Controlled drug delivery through a novel PEG hydrogel encapsulated silica aerogel system

Controlled drug delivery through a novel PEG hydrogel encapsulatedsilica aerogel system

Seda Giray, Tugba Bal, Ayse M. Kartal, Seda Kızılel, Can Erkey

Department of Chemical and Biological Engineering, Koc University, 34450 Sariyer, Istanbul, Turkey

Received 30 May 2011; revised 2 December 2011; accepted 8 December 2011

Published online 28 February 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.a.34056

Abstract: A novel composite material consisting of a silica aero-

gel core coated by a poly(ethylene) glycol (PEG) hydrogel was

developed. The potential of this novel composite as a drug

delivery system was tested with ketoprofen as a model drug

due to its solubility in supercritical carbon dioxide. The results

indicated that both drug loading capacity and drug release pro-

files could be tuned by changing hydrophobicity of aerogels,

and that drug loading capacity increased with decreased hydro-

phobicity, while slower release rates were achieved with

increased hydrophobicity. Furthermore, higher concentration of

PEG diacrylate in the prepolymer solution of the hydrogel

coating delayed the release of the drug which can be attributed

to the lower permeability at higher PEG diacrylate concentra-

tions. The novel composite developed in this study can be easily

implemented to achieve the controlled delivery of various drugs

and/or proteins for specific applications. VC 2012 Wiley Periodicals,

Inc. J Biomed Mater Res Part A: 100A: 1307–1315, 2012.

Key Words: PEG hydrogel, aerogel, photopolymerization,

supercritical CO2, ketoprofen

How to cite this article: Giray S, Bal T, Kartal AM, Kızılel S, Erkey C. 2012. Controlled drug delivery through a novel PEG hydrogelencapsulated silica aerogel system. J Biomed Mater Res Part A 2012:100A:1307–1315.

INTRODUCTION

There is a growing need for efficient and effective drugdelivery vehicle systems to enhance release profile, drugloading capacity, bioavailability, and selectivity. Compositematerials are currently of interest, because they address thelimitations of an individual material, while at the same timethey enable researchers to benefit from advantages of vari-ous materials. Recent advances in polymers and materialshave improved design possibilities for nanostructured com-posites tremendously.1,2

Porous silica aerogels are sol–gel derived nanostruc-tured materials with high surface areas, high pore volumes,and low densities.3 They are produced by supercritical dry-ing of gels obtained via hydrolysis and condensation reac-tions of a silicon alkoxide precursor such as tetraethylortho-silicate (TEOS) in a solvent. Due to their tunable pore sizeand volume, nontoxic, and biocompatible character, aerogelshave been receiving increased attention as suitable hosts formany applications including enzyme immobilization, biosen-sors, waste treatment, and drug release.4–8 Among these,drug-release studies demonstrated that high drug loadingscan be achieved with aerogels and the drugs adsorbed onhydrophilic silica aerogels dissolve faster than the crystal-line drugs. It was also proposed that hydrophilic aerogelscan be used as carrier materials for oral delivery of drugswhere immediate release is desirable. Also, due to their bio-

compatibility, their applications in pulmonary drug deliveryand feasibility to apply as oral drug delivery devices havebeen investigated. As a result, they are targeted as potentialdelivery vehicles for various drugs including diclofenac,9

griseofulvin, miconazole, and ketoprofen.8,10–12 Amongthese, ketoprofen, 2-(3-benzoylphenyl)-propionic acid, is ahydrophobic, nonsteroidal anti-inflammatory drug (NSAID)that inhibits prostaglandin synthase function (Fig. 1). Thistype of NSAID is usually applied to remove the symptomsrelating to rheumatoid artritis,12,13 osteoarthritis,14 andankylosing spondylitis as well as widely used in pain reliefand dysmenorrhea.15,16 For these diseases, there is a greateffort to control sustained release of ketoprofen from vari-ous carriers such as poly(vinyl alcohol) nanofibers,17 den-drimers,16 bioadhesive gels,15 and microparticles.18

