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A detailed insight into drug delivery from PEDOT based on analytical
methods: Effects and side effects
Christian Boehler,
1,2
Maria Asplund
1,2,3
1
Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universit€
at, Freiburg, Germany
2
Department of Microsystems Engineering (IMTEK), Albert-Ludwigs-Universit€
at Freiburg, Georges-Koehler-Allee 102,
79110 Freiburg, Germany
3
BrainLinks-BrainTools Cluster of Excellence, Albert-Ludwigs-Universit€
at, Freiburg, Germany
Received 11 February 2014; revised 28 May 2014; accepted 4 June 2014
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.a.35252
Abstract: The possibility to release drugs from conducting
polymers, like polypyrrole or poly(3,4-ethylenedioxythio-
phene) (PEDOT), has been described and investigated for a
variety of different substances during the last years, showing
a wide interest in these release systems. A point that has not
been looked at so far however is the possibility of other sub-
stances, next to the intended ones, leaving the polymer film
under the high voltage excursions during redox sweeping. In
this study we target this weakness of commonly used detec-
tion methods by implementing a high precision analytical
method (high-performance liquid chromatography) that
allows a separation and subsequently a detailed quantifica-
tion of all possible release products. We could identify a sig-
nificantly more complex release behavior for a PEDOT:Dex
system than has been assumed so far, revealing the active
release of the monomer upon redox activation. The released
EDOT could thereby be shown to result from the bulk mate-
rial, causing a considerable loss of polymer (>10% during six
release events) that could partly account for the observed
degradation or delamination effects of drug-eluting coatings.
The monomer leakage was found to be substantially higher
for a PEDOT:Dex film compared to a PEDOT:PSS sample.
This finding indicates an overestimation of drug release if
side products are mistaken for the actual drug mass. More-
over the full picture of released substances implements the
need for further studies to reduce the monomer leakage and
identify possible adverse effects, especially in the perspective
of releasing an anti-inflammatory substance for attenuation
of the foreign body reaction toward implanted electrodes.
V
C2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A:000–
000, 2014.
Key Words: PEDOT, neural electrodes, drug release, dexa-
methasone, HPLC, electrochemical release
How to cite this article: Boehler C, Asplund M. 2014. A detailed insight into drug delivery from PEDOT based on analytical
methods: Effects and side effects. J Biomed Mater Res Part A 2014:00A:000–000.
INTRODUCTION
Electrochemically controlled release from conducting poly-
mer based systems has gained substantial interest, espe-
cially within the field of neural engineering.
1
The proposed
mechanism thereby is that drugs, incorporated in the poly-
mer during synthesis, are released by electrostatical forces,
supported by a mechanical actuation due to interaction of
the polymer with the surrounding electrolyte during redox
cycling.
2–5
Such redox triggered release has been shown for
a variety of biologically relevant molecules, for example
Dex, nerve growth factor, brain-derived neurotrophic factor,
adenosine 50-triphosphate, risperidone and progesterone
2,4–13
and results show that release is influenced by the current
passed over the interface upon redox cycling as well as con-
formational changes in the film associated with the electro-
chemical processes. A detailed description of multiple
polymer based release systems can be found in the excellent
reviews of Svirskis et al.
14
and Pillay et al.
15
What is how-
ever not accounted for in most of the previous studies is
the possibility of other substances leaving the polymer film
as a result of the extensive voltage excursion. The main
methods used to quantify release are ultraviolet (UV)
absorption spectroscopy,
2–5,9,10
electrochemical quartz crys-
tal microbalance (EQCM),
4,16
enzyme-linked immunosorbent
assays (ELISA),
17
and radiometric measurements
18
(see
Table I). Unfortunately, all of these methods have limitations
when it comes to providing the full picture of what is
released from the system.
UV absorption has been successfully proven for the
detection of Dex, with a linear correlation between
absorbance of solution at 245 nm wavelength and concen-
tration of Dex down to 0.5 mg/mL. However, the method
does not discriminate between Dex and other UV active sub-
stances that could possibly be in the solution. EQCM is a
Correspondence to: C. Boehler; e-mail: christian.boehler@imtek.de
Contract grant sponsors: Freiburg Institute for Advanced Studies (FRIAS) and the BrainLinks-BrainTools Cluster of Excellence funded by the
German Research Foundation (DFG, EXC 1086)
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
V
C2014 The Authors. Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc.
highly precise method for quantifying mass changes in the
electrode film. The method is not selective but only presents
the summed up mass for substances leaving the electrode
which in principle can be anything from complete polymer
fragments to ions of the supporting electrolyte. Further-
more, alterations of viscoelastic properties of the film upon
redox cycling might add to changes in the frequency as
observed by Efimov et al.
