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Electrochemically assisted deposition of biodegradable polymer nanoparticles/

solgel thin lms


Efrat Gdor and Daniel Mandler
*
Received 24th March 2011, Accepted 3rd June 2011
DOI: 10.1039/c1jm11262g
Biodegradable nanoparticles represent a promising platform for controlled release and other
applications in medicine. To alter the interface of the medical device with the living tissue successfully,
a thin coating needs to be applied onto the surface. The traits and functionality of the coating depends
on its components, which in the presented work are solgel and biodegradable nanoparticles (NPs)
deposited onto the substrate using the electrochemical solgel method. Aspects affecting the deposition
process were investigated such as the applied potential and its duration. The properties of the deposits
with emphasis on the biodegradable NPs within the deposited lms were characterized and studied.
Another element examined was the loading ability of the NPs. A uorescent organic molecule was
incorporated in the biodegradable NPs as a drug model, to demonstrate loading capability.
Introduction
One of the more signicant and therefore researched aspects in
medicine is the interface between the living tissue and the medical
device, which is mostly altered by a coating layer. The device can
be coated with various materials, spanning from polymers
14
to
drugs,
5,6
and the coating procedure can be carried out in
a number of methods, such as dip-, spin- and spray-coating,
710
depending on the nature of the substrate.
Biocompatible and biodegradable materials have become an
increasingly important component in medical devices. Biode-
gradable polymers are materials that are eroded by natural
processes such as hydrolysis.
11
When considering medical
applications, these polymers must meet certain needs. The
possible applications range from sutures through temporary
organ replacements to permanent implants. Currently, the
general desire is to reduce surgical intervention to the minimum
and minimize exposure to infection and other risks. As a result,
there is high motivation to tailor the interfacial properties of
medical devices. An appealing approach for achieving this goal is
to apply biodegradable polymers as the coating matrix. The most
common biodegradable polymers are poly(lactic acid) (PLA),
poly(glycolic acid) (PGA) and their copolymer, poly(lactic-co-
glycolic acid) (PLGA).
12
The current procedures for coating medical devices and in
particularly medical implants meet the requirement for
simplicity, but lack in other aspects. Using dip- and spin-coating
is mostly restricted to at surfaces whereas spray-coating often
results in inhomogeneous layers. Nevertheless, the latter is the
most applied approach for coating medical implants.
10,13,14
Electrochemistry, on the other hand, offers a relatively simple
approach to coat complex geometries with thin homogeneous
lms. Organic polymers as well as inorganic materials, e.g.,
oxides have been electrodeposited to obtain protective thin lms
on medical devices.
15
More recently, we have reported on the
formation of organicinorganic polymers based on the solgel
technology by electrochemical means.
16
Specically, the appli-
cation of either negative or positive potentials in protic media
alters the pH on the electrode surface, which catalyzes the
condensation of the solgel precursors. The electrochemical
deposition of solgel is a selective process
17
(driven on the con-
ducting parts of the substrate) which can be manipulated and
tailored according to necessity. One of the advantages intro-
duced by this method is the incorporation of elements within the
solgel matrix via the selective deposition.
1821
It is this specic
advantage we exploit in this research.
Although electrodeposition of solgel was rst reported over
a decade ago,
22
the electrochemical codeposition of organic
nanoparticles (NPs) within the solgel matrix has not been
reported. Electrochemical codeposition of different substances,
such as metal ions,
23
metallic NPs,
24
dye molecules
25
and corro-
sion inhibition agents,
26
have been reported. This work is the
rst, to the best of our knowledge, to report the electrodeposition
of solgel and biodegradable NPs.
In medicine, biodegradable NPs have become increasingly
common, especially in drug delivery.
2729
Remarkable results
have been obtained in the area of controlled release via intrave-
nous and oral administration.
30
On the other hand, there are only
a few cases where biodegradable NPs have been utilized as
coatings.
3134
For example, Joo et al. showed the controlled
release prole of Paclitaxel fromPLGANP coatings on coronary
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem,
91904, Israel. E-mail: mandler@vms.huji.ac.il; Fax: +972-2-6585319;
Tel: +972-2-6585831
This journal is The Royal Society of Chemistry 2011 J. Mater. Chem., 2011, 21, 1214512150 | 12145
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stents.
33
The depositions were carried out by injecting a colloidal
suspension between the stent and a ring exploiting capillary
forces.