Although dosage concentration ranges from 25 to 200 mgper tablet in clinics, in these applications, amount of thedrug applied ranges from 4 to 285 mg.19–25 Due to its shortshelf life, this drug requires frequent dosage when adminis-tered orally, which results in increased level of adverseeffects such as gastrointestinal side effects (irritation, bleed-ing) and renal side effects. When it is applied transdermally,it faces the natural barrier, skin, which limits the penetra-tion of the drug.16,17

In addition to aerogels, hydrogels are commonly used intissue engineering and drug delivery as a matrix either by

Correspondence to: S. Kizilel; e-mail: [email protected] or C. Erkey; e-mail: [email protected]

Contract grant sponsor: College of Engineering at Koc University in Turkey, TUBITAK; contract grant number: 107M326

Contract grant sponsor: Marie Curie FP7-IRG; contract grant number: 239471

VC 2012 WILEY PERIODICALS, INC. 1307

themselves or as a part of a composite material for drugs,peptides, and proteins due to their three dimensional,hydrophilic, and tissue-like properties.26–33 Specifically,poly(ethylene) glycol (PEG)-based hydrogels have receivedsignificant attention, because of their nontoxic, nonimmuno-genic, and hydrophilic character. In previous studies, thekinetics of PEG hydrogel formation and diffusion of variousdrugs and/or proteins through various PEG-based hydrogelnetworks were investigated.15,34–38 For example, it has beenobserved that the release kinetics of proteins and drugscould be tuned by changing PEG chain length or concentra-tion of functional PEG monomer.39 Also, the size or weightof the guest material within the hydrogel is an importantparameter which affects hydrogel permeability. Anothereffective way to control the release of drugs or proteinsfrom hydrogels is to make them responsive to external stim-uli such as pH, temperature, and ionic strength.40 Under aproper stimulus, these responsive hydrogels can switchfrom a collapsed state to a swollen state, which then allowsfor the release of drugs/proteins encapsulated in PEGhydrogel network.

It is a big challenge to control the release of drugs orproteins through a network to provide sustained and se-quential release with a single material that can satisfy theintended application. For example, some materials mayrequire targeted drug to possess a certain degree of hydro-phobicity, while some other materials may have limiteddrug loading capacity. Therefore, there is an increasingtrend in the use of composite materials as drug deliverydevices.41 The use of multiple materials has the advantagethat makes it possible to cap one material as an outer layeron top of the inner material which may act as a reservoir.42–44 Thus, the capability to construct composite material withmultiple layers of varied composition in a single deviceincreases the range of applications and effectiveness ofthese systems. Aerogel–hydrogel composite structures, aswill be presented in this study, may provide more effectivedrug/protein release when a single material cannot meetthe requirements for the application. Furthermore, the pro-files may be adjusted by varying the composition and/orconcentration of the precursor in the PEG prepolymer solu-tion, or by changing the hydrophobicity of the core aerogel.It may also be possible to design PEG hydrogel layer to bedegradable in response to an external stimulus, such aspH34 and thus lead to faster release of the drug from theaerogel core.

Here, we report a novel drug delivery vehicle synthe-sized by encapsulation of hydrophobic or hydrophilic aero-

gels within PEG hydrogel via surface-initiated photopoly-merization. This system can be applied for controlleddelivery of drugs including ketoprofen as well as similardrugs as a part of an implant or oral tablet with a pro-longed site-directed delivery and minimized side effectscompared to the difficulties involved in its oral or transder-mal administration.45 In the first part of the article, detailsof the developed procedures to synthesize these novel com-posite materials are provided. Techniques developed to con-trol the pore structure and hydrophobicity of the core aero-gel material as well as the properties of the hydrophilic PEGhydrogel layer are also presented. In the second part,results on a drug delivery application of the synthesizedcomposites are given. Specifically, the effects of hydropho-bicity of aerogel and PEG concentration of the hydrogelcoating of hydrophilic aerogels on the release rates of keto-profen were examined. Ketoprofen (3-benzoyl-R-methylben-zeneacetic acid) was chosen as a model drug due to reasonsexplained previously. Furthermore, its relatively high solubil-ity in supercritical carbon dioxide (scCO2) enabled loadingof ketoprofen into aerogels by supercritical deposition.