19
which could further impair the
measurement. Using ELISA and radiometric labeling makes
it possible to truly single out the release of the intended
molecule from any background signal in the solution. On
the other hand, also these methods overlook the possibility
of by-products leaving the polymer as a result of
stimulation.
Most studies use a rather broad cyclic voltammetry
sweep range, that is 20.8 V to 1.4 V
2,3
, to drive the
intended drugs into solution. It is not unlikely that other
molecules, apart from the target substance, could be
expelled as a consequence of this activation. None of the
aforementioned methods would account for such an event
and would thereby lead to misinterpretation of results.
To give a more complete picture of the eluted substan-
ces from a conducting polymer film, this study addresses
the analysis of release samples using two different quantifi-
cation techniques, high-performance liquid chromatography
(HPLC) and EQCM. Due to recent interest in poly(3,4-ethyl-
enedioxythiophene) (PEDOT) films for drug release,
3,10
replacing the lastly more popular polypyrrole (PPy), elec-
tropolymerized PEDOT:Dex was chosen as drug delivery
system for this study. An HPLC protocol was established to
allow the quantification of Dex and further UV active sub-
stances at concentrations below 5 ng/mL. This method, in
contrast to pure UV absorption, first induces a separation
of the sample into its different chemical constituents,
which can be identified by the time they need to pass
through the analytical column. Signals from different UV
active substances, which in the absence of a separation
step would have been summed up by the detector, can
with the HPLC be distinguished as separate peaks over
time. With the given method we could see that the release
signal in fact was determined by three different substances
which could be identified as Dex, salt ions from the sup-
porting electrolyte and the monomer EDOT. As furthermore
the summation of the different substances did not account
for the full mass as detected by the EQCM method, para-
metric studies were performed to unravel a more complex
release mechanism.
MATERIALS AND METHODS
PEDOT:Dex deposition
Polymer films for release analysis were electropolymerized
from an aqueous solution containing EDOT and Dex (dexa-
methasone 21-phosphate disodium salt; purchased from
Sigma and used without further purification) at a concentra-
tion of 0.01 Meach, which was found efficient for the mono-
mer
20
and the counterion
21
concentration in previous
studies. The solution was mixed intensively on a vortex and
additionally sonicated (30 min at 135 W) for homogeniza-
tion before use. Polymer deposition was conducted in a con-
ventional three electrode setup using a potentiostat
(Autolab128N, Metrohm) in galvanostatic mode (80 mA/
cm
2
) for realization of homogeneous and well adhering
coatings. Layer thickness was determined by the charge
transferred during the polymerization and set to 100 mC/
cm
2
for the screen printed Pt-electrodes (SPE, Dropsens,
4 mm diameter) as well as the platinized EQCM electrodes
(6 mm diameter), which were connected as working electro-
des. Samples were carefully rinsed with MilliQ-water (30 s
exposed to a water jet, using a volume of 30 mL) after fabri-
cation as well as between each release experiment and
stored in separate containers, filled with 1 mL of electrolyte
[phosphate-buffered saline (PBS)].
Release triggering
Release of Dex was triggered by CV-sweeping the film in
PBS in the range of 20.6 V to 0.9 V versus Ag/AgCl except
for the parametric study where the range is split into a
cathodic sweep (20.6 V to 0 V) and the corresponding
anodic sweep (0–0.9 V). One release set covers five subse-
quent sweeps at a speed of 0.1 V/s. CV-sweeps were per-
formed in this broad range to ensure maximum release
efficiency and were further confined by the electrochemi-
cally safe limits associated with the water window for plati-
num in saline solution. The passive storage time in PBS
between the single actuations was kept at 96 h unless oth-
erwise specified.
Release quantification
The quantification was performed on a waters 2695 sepa-
ration module (HPLC) with a C18 column and a UV detec-
tor (Agilent 1260 infinity series) which was operated at a
wavelength of 245 nm. The mobile phase was based on
theworkofIqbaletal.