32
Nam et al. used electrophoretic deposition to coat stents
with curcumin-loaded PLGA NPs, using high potentials (up to
13 V) for long durations (up to 1 h).
31
Banai et al. reported
inhibition of in-stent stenosis using substance eluting PLGA NP
coatings on stents.
34
Awork performed by Dawes et al. suggested
the attachment of drug loaded PLGA microspheres to articial
joints to refrain from recurring joint surgery.
35
Here we present a novel method to electrochemically codeposit
hybrid lms made of solgel and biodegradable NPs. The latter
were synthesized by the emulsion-diffusion-evaporation tech-
nique. Thin lms of tetramethoxysilane (TMOS) and the
synthesized NPs were electrochemically codeposited by applying
a constant negative potential on ITO substrates. We investigated
the parameters affecting the deposition, such as the applied
potential and its duration. Finally, we synthesized coumarin-1
loaded biodegradable NPs and studied the codeposited lms by
various methods.
Experimental
Materials
Poly-(D,L-lactide) (PLA, M
w
75 000100 000 g mol
1
), chito-
san 7585% acetylated, poly(vinyl alcohol) (PVA, 99%), tetra-
methoxysilane (TMOS, 98%) and coumarin-1 (99%) were
purchased from Sigma-Aldrich. Potassium nitrate ($99.0%),
acetonitrile (ACN) and ethanol (99.9%) were acquired from
Merck, sodium chloride (99.0%), hydrochloric acid 32% and
acetic acid (99.7%) from J. T. Baker, ethyl acetate (99.5%) and
acetone (AR) from Frutarom (Haifa, Israel). All chemicals were
used as purchased.
Deionized water (18.3 MU cm
1
, EasyPure UV, Barnstead,
UK) was used for all the experiments. Indium tin oxide (ITO)
plates 7 50 0.7 mm
3
, R
s
1525 U) were supplied by Delta
technologies Limited (Stillwater, MN, USA).
Instrumentation
The size and charge of the NPs were measured by a Nano ZS
zetasizer (Malvern instruments, UK). Electrochemical experi-
ments were conducted using an AutoLab potentiostat (mAutolab
Type II, EcoChemie, Utrecht, The Netherlands). Electro-
chemical depositions were carried out using a conventional three-
electrode cell: the working electrode was an ITO plate, the
reference electrode was a home-made Ag/AgBr quasi-reversible
electrode (QRE), and the counter electrode was a Pt wire (99.99%
purity). The working electrodes were withdrawn from the
deposition solution using a home-made lifter with a velocity of
ca. 0.366 mm s
1
. Step height measurements were performed
using a P-15 prolometer (KLA-Tencor Co., San Jose, CA,
USA) by creating a notch in the lm with a wooden stick after
drying for one day. In the course of preparation of the NPs
several appliances were used: Ultra-Turrax T25 homogenizer
(Janke and Kunkel GmbH KG, Staufen, Germany) and CN-820
centrifuge (MRC, Israel). Images of the coatings were obtained
by high resolution scanning electron microscopy (HR-SEM
Sirion, FEI Company, USA). Images of the uorescent coatings
were acquired by a uorescent microscopy using an Olympus
BX6000 microscope (Tokyo, Japan) at l 365 nm (ENF-
260CIF, Spectroline, New York, USA).
Methods
Nanoparticles preparation. NPs were prepared using the
emulsiondiffusionevaporation technique. This synthesis was
carried out according to Kumar et al.
36
with modications.
Briey, 200 mg of PLA was dissolved in 10 mL ethyl acetate at
roomtemperature followed by 2 h stirring in ambient conditions.
An aqueous stabilizer mixture containing 100 mg of PVA and
30 mg of chitosan in 10 mL acetic acid 2% (v/v) was also stirred
for 2 h in ambient conditions. Then, the organic phase was added
to the aqueous phase under stirring. The resulting mixture was
stirred for 3 h at room temperature, and then homogenized at
13 500 rpm for 10 min using a homogenizer. The homogenized
emulsion was diluted to 50 mL volume with water. The addition
was carried out under stirring, which was continued to remove
the organic solvent.
The resulting dispersion was centrifuged at 7500 rpm for 15
min, followed by decantation. The decanted liquid was concen-
trated to 10 mL by evaporation under reduced pressure. Fluo-
rescent NPs were prepared simply by adding 5 mg of coumarin-1
to the organic phase in the rst step of the synthesis.
Solgel preparation. The precursor solution consisted usually
of 0.2 mL TMOS, 11.3 mL water and 1 mL HCl 0.1 M added in
the detailed order; this mixture was hydrolyzed for 1 h, either in
ambient conditions, or at 40

C with gentle stirring.