EXPERIMENTAL

MaterialsFor the synthesis of silica aerogels, tetraethylorthosilicate(TEOS) (98.0%) and NH4OH (2.0M in ethanol) were pur-chased from Aldrich, HCl was purchased from Riedel-deHaen (37%). Ethanol was obtained from Merck (99.9%). Forthe surface modification of aerogel, hexamethydisilizane(HMDS) was obtained from Alfa Aesar (98%). Model drug,ketoprofen (MW ¼ 254.30 g/mol) was obtained fromAldrich. For the hydrogel formation, eosin Y (98%), 1-vinyl2-pyrrolidinone (NVP) (99þ%), poly(ethylene glycol) diacry-late (PEGDA) (MW ¼ 575 Da) were obtained from Aldrich.Triethanolamine (TEA) (>99.5%) was obtained from Fluka.Carbon dioxide (99.998 %) was purchased from Messer Ali-gaz (Istanbul, Turkey). The chemicals were used asreceived.

Synthesis of silica aerogelDisk-shaped silica aerogels were synthesized by a two-stepprocedure using TEOS as precursor, HCl as hydrolysis cata-lyst, and NH4OH as condensation catalyst. A solution ofTEOS (50 wt % in ethanol) was prepared. Subsequently,water and acid catalyst were added to start hydrolysisunder continuous stirring. After about 30 min, the base cat-alyst was added to accelerate the condensation reaction andthe sol was taken into cylindrical molds with a diameter of1 cm for complete gelation [Fig. 2(a)]. The overall molar ra-tio of TEOS:water:HCl:NH4OH were kept constant at1:4:2.44 � 10�3:2 � 10�2, respectively. After gelationoccurred, the alcogels were taken out of the mold andplaced in an aging solution (50 vol % ethanol and water),and left in an oven at 323.2 K for 20 h. The aim of agingstep was to prevent shrinkage during supercritical dryingby improving the mechanical strength of the alcogel. Next,the alcogels were kept for three more days in pure ethanolin order to remove water and all impurities [Fig. 2(b)]. After

FIGURE 1. Structure of ketoprofen.

1308 GIRAY ET AL. DRUG DELIVERY THROUGH A PEG HYDROGEL/AEROGEL COMPOSITE

aging step, alcogels were contacted with eosin Y (2 mM inethanol) solution. The adsorption of eosin Y on the surface ofalcogel led to a reddish transparent composite of silica alcogelwith eosin Y [Fig. 2(c)]. The alcogels with eosin Y were subse-quently dried by scCO2 at 313 K and 10.3 MPa [Fig. 2(d)]. Theresulting disk-shaped aerogels were hydrophilic and had a di-ameter of 1 cm and a thickness of 0.2 cm.

Procedure for surface modification of silica aerogelsThe experimental apparatus for the surface modification ofhydrophilic silica aerogels was explained in the previousstudy by Kartal and Erkey.46 A vessel with an internal vol-ume of 54 mL and equipped with two sapphire windowsfor viewing the contents was used for surface modification.Another vessel was used for mixing HMDS with CO2, andhad a volume of 25 mL. For a typical experiment, a certainamount of hydrophilic silica aerogel sample (around 100mg) was placed in the 54 mL vessel and the vessel wasbrought to a temperature of 333.2 K by circulating waterusing a circulating heater (Cole-Parmer polystat tempera-ture controller). The vessel was then charged to 10.34 MPawith CO2 using a syringe pump (Teledyne ISCO model:260D) and isolated at these conditions. The mixing vessel

