ARTICLE IN PRESS

Prog. Polym. Sci. 32 (2007) 876–921

www.elsevier.com/locate/ppolysci

Conducting polymers in biomedical engineering

Nathalie K. Guimarda, Natalia Gomezb, Christine E. Schmidtb,c,
a
Chemistry Department, University of Texas at Austin, Austin, TX, USA
b
Chemical Engineering Department, University of Texas at Austin, Austin, TX, USA
c
Biomedical Engineering Department, University of Texas at Austin, Austin, TX, USA
Received 17 April 2007; received in revised form 23 May 2007; accepted 24 May 2007
Available online 11 June 2007

Abstract

Conducting polymers (CPs) were first produced in the mid-1970s as a novel generation of organic materials that have
both electrical and optical properties similar to those of metals and inorganic semiconductors, but which also exhibit the
attractive properties associated with conventional polymers, such as ease of synthesis and flexibility in processing. The fact
that several tissues are responsive to electrical fields and stimuli has made CPs attractive for a number of biological and
medical applications. This review provides information on desirable CP properties specific to biomedical applications and
how CPs have been optimized to generate these properties. The manuscript first introduces different types of CPs, their
unique properties and their synthesis. Then specific information is provided on their modification for use in applications
such as biosensors, tissue engineering, and neural probes. Although there remain many unanswered questions, particularly
regarding the mechanisms by which electrical conduction through CPs affects cells, there is already compelling evidence to
demonstrate the significant impact that CPs are starting to make in the biomedical field.
r 2007 Elsevier Ltd. All rights reserved.

Keywords: Electroactive biomaterial; Neural probes; Biosensors; Tissue engineering; Polypyrrole; Polythiophene

Contents

1. The discovery of conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877

2. Synthesis of conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
3. Conductivity and doping of conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
4. Use and modification of conducting polymers for biomedical applications . . . . . . . . . . . . . . . . . . . . . . . . . 882
4.1. General modification strategies for conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
4.2. Biosensor applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885
4.3. Tissue engineering applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
4.3.1. Polypyrrole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893

Abbreviations: CP, conducting polymer; CV, cyclic voltammetry; DRG, dorsal root ganglion; FN, fibronectin; HA, hyaluronic acid;
NGF, nerve growth factor; PANI, polyaniline; PC12, rat pheochromocytoma cell line; PEDOT, poly(3, 4-ethylenedioxythiophene); PLA,
poly(lactic acid); PLGA, poly(lactic-co-glycolic acid); PPy, polypyrrole; PSS, poly(styrene sulfonate); PT, polythiophene; PVA, poly(vinyl
alcohol); RGD, arginine–glycine–aspartic acid (peptide sequence); TCPS, tissue culture polystyrene
Corresponding author. Biomedical Engineering Department, University of Texas at Austin, Austin, TX, USA.
E-mail address: schmidt@che.utexas.edu (C.E. Schmidt).

0079-6700/$ - see front matter r 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.progpolymsci.2007.05.012
 ARTICLE IN PRESS
N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921 877

4.3.2. Polyaniline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900

4.3.3. Polythiophene and novel conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
4.4. Neural probe applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
4.4.1. Polypyrrole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
4.4.2. Poly(3,4-ethylenedioxythiophene) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
4.5. Other applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 908
5. Challenges and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
5.1. Electrical properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911
5.2. Biological and physical properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914

1. The discovery of conducting polymers
The electrically conducting polymer (CP) poly-
pyrrole (PPy) dates back to the 1960s, but little was
understood about the polymer at this time and the
discovery was essentially lost [1]. It was only in 1977,
when Alan MacDiarmid, Hideki Shirakawa, and
Alan Heeger reported a 10 million-fold increase in
the conductivity of polyacetylene doped with iodine
(Fig. 1A), that the first inherently conductive
polymer was recognized [2,3]. Although polyacety-
lene, a non-cyclic polyene, is still one of the most
studied polymers in this field, it has significant
limitations, such as difficulty with processing and
high instability in air. Unlike polyacetylene, poly-
phenylenes, which are cyclic polyenes, are known to
be thermally stable as a result of their aromaticity [4].
Consequently, the development of such aromatic CPs
for different applications has received much atten-
tion. Polyheterocycles, such as PPy, polythiophene
(PT), polyaniline (PANI), and poly(3,4-ethylenediox-
ythiophene) (PEDOT) (Fig. 1B), developed in the
1980s, have since emerged as another class of
aromatic CPs that exhibit good stabilities, conductiv-
ities, and ease of synthesis [5,6]. Refer to Table 1,
which lists a broad range of different CPs and their
conductivities.
2. Synthesis of conducting polymers
CPs can be synthesized either chemically or
electrochemically, with each having advantages
and disadvantages as summarized in Table 2 [7].
Different methods of chemical synthesis include
either condensation polymerization (i.e., step
growth polymerization) or addition polymerization

O O

n
N n n S n
S
Polyacetylene H
(PA)
Polypyrrole Polythiophene Poly(3,4-ethylene
(PPy) (PT) dioxythiophene)
(PEDOT)

H H
N N N N
n

Polyaniline
(PANI)

Fig. 1. Chemical structures of common conductive polymers: (A) polyacetylene, the first documented conducting polymer and (B) most
commonly explored conducting polymers for biomedical applications: polypyrrole, polythiophene, poly(3,4-ethylenedioxythiophene), and
polyaniline.
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Table 1
Conductivity of common CPsa
Reference Electrode Working Electrode
Conducting polymer Maximum Type of (e.g., Ag/AgCl, saturated (e.g., ITO or metal)
calomel electrode)
conductivity doping
(S/cm)b Counter Electrode
(e.g., platinum mesh)
Polyacetylene (PA) 200–1000 n,p
Polyparaphenylene (PPP) 500 n,p
Polyparaphenylene sulfide (PPS) 3–300 p Electrolyte Solution
Polyparavinylene (PPv) 1–1000 p (monomer and dopant)
Polypyrrole (PPy) 40–200 p
Polythiophene (PT) 10–100 p
Fig. 2. Three electrode setup for electrochemical synthesis:
Polyisothionaphthene (PITN) 1–50 p
reference electrode, working electrode (where polymerization
Polyaniline (PANI) 5 n,p
occurs), and counter electrode all submersed in a monomer and
a
Reproduced from [18]. electrolyte solution.
b
S ¼ Siemens.
Electrochemical synthesis is a common alterna-
tive for making CPs, particularly because this
Table 2 synthetic procedure is relatively straightforward
Comparison of chemical and electrochemical CP polymerization [7,8]. Electrochemical preparation of CPs dates
Polymerization Advantages Disadvantages
back to 1968 when ‘‘pyrrole black’’ was formed as
approach a precipitate on a platinum electrode by exposing an
aqueous solution of pyrrole and sulfuric acid to an
Chemical  Larger-scale  Cannot make oxidative potential [9]. Today, electrochemical
polymerization production thin films
polymerization is performed using a three-electrode
possible  Synthesis more
 Post-covalent complicated configuration (working, counter, and reference
modification of electrodes) in a solution of the monomer, appro-
bulk CP possible priate solvent, and electrolyte (dopant) (Fig. 2).
 More options to Current is passed through the solution and electro-
modify CP
deposition occurs at the positively charged working
backbone
covalently electrode or anode. Monomers at the working
electrode surface undergo oxidation to form radical
Electrochemical  Thin film  Difficult to cations that react with other monomers or radical
polymerization synthesis possible remove film from cations, forming insoluble polymer chains on the
 Ease of synthesis electrode surface
 Entrapment of  Post-covalent
electrode surface (Fig. 3). A number of important
molecules in CP modification of variables must be considered, including deposition
 Doping is bulk CP is time and temperature, solvent system (water con-
simultaneous difficult tent), electrolyte, electrode system, and deposition
charge. Each of these parameters has an effect on
film morphology (thickness and topography), me-
chanics, and conductivity, which are properties that
(i.e., chain growth polymerization). Condensation directly impact the utility of the material for
polymerization proceeds via the loss of small biomedical applications. For example, a non-protic,
molecules, such as hydrochloric acid or water. non-nucleophilic solvent generates stronger and
Radical, cation, and anion polymerizations are all more conductive CPs because protic solvents, like
examples of addition polymerization, which are nucleophilic solvents, can generate side reactions
distinguished by the respective radical, cation, or with the growing CP chain, limiting and disrupting
anion intermediate state of the live or reactive end of chain growth.
the polymer chain during synthesis. Chemical The most significant difference between electro-
synthesis not only provides many different possible chemical and chemical methods of CP synthesis is
routes to synthesize a variety of CPs, but also that very thin CP films on the order of 20 nm can be
permits the scale-up of these materials, which is produced using the electrochemical technique,
currently not possible with electrochemical synthesis. whereas powders or very thick films are typically
 ARTICLE IN PRESS
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-e
X = NH, S, O
X X X

H H
X
-2H+
X X X
H X X

-e X
-2H+ H H
X X X X X
n

X X X X X X
n n

Fig. 3. Mechanism for heterocycle polymerization via electrochemical synthesis. X ¼ NH, S, or O. This pathway is initiated by the
oxidation of a monomer at the working electrode to give a cation species, which can react with a neutral monomer species or radical cation
oligomeric species to generate the polymer. Adapted from [10].

produced with chemical polymerization. All CPs
can be synthesized chemically, but electrochemical
synthesis is limited to those systems in which the
monomer can be oxidized in the presence of a
potential to form reactive radical ion intermediates
for polymerization. The standard CPs (i.e., PPy, PT,
PANI, PEDOT) can be polymerized both chemi-
cally and electrochemically; however, several novel
CPs with modified monomers are only amenable to
chemical polymerization.
3. Conductivity and doping of conducting polymers
CPs are unique in that they are organic chains of
alternating double- and single-bonded sp2 hybri-
dized atoms, which endow the polymer with metal-
like semiconductive properties. The series of alter-
nating single and double bonds, which is generated
by electron cloud overlap of p-orbitals to form p
molecular orbitals, is referred to as a conjugated
system. Studies have demonstrated that planar
conformation of the alternating double-bond sys-
tem, which maximizes sideways overlap between the
p molecular orbitals, is critical for conductivity.
This p-bonded system is further described in terms
of electronic wave functions that are delocalized
over the entire chain. This delocalization allows
charge mobility along the polymer backbone and
between adjacent chains, but delocalization is
limited by both disorder and Coulombic interac-
tions between electrons and holes. Prior to doping,
these systems are insulative (1010 S/cm; S ¼ 1/O);
however, the electrical conductivity of polyhetero-
cyclic films, for instance, can be augmented up to 12
orders of magnitude (102 S/cm) depending on the
polymer system and the type and extent of doping,
as described later [10].
Conductivity is a measure of electrical conduction
and thus a measure of the ability of a material to
pass a current. Generally, materials with conductiv-
ities less than 108 S/cm are considered insulators,
materials with conductivities between 108 and
103 S/cm are considered semiconductors, and mate-
rials with conductivities greater than 103 S/cm are
considered conductors. Conductivity (s) is the
inverse of resistivity (r) and therefore has the units
of inverse ohms (O1), also known as Siemens (S),
per unit of distance, generally centimeters (i.e.,
S/cm). Resistivity is determined from a material’s
resistance (R), which is often measured using the
4-point probe technique [11].
The 4-point-probe technique involves applying a
constant current (I) across two electrodes at the
surface of a material and then measuring the change
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in potential (V), where V ¼ IR, between another
pair of electrodes. The following equations then
apply:
r ¼ ðR  AÞ=l (1)
rs ¼ ðR  wÞ=l (2)
where r is the bulk or volume resistivity, rs is the
surface resistivity, R is the resistance of a uniform
specimen (also called sheet or surface resistance,
Rs), A is the cross-sectional area, l is the length
between electrodes measuring current, and w the
sample width. Bulk resistivity takes into account
film thickness whereas surface resistivity does not.
For a film having the same width and length (i.e., a
square), surface resistivity is equal to surface
resistance and is usually reported in units of
O/square, simply in reference to the square surface
dimensions. Resistance in O/square (l ¼ w) can be
converted to bulk resistivity by multiplying by
sample thickness. Eqs. (1) and (2) are limited to
square or rectangular films and apply only to thin
films (thickness 5 spacing between electrodes). For
arbitrary-shaped films, the van der Pauw equation
can be used to more accurately calculate bulk
resistivity from measured resistance [11]. Cyclic
voltammetry (CV) is a technique often used in
conjunction with the 4-point probe method to
characterize a material’s redox properties. The setup
for generating a cyclic voltammogram is similar to
the three-electrode configuration for electrochemi-
cal synthesis of CPs, where a CP sample is deposited
on the working electrode. CV cannot be used to
quantitatively measure conductivity, as with the
4-point probe technique, but can be used to assess
whether a material is in fact conductive; this
technique can also provide information on stability
of electroactivity as well as oxidation/reduction
potential and reversibility. CV is also more sensitive
and thus can be used to gauge electroactivity of less
conductive materials.
Doping is the process of oxidizing (p-doping) or
reducing (n-doping) a neutral polymer and provid-
ing a counter anion or cation (i.e., dopant),
respectively. Upon doping, a CP system with a net
charge of zero is produced due to the close
association of the counter ions with the charged
CP backbone. This process introduces charge
carriers, in the form of charged polarons (i.e.,
radical ions) or bipolarons (i.e., dications or
dianions), into the polymer (Fig. 4). The attraction
of electrons in one repeat-unit to the nuclei in
*
X X X X X
*
n
electron acceptor
*
X X X X X
*
Polaron
n
electron acceptor
* *
X X X X X
n
Bipolaron
Fig. 4. Introduction of polaron and bipolaron lattice deforma-
tion upon oxidation (p-type doping) in heterocyclic polymers.
X ¼ S, N, or O. A polaron or radical cation is introduced into the
conjugated backbone after the loss of an electron. When
oxidation of the same segment of the conjugated backbone
occurs the unpaired electron of the polaron is lost and a dication
(i.e., bipolaron) is formed.
neighboring units yields charge mobility along the
chains and between chains, often referred to as
‘‘electron hopping’’. The ordered movement of these
charge carriers along the conjugated CP backbone
produces electrical conductivity. The smaller the
band gap (i.e., distance between conducting band
and valence band) energy for a CP the more
conductive it is considered to be. Fig. 5 illustrates
the change in band structure of PPy and PT
subsequent to doping. There are many factors that
influence this band gap and thus conductivity,
including dopant, oxidation level/doping percen-
tage, and synthesis method and temperature, there-
fore there are often discrepancies among results
presented by different research groups [10,12–14].
The reader is referred to Heeger [15,16] and Bredas
[17] for detailed explanations of conductivity
mechanisms.
Doping can be performed chemically or electro-
chemically and is dependent on oxidation potential.
The oxidation potential of oligomers decreases as
the number of monomers in the chain increases;
therefore during electrochemical synthesis doping
occurs as polymerization proceeds because the
oxidation potential for doping the CP polymer is
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Fig. 5. The valence-effective Hamiltonian band structure evolution of PPy (top) and PT (bottom) upon doping. PPy (top): (A) undoped
and (B) intermediate doping level. Formation of non-interacting bipolarons at 0.45 eV above the valence band (VB) and 0.9 eV below the
conductive band (CB). (C) 33% doping level (experimentally obtained with electrochemical doping). Formation of bipolaron bands with
width of 0.25 eV. (D) 100% doping level per monomer. Merging of bipolaron bands with VB and CB. Note the decrease in band gap from
4 to 1.4 eV. Adapted from [17]. PT (bottom): (A) undoped. (B) 0.1% doping level with polaron states in the gap. (C) Few (1–20%)
percent doping level, with the formation of non-interacting bipolarons at 0.61 eV above VB and 0.71 eV below CB. (D) 30% doping level,
where the bipolaron states overlap and form two bands. (E) Hypothetical 100% doping level, with quasi-metallic behavior. Adapted
from [10].