22
and purged at a flow-rate of
0.5 mL/min at room-temperature through the column. A
composition of 25.7% methanol, 29.8% acetonitrile and
TABLE I. Limitations of Commonly Used Release Quantification Methods
UV Absorption EQCM ELISA Radio Labeling
Selective quantification
of target substance
No No Yes Yes
Detection of byproducts No No No No
Expected consequence Incorrect release
information by
overestimation
Incorrect release
information by
overestimation
Incomplete
release
information
Incomplete
release
information
2 BOEHLER AND ASPLUND A DETAILED INSIGHT INTO DRUG DELIVERY
44.5% buffer solution was accordingly used with a 0.048
MNaH
2
PO
4
buffer, adjusted to a pH value of 5.4 using a
KOH solution. A sample volume of 100 mL was injected to
the column and the peak separation was observed over a
time of 15 min which covered all detectable peaks. Reten-
tion times were identified using separate injections of
either PBS, Dex, or EDOT at different concentrations,
which simultaneously formed the data basis for the cali-
bration curves. Mass calculation was done by peak inte-
gration and lead to successful quantification with a limit
of detection (LOD) of 0.4 ng/mL and a limit of quantifica-
tion (LOQ) of 1.3 ng/mL for Dex and, respectively, 0.9 ng/
mL and 3.1 ng/mL for the EDOT monomer. Calibration
curves were linear between 0.01 mg/mL and 4 mg/mL
with an R
2
of 0.99931.
EQCM measurements were performed with an Autolab
potentiostat using a platinized TiO
2
crystal (Metrohm) with
an oscillation frequency of 6 MHz. Mass calculation was
done according to the Sauerbrey equation Df5Dm3C
f
,
adopting a sensitivity constant (C
f
) of 0.0815 ng/Hz cm
22
for the used crystals. Minimum resolution was determined
by a frequency change of 10 Hz, corresponding to a mass
change of 35 ng.
RESULTS
HPLC-based release analysis
Electropolymerized PEDOT:Dex films with a coating-
thickness of 700 nm and a total polymer mass of nearly 16 mg
(for a deposition charge of 100 mC/cm
2
) were subjected
to redox-triggered drug release over a time period of one
month using PBS as release medium. The detailed analytical
investigation of the release solution in the HPLC revealed
that the signal was mainly determined by three different
species [Fig. 1(a)]. The first one appearing around 3 min
elution time is assigned to the ions in the release buffer
itself and shows some minor differences between passive
and active samples caused by the ion-exchange with the
polymer upon redox activation. The second peak with an
elution time of 4.6 min corresponds to Dex and shows varia-
tions in intensity, depending on the amount of released drug
under passive and active conditions. Next to these expected
peaks, there is however an additional peak (elution time of 9
FIGURE 1. Full picture of released substances unraveled by analytic chromatography. (a) HPLC-peak histogram showing the presence of EDOT
in the release solution. (b) Mass comparison for actively released Dex versus EDOT showing a significant EDOT signal. (c) Cumulative true Dex
release over time and (d) cumulative EDOT release upon redox activation of a PEDOT:Dex film.
ORIGINAL ARTICLE
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH A |MONTH 2014 VOL 00A, ISSUE 00 3
min) with substantial contribution to the signal. By running
corresponding calibration and reference samples containing
either Dex or EDOT in a PBS buffer, this could be identified to
result from the monomer EDOT. The monomer associated
peak also displayed a significant difference between the pas-
sive and the active release solution which clearly indicates an
active release characteristic similar to what could be identified
for the drug. This behavior can be seen in the cumulative
release curves displayed separately for Dex [Fig. 1(c)] and the
monomer [Fig. 1(d)] where the actively triggered release and
the slower passive leakage between the actual release meas-
urements are shown over time. It is worth mentioning, that a
single active release event is performed within a timeframe of
15 min whereas the passive storage time is almost 400 times
longer. Plotting the actively released mass for Dex and EDOT
next to each other [Fig. 1(b)], one can clearly see a substan-
tially higher mass coming from the monomer compared to the
targeted drug. The small peaks between 6 min and 9 min elu-
tion time [Fig. 1(a)] could not be correlated to any specific
substance but were found to be part of the background of the
PBS solution, either originating from the buffer itself or result-
ing from elution products from the storage vials. Since inter-
ference with the target peaks (Dex and EDOT) could be
excluded, these peaks were not further considered in the
detailed analysis.