was prepared by placing a known amount of HMDS into thevessel within a glass vial along with glass beads which keptthe glass vial intact and the vessel was charged with CO2.This vessel was also kept at 10.34 MPa at ambient tempera-ture for 48 h until all HMDS was dissolved in CO2. The sur-face modification of the hydrophilic aerogels was achievedby injection of CO2–HMDS mixture from the mixing vesselto the reaction vessel. This was realized by pressurizing themixing vessel up to 20.68 MPa by charging with CO2 fromthe syringe pump. The CO2–HMDS mixture at 20.68 MPaand at room temperature was injected into the main vesselby opening the valve between reaction vessel and mixingvessel. This procedure was repeated until the pressure inthe reaction vessel reached 20.68 MPa. The vessel was iso-lated at 20.68 MPa and at 333.2 K for the reaction of silicaaerogel surface with HMDS for 30 min. After reaction,extraction of excess HMDS and other reaction byproductswas carried out using scCO2 at 10.34 MPa and at reactiontemperature. Then, the vessel was depressurized at thesame temperature and modified samples were obtained af-ter the vessel was cooled. The surface modification reac-tions were carried out at different ratios of HMDS/aerogelin scCO2 ranging from 0 to 4.2.

Supercritical deposition of the ketoprofenon silica aerogelA certain amount of ketoprofen and aerogel was placed in the54 mL vessel described above. The vessel was heated untilthe temperature reached 333 K, and carbon dioxide wasadded until the pressure was 22 MPa. The system was kept atthis condition and the contents were stirred for 48 h. Afterreaching adsorption equilibrium, CO2 was vented and loadedaerogels was taken out of the vessel and weighed. For allloading experiments in scCO2, the ratio of the mass of aerogelto the mass of ketoprofen placed in the vessel was kept con-stant at unity. Since the aerogel density affected drug loadingcapacity of the aerogel, the density of the aerogel was alsokept constant at 0.2 g/cm3. The amount of loaded drug wascalculated by taking the difference of the aerogel mass beforeand after loading procedure.

Hydrogel coating of silica aerogelsThe hydrogel precursor solution was prepared with TEA(225 mM), 30% and 15% (w/v) PEG diacrylate (MW ¼ 575Da), and NVP (37 mM). The solution was adjusted to pH 8using 6M HCl. Precursor solutions were filter sterilizedusing a 0.2-lm syringe Teflon filter. Eosin and drug-loadedhydrophobic or hydrophilic aerogels were immersed in PEG-diacrylate prepolymer solution and photopolymerizationwas carried out using visible light (514 nm, flux ¼ 5.2 mW/cm2) for 3 min for each surface of the aerogels [Fig. 2(f)].Immobilized eosin Y on the surface of the aerogel initiatedthe formation of PEG diacrylate hydrogel on the surface.47,48

Eosin was used as the photoinitiator since its spectral prop-erties perfectly suit its application as an initiating systemfor an argon ion laser49–51 This step resulted in the forma-tion of a cross-linked thin PEG hydrogel coating around thehydrophobic or hydrophilic aerogels.

FIGURE 2. Scheme for synthesis of eosin Y functionalized hydropho-

bic aerogel formation and its subsequent coating within PEG hydro-

gel. [Color figure can be viewed in the online issue, which is available

at wileyonlinelibrary.com.]

ORIGINAL ARTICLE

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH A | MAY 2012 VOL 100A, ISSUE 5 1309

Ketoprofen release experimentsDrug release experiments were conducted at 310 K and underconstant string at 100 rpm. The release medium was selectedas HCl solution (0.1N) to mimic gastric fluid.52 Each aerogelsample was placed in a small bag made out of filter paper andimmersed into a glass vessel containing HCl solution (100 mL,0.1N). Three samples were used per condition. The glass vesselwas covered and placed on a stirrer which was kept inside anoven at 310 K. At specific time points, approximately 20 lLsamples were taken and placed into 0.5 mL eppendorf tubes.The concentration of ketoprofen was determined using a spec-trophotometer (Thermo Fisher Scientific Nanodrop 1000) at260 nm for release experiments, due to the specific absorptionof ketoprofen at this wavelength. In control samples, neitherPEG hydrogel nor aerogels gave significant absorbance at 260nm, which proves that absorbance at 260 nm was the result ofketoprofen release (data not shown).