lower than that required for polymerizing the CP.
Conductivity can be augmented by increasing
the doping percentage and varying the dopant
(Table 3). The chemical nature of the dopant not
only affects electroactivity, but also affects surface
and bulk structural properties. In addition, small
and large dopants can both modulate electrical
conductivities and surface structural properties, but
larger dopants, such as hyaluronic acid (HA), can
change polymer density and more dramatically
affect characteristics such as surface topography
and physical handling properties [18].
When CPs are doped, the reactive species used to
dope the CP oxidizes or reduces the CP and leaves
behind an anion or cation, respectively. The reactive
species is sometimes, but not always, the same as the
dopant counter ion left behind. For instance, in the
case of doping with I2, the dopant is I 
3 or I5 and
when FeCl3 is used as a reactive species, Cl or
FeCl4 is the dopant, whereas doping with BF4
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Table 3
Doping levels and conductivities of a variety of CPsa

Polymer Dopant (X) Structure Conductivity (S/cm)

Polypyrrole (PPy) CF3SO

3 (C4H3N)X0.3 150 (film)
10 (pp)
ClO
4 (C4H3N)X0.3 100 (film)
Polythiophene (PT) SO3CF
3 (C4H2S)X0.3 10–20 (pp)
None (C4H2S)X0.01 1.5  107 (pp)
BF 
4 or PF6 (C4H2S)X0.06 0.02 (pp)
Poly(3-methylthiophene) SO3CF
3 (C5H4S)X0.3 30–50 (pp)
SO3CF
3 (C5H4S)X0.5 100 (pp)
None (C5H4S)X0.005 107 (pp)

PF6 (C5H4S)X0.12 1 (pp)
Poly(3,4-dimethylthiophene) SO3CF
3 (C6H6S)X0.3 10–50 (pp)
Polyfuran SO3CF
3 (C4H2O)X0.3 20–50 (pp)

Polyazulene ClO4 (C10H6)X0.25 102–101 (pp)

Film: electrochemically polymerized films; pp: pressed pellet from chemically synthesized powder.
a
Adapted from [9].

generates BF 4 counter anions. CPs can be doped
with a variety of molecules, such as small salt ions,
peptides, or polymers, including polysaccharides
and proteins. Chloride anions are commonly used
to dope CPs because of their biological compat-
ibility, generating, for example, oxidized PPy doped
with chloride (i.e., PPyCl). To incorporate mole-
cules that are not capable of redox chemistry, such
as most biological dopants, it is necessary to
synthesize/dope CPs electrochemically. The biolo-
gical molecule to be used as a dopant must be
charged and present in solution with the CP
monomer as electrochemical polymerization occurs.
Alternatively, the biological molecule can simply be
entrapped in the presence of another dopant during
synthesis.
It should be noted that large molecule dopants
(e.g., poly(styrene sulfonate) (PSS), high-molecular-
weight HA) are to some extent physically trapped
and thus more stably integrated in the CP. These
large biomolecules are not as readily leached out or
exchanged under normal conditions or under
application of an electrical potential. Small dopants,
however, can more easily diffuse out of the CP and
can be exchanged with other ions within the
surrounding environment. Thus, CP properties
(e.g., volume) can be regulated via the dynamic
doping and de-doping process which occurs during
oxidation and reduction of the CP.
The reader is referred to the two-volume Hand-
book of Conducting Polymers [15], which provides
a comprehensive review of the fundamental char-
acteristics of CPs, including their synthesis and
electroactive properties.
4. Use and modification of conducting polymers for
biomedical applications
CPs have electrical and optical properties similar
to those of metals and inorganic semiconductors,
but also exhibit the attractive properties associated
with conventional polymers, such as ease of synth-
esis and processing [16]. This unique combination of
properties has given these polymers a wide range of
applications in the microelectronics industry, in-
cluding battery technology, photovoltaic devices,
light emitting diodes, and electrochromic displays
(reviewed in [19]), and more recently in the
biological field. Research on CPs for biomedical
applications expanded greatly with the discovery in
the 1980s that these materials were compatible with
many biological molecules such as those used in
biosensors. By the mid-1990s CPs were also shown,
via electrical stimulation, to modulate cellular
activities, including cell adhesion, migration, DNA
synthesis, and protein secretion [20–23]. Specifically,
many of these studies involved nerve, bone, muscle,
and cardiac cells, which respond to electrical
impulses. Most CPs present a number of important
advantages for biomedical applications, including
biocompatibility, ability to entrap and controllably
release biological molecules (i.e., reversible doping),
ability to transfer charge from a biochemical
reaction, and the potential to easily alter the
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electrical, chemical, physical, and other properties
of the CPs to better suit the nature of the
specific application. These unique characteristics
are useful in many biomedical applications, such as
biosensors, tissue-engineering scaffolds, neural
probes, drug-delivery devices, and bio-actuators
(Table 4).
Other electroactive materials, in addition to CPs,
have been used in biological applications. For
example, electrets (materials with a quasi-perma-
nent surface charge provided by trapped charge
carriers) and piezoelectric materials (materials
which generate transient electrical charges under
mechanical deformation) have been used in tissue
engineering as nerve conduits [24,25]. Metals and
semiconductors such as gold, iridium, and silicon
have been used in neural probes and sensors [26,27].
However, CPs exhibit many advantages over these
materials. In comparison, CPs are inexpensive, easy
to synthesize, and versatile because their properties
can be readily modulated by the wide range of
molecules that can be entrapped or used as dopants.
In addition, CPs permit control over the level and
duration of electrical stimulation for tissue engi-
neering applications, a limitation of electrets. CPs
can also be tailored to create substrates with high
surface area, a key aspect to decreasing impedance
in neural probes. In particular, CPs can have as
much as 50 times the surface area of bare iridium
electrodes [28]. Furthermore, CPs can be precisely
deposited on metal electrodes for biosensors, and
can be intimately interfaced with biomolecules for a
more effective transduction mechanism [29].
4.1. General modification strategies for conducting
polymers
As already mentioned, CPs offer many advan-
tages over other materials, with electrical activity
being the most attractive property. However, there
is always the desire to further optimize a material
when targeting a specific application. The two
common properties desired for all biomedical
applications, aside from conductivity, are biocom-
patibility and redox stability, but beyond these
needs, CP modification tends to be specific for the
application. In particular, most research has
focused on biological and physical modification of
CPs. For biosensors, it is important to tune the
hydrophobicity, conductivity, and reactive function-
alities for modification of CPs to successfully
incorporate biomolecules and to improve detection
883
of binding events. For tissue engineering, CP
properties including biomolecule functionalization,
surface roughness, hydrophobicity, three-dimen-
sional geometry, redox stability, and degradability
are critical. Neural probe applications require
materials with high surface area, hydrophobicity,
and cell specificity to improve and maintain good
signal-to-noise ratio for detection of neuron signals.
A popular strategy for optimizing the biological
properties of a CP is the incorporation of bioactive
molecules. This can be achieved through a number
of techniques, including physical adsorption, en-
trapment, doping, and covalent attachment of
desired biomolecules (Fig. 6). Physical adsorption
is straightforward, but the adsorbed molecule can
dissociate and render the material ‘‘inactive’’.
Another non-covalent method is entrapment, which
can be achieved by having the desired molecule
present in the monomer/electrolyte solution during
synthesis. The process of doping CPs, necessary to
induce conductivity, can also be exploited to modify
CPs non-covalently and to introduce new properties
for a desired application. The range of possible
dopants is vast as long as the selected dopant is
charged. Alternatively, covalent methods can be
used to more permanently functionalize CPs. The
monomer can be synthesized with desired functional
groups and then polymerized. Post-polymerization
covalent modification is also possible, but is more
challenging for insoluble polymers. It is important
to note that the steric effects of any incorporated
functional group may disrupt the planarity of the
conjugated system, which could in turn decrease
conductivity. Functionalization of CPs with differ-
ent biomolecules has allowed biomedical engineers
to modify CPs with biological sensing elements,
and to turn on and off different signaling pathways
to create CPs that enhance adhesion and prolifera-
tion of a variety of cell types and improve their
biocompatibility.
It is just as important to consider physical and
electrical properties of CPs as their chemical
composition. For example, many CPs are crystalline
and have limited porosity. To overcome the draw-
backs associated with crystalline materials there
have been efforts to coat some CPs with or
covalently tether CPs to a more malleable material,
such as a polyester (e.g., poly(lactic-co-glycolic acid)
(PLGA)). In general, manipulation of CP properties
(e.g., roughness/topography, porosity, hydrophobi-
city, mechanical strength, malleability, degradabil-
ity, redox stability, conductivity) can be achieved
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Table 4
Conducting polymers in biological applications

Application Description of Advantages of Limitations of Polymers currently explored [Ref]

application conducting conducting
polymers polymers

Tissue engineering Biocompatible,  Biocompatibility  Not  PPy and derivatives

biodegradable  Good biodegradable [18,22,23,106,129,130,131,133–140,
scaffolds containing conductivity  Not highly 146,147,151–154,159-162]
stimuli to enhance  Possible porous  PANI [171–175]
tissue regeneration modification to  Hydrophobicity  PT and derivatives [176]
include chemical  Novel CPs [177]
cues

Neural probes Implantable  Biocompatibility  Decreased  PPy [28,132,178–181]

electrodes for  Good electrical contact  PEDOT [183–186]
recording or conductivity at interface
stimulating neurons,  Good stability
primarily in the brain  Electrochemical
synthesis on
metal electrodes
 Increased surface
area (decreased
impedance)

Biosensors Devices containing  Ability to entrap  Hydrophobicity See Table 5

biomolecules as biomolecules in can denature
sensing elements, films entrapped
integrated with  Possible surface proteins
electrical transducers modification  Diffusion barriers
 Efficient electric for entrapped
charge transfer enzymes
from bio-
reactions
 Electrochemical
synthesis on
metal electrodes

Drug Delivery Devices for storage  Ability to entrap  Hydrophobicity  PPy [190]
and controlled biomolecules can denature  PEDOT [189]
release of drugs  Controlled entrapped
release with proteins
reduction  Rapid release

Bio-actuators Devices to create  Biocompatibility  Short-term redox  PPy [193–195,197,198]

mechanical force that  Good stability  PANI [196,198,199]
could be used as conductivity  Delamination of  Polymer-carbon nanotube
‘‘artificial muscle’’-  Can control CP films composites [196,198]
type actuators dopant uptake/  Response limited
release (control by ion mobility
volume)
 Lightweight
 Work at body
temp. and with
body fluids

via previously mentioned chemical means, such as functional groups into the CP backbone that
the incorporation of molecules as dopants or via may, for example, increase conductivity or permit
entrapment, or through covalent insertion of degradation. Micropatterning and modification of
 ARTICLE IN PRESS
N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921 885

Fig. 6. Examples of modification strategies used with conducting polymers. CPs have been modified chemically and physically using a
number of approaches as a means to change conductivity, bioactivity, and physical topography/geometry. A few common modification
approaches are depicted, including non-covalent chemical methods (molecule entrapment and adsorption), covalent chemical conjugation,
and micropatterning using standard lithography techniques.

synthesis parameters, such as using surfactants and Analyte

regulating temperature and deposition charge for
electrochemical synthesis of CPs, are strategies that
have also been used to successfully manipulate Sensing
element
several physical properties. Biochemical
CPs have thus far proven straightforward to Transducer Signal
modify, like other polymers. However, it is difficult (CP) Electronic
to compare modified CPs from different research signal
groups because of the large number of techniques
Electronics
available for modifying CPs, which result in little
consistency from one investigation to the next. Fig. 7. Schematic of a biosensor. A biological sensing element
Although a wide range of CP variants has been (e.g., enzyme, antibody) detects a specific analyte producing a
explored for a number of applications, as described biochemical signal that is transferred to the transducer (e.g.,
conducting polymer), which ultimately produces a digital
in more detail below, considerable research remains electronic signal that is proportional to the amount of analyte
to be performed. present.