Deposition solution. Electrochemical deposition was conducted
in 12.5 mL of the hydrolyzed solgel solution to which 2.5 mL
(unless otherwise specied) of the NPs dispersion and KNO
3
to
a nal concentration of 0.1 M were added.
Electrodeposition. A constant negative potential (0.8 to
1.2 V vs. Ag/AgBr) was applied to the ITO electrodes for 130
min. The immersed electrodes were then withdrawn from the
deposition solution while still applying the constant potential
and dried for 24 h in ambient conditions.
Characterization
For z potential (ZP) measurements NaCl was added to the NPs
dispersion to achieve an electrolyte concentration of 20 mM. The
measurements of ZP as a function of pH were carried out by
preparing 3.6 mL solutions with calculated pH followed by
adding a xed amount of NPs dispersion (400 mL). The pH was
measured just prior to the ZP measurement.
HR-SEM images were acquired after sputtering the deposits
with a thin Pd/Au lmto increase the surface conductivity. Cyclic
voltammetry (CV) of the coumarin-1 loaded NPs and TMOS
coated plates were carried out in 20 mM NaCl solution, from 0.0
to 1.5 V and a scan rate of 100 mV s
1
. Degradation of the
electrochemically codeposited NPs in ACN was carried out by
immersing the coated ITO plates in ACN : water (3 : 1 v/v) for
different durations followed by washing with water, after which
the plates were left to dry in air.
12146 | J. Mater. Chem., 2011, 21, 1214512150 This journal is The Royal Society of Chemistry 2011
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Results and discussion
In the last few years, TMOS-based solgel lms have been used
as biocompatible matrices.
37
Biodegradable polymer based NPs
have also been extensively used for medical uses, e.g. drug
delivery.
3841
Our intention was to combine the two in order to
form a framework-like matrix consisting of solgel and NPs.
The preparation of the NPs, as depicted in the previous
section, was carried out using the emulsiondiffusionevapora-
tion technique.
36
Post synthesis, the size and z potential of the
NPs were measured to be 97.4 12.4 nm and 46.4 6.3 mV,
respectively. These measurements were performed after centri-
fugation, which removed the larger particles of micrometre size.
Clearly, the positive potential is attributed to the amino moieties
of the chitosan polymer. Moreover, the charge of the NPs is pH
dependent, vide infra. The z potential (ZP) mentioned above was
measured by diluting the NPs dispersion in water to give pH 45.
Fig. 1 shows the ZP as a function of pH of the NPs dispersion.
Small volumes of the dispersion were added into a buffered
solution (nal dilution by a factor of 10), which explains the low
values of the z potential shown in Fig. 1.
Expectedly, as the pH increases the ZP decreases which indi-
cates a decrease in the stability of the NPs. At pH ca. 7 the z
potential is zero, which is in agreement with the pK of chitosan
that is ca. 6.87.2.
4245
In addition, turbidity was observed in the
dispersion sample for this measurement. Evidently, at this pHthe
NPs are no longer stable and thus aggregate. In the high pH
region, the ZP is slightly negative, indicating that the NPs are
slightly negatively charged which can be attributed to the
adsorption of OH

or some deprotonation of PVA.


Our goal has been to deposit biodegradable NPs by altering
the pH electrochemically. In principle, this could have been
achieved by applying a negative potential in a dispersion of these
NPs. The reduction of oxygen and water should increase the
concentration of hydroxyl ions on the electrode surface and
induce the precipitation of the NPs. However, our attempts to
carry out such experiments failed. Inhomogeneous and discon-
tinuous thin lms were formed. The introduction of solgel, due
to its biocompatibility, as a means of assisting the electro-
chemical deposition was a logical next step. Fig. 2 shows sche-
matically the essence of our approach. Specically, codeposition
was carried out in a TMOS solution that was hydrolyzed under
acidic conditions prior to the electrochemical process. After the
hydrolysis, electrolyte and NPs dispersion were added, followed
by applying a negative potential to an ITO electrode. Water and
oxygen reduction leads to hydroxide evolution which catalyzes
both the condensation of the solgel hydrolyzed monomers and
the aggregation of the NPs. This resulted in the formation of thin
solgel/NPs lm on the electrode surface.
To assess the potential needed for the deposition, we rst
conducted cyclic voltammetry (CV), shown in Fig. 3. The CV is
typical for an aqueous solution consisting of solgel precursor.