Calculations for diffusion coefficientsThe effective diffusion coefficients for coated and noncoatedaerogels were calculated using Fick’s law53,54:

Mi

Minfffi 2

Det

pd2

� �1=2(1)

Here, Mi and Minf are the released concentrations of thedrug at time i and at time infinity, respectively. De is theeffective diffusion coefficient (cm2/min), t is time (min), andd is the half of the thickness of the aerogel (cm). This equa-tion shows that De can be calculated from the plot of Mi/Minf versus t1/2. In order to calculate, Mi, solute diffused attime i, a mass balanced was carried out as follows:

Mi ¼ CiV (2)

where Ci is the concentration of the drug at time i, V is the totalvolume of the release solution (100 mL). Calculated De valuesare also normalized by using D0 which is the diffusion coeffi-cient of ketoprofen in water at 37�C (7.68 � 10�6 cm2/s).54,55

Contact angle determinationContact angle was measured by using a home-made devicewhich included a camera connected to a computer. First ofall, a 2 lL drop of water was put onto the aerogel surfaceusing a micropipette and placed in front of the camera. Aftertaking a picture of this image, angle between the water drop-let and the surface was measured by set-squared ruler. Foreach surface, measurement was repeated more than threetimes and the average of them was reported as final value.

Nitrogen adsorption–desorption measurementsEffects of eosin loading and surface modification steps onthe pore structure of the aerogel were investigated with theadsorption/desorption isotherms of nitrogen at 77 K (Mi-cromeritics ASAP 2020 surface analyzer). Each sample wasdegassed at 573 K for at least 150 min before analysis. Forhydrogel-coated aerogels, in order to separate hydrogelfrom the aerogel, they were left in the furnace at 323 K. As

water evaporated from the hydrogel, it shrank and sepa-rated from the aerogel surface. The resulting pieces of theaerogel were used in the pore structure analysis.

Statistical analysisThe results of all data sets are analyzed using one-way anal-ysis of variance (ANOVA). The results are represented as themean value (6SD) of the triplicate samples unless other-wise stated. Differences between datasets are consideredstatistically significant for p-values less than 0.05.

RESULTS AND DISCUSSION

Functionalization and coating of silicaaerogel within PEG hydrogelVisual examination of silica aerogels after surface modifica-tion steps showed that the originally colorless transparentaerogels retained a red color due to the presence of eosinwithin the aerogel structure [Fig. 3(a,b)]. It is clearlyobserved from these figures that eosin molecules werehomogeneously distributed throughout the aerogel. Uniformeosin distribution on the surface of aerogel is important asnonuniform distribution would compromise homogeneouscoating of aerogel within PEG hydrogel. The penetrationdepth of the eosin molecules can also be adjusted by con-tact time of the ethanol solution with the aerogel.

The hydrophobicity of aerogel after HMDS functionaliza-tion step was quantified by placing a water droplet, andmeasuring the contact angle on the surface of the aerogel[Fig. 3(c)]. For one of the conditions, it was found that thecontact angle of water droplet for the eosin-modified hydro-phobic aerogel was 128� [Fig. 3(c)]. Figure 3(d) shows theimage of a PEG hydrogel-coated eosin functionalized hydro-phobic aerogel. The thickness of the hydrogel coating wasapproximately 300 lm.

Characterization of functionalizedand hydrogel-coated silica aerogelsEffects of eosin loading and surface modification step on thepore structure of the aerogel were investigated. Pore size andpore size distribution were determined by nitrogen adsorp-tion analysis. In Table I, BET (Brunauer–Emmett–Teller) spe-cific surface area, Barrett–Joyner–Halenda (BJH) cumulativedesorption pore volume, and average pore radius were com-pared for pure aerogel, eosin-loaded aerogel, hydrophobicaerogel, and hydrophobic aerogel after hydrogel coating. Theresults suggest that the presence of eosin on the aerogel sur-face caused BET specific surface area to decrease slightlywith no significant changes in the average pore diameter.Further modification of the eosin-functionalized aerogel sur-face with HMDS decreased the surface area from about 820to 529 m2/g, cumulative pore volume from 2.5 to 2.2 cm3/g,and increased the average pore radius from 6 to 6.7 nm. Thiscould be attributed to the presence of some bottleneck typepores, which are blocked by SiA(CH3)3 groups after surfacemodification reaction. However, pore volumes and surfaceareas are still high enough for carrier applications.

