Electrochemically Assisted Deposition of Biodegradable Polymer Nanoparticles

8/11/2019 Electrochemically Assisted Deposition of Biodegradable Polymer Nanoparticles

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Electrochemically assisted deposition of biodegradable polymer nanoparticles/

solgel thin filmsEfrat 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 films were characterized and studied.

Another element examined was the loading ability of the NPs. A fluorescent organic molecule was

incorporated in the biodegradable NPs as a drug model, to demonstrate loading capability.

Introduction

One of the more significant 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 polymers14 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 flat 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

films. Organic polymers as well as inorganic materials, e.g.,

oxides have been electrodeposited to obtain protective thin films

on medical devices.15 More recently, we have reported on the

formation of organicinorganic polymers based on the solgel

technology by electrochemical means.16 Specifically, 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 process17 (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 specific

advantage we exploit in this research.

Although electrodeposition of solgel was first 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 molecules25 and corro-

sion inhibition agents,26 have been reported. This work is the

first, 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 profile of Paclitaxel from PLGA NP coatings on coronary

Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem,91904, Israel. E-mail: [email protected]; 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 Namet 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 A work performed by Dawes et al. suggested

the attachment of drug loaded PLGA microspheres to artificial

joints to refrain from recurring joint surgery.35

Here we present a novel method to electrochemically codeposit

hybrid films made of solgel and biodegradable NPs. The latter

were synthesized by the emulsion-diffusion-evaporation tech-

nique. Thin films 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 films by

various methods.

Experimental

Materials

Poly-(D,L-lactide) (PLA, Mw 75 000100 000 g mol1), 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 cm1, EasyPure UV, Barnstead,

UK) was used for all the experiments. Indium tin oxide (ITO)

plates 7 50 0.7 mm3,Rs 1525U) 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 thedeposition solution using a home-made lifter with a velocity of

ca. 0.366 mm s1. Step height measurements were performed

using a P-15 profilometer (KLA-Tencor Co., San Jose, CA,

USA) by creating a notch in the film 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 fluorescent coatings

were acquired by a fluorescent 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 modifications.

Briefly, 200 mg of PLA was dissolved in 10 mL ethyl acetate at

room temperature 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 first 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 specified) of the NPs dispersion and KNO3to

a final concentration of 0.1 M were added.

Electrodeposition. A constant negative potential (0.8 to

1.2 Vvs. 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

Forz 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 byadding a fixed 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 film to 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 s1. 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 films 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. Thez 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 (final 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 pKof chitosan

that isca. 6.87.2.4245 In addition, turbidity was observed in the

dispersion sample for this measurement. Evidently, at this pH the

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 andinduce the precipitation of the NPs. However, our attempts to

carry out such experiments failed. Inhomogeneous and discon-

tinuous thin films 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. Specifically, 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 film on the electrode surface.

To assess the potential needed for the deposition, we first

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 at0.7 Vvs.Ag/AgBr

QRE is seen and attributed to the reduction of water. Based on

our experience the current needed for efficient solgel electro-

deposition is at least0.25 mA cm2. We applied a potential of at

least 0.8 V.

Fig. 1 zPotential 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 s1. (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 film 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 first 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, whichare connected by patches with no defined 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 film is relatively high, which

alludes to the efficient 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. Theapplied potential and its duration were first studied. Fig. 5A

shows the film thickness dependency on the deposition time. The

potential applied was 1.1 V.

As seen in Fig. 5A, the thickness of the film increased with the

time that a sufficiently 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/film interface,whereas deposition occurs at the film/electrolyte interface, it is

plausible that the growth of the film will cease as the pH at the

film/electrolyte interface approaches that of the bulk. Thicker

films 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 film 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 film formed. Yet, there is

a threshold potential, ca. 0.8 V, required to electrochemically

codeposit the NPs/solgel. The effect of the negative potential ondeposition is significant because it affects not only the thickness but

also the quality of the film. As we apply more negative potential the

rate of hydroxide evolution increases, which explains the increase

of film thickness for a given time. In addition, the higher reduction

rate resulted in more aggressive evolution of hydrogen, interfering

with film 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 films, we synthesized NPs

that were loaded with coumarin-1, a fluorescent compound that

was incorporated in the NPs in the course of the synthesis. The

NPs were thereafter used to produce thin films on ITO using thesame electrochemical method for the codeposition with TMOS.

Since coumarin-1 is fluorescent, we were able to obtain a fluo-

rescent image of the codesposit, as seen in Fig. 6. The micrograph

was taken under illumination at 365 nm. Clear fluorescent

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 low solubility in water, it is conceivable

Fig. 5 The effect of the deposition time (A) and potential (B) on film

thickness. All other parameters are as in Fig. 4.

Fig. 6 Fluorescence micrograph of an electrochemically deposited film

of TMOS and NPs loaded with coumarin-1. The film was deposited by

applying 1.1 V for 15 min. In the micrograph the film is illuminated in

365 nm UV light.

Fig. 7 The first and fifth CV cycles of coumarin-1-loaded NPs/TMOS

coated ITO electrode in 20 mM KNO3, scan rate 100 mV s1. The

codeposition was carried out at 1.1 V for 15 min.


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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 fluorescence. Furthermore, since the darker parts of

the micrograph are not entirely black, we suggest that NPs are

located within the entire film, and not only on the surface. It is

likely that a significant fraction of the fluorescence originatingfrom the NPs within the film 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 first and

fifth of six consecutive cycles are shown. A clear oxidation wave

at 1.1 V can be seen in the first cycle, which drastically decreasedand 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 first cycle the oxidized

coumarin-1 originates from the NPs on the surface. This suggests

that in the following cycles we exposed more coumarin-1 from

NPs within the film. This requires alteration of the film as 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. 4.7 108 mol cm2, 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 findings are in agreement with those from the fluorescent

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 films to a mixture ofacetonitrile 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 sufficient 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

films 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 film thickness is in microns, this approachfits 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.

Notes and references

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