4.2. Biosensor applications

The first biosensing device was created by
integrating an enzyme into an electrode [30], and
since that time, much progress has been made in
monitoring and diagnosing metabolites (e.g., glu-
cose, hormones, neurotransmitters, antibodies, anti-
gens) for clinical purposes. A biosensor is composed
of a sensing element (i.e., biomolecule) and a
transducer [29]. The sensing element interacts with
the analyte of interest producing a chemical signal
that is transmitted to the transducer, which ulti-
mately transforms the input into an electrical signal
(Fig. 7). CPs are extensively used as transducers that
integrate the signals produced by biological sensing
elements such as enzymes (Table 5). Depending on
how the chemical signal is sensed and transmitted,
biosensors can be divided into several categories:
amperometric (measures current), potentiometric
(measures potential), conductometric (measures
change in conductivity), optical (measures light
absorbance or emission), calorimetric (measures
change in enthalpy), and piezoelectric (measures
mechanical stress) (reviewed in [29]).
The most common types of transducers are
amperometric and potentiometric. An ampero-
metric biosensor measures the current produced
when a specific product is oxidized or reduced (e.g.,
redox reaction of a substrate in an enzyme) at a
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Table 5
Examples of biosensors using conducting polymersa

Analyte (sensing element) Types of sensor Polymers explored [Ref.]

Glucose (glucose oxidase) Amperometric  PPy [20,21,49,51–54,56,105]

Potentiometric  PANI [68,216,217]
 PT [68,87]

Cholesterol (cholesterol oxidase/esterase) Amperometric  PPy [63,218,219]

 PANI [104]

L-lactate (lactate oxidase/dehydrogenase) Amperometric  PPy [220]

 PANI [221,222]
 PT [88]
Urea (urease) Amperometric  PPy [40,41,223]
Potentiometric
Conductometric
DNA (DNA hybridization) Amperometric  PPy [50,64–67,78,79,81–84]
Gravimetric  PT [90,91]

a
Modified from [28].

Substrate Product of NH3, which interacts with PPy to produce an

Enzyme
Conducting Conducting
Polymer Polymer
(oxidized) (reduced)
electrons
Measures
current
Fig. 8. Schematic of electron transfer in an amperometric
biosensor. An enzyme catalyzes a redox reaction of a specific
analyte, which results in the reduction of the conducting polymer
(transducer) and the measurement of a current.
constant applied potential [29] (Fig. 8). The CP
mediates the electron transfer (e.g., via hydrogen
peroxide) between an enzyme, such as an oxidase or
dehydrogenase, and the final electrode; however, the
exact mechanism is not completely understood [29].
Redox mediators such as ferrocene, viologen,
Prussian Blue, or their derivatives are used to
improve electron transfer from the biochemical
reaction to the CP and therefore improve sensor
sensitivity and selectivity. These redox mediators
can be entrapped, incorporated as dopants, or
chemically conjugated to the monomer [31–39].
Potentiometric biosensors use ion-selective electro-
des as physical transducers. For example, detection
of urea by ureases is performed via the production
electrical signal. This signal could be a product of a
change in pH and the subsequent ion mobility in the
polymer matrix triggered by an equilibration of the
dopants with the free ions in solution [40,41].
A key aspect in biosensor applications is the
integration of the electrical component (i.e., CP)
with the biological recognition components. The
immobilization of bioactive macromolecules in or
on electrically conductive polymers has been exten-
sively explored in an effort to provide intimate
contact between these two elements [29,42–46]. This
section focuses on describing the different available
techniques for the immobilization of biologically
active molecules on CPs. For this immobilization, it
is critical to maintain the activity of the molecules,
increase stability, and ensure accessibility of the
analyte to perform biological events such as
hybridization of complementary oligonucleotides,
antigen–antibody binding, or enzyme-catalyzed
reactions.
Table 6 summarizes the main categories of
immobilization techniques of biological sensing
elements on CPs. Two main classes are distin-
guished: non-covalent and covalent modifications.
Non-covalent modifications include adsorption,
physical entrapment, and affinity binding. Covalent
immobilization includes all techniques that create a
covalent bond between the conducting substrate
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Table 6
Immobilization techniques of biomolecules on conducting polymers for biosensing devices

Immobilization Principles of Advantages Limitations

technique immobilization

Non-covalent techniques
Adsorption Electrostatic forces,  Simple  Biomolecule loss (desorption)
hydrogen bonding, Van over time
der Waal’s forces, etc.  Limited control over
immobilization
 Random orientation on surface
Entrapment Molecule incorporation  Simple  Potential loss of biomolecule
during  Good proximity between activity
electropolymerization elements  Steric and diffusion constraints
 Requires high biomolecule
concentration

Affinity binding High affinity interactions  Control over molecule
such as avidin-biotin orientation
 High accessibility of analytes
 Minimal loss of biomolecule
activity
 Requires pre-immobilization of
one of the affinity molecules
(e.g., biotin)

Covalent techniques
Chemical conjugation Surface chemical reaction  Tighter control over
between functional immobilization
groups  High accessibility of analytes
 Minimal biomolecule loss over
time
 Control over biomolecule
orientation
 Complex
 Conditions are not always
appropriate for biomolecules
 Potential loss of biomolecule
activity

and the biomolecule via functional moieties. Recent
reviews provide multiple examples of these methods
[47,48], in addition to the ones described below.
Physical adsorption is the simplest method of
immobilization and one of the first approaches used
for biosensors. As an example, glucose oxidase has
been adsorbed onto PPy for an amperometric
sensor and was shown to detect glucose over a wide
range of concentrations (2.5–30 mM) using di-
methylferrocene as an electron transfer mediator
[49]. DNA biosensors have also been created using
adsorption techniques. To achieve this, DNA has
been indirectly adsorbed to PPy surfaces via
mercapto-oligonucleotide probe immobilization
onto Au–Ag nanocomposites adsorbed onto PPy
[50]. Although adsorption is simple, controlling the
concentration of the immobilized compound is
difficult and immobilization is not stable because
of the weak non-covalent forces involved, which
decrease the lifetime of the biosensor [48]. Another
drawback is that compound adsorption occurs as a
monolayer, which limits the quantity of sensing
element.
An alternative to adsorption is physical entrap-
ment of the desired biomolecule during electropo-
lymerization, which is one of the most extensively
used techniques. During this process monomer,
dopant, and biomolecules are mixed in a single
solution used for electrochemical polymerization.
This process is usually performed under mild
conditions (i.e., neutral pH, aqueous, low oxidation
potentials) without chemical reactions that could
alter the activity of proteins, and only requires a
single step for both polymerization and molecule
immobilization. For this reason CPs, such as PPy,
are frequently used to entrap biomolecules [46].
Many early applications successfully entrapped
glucose oxidase (GOx) in PPy films [20,21,51,52].
Improvements continue to be made on glucose
biosensors, which also serve as models for other
biosensors. Recent advancements include the GOx-
initiated polymerization of pyrrole to form sensitive
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PPy-coated GOx nanoparticles that act as glucose
biosensors [53], and a PPy-coated ultramicroelec-
trode glucose sensor fabricated using photolitho-
graphy with nA/(mmol L) sensitivity [54]. Wang and
coworkers [55] discovered that the sensitivity of
biosensors utilizing entrapped enzymes is enhanced
with increasing microscopic roughness of the
electrode’s surface; therefore these authors have
targeted high surface area PPy-coated platinum
electrodes. Other enzymes such as horseradish
peroxidase, phosphorylases, polyphenol oxidase
lactate dehydrogenase, and deaminases have also
been entrapped in CP films for biosensors [56–61].
For example, a PANI-derivative polymer was mixed
with polylysine to render it water-insoluble for
aqueous-based biosensors and then subsequently
modified with horseradish peroxidase (via entrap-
ment) [58]. PEDOT has also been used to entrap
enzymes. For instance, the ability of PEDOT
(synthesized by chemical vapor-phase polymeriza-
tion) to shrink to 5% of its original thickness once
washed with ethanol has been exploited to entrap
horseradish peroxidase [62]. Detection of cholester-
ol has been performed in amperometric biosensors
by entrapment of cholesterol oxidase/esterase in
derivatives of PPy and polynaphthalene [63].
Entrapment methods have also been used for
immobilization of antibodies [64] and DNA
[64–67]. Most entrapment methods involve co-
deposition during electrochemical synthesis. An
alternative to this is sol–gel encapsulation, which
has been performed using silica and PT or silica
and PANI to entrap glucose oxidase for glucose
sensing [68].
Entrapment of living cells within CPs has also
been reported in an effort to create novel biosen-
sors. Detection of dopamine was achieved by
entrapment of cells extracted from banana pulp in
PPy films in which the enzyme polyphenol oxidase
catalyzes the conversion of dopamine to quinine
with a corresponding consumption of oxygen [69].
This study was based on the finding that the
browning reaction of the banana tissue was
produced by the conversion of dopamine to quinine
by polyphenol oxidase [70]. In a different study,
whole intact human erythrocytes containing viable
antigens were entrapped within a poly(vinyl sulfo-
nate)- and heparin sulfate-doped PPy electroactive
matrix from which signals were induced directly
using resistometry techniques. These composites of
cells and conductive matrices served as proof-of-
principle for potential biosensors for blood group
determination [71,72], which could eventually be
used by the medical profession to transfuse human
blood and blood products to patients.
Although entrapment is a popular immobilization
technique, it has some important limitations. For
example, the hydrophobic nature of the polymer
compromises the quaternary structure of proteins,
decreasing their biological activity. To overcome
this limitation, new alternatives have focused on
creating more hydrophilic polymers using modified
monomers, such as pyrrole rings with long hydro-
philic chains [73,74]. Also, entrapment methods
require a high concentration of the biomolecule
(0.2–3.5 mg/mL), which is not always available
and increases the cost of the process. Finally, the
entrapment procedure diminishes the accessibility of
analytes to the sensing element and thus affects
affinity complex formation (e.g., antibody–antigen,
hybridization of nucleotides). As a result, other
immobilization techniques, such as affinity binding
and covalent modification, have been explored to
overcome these limitations.
Affinity binding methods are based on immobi-
lizing molecules on the surface of CPs via strong
non-covalent interactions. As a conventional ap-
proach in this category, the use of the avidin–biotin
complex presents advantages over other immobili-
zation techniques because of the extremely specific
and high-affinity interactions between biotin and
the glycoprotein avidin (Ka ¼ 1015 mol–1 L) [75].
This technique allows control over orientation of
the immobilized molecules by adjusting the location
of the binding elements, which increases the activity
and accessibility of the biological sensing elements.
In contrast with conventional grafting, this ap-
proach can also be applied to prepare assemblies
containing multilayers of biological molecules. The
use of an avidin-immobilized biotin association was
achieved by copolymerizing pyrrole monomers with
biotinylated hydrophilic pyrrole monomers with
different poly(ethylene glycol) (PEG) lengths as
spacer arms (Fig. 9) [76]. The amount of anchored
avidin on the hydrophilic PPy was modulated by the
immobilized biotin density and by the length of
the PEG spacer arm linking the biotin moiety to
the PPy backbone. Recently, the biotin–avidin
affinity immobilization technique was utilized in
combination with scanning electrochemical micro-
scopy technology to deposit and functionalize
biotinylated PPy to create biologically active micro-
spot biosensors [77]. The design of complex
biological architectures was further demonstrated in
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O
HN NH

S
N-(CH2)3-(O-CH2-CH2)2-O-(CH2)3-NH-CO-(CH2)4

O
HN NH

S
N-(CH2)3-(O-CH2-CH2)2-O-(CH2)3-NH-CO-(CH2)5-NH-CO-(CH2)4

Fig. 9. Hydrophilic pyrrole-biotin monomers with different lengths of the spacer arms: 1 (13 atoms) and 2 (20 atoms) [76]. Reproduced
from Torres-Rodriguez et al. by permission of Elsevier Science Ltd.

-1

polypyrrole-biotin polypyrrole-biotin/avidin

4 2

Cpbio

-3

Cpbio
Detection - Hybridization Biosensor

polypyrrole-biotin/avidin/ODN-probe Cpbio polypyrrole-biotin/avidin/ODN-probe Cpbio

ODN-target Cpbio

Fig. 10. Schematic of the oligonucleotide (ODN) sensor, ODN sensing and sensor regeneration, where Cpbio and Cp*bio represent the
biotinylated DNA probe and complementary biotinylated DNA probe, respectively [78]. Reproduced from Dupont-Filliard et al. by
permission of Elsevier Science Ltd.