Adsorption isotherms and pore size distributions ofmodified aerogels are compared in Figure 4(a,b). All


samples exhibited similar pore size distribution and typicaltype H1 type isotherms which indicate that the materialsconsist of compact agglomerates of approximately uniformspheres of silica and such a network is not disrupted by eo-sin loading, surface modification, and PEG hydrogel coating.

The BET specific surface area and pore size distributionmeasurements for noncoated and coated aerogels showedthat the surface area of the hydrophobic aerogel did notchange after encapsulation within PEG hydrogel. Also, iso-therms and pore distributions of the two samples werenearly identical which indicated that hydrogel coating wasonly restricted to the external surface of the monolithicdisks and water-based prepolymer solution did not pene-trate through the hydrophobic pore structure of the aerogelbefore and during photopolymerization. These results indi-cate that the pore properties of aerogels during sol–gel syn-thesis do not change significantly by various functionaliza-tion techniques used in this study.

Ketoprofen-loaded silica aerogelsThere are mainly two methods for loading of aerogels withdrugs or proteins. One of these is supercritical depositionwhich involves placing the aerogel in a solution of the drugdissolved in scCO2. After adsorption of the drug on the silicaaerogel surface, CO2 can be vented out leaving behindadsorbed drug on the internal surface with varying degreesof hydrophobicity. The second method involves contactingthe gels with a solution of the drug in a solvent during oneof the steps in the sol–gel synthesis before supercritical dry-ing. The first method is more favorable for drug deliveryapplications, since CO2 is nontoxic and leaves no residue inthe medium. The drug may be desorbed from the surfaceduring supercritical drying step with the second method.Therefore, in this study, drug was loaded into the aerogelstructure from the supercritical CO2 phase. Ketoprofen has ahigh enough solubility in scCO2 (15.5 � 10�5 mole fractionat 331.5 K and 22 MPa) for supercritical deposition.

FIGURE 3. Image of (a) pure aerogel, (b) eosin-doped hydrophilic aerogel, (c) water droplet on the eosin-doped hydrophobic aerogel, and (d)

hydrogel-coated hydrophobic aerogel. Images are taken using a computer equipped with a Q Imaging Micropublisher 3.3RTV camera. [Color fig-

ure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

TABLE I. Variation of Pore Structure of Aerogel After Surface Modification Steps

SampleBET surfacearea (m2/g)

BJH cumulativepore volume (cm3/g)

BJH averagepore radius (nm)

Pure aerogel 926 6 9 2.90 6 0.03 5.90 6 0.06Eosin-loaded aerogel 820 6 8 2.500 6 0.025 6.00 6 0.06After surface modification 528 6 5 2.10 6 0.02 6.40 6 0.07After hydrogel coating 529 6 5 2.20 6 0.02 6.70 6 0.07

BET surface area of pure aerogel and eosin-loaded aerogel are different from the surface modified or hydrogel-coated aerogel samples (p <

0.05). BET surface area between the surface modified and hydrogel-coated aerogel samples do not significantly differ from each other. BJH cu-

mulative pore volume in all groups statistically differs from each other (p < 0.05). BJH average pore radius for pure aerogel and eosin-loaded

aerogel do not significantly differ from each other, whereas significant differences (p < 0.05) are observed between the remaining groups.

ORIGINAL ARTICLE


Ketoprofen was loaded into aerogels with differentdegrees of hydrophobicity which were obtained by changingthe ratio of HMDS/aerogel (mg/mg) in scCO2 during surfacefunctionalization from supercritical solutions (SFFSS). Sinceincreasing hydrophobicity is due to the replacement of sur-face hydroxyl groups on the silica surface by the Si(CH3)3groups of HMDS, decreasing or increasing the amount ofHMDS in scCO2 provides a control in the number of OHgroups on aerogel surface. The results showed that the con-tact angle increased from 0 to 128�C as HMDS/aerogel (mg/mg) ratio in scCO2 was increased from 0 to 4.2 (Table II,Fig. 5). This resulted in a decrease of the drug loadingcapacity from 96 to 7% (w/w) (Table II). These percentages

correspond to 40 mg and 5 mg total drug amount, respec-tively, for the disk-shaped aerogels used in this study. Previ-ous studies have shown that the adsorption isotherm of keto-profen on silica aerogel in the presence of scCO2 at constanttemperature and pressure strongly depends on the hydropho-bicity of silica aerogel.10 The ketoprofen loading obtained ona hydrophobic aerogel was lower than that of a hydrophilicaerogel, which was attributed to the decreased number of OHgroups that provide active sites for hydrogen bonding withketoprofen. This behavior is also observed in our studies andthe results suggest that it is also possible to control drugloading by controlling the hydrophobicity of aerogel.