That is, a reduction wave that commences at 0.7 V vs. Ag/AgBr
QRE is seen and attributed to the reduction of water. Based on
our experience the current needed for efcient solgel electro-
deposition is at least 0.25 mAcm
2
. We applied a potential of at
least 0.8 V.
Fig. 1 z Potential of the biodegradable NPs dispersion in solutions with
different pH.
Fig. 2 Schematics of the experimental system.
Fig. 3 (A) Cyclic voltammetry of an ITO electrode in the deposition
solution, scan rate equals 100 mV s
1
. (B) Currenttime transient of the
deposition process using an ITO electrode. The potential of deposition
was 0.9 V.
Fig. 4 HR-SEM image of NPs/TMOS codeposited lm on ITO at 1.1
V for 15 min.
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Fig. 3B shows the chronoamperometry recorded with an ITO
electrode upon applying 0.9 V in an aqueous solution consist-
ing of the solgel precursor (TMOS), NPs and electrolyte. As can
be seen, the current rst peaks, then decays to a constant value.
The peak is a result of the charging current and other effects, and
the decay is due to the faradic processes occurring, i.e. water
reduction. Since deposition was carried out in water, the current
decays to a constant value.
A SEM image of a resulting codeposition is shown in Fig. 4.
The deposit is clearly of a dual nature: spherical shapes, which
are connected by patches with no dened shape. The average size
of the spherical shapes as measured in the image is consistent
with the size measured by dynamic light scattering, i.e. 97.4
12.4 nm. According to energy dispersive X-ray spectroscopy
(EDS) results, the spherical shapes are the biodegradable NPs,
and the patches are the solgel that acts as the binding matrix.
The concentration of NPs in the lm is relatively high, which
alludes to the efcient electrochemical codeposition process.
Blank experiments carried out in the absence of TMOS resulted
in inhomogeneous and non-continuous patches of polymer,
without noticeable NPs.
To improve and optimize the deposition process we examined
a number of parameters, which we suspected to control it. The
applied potential and its duration were rst studied. Fig. 5A
shows the lm thickness dependency on the deposition time. The
potential applied was 1.1 V.
As seen in Fig. 5A, the thickness of the lm increased with the
time that a sufciently negative potential was applied. As long as
the potential is applied, the reduction of water continues and the
deposit accumulates. A longer deposition than 20 min was not
carried out, however according to the trend as well as our
previous experience in electrochemical solgel deposition, the
thickness will reach a plateau. It should be noted that the
deposition solution was continuously stirred. Since the electro-
chemical reaction takes place at the electrode/lm interface,
whereas deposition occurs at the lm/electrolyte interface, it is
plausible that the growth of the lm will cease as the pH at the
lm/electrolyte interface approaches that of the bulk. Thicker
lms obtained as a result of longer deposition times were porous
or discontinuous, which is evident by the penetration of elec-
troactive species across the formed layer.
Another studied aspect was the effect of the deposition potential
on the lm thickness (Fig. 5B). Chronoamperometry was used,
whereby a constant potential was applied for a given time. Simi-
larly to the deposition time effect, the more negative the deposition
potential applied, the thicker the lm formed. Yet, there is
a threshold potential, ca. 0.8 V, required to electrochemically
codeposit the NPs/solgel. The effect of the negative potential on
deposition is signicant because it affects not only the thickness but
also the quality of the lm. As we apply more negative potential the
rate of hydroxide evolution increases, which explains the increase
of lm thickness for a given time. In addition, the higher reduction
rate resulted in more aggressive evolution of hydrogen, interfering
with lm formation. The gas bubbles generated on the electrode
surface prevented the formation of the layer on the ITO plate.
Consequently, in potentials more negative than 1.3 V hardly any
deposition was observed.
In order to further investigate the lms, we synthesized NPs
that were loaded with coumarin-1, a uorescent compound that
was incorporated in the NPs in the course of the synthesis. The
NPs were thereafter used to produce thin lms on ITO using the
same electrochemical method for the codeposition with TMOS.
Since coumarin-1 is uorescent, we were able to obtain a uo-
rescent image of the codesposit, as seen in Fig. 6. The micrograph
was taken under illumination at 365 nm. Clear uorescent
microparticles can be seen that represent mostly aggregates of
NPs. At the same time, bright areas in which individual aggre-
gates cannot be detected are also observable. Due to the fact that
coumarin-1 has relatively lowsolubility in water, it is conceivable
Fig. 5 The effect of the deposition time (A) and potential (B) on lm
thickness. All other parameters are as in Fig. 4.