the fabrication of PPy chips (Fig. 10) [78] and PPy allowed the detection of hybridization events. Thio-
nanowires [79], in which the successive immobiliza- phenes have also been biotinylated and incorporated
tion of avidin and biotinylated oligonucleotides into CPs used for biosensors, which rely on a
 ARTICLE IN PRESS
890 N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
transduction mechanism induced by the binding of
avidin to produce a change in polymer electroactivity.
In particular, avidin has been detected by drastic
changes in the cyclic voltammograms of the polymer,
which is attributed to the bound protein blocking ion
motion [80].
There are other affinity binding molecular com-
plexes, similar to the avidin–biotin complex, that
have been explored for the immobilization of DNA
to CP surfaces. Cosnier et al. [81] developed a
unique intercalator (i.e., a molecule that inserts itself
into double-stranded DNA)-based immobilization
technique to amperometrically detect single-
stranded DNA. Target DNA strands are detected
when they form DNA duplexes with labeled DNA
probes and are subsequently immobilized by the
affinity binding of the intercalator, which is
covalently bound to PPy. Not only can these PPy
surfaces be used for the detection of any single-
stranded DNA, but detection limits are very low
(1 pg/mL). Alternately, a label-free DNA biosensor
detects hybridization based on the electrostatic
changes in the ion-exchange kinetics at a PPy-
coated microelectrode surface. Pyrroles functiona-
lized with a phosphonic acid group are grafted
to the PPy surface so that DNA probes can be
immobilized via electrostatic complexation of the
DNA phosphate group with phosphonic acid
groups via magnesium cations. In addition to
having low detection limits, these sensors offer
label-free detection and can be regenerated for
repeated use [82].
An attractive alternative to affinity binding for
biomolecule attachment involves the introduction of
appropriate functional groups into CP backbones
or the surface modification of the polymers,
followed by covalent bonding (i.e., grafting) of
bioactive macromolecules to the surfaces. In com-
parison to adsorption, entrapment, and affinity
binding immobilization, this approach is typically
more robust and stable to external environmental
factors, allows high loading, and increases biosensor
lifetime; however, it is usually more complex and
sometimes requires reaction conditions not suitable
for biomolecules. Compared to entrapment meth-
ods, surface chemical conjugation increases the
accessibility of the analytes and enhances the
formation of affinity interactions.
Conducting copolymers containing covalently
substituted monomers have been fabricated as a
means to facilitate the immobilization of biomole-
cules. One strategy for this type of immobilization is
to functionalize CP monomers prior to polymeriza-
tion. For example, copolymers of PPy and oligo-
nucleotides bearing a pyrrole group have been
reported for DNA sensors [83,84]. Other copoly-
mers have been formed with monomers functiona-
lized with amine or carboxylic acid groups, which
subsequently react with functional groups on the
biomolecules to be immobilized. As an example,
immunosensors for detecting Listeria monocyto-
genes were created by covalently binding the
Listeria monoclonal antibody to a copolymer of
carboxylic acid-functionalized PPy and regular
PPy [85,86]. Carboxylic acid-functionalized PT has
also been developed and used for glucose oxidase
and lactate oxidase immobilization [87,88]. A novel
use for carboxylic acid substituted PT is P-amino-
phenyl-a-D-mannopyranose immobilization, which
binds selectively to several viruses. Therefore this
novel glycoPT can be used to detect viruses [89].
Protection of electron withdrawing functional
groups, (e.g., carboxylic acid), on monomers is not
uncommon because they hinder polymerization.
For example, the protection of carboxylic acid
functionalized thiophene with substituted benzyl
groups facilitated the electrochemical synthesis of a
PT derivative, which later could be used for DNA
immobilization to detect DNA [90]. DNA immobi-
lization on PT has also been achieved via covalent
linkage to sulfonyl chloride functionalized PT,
synthesized through the co-polymerization of
methylthiophene and sulfonamide (protected sulfo-
nyl chloride) functionalized thiophene [91].
Other procedures incorporate activated esters such
as N-hydroxysuccinimide by functionalizing thio-
phene or pyrrole monomers [81,92–94] (Fig. 11). This
functional group reacts with amines in proteins and
other biomolecules under mild conditions. An inter-
esting extension of this type of functionalization was
reported for the formation of PPy nanoparticles for
visual diagnostic assays [95]. In this investigation,
pyrrole and N-succinimidyl ester pyrrole were poly-
merized in the presence of silica nanoparticles, which
were subsequently used for immobilization of human
serum albumin. A more recent approach for chemical
grafting is the use of photo-activated chemistries. For
example, electropolymerization of pyrrole–benzophe-
none polymers has been reported. The benzophenone
group can be activated with UV irradiation after
polymerization for reaction with groups present in
biomolecules (Fig. 12) [96,97].
Another conjugation method is chemical grafting
after polymerization of unmodified CPs. One common
 ARTICLE IN PRESS
N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
Fig. 11. Immobilization of DNA on PPy derivatives with N-hydroxysuccinimide groups. Polypyrrole copolymers functionalized with
ferrocenyl groups and an activated ester reacted with oligonucleotides with a terminal amino group. Upon addition of complementary
oligonucleotide sequences and hybridization, a large modification of redox activity of ferrocenyl groups occurs, which is determined by
amperometric methods [93]. Reproduced from Korri-Youssouri et al. by permission of Elsevier Science Ltd.
BM
C O C
hv OH
BM
C O C O
O O
N
N
POLYMER
n n
ELECTRODE
Fig. 12. Immobilization of biomolecules (BM) on polypyrrole–
benzophenone substrates. The biomolecule is grafted to the
polymer upon UV irradiation [96]. Reproduced from Cosnier and
Senillou et al. by permission of Royal Society of Chemistry.
method for post-CP modification is the use of
glutaraldehyde (often in conjunction with bovine
serum albumin). Glutaraldehyde crosslinking tech-
niques have been used to immobilize enzymes, such
as glucose oxidase, glutamate oxidase, lactate
oxidase, xanthine oxidase, choline oxidase, alcohol
oxidase, uricase, trypsin, and acetylcholinesterase
on PPy [34,36–38,98–103]. Cholesterol esterase,
cholesterol oxidase, and peroxidase have all been
immobilized on PANI using glutaraldehyde cross-
linking as well [104]. Another good example of post-
polymerization covalent modification is the immo-
bilization of glucose oxidase and viologen on PPy
via acrylic acid grafting [105]. Regular PPy sub-
strates were immersed in acrylic acid solutions and
irradiated with UV light. This reaction facilitated
891
the insertion of acrylic acid residues on the surface
of PPy, which introduced carboxylic acid functional
groups used for the subsequent immobilization of
glucose oxidase (Fig. 13). CPs modified in this
fashion retained relatively high conductivity (only
10–50% decrease). These surface-modified poly-
mers typically have higher conductivities compared
to most bulk-modified polymers. For example,
polymers with substituted monomers exhibit a
significant decrease in conductivity (3–5 orders of
magnitude) [106].
Regardless of the immobilization technique em-
ployed there have been efforts to miniaturize
biosensors in the last few years. A couple of
examples of microelectrode biosensors employing
affinity or entrapment immobilization techniques
have been previously discussed. Often these micro-
electrode biosensors are made with surface micro-
machining techniques, but a novel technique
developed by Liu et al. [107] involves consecutive
platinization and pyrrole polymerization on a
silicone substrate. Biomolecules can be immobilized
in a number of ways; however, covalent immobili-
zation was easier and produced better results. The
advantages of this biosensor fabricated with bulk
micromachining technology include its compatibil-
ity with complementary metal oxide semiconductor
(CMOS) technology, smaller sensitive surface area,
lower detection limit, and larger sensitivity per
unit area.
In addition to the methods described above, there
are other novel modifications of CPs for sensing
applications. A recent study described the use of
caffeine-imprinted PPy for a piezoelectric caffeine
sensor [108]. Molecular imprinting techniques were
used by electropolymerizing PPy in the presence
of caffeine and removing the template caffeine
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PPy
C N R1

UV COOH COOH N R (WSC)

+ AAc O

A 40min, 25°C COOH

1 h, 4 °C

O O
H
COOH C N E H2N E C COOH C O C N R1
O O
HN R
COOH 24 h, 4 °C, pH = 7.4 COOH

Fig. 13. Post-polymerization covalent immobilization of enzymes, E, on PPy. (A) Graft copolymerization of acrylic acid (AAc) on PPy
film surface. (B) Preactivation with water-soluble carbodiimide (WSC). (C) Glucose oxidase immobilization on polypyrrole matrix [105].
Reproduced from Cen et al. by permission of Elsevier Science Ltd.

molecules at the end of the polymerization via
washing. This allowed the formation of unique
three-dimensional sites used for the selective recog-
nition of caffeine, a process applicable to the food
and pharmaceutical industries. Following the same
concept of imprinting, polythiophene polymers
modified with zwitterionic, peptide-like side chains
have been used in sensors by imprinting biomole-
cules via electrostatic and hydrogen binding. These
sensors have been tested for both DNA and protein
detection [109]. Another unique biosensor technique
involves coating gold electrodes, upon which
aptamers have been covalently immobilized, with
ferrocene-modified PT. In this instance, the bioac-
tive molecule (the aptamer) is not immobilized
directly to the CP; however, the CP surrounds
the bioactive molecule allowing the CP to act as
an electrical transducer [110]. A similar strategy
was used for the detection of double-stranded
DNA [111].
In other studies, PPy has been polymerized in the
interstitial spaces of a hydrogel containing immobi-
lized enzymes. Because of the highly hydrophilic
environment provided by the hydrogel, the perfor-
mance and characteristics of the biosensor were
greatly improved [112]. More specifically, PPy
hydrogels, such as PPy–alginate [113] and PPy–po-
lyacrylamide [114], have recently been explored to
optimize GOx entrapment, retention, and function.
PPy–alginate gels have also been reported for the
entrapment of algal Chlorella vulgaris cells to detect
algal alkaline phosphatase activity. The alginate
component of the matrix serves to create a more
cell-compatible environment, while pyrrole in-
creased the overall stability of the biosensor [115].
PPy–methacrylate/tetraethylene glycol-based hy-
drogels have also been explored for potential
application in vivo as subcutaneous implantable
biochips to monitor biomolecules, such as glucose
and lactate [102].
Recent advances in carbon nanotubes (CNTs)
include the incorporation of CNTs into a number of
CP-based biosensors. For example, preliminary
studies have been performed exploring the proper-
ties of both PPy/CNT and PANI/CNT devices as
pH sensors [116]. One application used DNA-doped
PPy in conjunction with CNTs for label-free
detection of DNA. In particular, the unique proper-
ties of the PPy–CNTs allowed the detection of
hybridization reactions with complementary DNA
sequences via a decrease in impedance [117].
Alternatively, similar DNA sensors have been
created from a composite of PPy and CNTs
functionalized with carboxylic groups to covalently
immobilize DNA onto CNTs [118,119]. CNTs have
also been incorporated into biosensors as nanotube
arrays onto which enzymes, such as GOx, can be
immobilized along with a CP [120] and as a PPy
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N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
dopant [121,122]. In general, the presence of CNTs
tends to increase the overall sensitivity and selectiv-
ity of biosensors.
4.3. Tissue engineering applications
The development of biosensors has created a
foundation for using CPs in many biological
environments. In fact it was a logical next step to
explore CPs as biomaterials for different cell types
and functions because previous studies had shown
that cells such as fibroblasts, neurons, and osteo-
blasts responded to electrical fields created by
electrets [24,123] or between electrodes in vitro and
in vivo [124–126]. The general CP properties desired
for tissue engineering applications include conduc-
tivity, reversible oxidation, redox stability, biocom-
patibility, hydrophobicity (40–701 water contact
angle promotes cell adhesion), three-dimensional
geometry, and surface topography. However, there
are always exceptions, as described below.
4.3.1. Polypyrrole
PPy was one of the first CPs studied for its effect
on mammalian cells [22]. To date, PPy has been
reported to support cell adhesion and growth of a
number of different cell types, including endothelial
cells [22,127,128], rat pheochromocytoma (PC12)
cells [71,129], neurons and support cells (i.e., glia,
fibroblasts) associated with dorsal root ganglia
(DRG) [130,131], primary neurons [132,133], kera-
tinocytes [134], and mesenchymal stem cells [135].
As previously stated, PPy in its simplest unmodified
form can be synthesized to have a small molecule
anion (e.g., Cl) as a dopant, which generally is not
considered to contribute additional biological prop-
erties to PPy. Although such versions of PPy have
been studied, most research has focused on either
the non-covalent or covalent modification of PPy to
optimize interactions with specific cell types and
other material properties that are important for
PPy’s use in vivo. The reader is referred to an
excellent review on PPy and its interactions with
biological tissues [136].
Several studies have demonstrated cell and tissue
compatibility of PPy in vitro and in vivo. For
example, one of the earlier studies showed that PPy
doped with p-toluene sulfonate (PPyTS) is cyto-
compatible with mouse fibroblasts and neuroblas-
toma cells [137]. In vivo, there is minimal tissue
response to implanted PPy [130,137] and PPy can
support the regrowth of regenerating axons, for
893
example [138–130]. Because the advantage of using
CPs in tissue-engineering applications is the ability
to subject cells to an electrical field, studies have
also addressed cell compatibility when a current or
voltage is applied to PPy [129,137]. Although there
is some evidence of cytotoxicity after long time
exposure to current (e.g., 96 h exposure to 1 mA),
shorter periods of exposure to current have not
been found to have negative effects on cells in
culture [137].
In addition to the biocompatibility of PPy, a
number of studies have shown that electrical
stimulation using PPyTS can modulate cellular
response. Most of these early studies simply relied
on the passive adsorption of biomolecules from
serum or the coating of purified protein solutions to
the surface of PPy. In one of the first studies
performed to assess the suitability of CPs for
sustaining cell growth and controlling cell function,
aortic endothelial cells were cultured on fibronectin
(FN)-coated PPy films and exposed to oxidizing
potentials [22]. Oxidized PPy resulted in cell
spreading, whereas reduction of PPy to its neutral
state caused cell rounding (Fig. 14) and a con-
comitant drop (98%) in DNA synthesis. Despite
the change in cellular morphology, cell viability
(490%) and adhesion were very good on both
oxidized and neutral PPy. Other studies have shown
that electrical stimulation of PPy in its oxidized
form can also be used to modulate cell function
[129]. PC12 cells seeded on electrochemically
synthesized PSS-doped PPy (PPyPSS) films having
a resistivity of 1 kO were found to exhibit a 91%
increase in median neurite length when a positive
potential of 100 mV was passed through the PPy
for 2 h (Fig. 15). These studies demonstrate that
cell growth and function can be drastically en-
hanced at the interface of PPy undergoing electrical
stimulation.
Although very little is known about the effects of
an electric potential and/or an electrical field on cell
activity, it is speculated that reduction of PPy and
electrical conduction through PPy can both affect
cells in several ways. For example, the process of
neutralization of PPy, in which a reducting potential
is applied, causes the expulsion of negative ions in
the case of small dopants or the uptake of positive
ions from the medium in the case of large,
entrapped dopants. For PPyPSS, an uptake of
positive ions such as Na+ from the medium is
speculated to affect several processes, including
protein adsorption and the cell cycle [22]. Along
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894 N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
Fig. 14. Photomicrograph of endothelial cells cultured on
fibronectin-coated PPyTS for 4 h: (A) PPy in native oxidized
state and (B) PPyTs reduced by application of 0.5 V for 4 h
(  700) [22]. Reproduced from Wong et al. by permission of the
National Academy of Sciences.
these lines, the effects of electrical stimulation of
PPyPSS on FN adsorption and thus cell shape and
growth were further elucidated [140]. Stimulation of
these PPy films during protein incubation increased
FN adsorption to these surfaces from both purified
FN and heterogenous serum-containing solutions.
The authors also observed PC12 cell adhesion and
demonstrated that with the aid of electrical stimula-
tion FN adsorption to PPy films could be increased,
producing a surface that subsequently enhanced
neurite extension.
An alternative to adsorbing bioactive molecules
to PPy is the entrapment of such molecules during
electrochemical synthesis either as the dopant or in
addition to the dopant. Recently this technique was
used to entrap large molecules, poly(vinyl alcohol)
(PVA), within PPyClO4 (tetraethylammonium per-
chlorate was the oxidant) [141]. The authors were
able to generate a substrate with high surface area
Fig. 15. PC12 cell differentiation on PPyPSS in the (A) absence
and (B) presence of electrical stimulation. (A) Cells grown for
48 h but not subjected to electrical stimulation are shown for
comparison. (B) PC12 cells were grown on PPy for 24 h in the
presence of nerve growth factor, then exposed to electrical
stimulation (100 mV) across the polymer film. Images were
acquired 24 h after stimulation. Scale bar ¼ 100 mm [129].
Reproduced from Schmidt et al. by permission of the National
Academy of Sciences.
that promoted enhanced PC12 cell adhesion and
proliferation compared to TCPS controls. However,
as commonly seen with the entrapment of large
biomolecules, conductivity of PPyClO4 with PVA
entrapped was decreased 10-fold compared to PPy
doped with toluenesulfonic acid controls. Despite
this decrease its conductivity was still significant
(7 S/cm).
There have also been many studies that
have entrapped biomolecules, such as adenosine
50 -triphosphate (ATP) [142–144] and nerve growth
factor (NGF) [71] in PPy and other CPs for both
drug delivery and tissue engineering applications. In
particular, co-entrapment of NGF and dextran
sulfate, followed by the controlled release of NGF
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upon PPy reduction, was shown to stimulate PC12