It should be noted that a gradient in hydrophobicity wasobtained through the core of the disk-shaped aerogels,when lower amounts of HMDS was used. This resulted inhigher hydrophobicities at the regions closer to outer sur-face compared to regions closer to the center of the aerogel.This is due to the fact that the reaction between OH groupsand HMDS starts at the outer surface of the aerogel andmoves toward the center of the aerogel. Such a gradientmay provide an additional parameter for release control.

Effect of hydrophobicity on ketoprofen release behaviorAs shown in Figure 6, drug release rates varied with thedegree of the hydrophobicity of the aerogel. As aerogelsbecame more hydrophobic, release rate was decreased. Forhydrophilic aerogels, release was completed nearly within10 h [Fig. 6(a)]. However, for aerogel with a contact angleof 66�, release was completed in approximately 24 h. Whenhydrophobicity of the aerogel was increased further (up toa contact angle of 128�), a slower release rate for ketopro-fen was observed [Fig. 6(b,c)].

FIGURE 4. Effect of eosin loading and surface modification on (a)

nitrogen adsorption isotherms and (b) pore size distribution.

TABLE II. Results of Contact Angle and Drug Loading of

Different Hydrophobic Aerogels

Ratio ofHMDS/aerogel

(mg/mg)in scCO2 Contact angle

Mass percentageof drug loadingto the aerogelmass (% w/w)

0 0 96 6 11.1 0 –1.8 66 6 1 25.00 6 0.252.3 87 6 1 13.0 6 0.13 128 6 1 –4.2 128 6 1 7.00 6 0.07

Mass percentage of drug loading to the aerogel mass (% w/w) sig-

nificantly differ from each other for all groups (p < 0.05).

FIGURE 5. Image of water droplets on aerogels with different hydrophobicities. [Color figure can be viewed in the online issue, which is avail-

able at wileyonlinelibrary.com.]


In addition, it was observed that the hydrophilic aerogellost its disk shape during the drug release experiments andmatrix erosion occurred, while all hydrophobic aerogels pre-served their original shapes during the drug release experi-ments. The absence of matrix erosion was an indication thatthe release was governed by diffusion (Fig. 6).

Ketoprofen release from coated andnoncoated hydrophilic aerogelsThe ketoprofen-loaded aerogels were coated with PEGhydrogel layer by applying the same method for coating theaerogels with PEG hydrogel. Figure 7 shows ketoprofenrelease profiles from noncoated aerogel, and hydrogel-coated aerogels with two different PEG diacrylate concentra-tions; 15% and 30% by weight. As shown in Figure 7, dur-ing the first 51 h (3060 min), only 55% of the drug wasreleased through 30% PEG hydrogel-coated silica aerogel.For the case of 15% (w/v) coated aerogels, 80% of thedrug was released within 72 h (4320 min). These resultsshow that coating with PEG hydrogel can retard drugrelease from silica aerogels and the release rate is slowerwith the coating prepared using 30 wt % prepolymer solu-tion. This is because, PEG hydrogel mesh size, whichdepends on the crosslink density, modulates the diffusion ofthe drug through the hydrogel membrane, and thus affectsthe release rate of the drug [Fig. 7(a,b)]. Hydrophilic aero-gels crumbled when they were wetted in water which ledto faster release of ketoprofen.8 Coating of aerogels withPEG hydrogel retarded this process. Thus, hydrogel coating

FIGURE 6. Release behavior of ketoprofen from aerogels with different

hydrophobicities. (h: contact angle) (a) and (b) percent release, (c) fractional

release in the regionMi/Minf< 0.6 (R2¼ 0.98 for hydrophobic hydrogel (h¼66�), R2 ¼ 0.99 for hydrophobic (h ¼ 128�) and R2 ¼ 0.99 for hydrophilic

aerogels).

