably surface chemistry, topo-
graphy and micro-mechanics. The reported studies
highlight the versatile nature of PPy whose properties
may be tailored depending on the chosen synthesis
conditions including choice of dopant ion and modifi-
cation through electrical stimulation post-synthesis.
They also show that there are distinct outcomes of
interactions with tissue depending on choice of
synthesis conditions and the precise tissue or cell type
considered. Interpretation is further complicated by a
lack of understanding of mechanisms or a consensus on
the effect of electric fields and charged surfaces on
biological tissue, although this prospect seems to be
improved with new discoveries in biological electric
field physiology (Martindale 2004). This means there
are no clear rules as yet, such as a defined correlation
between hydophilicity, redox state or applied current/
potential with improved cell growth for instance, but
with more research these should emerge.
It is likely that surface modification post-synthesis
such as the novel strategy that developed a PPy-
chloride binding peptide from a bacteriophage library
(Sanghvi et al. 2005) will prevail over dopant
approaches since the latter can often result in a loss of
electrochemical properties including conductivity.
Other advances in PPy synthesis methods, such as
preparation routes for biodegradable conducting PPys
synthesized with degradable ester linkages (Rivers et al.
2002) or from b-substituted pyrrole monomers with
ionizable/hydrolysable side groups (Zelikin et al. 2002)
and stretchable PPy films made with dopants that act
as plasticizers (Oh et al. 2001) also enhance their
potential as an adaptable biomaterial. Research in this
area is still in its infancy but PPy-based conducting
polymers have the potential to be coatings or stand
alone substrates that could be tailored to support
various tissue/cell types. They could also electrically
modulate behaviour through induced drug delivery,
property changes or just electric field provision. Films
could also be used to report on tissue/cell interactions
through induced impedance changes. Future research
should aim to go beyond our current understanding by
linking advances in surface science with cell biology to
improved PPy substrates and focusing on biological
interactions at the molecular level, including gene
expression changes and proteomics. This would further
clarify cause and effect during PPy-tissue interactions
so as to help achieve ‘real world’ biomaterials.
The authors are grateful to the EPSRC for support to D.D.A.
and Miss Bo Su is thanked for her translation of the Chinese
paper (Pu et al. 2001).
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