cell neurite extension [71]. Very recently a study
found that neurite outgrowth from auditory neu-
rons could be specifically targeted upon electrical
stimulation of PPy entrapping neurotrophin-3 [145].
The dopant introduces new properties into the
material; thus, PPy can be optimized to promote the
growth of different cell types or to induce specific
aspects of wound healing simply by varying the
dopant. For example, HA-doped PPy has been
synthesized and explored for tissue-engineering
applications because of HA’s inherent role in
wound healing and angiogenesis [18]. Conductivity
of electrochemically polymerized PPyHA films was
reported to be greatly reduced (3.08  103 S/cm)
compared to the conductivity of PPyPSS films
(9.25 S/cm). To improve conductivity, PPyHA
bilayer films were fabricated and shown to have
conductivities comparable to PPyPSS (8.02 S/cm).
These films had PSS as the dopant in the bottom
layer (to retain conductivity) and HA as the dopant
only in a thin layer on the top (to provide biological
activity). In vivo studies showed that the PPyHA
bilayer films were biocompatible and promoted
vascularization as a result of the presence of HA
(Fig. 16) [18]. Other studies have also explored
modification of PPy via different dopants, including
doping with dermatan sulfate for increasing kerati-
nocyte viability [134], doping with heparin for Fig. 16. In vivo tissue response to (A) PPyPSS films and (B)
increasing endothelial cell proliferation [127,128], PPyHA bilayer films. Films were implanted in subcutaneous
and doping with laminin-derived peptides to control pouches in rats. Tissues surrounding the material were harvested
neuron and astrocyte adhesion [132]. It is important after 2 weeks, fixed, imbedded and stained with hematoxylin and
to note that both surface topography and conduc- eosin. The heavy black lines in the images are the films. Blood
vessels are denoted by arrows. Scale bar is 100 mm [18].
tivity are often significantly altered when biomole- Reproduced from Collier et al. by permission of John Wiley &
cules are exclusively used as dopants [18,134]. Sons, Inc.
Although large biomolecule dopants are known to
significantly decrease conductivity and have more of
an effect on topography compared to small dopants, technique. This functionalization technique loca-
the exact effects of particular dopants are not very lizes the bioactive molecules at the surface, while in
predictable (Fig. 17) [134]. theory maintaining the bulk properties of PPyPGlu;
Dopants can also be used as intermediate however, it is possible that the dopant (PGlu) itself
‘‘tethers’’ to allow further modification of PPy with reduces bulk conductivity compared to large poly-
biomolecules. A good example of this technique is meric anions containing aromatic rings or small
doping with poly(glutamic acid) (PGlu) to provide a anions. This novel technique is advantageous in that
handle (i.e., carboxylic acid pendant group) for a single material can be used to easily incorporate a
future functionalization [131]. The carboxylic acid range of different biomolecules, including those that
groups on PGlu could be covalently linked using are not charged.
carbodiimide chemistry to any amino group, such as Besides using dopants to modify PPy properties,
those found in polylysine and laminin (Fig. 18). there are other emerging non-covalent approaches to
DRG neurons were observed to preferentially further modify PPy for biomedical applications. For
adhere to and extend neurites on the PPy surfaces instance, one approach to modifying PPy non-
modified with polylysine and/or laminin using this covalently was achieved using a peptide, selected
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0.4

0.2
I / mA

0.0

-0.2

-0.4

-0.6

0.4

0.2
I / mA

0.0
-0.2

-0.4

-0.6
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4
E / V vs Ag/AgCl E / V vs Ag/AgCl

Fig. 17. Topography of thick PPy films as assessed using scanning electron microscopy (SEM) (top) and corresponding cyclic
voltammograms (CVs), indicating electrical activity of the materials (bottom). (A) PPyCl. (B) PPy doped with poly(vinyl sulfate). (C) PPy
doped with dermatan sulfate. (D) PPy doped with collagen (inset: thin film of collagen-doped PPy). A narrow CV spectrum correlates to
decreased electroactivity. Scale bars are 100 mm [134]. Reproduced from Ateh et al. by permission of Mary Ann Liebert, Inc.

from phage display libraries, that specifically binds to
PPyCl [146]. This study demonstrated that the
peptide could be used to modify the PPyCl surface
with the arginine–glycine–aspartic acid (RGD) pep-
tide and promote PC12 cell adhesion in serum-free
media, whereas no cell adhesion was seen on
unmodified surfaces. An advantage to this surface
modification technique is that, in theory, it should not
modify bulk properties such as conductivity and like
the PGlu approach described above, could be used to
modify PPy with a range of different biomolecules
that do not need to be charged.
In addition to non-covalent approaches to
modifying PPy as discussed above, modification
via covalent bonds has also been extensively
explored. Multiple techniques have been reported,
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N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921 897

Fig. 18. (A) Schematic of polypyrrole doped with poly(glutamic acid) (abbreviated as pPy[pGlu] in the figure) followed by the covalent
attachment of polylysine (pLys) and/or laminin (Lmn). (B) Phase contrast and fluorescence images of DRGs adhered to the surface of
pPy[pGlu]-X, where X ¼ 1. pLys, 2. Lmn, and 3. pLys-Lmn. Cell nuclei were labeled with DAPI (blue florescence). All images were taken
at 10  magnification and the 200 mm scale bar applies to all images shown [131]. Reproduced from Song et al. by permission of Elsevier
Science Ltd.
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some of which are described here. Modification of
the b-positions on PPy was achieved by creation of
strong sulfide bonds with cysteines [147,148]. These
cysteines served as ‘‘handles’’ to attach bioactive
molecules via peptide bonds or peptides containing
a terminal cysteine (S) group that could be directly
bound to PPy. In particular, osteoblast adhesion
was enhanced up to 230% on RGDS peptide-
modified PPy surfaces. Covalent modification of
pyrrole at the N-position is another common
method of functionalizing PPy, although this
modification does decrease the conductivity of PPy
more than b substitution [7]. The most prevalent
technique for N-functionalization consists of hydro-
lyzing 1-(2-cyanoethyl) pyrrole to 1-(2-carboxyethyl)
pyrrole [106,149,150]. The carboxylic acid func-
tional groups can be activated for future protein
immobilization with hydroxysuccinimide (NHS) in
the presence of a water-soluble carbodiimide before
[150] or after pyrrole polymerization [106]. For
example, the cell adhesive RGD peptide sequence
was covalently conjugated to the surface of NHS-
functionalized PPyCl [106,151]. Although, as ex-
pected, the conductivity of these films decreased
from 2.81  102 to 4.65  102 S/m, human umbili-
cal vein endothelial cell (HUVEC) adhesion and
proliferation were improved.
Other covalent techniques create covalent bonds
only at the PPy surface, rather than modifying PPy
in bulk. In one of these studies, NGF was surface-
immobilized on PPyPSS (thickness ¼ 200 nm),
using an intermediate photo-crosslinker consisting
of polyallylamine conjugated to an arylazido func-
tional group [152]. On exposure to UV light, NGF
was fixed to the substrate via photoactivation and
non-specific reaction of the arylazido moieties.
Similar levels of neurite extension were observed
for PC12 cells and DRG neurons in the presence of
immobilized NGF compared to positive controls
with soluble NGF. Additionally, electrical stimula-
tion experiments were conducted with the modified
polymer and revealed a 50% increase in neurite
outgrowth in PC12 cells compared to experiments
without electrical stimulation. This novel modifica-
tion of PPyPSS provides both electrical and
biological stimulation by presenting tethered growth
factors and producing only a small decrease in the
material’s conductivity (modified PPy ¼ 9.372 S/
cm; unmodified PPy ¼ 14.572 S/cm), which repre-
sents a major advantage when compared to other
covalent techniques that produce a decrease in
conductivity by orders of magnitude.
In another investigation, HA was attached to
PPyTS via grafting of acrylate groups and silaniza-
tion with amine-containing silanes [153,154]. HA
was subsequently immobilized using carbodiimide
chemistry for the reaction of amine groups from the
grafting procedure with the carboxylic groups from
HA. These studies are similar to the reported
PPyHA films using HA as a dopant [18], described
earlier, but in this approach the authors use a
covalent attachment method at the surface of PPy
to avoid bulk incorporation of HA and to better
preserve conductivity [153,154]. As predicted, this
modification approach resulted in good conductiv-
ity (only a 4–38% decrease, depending on the degree
of functionalization), as well as unaffected mechan-
ical properties of the polymer and increased
hydrophilicity of the surface. An increased hydro-
philicity enhances interactions between the CP and
extracellular matrix components. The authors
found that HA-modified PPy supported PC12 cell
adhesion and when this material was sulfated,
platelet adhesion was reduced in vivo. In general,
covalent surface modifications increase the stability
of the biomolecules and have a minor impact on the
CP conductivity (compared to dopant and entrap-
ment methods).
A great number of studies have focused on
optimizing PPy–cell interactions by the incorpora-
tion of biomolecules, but it is necessary also to
consider other material properties such as redox
stability, mechanical properties, degradability, and
surface topography. In particular, the development
of a PPy analog that would decrease the redox
potential of PPy and render it stable and more
conductive under the oxidative conditions of
biological systems was investigated [155]. PPy not
only has a relatively high oxidation potential and so
is susceptible to polymer breakdown due to over-
oxidation, but there is also a significant amount of
a–b0 coupling, which induces structure disorder that
disrupts electroactivity and is the primary site of
polymer breakdown. PPy derivatives, poly(3,4-
ethylenedioxypyrrole) (PEDOP) and poly(3,4-pro-
pylenedioxypyrrole) (PProDOP), were synthesized
to address this latter issue and were found to have a
good range of conductivities (50 S/cm) and good
oxidative stability in the presence of dithiothrietol
and glutathione.
In addition to fine tuning the electrical properties
of PPy, it is important to consider its mechanical
properties. As noted earlier, unmodified PPy, like
most other CPs, is crystalline and brittle, which does
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N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
not make it an ideal candidate for tissue scaffold
materials. Several research groups have explored in
vitro and in vivo properties of PPy-coated polyester
fabrics. PPy coating of substrates has been achieved
non-covalently by both chemical [156] and electro-
chemical [157] deposition; however, these materials
are susceptible to delamination. Alternatively,
covalent modification of phosphorous trichloride-
activated polyester fabric with N-modified PPy
generates PPy-coated polyester that is much less
susceptible to delamination [158]. As expected, PPy-
coated polyester fabrics are only slightly conductive
(surface resistivity of 104–105 O/square); however,
these materials are flexible and exhibit good in vitro
and in vivo biocompatibility [159–161].
Degradability and surface topography are also
important parameters for interfacing CPs with
cells. The development of a bioresorbable form
of PPy was obtained by electrochemically synthesiz-
ing small, slightly water-soluble PPy chains (1700–
3200 Da), which would enable the gradual erosion
and renal clearance of the polymer to occur in vivo
[162]. The monomer unit of this modified PPy was
functionalized at the b position with either a methyl
ester or a carboxylic acid side chain. The methyl
ester-modified polymer was soluble in organic
solvents and eroded much more slowly (6% mass
loss over 80 days) compared to the carboxylic acid-
modified form, which was insoluble in organic
Fig. 19. SEM images of the surface of PPy nanoparticle-PLA composite membranes with various PPy content: (A) 5%, (B) 7%, (C) 9%,
(D) 17% [23]. Reproduced from Shi et al. by permission of Elsevier Science Ltd.
899
solvents and slightly soluble in water with a
degradation rate of about 27% over 80 days.
Although these novel polymers are not inherently
degradable (i.e., the backbones of the polymers are
not actually cleaved), the ability of the polymers to
erode achieves the same goal. Along similar lines,
other studies have introduced the property of
biodegradation by creating blends of PPy with
degradable polymers such as polylactide (PLA). For
example, PPy nanoparticle–PLA composites were
created and shown to be both degradable and
conductive (resistivity ranging from 2  107–15 O/
square) [23]. Both parameters could be modulated
by varying the amount of PPy in the blend, which
additionally impacted topography (Fig. 19). The
authors found that fibroblasts attached and grew on
the PPy nanoparticle–PLA composites with an
increased viability when stimulated at currents of
10–50 mA. This material offers the advantage of
permitting electrical stimulation at biologically
significant currents, maintaining electroconductivity
for long times (15% of conductivity retained after
1000 h), as well as being both degradable and
biocompatible in vivo [23,163,164].
Several studies have exclusively explored the role
of surface topography for CPs. For example,
admicellar polymerization has been used to precisely
control PPy film thickness and to modulate surface
topography (Fig. 20), thereby influencing mesenchymal
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stem cell adhesion and differentiation to osteoblasts
[135]. In another approach, cellulose fibers were
used as a substrate to generate nanoscale topogra-
phy within PPy [165]. The morphologically complex
nanofeatures of the cellulose were preserved and
transferred to PPy coatings by means of polymer-
ization-induced adsorption. Microfabrication tech-
niques have also been used for creating PPy
topographical patterns that provide contact gui-
dance cues to primary neurons [133]. In particular,
patterning of 1 and 2 mm wide PPyPSS microchan-
nels was obtained using electropolymerization and
electron beam lithography. To demonstrate the
effect of these surface patterns on cells, embryonic
hippocampal neurons were cultured on patterned
PPy and found to polarize (i.e., define an axon)
faster on this modified material, having a two-fold
increase in the number of cells with axons compared
to cells cultured on unmodified PPyPSS (Fig. 21).
There have been other micro- or nano-patterned
CP surfaces created for potential tissue engineering
applications, including three dimensional honey-
comb, porous CP films [166,167] and microsized
circles and microfluidic mimics of the vascular
network [168]. In a slightly different approach,
electrochemical coating of PPy and PPy derivatives
onto metallic surfaces was used as a technique
to impart metallic surfaces with topography and
functionality in the hope of generating more
biocompatible and biofunctional interfaces on
metallic medical implants such as stents [169].
4.3.2. Polyaniline
The exploration of PANI for tissue engineering
applications has progressed more slowly than the
development of PPy for similar applications; how-
ever, recently there has been more evidence for the
ability of PANI and PANI variants to support cell
growth. The cell compatibility of only a few different
cell lines has been explored, including cardiac
myoblasts and PC12 cells. It has been suggested
that perhaps the compatibility of PANI is specific to
particular cells [170]. A handful of strategies have
been explored for the development of PANI with
good biocompatibility, conductivity, and mechanical
properties. These strategies most often involve non-
covalent and covalent techniques, as is the case for
strategies used for PPy modification.