FIGURE 7. Release behavior of ketoprofen from coated hydrogels. (a)

Percent release, (b) fractional release in the region Mi/Minf < 0.6. (R2

¼ 0.99 for hydrophilic, R2 ¼ 0.94 for coated (15%) and R2 ¼ 0.95 for

coated (30%) aerogels).

ORIGINAL ARTICLE


acts as not only as a barrier for the diffusion of the drugmolecules, but also as a barrier which retards the crumblingof the hydrophilic aerogels.

The release rate of a drug from a medium depends ondifferent parameters such as diffusion coefficient of thedrug in the matrix, drug particle diameter, molecular weightof the drug, and drug solubility in the released medium.The results presented in this study are consistent with thefundamental fact that diffusion coefficients of proteins ordrugs are higher in membranes with higher permeabilitycompared to the values observed through membranes withlower permeability.39,56,57 It is clearly observed that increas-ing hydrophobicity decreased drug release rates, thus low-ered both diffusion rate and effective diffusion coefficients(Table III). Furthermore, coating of aerogels retarded releaseof ketoprofen from the composite structure, since normal-ized effective diffusion coefficients of ketoprofen withrespect to its diffusivity in water through aerogel coatedwith 15% (w/v) and 30% (w/v) PEG hydrogel have beenmeasured as �0.9 and 0.07%, respectively (Fig. 8). Suchlower diffusivities could be attributed to the differences indiffusion mechanism of the drug through aerogel structure.Commonly, release of small molecular weight drugs or pro-teins involve diffusion of these compounds through water-filled networks, such as hydrogels, however, in this systemthe release of ketoprofen involves both its desorption fromaerogel scaffold and its diffusion through water-filled aero-gel pores. As hydrophobicity of aerogel increase, it takes

longer for water molecules to hydrate the pores of aerogel,and hence this causes delays in the release of drug throughthis composite structure. As a result, low values for the nor-malized effective diffusivities have been observed for keto-profen through the composite structure developed.

CONCLUSIONS

In summary, we have developed a novel aerogel/PEG hydro-gel composite, and examined the delivery of a model drug,ketoprofen, from this composite structure. The core-shellstructure can be synthesized by coating of hydrophilic and/or hydrophobic aerogels via surface-initiated photopolymeri-zation of PEG hydrogel precursors. By incorporating the ini-tiator, eosin Y, into aerogel structure, it was possible to coataerogel with PEG hydrogel membrane. By adjusting thedegree of hydrophobicity of the aerogel core and permeabil-ity property of the PEG hydrogel shell, it was possible tocontrol the release profile of ketoprofen. This compositecould be easily implemented as a potential drug delivery ve-hicle to achieve sequential release of drugs with differenthydrophobicities, such that hydrophobic and hydrophilicdrug could be loaded into the aerogel core and PEG hydro-gel shell, respectively. Moreover, the use of pH- or tempera-ture-responsive PEG hydrogel in the composite structuremay allow for the degradation of PEG hydrogel network toachieve faster release of a drug loaded within the aerogelcore.

ACKNOWLEDGMENTS

Authors thank Prof. Levent Demirel for allowing them to usegoniometer for contact angle measurements.

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TABLE III. Summary of the Results for Effective Diffusivities

of Different Hydrophobic Aerogels and Hydrogel-Coated

Hydrophilic Aerogel Samples

Aerogel sample De (cm2/min)

Hydrophilic 1.38 �10�5 6 1.20 �10�6

Hydrohobic, (66�) 9.82 �10�6 6 1.02 �10�6

Hydrophobic, (128�) 1.84 �10�6 6 1.72 �10�7

30% PEG hydrogel coated 3.16 �10�7 6 6.13 �10�8

15% PEG hydrogel coated 4.03 �10�6 6 1.08 �10�7

FIGURE 8. Effective diffusion coefficient normalized with D0, diffusion

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Controlled drug delivery through a novel PEG hydrogel encapsulated silica aerogel system

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