Mass determination using EQCM and HPLC
A comparison of the mass determination based on the EQCM
technique versus the HPLC measurement is shown in Figure 2
for a PEDOT:Dex film deposited with 100 mC/cm
2
charge
density. The release triggering is performed in the range of
20.6 V to 0.9 V with 10 CV-sweeps comprising one release
event for this sample to ensure a significant mass change on
the EQCM. The cumulative data displays a clear difference
between the two mass measurements, performed on one and
the same sample with two different and independent (nonin-
terfering) techniques. Thereby not only an overestimation
due to the nonobservance of EDOT is apparent, as has been
predicted from the previous results, but additionally the
EQCM measurement shows significantly higher release values
with a difference of more than factor two.
Influence of the polymer:dopant system on the EDOT
release
A comparison of a PEDOT:Dex coating with a PEDOT:PSS film,
deposited under equal conditions, is provided in Figure 3(a)
with focus on the EDOT-release. Albeit both sample types
show an actively triggered release of the monomer a clear
difference between the two films is apparent, indicating a
weaker polymer structure for the drug loaded film. The
coating with the Dex counterion lost a substantial amount
of EDOT during five activation steps while the sample hav-
ing the PSS counterion mainly lost some monomer during
the first activation, followed by a subsequent insignificant
expulsion at levels close to the detection limit.
Sweeping the PEDOT:PSS film after initial stabilization of
the monomer leakage for 250 CV scans however results in
an expulsion of 68 ng of EDOT (62 ng for another 250
scans) which demonstrates that also the more stable poly-
mer:dopant configuration is subject to a redox driven mono-
mer loss even though the absolute loss (1% over 250 CVs)
is significantly lower compared to the PEDOT:Dex films
(10% over 6 CVs).
As expected, there was no Dex peak visible in the
PEDOT:PSS sample while the EDOT peak clearly remained
(spectrum not shown). This supports that the second peak is
truly attributed to the monomer EDOT and not an oxidation
or reduction product of the Dex due to the applied stimula-
tion. A further confirmation that the peak can be assigned
to EDOT is additionally given by the data in Figure 3(b),
where a PPy:Dex film (fabricated equally to the PEDOT:Dex
equivalent) was analyzed, showing an overlap of the Dex
and the Py-monomer peak at 4.4 min but lacking any sig-
nal at 9 min, which would correspond to the elution time
for the EDOT-monomer. The quantification of the influence
from possible Py-release during redox activation could not
be done with the present HPLC-method as the partitioning
conditions do not separate this peak sufficiently from the
others.
Redox and interface dependency of EDOT release
A parametric study was conducted to further identify the
origin and the redox-dependency of the EDOT in the release
solution. Therefore, PEDOT:Dex samples were subjected to
separated redox sweeps according to Figure 4(a,b) with
either a cathodic sweep from 20.6 V to 0 V or an anodic
sweep from 0 V to 0.9 V. Results show a clear release of the
anionic drug during the cathodic sweep, however, there is
also a distinct release of Dex for the sample only experienc-
ing the anodic sweep. The total amount of released substan-
ces is generally lower for the anodic sweep range even so
the transferred charge in the anodic sweep was 1.6 times
higher compared to the cathodic one. Overall, the release of
FIGURE 2. Release quantification comparison using HPLC and EQCM
methods proves a significant overestimation of drug-release if the full
range of expelled substances is not considered. Next to the actual drug
expulsion, the release of EDOT as well as the possible loss of complete
polymer fragments needs to be considered for true drug-level estima-
tions. The figure shows data obtained for n51.
4 BOEHLER AND ASPLUND A DETAILED INSIGHT INTO DRUG DELIVERY
Dex and EDOT is affected by the full sweep potential show-
ing a higher efficiency of the Dex:EDOT release ratio in the
anodic area for activation #1 and #2 (with 5 CV sweeps per
activation). Increasing the amount of redox cycles by factor
2 (10 CV sweeps per activation) for release events #3 and
#4 leads to equalization in the Dex:EDOT ratio between
anodic and cathodic sweeps. However, there is no clear sup-
pression on either the positive or the negative range for
actively releasing EDOT from the coating.