Fig. 20. Representative atomic force microscopy images of PPy thin films made by admicellar polymerization (AP) and chemical
polymerization without surfactant (no SDS) on polystyrene dishes. (A) 20  103 M pyrrole (AP). (B) 35  103 M pyrrole (AP).
(C) 50  103 M pyrrole (AP). (D) 5  103 M pyrrole (no SDS). The vertical scale was adjusted to 1000 nm. The thickness ranged from 35 to
154 nm for 20  103 M (AP), 48–466 nm for 35  103 M (AP), 85–697 nm for 50  103 M (AP), and 46–199 nm for chemical polymerization
without surfactant (no SDS) [135]. Reproduced from Castano et al. by permission of Wiley-VCH Verlag GmbH & Co. KGaA.
 ARTICLE IN PRESS
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Fig. 21. Patterning of PPy to create microchannels for contact guidance of neurons. Phase-contrast (left) and fluorescence (right)
photomicrographs of hippocampal neurons on PPy. (A,B) Cells cultured on 2 mm wide and 200 nm deep PPy microchannels. (C,D) Cells
cultured on unmodified PPy. The green labeling (Alexa 488) corresponds to Tau-1 (axonal marker) immunostaining. Cells polarized (i.e.,
established a single axon) more readily on microchannels than on unmodified PPy. Scale bar ¼ 20 mm. Images are at the same
magnification [133]. Reproduced from Gomez et al. by permission of John Wiley & Sons, Inc.

The demonstration of PANI’s biocompatibility in
vivo has sparked interest in its use for tissue
engineering applications. Studies have assessed the
in vivo response to implants of different oxidation
states of PANI (emeraldine, nigraniline, and leu-
coemeraldine) [171]. In general, there was an
absence of significant inflammation at the implant
sites. There were, however, thin layers of fibrous
tissue encapsulating these unmodified PANI im-
plants and immune response cells (i.e., mast cells)
were observed. There were no signs of abnormality
of muscle and adipose tissues in the vicinity of the
implants. Although this study lacked controls (e.g.,
comparison with acceptable implant materials such
as PLGA) and detailed quantitative assessment of
compatibility, the study nonetheless had promising
results and encouraged further exploration of the
application of PANI in biological systems. Cell
biocompatibility of doped PANI (with HCl) has
been observed in vitro [170]. However, an initial lag
in cell (cardiac myoblast) growth rate was found in
the presence of doped PANI; it was proposed that
this correlated to acid leaching from doped films
and a subsequent decrease in conductivity.
Although a few studies have suggested the
biocompatibility of unmodified PANI, as described
above, there have also been conflicting reports that
demonstrated poor cell adhesion and growth on this
unmodified CP [172]. For this reason, other
methods have been sought to modify PANI to
render it biocompatible while maintaining the
desirable electrical properties of the material.
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Fig. 22. SEM image of PANI films. (A) PANI immersed in N-methylpyrrolidinone (NMP) for 300 s followed by dipping in water. (B)
PANI immersed in 0.03 g/mL Pluronic polymer/NMP solution followed by dipping in water [173]. Reproduced from Li et al. by
permission of Elsevier Science Ltd.

Fig. 23. (A) SEM image of PANI-gelatin blend fibers with ratio 45:55. Original magnification is 5000  . (B) Morphology of H9c2
myoblast cells at 20 h post-seeding on 45:55 PANI-gelatin blend fiber. Staining is for nuclei-bisbenzimide and actin cytoskeleton-
phalloidin; fibers autofluoresce. Original magnification is 400  . (C) SEM images of H9c2 cells cultured on 45:55 PANI-gelatin blend
fibers [175]. Reproduced from Li et al. by permission of Elsevier Science Ltd.

For example, hydrophilicity of PANI has been
modified by a two-liquid adsorptive entrapment of
poly(ethylene oxide)–poly(propylene oxide)–poly
(ethylene oxide) (PEO–PPO–PEO) triblock copolymer.
This technique results in the entrapment of PPO
within PANI, while the PEO ends remain exposed
at the surface (Fig. 22). The exposure of the
hydrophilic PEO segments consequently decreases
subsequent protein adsorption. Because this techni-
que targets the PANI surface, bulk conductivity is
maintained (0.6 S/cm) [173]. Similarly, PANI–
chitosan nanocomposites have been explored to
increase biocompatibility and enhance surface
characteristics [174]. PANI–gelatin crosslinked
composites have been demonstrated to have
good biocompatibility in vivo. In addition, gelatin
has desirable mechanical properties that allow it
to be electrically spun into fibers to generate
three-dimensional scaffolds (Fig. 23) [175]. Varying
the ratio of PANI to gelatin allowed for the
optimization of conductivity and fiber diameter,
where cells were found to prefer smaller diameter
fibers.
The optimization of PANI biocompatibility has
been targeted by covalent modification as well.
There are a number of methods to modify a CP
covalently and thus functionalize the surface;
however, the primary concern is to avoid disrupting
the conductivity of the CP. Graft copolymerization
of emeraldine PANI with acrylic acid was used to
immobilize collagen, which was found to reduce
inflammation in vivo [171]. Direct modification
of the aniline monomer to create a functional
group (methyl chloride) that can be linked to any
amino acid has also been investigated [172]. In
this approach the conjugation of PANI was not
interrupted by the addition of a copolymer and
therefore, the conductivity was better maintained
(4–10 S/cm versus about 10 S/cm for unmodified
PANI). Functionalization of PANI with tryptophan
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N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
was demonstrated with this technique, and resulted
in good PC12 cell attachment, proliferation, and
response to NGF.
4.3.3. Polythiophene and novel conducting polymers
PPy and PANI remain the most extensively studied
CPs for tissue engineering purposes to date, but a few
other CPs have been explored, such as polythiophene
(PT) and novel CPs. In one study, a small library of
polymers consisting of a PT backbone with oligosi-
loxane grafted to the b position of the thiophene rings
was generated [176]. The authors created different PT
homopolymers by varying the chain length of the
oligosiloxane, but they also created copolymers with
oligosiloxane-grafted thiophene and 3-methylthio-
phene. Conductivity of the PT homopolymers
decreased in general as the length of the oligosiloxane
increased (maximum conductivity of 1.7  106
S/cm), but the corresponding copolymers were more
conductive (maximum conductivity of 5  105
S/cm). Unfortunately, these polymers were doped
with iodine, which is toxic to cells. In vitro
biocompatibility studies with human ovarian cancer
cells (HeLa) were only performed on undoped
polymers.
Perhaps the biggest limitation of CPs for in vivo
applications is their inherent inability to degrade.
Thus far two examples of modified PPy have been
mentioned, which attempt to overcome this draw-
back: slightly water-soluble oligopyrrole variants
and PPy nanoparticle-PLA composites [23,162].
Although these PPy variants do not have degrad-
able backbones, they have been designed to be small
enough, such that upon the surface erosion of the
material, the CP can be renally cleared. Rivers et al.
reported an alternative approach in which the CP
backbone was designed to degrade. This CP,
biodegradable electrically conducting polymer
(BECP), was designed to have conducting regions
H O O O
N S
O H
O O
H S S S
Fig. 24. Chemical structures of (A) biocompatible electrically conductive polymer (BECP) and (B) poly(5,5000 -dialcohol-3,3000 -dimethyl-
quaterthiophene-co-adipic acid) (PAMQAA).
903
composed of heterocycles, which were tethered
together by degradable ester linkers (Fig. 24a)
[177]. The goal was to create a polymer that would
be conductive, thus permitting in vivo electrical
activation of cells, and also be degradable, eliminat-
ing the need to remove these scaffolds surgically.
The overlap of conjugated regions would enable
inter and intra ‘‘electron hopping’’ to give rise to
conductivity and the polymer would degrade in the
presence of esterases in vivo. The goal was realized;
however, doping of the polymer to render it
conductive (104 S/cm), was again only achieved
with iodine. Despite this drawback, the undoped
version of this polymer was degradable (Fig. 25)
and also biocompatible in vivo and in vitro [177].
These results were considered promising and cur-
rently research is focused on the synthesis and
characterization of a modified polymer that will be
degradable, more conductive and doped by bio-
compatible chloride anions. A novel polymer,
poly(dialcoholdimethylquaterthiophene-co-adipic acid)
(Fig. 24b), has been synthesized and is currently
being characterized by Schmidt and coworkers.
4.4. Neural probe applications
Many of the advance made in CPs for tissue
engineering applications, particularly with respect
to neurons, are relevant to the development of
optimized neural electrodes. Especially important to
this area of research is the need to intimately
interface electrodes with neural tissue and to relay
signals efficiently between the cells and the elec-
trode, thus integrating the device seamlessly with
the native neuronal signaling network. CPs are
attractive candidates for interfacing electrodes with
neurons because they can achieve high surface area,
helping to promote effective ion exchange between
recording sites and the surrounding tissue. The goal
O
O
OH
N
H O O n
O
S OH
O n
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904 N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
0.6
0.5
esterase (in PBS)
0.4
0.3
polymer + esterase (in PBS)
0.2
0.1
polymer (in PBS)
0 made at 25 1C. This is a significant observation
200 300 400 500 600 700 800
Wavelength (nm)
Fig. 25. Degradation studies of BECP films (3.0 cm  2.2 cm 
2.0 mm) were performed in PBS with and without cholesterol
esterase for 2 weeks. The supernatants of the solutions were
evaluated by measurement of their UV–vis absorption. The
aromatic rings found in the polymer and its degraded species
absorb at 340 nm in PBS and the esterase absorbs at 280 nm. The
supernatant of the polymer+esterase shows a strong absorption
peak at 340 nm compared to the supernatant of the polymer
without the esterase. This demonstrates that BECP is degradable
by enzymes that are known to be secreted during in vivo wound
healing events. Note: The y-axis is reported in absorbance units
(a.u.) [177]. Reproduced from Rivers et al. by permission of
Wiley-VCH Verlag GmbH & Co. KGaA.
is to increase surface area of the recording site, while
maintaining a sufficiently small geometric area to
isolate the action potential from a single neuron. A
larger surface area results in an increase in
capacitance, which corresponds to a decrease in
impedance, thus improving signal-to-noise ratio.
Ideally, a neural probe would maximize neural
signals recorded, minimize noise, maintain high
capacitance, and remain conductive over the long
term. Although PPy is commonly explored for
coating neural probes, more recent studies have
focused on the polythiophene derivative PEDOT
(poly(3,4-ethylenedioxythiophene)) because of its
stable oxidative state and higher conductivity.
4.4.1. Polypyrrole
Similar to research progress in biosensor and
tissue engineering applications, most of the initial
studies exploring the application of CPs to neural
probes focused on PPy. Most CPs explored for
neural probe applications have been modified to
improve neural signal detection. In one study, the
authors designed a neural probe, which could also
be used as a neural scaffold, from PPy doped with
PSS or sodium dodecylbenzenesulfonate (NaDBS)
[178]. This research group was interested in inves-
tigating the effectiveness of an implant specially
fabricated from the electrochemical deposition of
PPy onto a patterned gold template. The dopant
and the temperature at which electrochemical
deposition proceeded were varied. PPy doped with
NaDBS was more conductive than PPyPSS, which
could increase signal transportation from the cells
to the electrode. With regard to temperature, PPy
films synthesized using either dopant but at a lower
temperature (4 1C) were rougher than the same films
because rougher topography correlates to increased
surface area, which would increase signal conduc-
tion by increasing the interface with neurons. In
vitro, neural networks consisting of glia, axons,
dendrites, and synapses were observed for all PPy
films (Fig. 26). In vivo, the implants with rougher
surfaces had increased implant integration and
decreased gliosis compared to controls [178].
PPy augmented with biological moieties may
offer advantages for neural probe applications.
Several studies have focused on doping PPy with
peptides derived from extracellular matrix proteins
including laminin-derived peptides, such as p31
(CDPGYIGSR) [132,179], p20 (RNIAEIIKDI)
[132] and YIGSR-containing sequences (DCDPG-
YIGSR) [180], in addition to FN peptide variants
such as the silk-like polymer having FN fragments
(SLPF) [179], which is a synthetic copolymer
consisting of amino acid sequence blocks of silk
fibroin and the cell attachment domain of FN
(RGD). Careful selection of the bioactive molecule
to be incorporated at the electrode surface is
essential to enhance neuron adhesion and growth
and thereby increase the signal received from
neurons, while simultaneously minimizing astrocyte
adhesion, which would interfere with neuron
signaling.
In one example, a silicon-based, 4-pronged neural
probe was micropatterned with a layer of gold. PPy
doped with either SLPF or laminin-derived non-
apeptide p31 was deposited on the gold recording
sites [179]. Not only did the entrapment of these
peptide sequences enhance cell attachment, growth,
and migration, but at a particular intermediate
deposition time, the surface area and the conduc-
tivity of PPy were maximized. An increase in surface
area (Fig. 27) aided integration of the probe into the
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N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
Fig. 26. PPy surfaces. The surface texture of PPy can be
controlled through electrochemical polymerization temperature.
(A) Smooth morphology when PPyNaDBS is polymerized at
24 1C. (B) Rough morphology when PPyNaDBS is polymerized
at 4 1C. Scale bars are 200 mm. (C) Fluorescently labeled
explanted cortical neurons growing and forming networks on a
PPyNaDBS surface after 21 days. Green: neurons, red: glia, blue:
nuclei. Scale bar is 50 mm [178]. Reproduced from George et al.
by permission of Elsevier Science Ltd.
neural tissue and, along with the increase in
conductivity, this improved signal transportation.
Finally, the authors demonstrated that glial cells
905
preferentially attached to PPySLPF (compared to
gold), and neuroblastoma cells adhered significantly
better to PPyCDPGYIGSR as compared to
PPyCH3COO, further suggesting the enhancement
of electrode-neuron interactions in the presence of
PPy doped with bioactive peptides [179].
This work was extended to monitor in vivo neural
recordings from DCDPGYIGSR-modified PPy
probes. Even though conductivity decreased as a
result of the entrapped molecules within PPy,
impedance values were still low enough to detect
neural activity one week after neural probe im-
plantation. Unfortunately, the PPyDCDPGYIGSR
coating was not sufficient to prevent gliosis after
two weeks of implantation and further work is being
performed to minimize astrocyte and fibroblast
encapsulation of neural probes [180].
Further efforts to optimize cell attachment to PPy
neural probes have been made. A study comparing
PPy doped with two different laminin sequences or
both of these laminin sequences together was
performed to optimize neural interfacing [132].
The p31 laminin fragment is known to promote
cell binding, whereas the p20 laminin fragment
specifically promotes neurite initiation and out-
growth. As expected, neuron density was greatest on
laminin-doped controls, with the combination of
p31 and p20 dopants giving rise to the second
highest neuron density compared to PPy doped with
p31 or p20 individually. Neurites extended equally
well on PPy doped with p20 and PPy doped with
both p31 and p20. Although these laminin-modified
PPy surfaces exhibited lower astrocyte cell adhesion
compared to gold surfaces, there was a larger
number of astrocytes versus neurons adhered to
the laminin-modified PPy (Fig. 28). Consequently,
the optimization of this system is still in progress
with more recent work having been directed toward
gaining finer control over neuronal signal detection
[Stauffer and Cui, personal communication, 2006].
Just as positive cues can be entrapped in PPy
electrodes, these investigators have found that
detectable neuronal waveforms can be inhibited
with the entrapment and release of an antagonist
of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro-
prionic (AMPA)/kainite receptors from PPy elec-
trodes (Fig. 29).
In addition to modification of the CP with
peptides, deposition of the CP within a hydrogel
network is another attractive strategy to better
integrate the CP with target cells. Hydrogels are
attractive because they are biocompatible, porous,
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Fig. 27. SEM images of PPySLPF-coated electrode sites. From (A) to (D) the deposition time increased, corresponding to a total charge
passed of (A) 0 mC, (B) 1 mC, (C) 4 mC, and (D) 10 mC. The area of the uncoated electrode is 1250 mm2 [179]. Reproduced from Cui et al. by
permission of John Wiley & Sons, Inc.