Fig. 6 Fluorescence micrograph of an electrochemically deposited lm
of TMOS and NPs loaded with coumarin-1. The lm was deposited by
applying 1.1 V for 15 min. In the micrograph the lm is illuminated in
365 nm UV light.
Fig. 7 The rst and fth CV cycles of coumarin-1-loaded NPs/TMOS
coated ITO electrode in 20 mM KNO
3
, scan rate 100 mV s
1
. The
codeposition was carried out at 1.1 V for 15 min.
12148 | J. Mater. Chem., 2011, 21, 1214512150 This journal is The Royal Society of Chemistry 2011
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that it is accommodated within the NPs or at least on their
surface. This means that the solution itself does not contribute to
the observed uorescence. Furthermore, since the darker parts of
the micrograph are not entirely black, we suggest that NPs are
located within the entire lm, and not only on the surface. It is
likely that a signicant fraction of the uorescence originating
from the NPs within the lm is absorbed by the solgel matrix.
Most of the foreseen medical applications using NPs require
accessibility and controlled release of the substance loaded in the
particles. Electrochemistry can provide a simple and quantitative
tool for estimating the accessibility of incorporated electroactive
species. CV revealed that coumarin-1 (as well as other coumarin
derivatives)
46
is electroactive and undergoes irreversible oxida-
tion. This enabled us to determine the amount of accessible
coumarin-1.
Fig. 7 shows the CV of an ITO electrode electrochemically
coated with NPs/TMOS loaded with coumarin-1. The rst and
fth of six consecutive cycles are shown. A clear oxidation wave
at 1.1 V can be seen in the rst cycle, which drastically decreased
and became less positive upon repetitive cycling. The peak is
associated with oxidizing an amine group (coumarin-1 has
a tertiary amine group) and is in accordance with previous
reports.
46
The decrease of the current is probably due to the
irreversible oxidation of coumrain-1. Alternatively, this can be
explained by assuming that in the rst cycle the oxidized
coumarin-1 originates fromthe NPs on the surface. This suggests
that in the following cycles we exposed more coumarin-1 from
NPs within the lm. This requires alteration of the lmas a result
of applying electrochemical potential. To further analyze the CV,
we calculated the charge per area (derived from the peak area).
Assuming a one electron transfer,
46
we deduced the number of
molecules per area. The amount, ca. 4.7 10
8
mol cm
2
, is well
above a monolayer, by at least two orders of magnitude. This
indicates that the oxidized coumarin-1 is indeed from the NPs.
These ndings are in agreement with those from the uorescent
micrograph. Hence, we conclude that the amount of accessible
coumarin-1 is very large.
Recalling that the NPs are biodegradable, we examined their
degradation as a result of exposing the lms to a mixture of
acetonitrile and water (Fig. 8). Such mixture has been reported as
a hydrolysis promoter of polyesters.
47
Therefore, the coated
plates were immersed in this mixture of ACN and water for
different durations.
As can be seen from Fig. 8, 5 minutes of immersion in the
ACN : water mixture was sufcient to induce almost complete
degradation of the NPs on the surface. The size of the remaining
holes in the solgel matrix was consistent with the measured size
of the NPs. The rapid degradation might have been assisted by
the dissolving qualities of the ACN, although the degradation is
self-catalyzed, as suggested by previous works.
47
The holes form
a pattern in the surface which supports our hypothesis that the
particles are embedded in the solgel matrix and are not cova-
lently bound to it, in which the interaction is stronger.
Conclusions
Electrochemical codeposition of thin biodegradable NPs/TMOS
lms on ITO plates was demonstrated, as well as the different
parameters controlling the deposition. The process utilizes
a negative potential to generate a change in the pH in the vicinity
of the electrode to induce precipitation of both the solgel olig-
omers and the nanoparticles. This approach is not limited to
ITO, but is applicable to other conducting surfaces. In addition,
the electrochemistry allows coating of complex geometries as
well. Given that the lm thickness is in microns, this approach
ts well with different applications such as coating of stents and
other medical devices, to alter the interface. In this work we
demonstrated the possibility of incorporating a substance within
the NPs and their degradation, which suggests the prospect of
incorporating drugs for controlled release. This, of course,
requires further research.
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Fig. 8 HR-SEM images of electrocodeposited biodegradable NPs/
TMOS thin lms on ITO after (A) 5 min, (B) 1 h in a 3 : 1 mixture of
ACN : water.
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12150 | J. Mater. Chem., 2011, 21, 1214512150 This journal is The Royal Society of Chemistry 2011
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