Figure 4(c,d) shows the second parametric study where
a composite layer was used to identify whether the EDOT
release is associated with the interface to the substrate or
rather originates from the polymer bulk. Sample A consists
of a thin PEDOT:PSS layer (10% of the film) in contact to
the substrate with a PEDOT:Dex layer (90% film thickness)
on top, while sample B has the reversed layer composition.
Release for Dex [Fig. 4(a)] showed as expected high mass
values for sample A with the thick PEDOT:Dex layer. Sample
B, featuring a capping layer of PEDOT:PSS on top of the
drug-film, surprisingly also showed Dex release upon redox
activation, even so less drug was released in comparison to
sample A. More interestingly however, the release of EDOT
is basically only present for sample A if neglecting the initial
minor release at sample B. This finding demonstrates that
the monomer leakage results from the polymer bulk rather
than the interfacial layer and hence is not attributed to a
failure at the interface to the substrate. At this point it
should be mentioned, that the samples were carefully rinsed
between all measurements so that no loosely attached
EDOT was left on the surface. The generally very low pas-
sive release over 96 h compared to the significantly
increased release within 15 min of actuation supports that
the monomer leakage does not result from loose EDOT but
is truly a consequence of redox sweeping.
DISCUSSION
Toward a more comprehensive understanding of the
species released upon electrical stimulation
Conducting polymer coatings have often been suggested to
enable the release of biologically relevant substances on
demand upon applying an electrical trigger signal. Thereby
various methods have been applied to quantify the amount
of released molecules in solution, for example, UV absorp-
tion, EQCM and ELISA. However, these methods have limita-
tions, with a substantial problem being that they fail to
detect if additional species are released from the film apart
from the intended ones.
Using highly precise chromatographic measurement
methods (HPLC), we were able to identify a significantly
more complex release behavior for a PEDOT:Dex system
than has commonly been assumed so far. The most impor-
tant finding, that the monomer EDOT is released next to the
Dex, has impact on the current understanding of electro-
chemically triggered release from PEDOT films. As the mono-
mer is UV active at the same wavelength than the Dex
(245 nm), release measurements neglecting the separation
of released substances might be affected by a significant
overestimation of release.
3,10
Based on these findings we
believe that similar effects might influence also the formerly
more popular PPy:drug
2
systems, and data indicating this
has already been shown in the work of Svirskis et al.
11
In
their studies they target risperidone release upon electrical
activation of a Polylpyrrole:drug film, but next to the drug,
also a monomer signal could be identified in the release
solution, revealing an expulsion of Pyrrole.
11,12
Even so this
finding was not further analyzed regarding an actively trig-
gered expulsion, it supports the herein proposed theory that
monomers can leave the polymer film upon redox activation.
The comparison between a PEDOT:Dex and a PEDOT:PSS
film, actuated and measured under equal conditions,
showed that the PEDOT:PSS sample released significantly
less monomer than the drug loaded film. This observation is
FIGURE 3. EDOT release from different polymer systems. (a) Cumula-
tive release of EDOT from a PEDOT:Dex film in comparison to a
PEDOT:PSS film showing the higher monomer loss on the drug-
loaded sample due to lower polymerization/doping efficiency as for
the PEDOT:PSS. (b) HPLC analysis of a PPy:Dex reference sample
does not show any peak at an elution time of 9 min which proves the
correlation of this peak to EDOT. A Py-monomer peak is not visible
due to overlap with the Dex and PBS peaks between 2 min and 5
min. The peak at 8.2 min in the inset is attributed to the salts in the
solution and the tiny peak in the passive solution at 8.7 min results
from elution products of the plastic vial during passive storage, hav-
ing a different peak center than the EDOT-monomer. The figure
shows data obtained for n51.
ORIGINAL ARTICLE
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH A |MONTH 2014 VOL 00A, ISSUE 00 5
in good agreement with the commonly reported higher
polymerization/doping efficiency of the PEDOT:PSS system,
resulting in a more stable polymer matrix. Due to the differ-
ent behavior of the two polymer systems upon redox cycling
(loss of dopant with partial replacement of electrolyte ions
for PEDOT:Dex versus incorporation and expulsion of elec-
trolyte ions at stable dopant level for PEDOT:PSS), the sub-
sequent release of the dopant in form of the drug is further
assumed to affect the polymer integrity. As the CV-sweeping
parameters are equal for both film types we conclude that
the potential excursions are not solely responsible for the
EDOT loss during stimulation but the polymer-dopant inter-
action plays a substantial role. The generally weaker doping
efficiency in combination with a loss or exchange of the
dopant for a different species (electrolyte anions) accord-
ingly leads to the significantly higher monomer loss of the
PEDOT:Dex coating. However, there is nevertheless an active
EDOT release for the PSS-sample, stressing the need for fur-
ther investigations on the stability of conducting polymers
under redox cycling.