and can be tailored to possess the mechanical 4.4.2. Poly(3,4-ethylenedioxythiophene)

properties of the surrounding tissue (e.g., brain
tissue), which would create a better electrode–cell
interface. In a recent study, PPyPSS was electro-
chemically grown in alginate gels coated on electro-
des [181]. PPy was found to grow vertically from the
gold patterned surface up through the gel, demon-
strating controlled PPy deposition (to one specific
recording site). This would permit the modification
of each site with different bioactive agents. Increas-
ing deposition time of PPy decreased the impedance
of PPy–alginate blends. At the biologically relevant
frequency of 1 kHz this impedance value (7 kO) after
40 min of deposition was found to be even less than
that of unmodified PPy. Moreover, PPy deposited
within a hydrogel served to increase the surface
area of the PPy film. Optimizing freeze-drying
conditions allowed for control over hydrogel
porosity; larger pores are important for growth of
cells to improve signal transfer and vascularization
of the hydrogel. Overall, these studies demonstrated
that PPy–alginate-coated electrode recording sites
could transport charge as efficiently as uncoated
gold probes [181].
PPy is often the first CP explored for new
applications because it is so well understood;
however, as previously mentioned, PPy is suscep-
tible to irreversible oxidation [155]. In one study,
PPyPSS was found to retain only 5% of its original
charge after polarization for 16 h [182]. Maintaining
a high capacitance over long periods is necessary to
record chronic neural activity. PEDOT has recently
been explored as an alternative to PPy because it is
much more stable to oxidation and more conductive
than PPy. Unlike PPy, PEDOT was found to retain
89% of its conductivity under similar conditions
[182]. Two studies have characterized the electro-
chemical deposition of PEDOT and PEDOT–
MeOH on neural probes [183,184]. Both materials
resulted in improved electrochemical stability and
increased surface area compared to controls, which
lowered impedance. Both forms of PEDOT were
successfully doped with the laminin-derived
DCDPGYIGSR peptide and rat glial cells prefer-
entially grew on PEDOT–DCDPGYIGSR. PED-
OT–MeOH has not been tested in vivo, but the
advantage of using this CP over regular PEDOT is
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N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921 907

Fig. 28. Fluorescence (left) and corresponding SEM (right) images of neurons on different PPy surfaces. (A,B) PPy doped with p31 and
p20. (C,D) PPy doped with p31. (E,F) PPyPSS [132]. Reproduced from Stauffer and Cui by permission of Elsevier Science Ltd.

Fig. 29. A polypyrrole based electrically controlled release system applied in a cultured neuronal network. (A) the arrows indicate
electrodes that have been modified with a PPy film loaded with neurochemical CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a specific
antagonist of AMPA/kainate receptors. CNQX is released directly from the electrodes and affects cells in the nearby region. (B) Neuronal
waveforms recorded near a PPy/CNQX-modified electrode can be seen before release and (C) is not seen after release. (Unpublished work
by William Stauffer and X. Tracy Cui, Bioengineering Department, University of Pittsburgh.)
 ARTICLE IN PRESS
908 N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
that its monomer is more soluble in water, which
would permit polymer synthesis in the aqueous
systems that are necessary for incorporation of
many biomolecules [183,184].
As for PPy-coated electrodes, PEDOT-coated
electrodes require maximum surface area to mini-
mize impedance. Surfactants have commonly been
used in other applications to precisely control
material surface structure; thus, the use of surfac-
tants was recently explored in the synthesis of CP
films on neural probe sites [185]. The authors found
that the surfactant-templated PEDOT surface had a
minimum impedance of 35 kO, which was less than
that of controls (PEDOT and PPy). Additionally,
CV analysis demonstrated that these templated
films had increased charge capacity and were more
electrochemically stable than controls. These im-
proved properties are likely a result of the increased
surface area (as confirmed by SEM imaging)
generated by templating PEDOT. Although poly
(oxythylene)10-oleyl ether surfactant is considered
toxic to cells, careful selection of the surfactant
concentration and proper washing permitted survi-
val of SH-SY5Y human neuroblastoma cells on
templated PEDOT [185].
In a subsequent study, the efficacy of surfactant-
templated PEDOT electrodes for recording chronic
neural activity was compared to that of uncoated
iridium sites over six weeks [186]. Parameters such
as impedance, root mean square noise, signal
amplitude, and signal-to-noise ratio were recorded.
As expected, the PEDOT-coated electrode sites had
lowered impedance, and thus reduced noise and
decreased signal loss, compared to control iridium
sites. Unfortunately, the advantages of reduced
noise and decreased signal loss were mitigated by
encapsulation of the electrode, and thus signal-to-
noise ratios were similar for both PEDOT and
control electrode sites. Future studies are focused
on depositing agents to minimize the immune
response, reduce encapsulation, and induce nerve
growth toward the electrode [186].
4.5. Other applications
In addition to biosensors, tissue engineering, and
neural probes, there are other important investiga-
tions of CPs for biological applications. These
include employment of CPs as drug-delivery med-
iators, actuators, and antioxidants. This section
briefly describes the most representative advances in
these areas. As explained below, many of the drug
delivery and actuator approaches are based on
the reduction of CPs, which triggers expulsion of
ions (i.e., de-doping) and an associated change in
volume [187].
With respect to drug delivery applications,
electrical stimulation of CPs has been used to
release a number of therapeutic proteins and drugs
including, for example, NGF [71], dexamethasone
[188,189], and heparin [190]. An early investigation
demonstrated entrapment and electrically stimu-
lated release of bovine serum albumin and NGF
from PPy doped with polyelectrolytes (e.g., dextran
sulfate) [71]. The use of polyelectrolytes induced
high water content in the CP, allowing an easy
release of the entrapped protein. For this release,
PPy was reduced with negative potential, producing
a rapid expulsion of anions in less than one minute.
The retained activity of the released NGF was
corroborated with a neurite extension assay with
PC12 cells. Although protein entrapment in CPs
often affects the protein’s folding and activity
because of the hydrophobicity of the polymer (as
discussed in the biosensor section), the use of
polyelectrolytes and high water content in this
study might have overcome this limitation.
Another recent study investigated the release of
NGF from PPy by using biotin as a co-dopant
during the electrical polymerization [191]. In this
investigation, NGF was biotinylated and immobi-
lized to streptavidin entrapped within PPy films
doped with both biotin and dodecylbenzenesulfo-
nate. The authors showed that NGF was exclusively
released when PPy was electrically stimulated. In
particular, a 3 V pulse for 150 s resulted in a release
of 22 ng/cm2 of NGF from the surface of the
polymer. The activity of the released protein was
confirmed by observing PC12 cell neurite extension
in the presence of the released NGF. This approach
provides great flexibility in the number and types of
drugs that could be delivered using the conventional
biotin–streptavidin strategy.
The release of heparin from hydrogels immobi-
lized onto PPy films can also be triggered by
electrical stimulation [190]. PVA hydrogels were
covalently immobilized onto PPy films via grafting
of aldehyde groups to PPy and chemical reaction
of these with hydroxyl groups from the hydrogel
(Fig. 30). An accelerated release of heparin from
the hydrogel was reported when PPy was electri-
cally stimulated. The authors discussed various
mechanisms that could influence these results,
including changes in pH as a result of electrolysis,
 ARTICLE IN PRESS
N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
O OH
UV induced graft copolymerization OH
O PEGMA, 28°C, 60 min
O
PPy-PEGMA
Ar plasma
pretreated PPy
25°C, 36 h
Mixture of:
PVA, FA, and HCl
cast
CHO CHO CHO CHO CHO
PPy-CHO 45°C, 6 h
Fig. 30. Controlled release of heparin from poly(vinyl alcohol) (PVA) hydrogels immobilized on PPy. (A) Post-polymerization of PPy to
incorporate aldehyde groups. (B) Covalent immobilization of PVA hydrogels containing heparin on PPy substrates. Controlled release of
heparin was obtained by electrical stimulation of PPy [190]. Reproduced from Li et al. by permission of John Wiley & Sons, Inc.
electrophoresis, changes in temperature, and the
polyanionic nature of heparin.
A recent publication demonstrated the use of CP
nanotubes for drug release, in which PEDOT was
polymerized on top of electrospun PLGA fibers
(100 nm diameter) loaded with dexamethasone
(Fig. 31) [189]. PLGA was subsequently removed to
produce PEDOT nanotubes encapsulating small
molecules. The PEDOT nanotubes released the drug
in a controlled fashion upon electrical stimulation,
probably as a consequence of expansion/reduction of
polymer cavities produced by the expulsion of anions.
The change in volume of CPs upon electrical
stimulation has also been exploited for the devel-
opment of actuators to create both drug delivery
devices [192] and ‘‘artificial muscle’’-type (i.e.,
electrochemical–mechanical) devices. For example,
the actuating properties of CPs have been harnessed
to release drugs from reservoirs covered by thin PPy
bi-layer flaps upon application of a small potential
to the PPy [192]. In artificial muscle applications,
two layers of a CP are placed in a triple layer
arrangement separated by a non-conductive materi-
al, as illustrated in Fig. 32 [193,194]. When current
909
OH Ac2O/DMSO CHO OH
OH OH OH CHO
25°C, 8 h
PPy-CHO
heparin
PPy-PVA-heparin
is applied across the two CP films, one of the films is
oxidized and the other is reduced. The oxidized film
experiences an inflow of dopant ions and an
associated expansion, whereas the reduced film
expels ions and shrinks [193,195]. The combined
effect is translated into a mechanical force that
bends the polymer, which has been compared to the
mechanisms in natural muscles. PPy, PANI, PPy–
PANI composites, and composites of these poly-
mers with carbon nanotubes (CNTs) (e.g., PA-
NI–CNT, PANI–CNT–PPy) have all been explored
for their ability to function as actuators. Of these
materials, PPy–PANI produced the highest work-
per-cycle [196–199]. Also, the addition of CNTs to
PANI fibers was found to increase the electro-
mechanical actuation because the CNTs improved
the mechanical, electronic, and electrochemical
properties of PANI fibers [200]. These types of
devices have potential as actuators for many
biomedical applications, such as steerable catheters
for minimally invasive surgery [201], micropumps
and valves for labs-on-a-chip [202,203], blood vessel
connectors (Fig. 33), and microvalves for urinary
incontinence (reviewed by Smela [204]).
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Fig. 31. PEDOT nanotubes for drug controlled release. (A) Electrospun PLGA fibers are loaded with drug (dexamethasone). (B)
Degradation of PLGA fibers release the drug. (C) PEDOT is electropolymerized around PLGA fibers loaded with drug. (D) After
degradation of PLGA fibers, PEDOT nanotubes are loaded with drug. (E) PEDOT nanotubes do not release drug in a neutral electrical
condition. (F) PEDOT nanotubes release the drug upon external electrical stimulation with a positive voltage, which produces contraction
of the nanotubes and the subsequent expulsion of the drug. (G) SEM image. Electropolymerized PEDOT nanotubes on the electrode site
of an acute neural microelectrode after removing the PLGA core fibers. (H) SEM image. Higher magnification of a single PEDOT
nanotube on a neural microelectrode array [189]. Reproduced from Abidian et al. by permission of Wiley-VCH Verlag GmbH Co. KGaA.