New perspective on released masses
A comparison between the released masses from a PEDOT:
Dex film, estimated using either an EQCM or the HPLC
method, showed a difference of more than a factor two
between the two methods. This demonstrated descriptively
the effect of the previously described overestimation if
released substances are summed up and misinterpreted for
the actual drug mass as shown in Figure 2. It should be
noted here, that alterations of the viscoelastic properties of
the film upon redox cycling might additionally affect the
mass calculation for the EQCM method relying on the Sauer-
brey equation Df5Dm3C
f
. The linear approximation
between frequency change and mass does not take into
account influences such as surface roughness and viscosity
of the coating or the solution as described by Efimov
et al.
19
However, based on the significant offset, we believe
that this effect cannot entirely explain the observed results.
The difference indicates that the release behavior from
PEDOT:Dex films is rather complex and next to the EDOT
release, also the ion-exchange with the supporting
FIGURE 4. Parametric study of the EDOT release. (a) and (b) show the release of Dex and, respectively, EDOT under solely anodic or cathodic
release conditions. The overall present release shows no clear correlation to a specific voltage range but implies that next to the electrostatical
release mechanism also the swelling upon activation contributes significantly. The ratio of Dex versus EDOT release is additionally given as
numerical values in the EDOT release graph. (c) and (d) show the release of Dex and EDOT for a stacked layer as shown in the center. Release
data leads to the assumption that the monomer expulsion originates from the polymer bulk rather than the interface. The figure shows data
obtained for n51 in each configuration.
6 BOEHLER AND ASPLUND A DETAILED INSIGHT INTO DRUG DELIVERY
electrolyte and a plausible release of complete polymer frag-
ments play a role for the redox-based release. The expulsion
of larger fragments cannot be seen in the HPLC due to the
required prefiltering of the sample solution with a mem-
brane of 0.45 mm pore size which excludes particles but
does not affect the ionic drug and monomer molecules.
The calculation of the deposited mass for the polymer
and its anion using the deposition charge Q
dep
and
the molecular mass M
x
according to equation m
dep
5
Q
dep
F
21
(M
EDOT
1cM
Dex
)(2 1c)
21
with the Faraday constant
Fand doping level c50.3
23
leads to a theoretically depos-
ited mass of 16.8 mg for the 100 mC/cm
2
film. This number
splits into 8 mg for the monomer and 8.8 mg for the drug
which is close to the total mass of 15.4 mg that has been
determined during the deposition with the EQCM. Compar-
ing these values with the release data, it is apparent that a
significant part of the monomer is lost during stimulation of
the drug-loaded film [>10% within 6 actuations, Fig. 1(b)].
This loss of polymer substance is further assumed to lead
to a progressing weakening of the polymer film itself. Con-
sequently, this process is likely to contribute significantly to
the manifold observations of delamination and/or degrada-
tion of polymer coatings from the substrate under redox
based drug delivery.
2,3,24
Redox and interface dependency
Parametric studies, performed to identify the correlation
between actuation signal and released mass, showed higher
drug and EDOT expulsion for the cathodic range (20.6 V to
0 V). This is in good accordance with the expected electro-
statical release mechanism reported by others.
2
However,
there is also a considerable release of both Dex and EDOT in
the anodic sweep, which indicates that not only the electro-
statical mechanism but also the swelling and deswelling of
the film during actuation contribute significantly to the drug
release. Studies by Svirskis et al.
11,13
showed the successful
release of cationic (risperidone) as well as neutral (proges-
terone) substances during electrical activation of a PPy film,
which demonstrates the substantial effect of mechanical film
actuation on the expulsion of charged and uncharged mole-
cules. This mechanical release mechanism is further believed
to dominate the active EDOT release from our samples as no
clear suppression can be seen in any of the sweep ranges,
which would be expected for a direct correlation to the
sweeping potential. The EDOT loss was found to be generally
lower in the anodic range, even so the transferred charge
was 1.6 times higher than for the cathodic range. We
hypothesize that a possible re-polymerization of monomers
(or oligomers) under sufficiently high positive potentials, as
provided in the anodic sweeps, leads to this observation.
The origin of EDOT molecules, leaving the polymer film
upon redox activation, was assessed by investigating stacked
layer samples as illustrated in Figure 4. Using these probes,
we were able to identify that the monomer loss is mainly
attributed to the polymer bulk and not determined by weak
interfacial adhesion of the PEDOT to the substrate. An inter-
esting finding here is that sample B (buried PEDOT:Dex
layer) still features an active release of the drug even so the
molecules have to pass all the way through the PEDOT:PSS
before they reach the supporting electrolyte. This leads to
the conclusion that redox release of the polymer does not
only affect the top few nanometers of the coating but the
complete polymer mass down to the substrate is involved.
It is worthwhile mentioning that the PEDOT:PSS is not read-
ily able to release the dopant anion in the same way as the
PEDOT:Dex. In the latter case the top part of the polymer is
assumed to be able to compensate the applied charge dur-
ing release by expulsion of the anion so that no release
from deeper structures is required, even so theoretically
possible.
Although not shown in graphs, a broader set of samples
was studied under similar conditions. Due to slight varia-
tions during the fabrication, samples do not acquire identi-
cal conductivity. Therefore, the potential driven release will
also not induce identical current flow in each sample which
makes a one to one comparison more difficult. It should be
noted that release data was overall consistent with the rep-
resentative samples shown in this report and no substantial
deviations from the behavior described here could be seen
in the larger sample set. Independent of the polymerization
mechanism (galvanostatic vs. potentiostatic) or the film
thickness, an active EDOT expulsion could consistently be
identified for five additional samples (not shown here)
whereas the ratio of released Dex:EDOT was found to vary
between 1.02 and 2.44 (excluding the initial burst and
depending on the actual sample configuration).
CONCLUSION
An analytical method could be successfully established to
provide a deeper insight into the full release spectrum of
substances leaving a PEDOT:Dex film upon redox activation.
The separation of the single substances in the release solu-
tion thereby showed that next to the intended drug, also a
significant portion of the monomer EDOT left the film. This
EDOT release was found to be directly coupled to the redox
activation. Furthermore the EDOT was found UV active at
the same wavelength as the Dex (245 nm), which leads to a
significant overestimation of drug release if separation
would be disregarded like, for example, in the commonly
used UV absorption technique. A comparison with the
EQCM method confirmed this finding, displaying a differ-
ence of more than factor 5, which shows the relevance of
implementing a proper release analysis for true quantifica-
tion of released drug.
A parametric study, implementing different CV-ranges,
unraveled that release triggering is not solely based on the
elimination of the electrostatical binding of the dopant to
the polymer. Moreover, the mechanical actuation of the poly-
mer contributes significantly to the release of the drug and
the monomer as has been described by others for different
drugs.
2,3,5,11
The EDOT could be shown to originate from
the polymer bulk. This substantial release of EDOT during
redox is assumed to contribute to a progressive weakening
of the polymer matrix. This consequently would lead to the
delamination/degradation effects of conducting polymers
ORIGINAL ARTICLE
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH A |MONTH 2014 VOL 00A, ISSUE 00 7
under release conditions, which has been often
observed.
2,3,24
Interestingly, redox-triggered polymer degra-
dation also affected the more stable PEDOT:PSS system
which would have implications for the outcome of long-
term cycling of the film. It could not be excluded that also
PPy films release monomers. Such unintentional release of
monomers might interfere with the target application (i.e.,
Dex release for anti-inflammatory treatment of tissue
around implants) and counteract the benefit of releasing a
drug in the first place. Therefore, future work should be
invested into increasing the ratio of intentional versus unin-
tentional release.
ACKNOWLEDGMENTS
We thank Prof. Thomas Stieglitz for enabling this work within
the Lab. for Biomedical Microtechnology at IMTEK Freiburg.
The authors also thank Dr. Karen Lienkamp (IMTEK) for sev-
eral helpful discussions on the HPLC analysis and permitting
us to use her device. We finally thank Anika Schopf for techni-
cal assistance with measurements.
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8 BOEHLER AND ASPLUND A DETAILED INSIGHT INTO DRUG DELIVERY