Finally, the ability of CPs to scavenge harmful
free radicals from the environment has recently been
explored as an additional benefit of these materials
in biological applications [205]. In particular,
polymers such as PANI and PPy in their neutral
form were found to react effectively with 2–4 free
radicals per monomer unit. The effectiveness of CPs
to scavenge free radicals results from their ability to
be easily oxidized and therefore does not necessitate
electrical stimulation. The authors of this investiga-
tion highlighted the important role of this special
property of CPs in biomedical applications where
tissues experience high oxidative stress.
5. Challenges and future directions
In roughly 30 years, dozens of CPs have been
discovered and characterized. Thus far only a small
number of these (excluding variants of unmodified
CPs) have been found to be well suited for
biomedical applications. Targeted attributes include
biocompatibility, conductivity, and stability in bio-
logical systems. A number of CPs have yet to be
explored for biocompatibility. Perhaps there is no
need to extend the library of CPs available for
biomedical applications if CPs, such as PPy and
PEDOT, can be modified to generate the ideal CP for
specific biomedical applications. But what is an
‘‘ideal’’ CP, given the target application? Some of
the most significant unanswered questions for apply-
ing CPs to biomedicine are: What is the range of
conductivity necessary for tissue engineering? How
can a specific cell be targeted for adhesion and/or
regeneration? How can neuronal signaling be en-
hanced? How can a CP be made to degrade and still
maintain electroactivity? How can the redox activity
 ARTICLE IN PRESS
N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921 911

PPy PPy PPy PPy

(anode) (cathode) (cathode) (anode)

ClO4- ClO4- ClO4- ClO4-

+ ClO4-
ClO4- ClO4- + ClO4-
+ +
ClO4-
ClO4- ClO4- ClO4-
+
+ ClO4-
ClO4-
ClO4- ClO4-

ClO4- ClO4- ClO4- ClO4-

PPY PPy PPy PPY

(anode) (cathode) (cathode) (anode)

Fig. 32. Schematic of artificial muscle devices. (A) When current is applied, the left PPy film acts as anode and swells by the entry of the
hydrated counter ions. Simultaneously, the right film acts as cathode and contracts by the expulsion of the counter ions. These volume
changes and the constant length of the non-conducting film promotes the movement of the triple layer device. (B) By changing the
direction of current the movement takes place in the opposite direction [194]. Reproduced from Otero et al. by permission of Elsevier
Science Ltd.

and conductivity be preserved in the long term? How
can entrapment of hydrophilic molecules be max-
imized? A more detailed discussion of these chal-
lenges and efforts to overcome them will follow.
5.1. Electrical properties
Two of the more fundamental goals in this field
have been to optimize conductivity and maximize
electrical stability, which would improve biosensing
and neural probe measurements, as well as enhance
tissue regeneration [155]. The issue of CP conduc-
tivity is an especially challenging one because it is
not clear what conductivities should be targeted
given particular conditions. There is, however,
evidence of an upper limit on useful CP conductiv-
ities in order to avoid protein denaturation and cell
death, as well as a lower limit at which little or no
useful conductance effects are seen. These bound-
aries are likely dependent on cell type and applied
current or potential. Although these boundaries
generally remain undefined, it would be of great
benefit to the biomedical community to explore/
define them for particular applications involving
CPs. It can be stated, however, that CP conductiv-
ities ranging from 104 to 9 S/cm have been found
to enhance cell growth to varying extents (see tissue
engineering section), albeit parameters in each
instance are rarely held constant. When considering
the effects of CP conductivity it must be recalled
that the current or potential applied to the CP can
be varied and also contributes to the field effects
that cells and proteins experience in the presence of
a CP. Therefore, it is not surprising that there seems
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Fig. 33. PPy blood vessel connector insertion surgery. (A,B) A
PPy–Au bilayer device in the reduced state is curled into a roll
that is inserted half-way into one of the ends of the severed blood
vessel. (C,D) The other half of the device is inserted inside the
other end of the vessel and the bilayer expands a few minutes
after PPy is oxidized. The PPy tube holds the two parts of the
blood vessel together during healing, which replaces sutures. The
connector is non-thrombogenic and very thin to avoid restricting
the space inside the blood vessel [204]. Reproduced from Smela
by permission of Wiley-VCH Verlag GmbH Co. KGaA.
to be an optimal current or potential range to
maintain cell viability. For instance, Shi and co-
workers reported that fibroblast viability is max-
imized at currents between 10 and 50 mA for a
PPy–PLA composite (3% PPy) with resistivity of
1  103 O/square [23]. Optimization of a CP’s
conductivity for a particular application is an issue
that begs attention on many levels.
With regard to biosensors, it is essential to
increase the charge transfer (i.e., conductivity) and
electrical wiring between enzymes and the CP.
Common redox mediators such as ferrocene are
typically used as counter ions during polymeriza-
tion, but these compounds suffer from poor
stability. To overcome this limitation, the function-
alization of pyrrole monomers with ferrocene and
viologen groups has been studied, but some of these
monomers are difficult to electropolymerize, and as
a result copolymerization with regular pyrrole is
sometimes necessary.
In addition to charge transfer mechanisms, other
transduction mechanisms, such as conductimetric,
impedimetric, or optical mechanisms, have been
investigated. For example, impedance spectroscopy
has been used to monitor the change in capacitance
of PPy films on biological events such as anti-
gen–antibody binding [206]. As another example,
PPy films doped with CNTs functionalized with
oligonucleotides have been successfully implemen-
ted for DNA biosensors using direct impedance
measurements [117]. Optical biosensors measure the
amount of light absorbed or emitted as a result of a
biochemical reaction, and these devices can be
directly coupled to fiber optics. As an illustration
of this approach, biotinylated PPy was polymerized
on an indium tin oxide (ITO)-coated optical fiber
and used for binding avidin and biotinylated
peroxidase; detection was performed via chemilu-
minescence [207]. In another approach, a PT variant
is used as an optical transducer. DNA hybridization
can be detected via fluorescence measurements as a
result of the inherent physical interaction of this PT
variant with double-stranded DNA versus single-
stranded DNA, which brings about a change in
fluorescence. This detection system results in very
low detection limits (1021 M) from large sample
volumes [208,209]. The development of methods to
improve the transduction mechanism for biosensor
applications continues to be an active area of
research.
Maximum conductivity is also critical for tissue
engineering and neural probe applications. For
instance, several studies have attempted to maintain
conductivity while attempting to preferentially
target a specific cell type through the incorporation
of bioactive peptides. For instance, laminin peptides
have been incorporated into PPy to target neural
cells and not astrocytes, which are associated with
undesired glial scar formation [132,179,180]. Un-
fortunately, these materials are not selective enough
for neurons and over time the neural signal
decreases. Such decreases in conductivity continue
 ARTICLE IN PRESS
N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
to be a challenge in neural probe applications as
well as in tissue engineering applications as a result
of non-specific cell encapsulation, the entrapment of
large molecules, and the oxidizing biological envir-
onment, which all interfere with conductivity.
Recently, Martin and coworkers proposed a novel
method of bypassing the insulating scar tissue that
forms at device–tissue interfaces [210]. This method
consists of in situ polymerization of ethylenediox-
ythiophene around living neural tissue to form an
electrically conducting PEDOT network which
branches from the electrode out into the extra-
cellular space where it is in intimate contact with
cells. This technique is still in the early stages of
development, but it offers a biocompatible method
for integrating electrodes into a target tissue such
that conductivity is maintained.
The electrical properties of CPs make them
exceptionally promising materials for use in bioac-
tuator applications. CP-based actuators can be
electrically controlled, require low voltage (less than
1 V), can be continuously switched between max-
imum and minimum strains, and can work with
liquid electrolytes, such as body fluids; however,
there is still a need to increase ion mobility in the
polymers to achieve faster responses.
5.2. Biological and physical properties
The hydrophobicity of CPs is a major limitation
for successfully entrapping proteins and maintain-
ing their bioactivity, which is particularly critical for
biosensors and drug delivery applications. Different
approaches have been studied to overcome this
drawback, including the use of monomers that
contain both redox centers and hydrophilic chains
[31,73,74], blends with polyelectrolytes [71], and
composite devices containing hydrogels and CPs
[112,211,212].
Surface properties are critical for tissue engineer-
ing and neural probe applications, in which the
goal is to promote the attachment of specific subsets
of cells. However, it is still not clear what the
desirable properties, such as slight hydrophobicity,
surface roughness, and conductivity, are for optimal
growth of certain cells. Some studies suggest that
desired properties are specific to cell type, but
additional studies need to be performed, holding
more parameters constant, to determine a set of
guidelines for different cell types. As the modifica-
tion of CPs continues to diversify their properties,
913
more cell types will be analyzed for their interaction
with CPs.
As noted previously, surface area is of great
importance for many biomedical applications. In-
creasing the surface area of a biosensor or neural
probe, for instance, will increase the signal detected
and therefore lower the detection limit. As alluded
to in the application section, CPs already serve to
increase the surface area of inorganic conducting
surfaces; however, there have been great strides to
increase the surface area even further. Currently, the
most common strategy is to electrospin CPs to
create nanofibers, and some applications involving
such surfaces have been mentioned. Nonetheless, it
has been and continues to be a challenge to create
nanofibers from most (unmodified) CPs due to their
insolubility. In an effort to overcome this issue
Chronakis et al. used poly(ethylene oxide) as a
carrier to successfully electrospin PPy [213]. Re-
cently, a novel approach was developed, which uses
V2O5 to initiate PPy or PEDOT nanofiber forma-
tion directly from pyrrole and 3,4-ethylenediox-
ythiophene monomers, respectively [214,215].
Although CPs generally have fairly good mechan-
ical properties, ideally CPs used for tissue engineer-
ing and neural probes would be less brittle, more
malleable, and degradable. Several studies at-
tempted to address the former two challenges by
coating PPy on malleable polyester fabrics; how-
ever, despite improved mechanical properties, con-
ductivity dropped significantly and some delami-
nation occurred over time [158,161]. Other methods
for improving the mechanical properties of CPs
include creating composites or blends and doping
with large molecules that possess the desired
mechanical properties [175]. These processes un-
fortunately result in interference with ‘‘electron
hopping’’ within the CP due to the presence of
insulating molecules. Similar issues arise for the few
attempts that have been made to synthesize
degradable CPs [162,177]. Therefore, improving
mechanical properties of CPs while maintaining
conductivity still remains an important goal.
For bioactuator applications, advantages of CPs
include their strength, their ability to function at
room or physiological temperatures, and that they
can be microfabricated and are lightweight [204].
However, there are important hurdles in this field as
well, beginning with the necessity of a thorough
understanding and modeling of the actuation
mechanism, which would allow a high degree of
control by modifying the CP properties. A key
 ARTICLE IN PRESS
914 N.K. Guimard et al. / Prog. Polym. Sci. 32 (2007) 876–921
technical challenge is the delamination of the CP
from the electrode surface because of continuous
cycling.
6. Conclusion
Conducting polymers (CPs), unlike many other
materials, have uses in a diverse array of applica-
tions ranging from photovoltaic devices to nerve
regeneration. The unique property that ties all these
applications together is the conductivity of the CP.
CPs are organic in nature, making them more likely
to be biocompatible; further, the presence of a
conjugated backbone within the polymer endows it
with the ability to conduct electrons, like metals/
semiconductors, and unlike any other polymer. In
addition to these highly desirable properties, the
ease of preparation and modification of CPs have
made them a popular choice for many applications.
This is especially true in biomedicine, where many
applications benefit from the presence of conductive
materials, whether for biosensing or for control over
cell proliferation and differentiation. Despite the
vast amount of research already conducted on CPs,
for biomedical applications, the field is still growing
and many questions remain to be answered.
Acknowledgments
We would like to recognize Joo-Woon Lee for
initial discussions and ideas regarding the content of
the article. We would like to acknowledge Davidson
Day Ateh, Tracy Cui, Paul Matthew George, Diane
Hoffman-Kim, Robert Langer, Peter Lelkes, Dave
Martin, Tayhas Palmore, Eli Ruckenstein, Vassilios
Sikavitsas, Elizabeth Smela, Gordon Wallace, Joyce
Wong, and Ze Zhang for contributions of figures.
We would also like to thank and acknowledge
Maeve Cooney for assistance with figure copyrights,
schematics, and editing. Finally, we would like to
thank the many members of the Schmidt lab who
provided valuable feedback and input on this
project.
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