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Polymer 52 (2011) 91e97

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Polymer

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A novel route for the preparation of thermally sensitive core-shellmagnetic nanoparticles

Muhammad Omer a, Sajjad Haider a,b, Soo-Young Park a,*

aDepartment of Polymer Science, Kyungpook National University, #1370 Sankyuk-Dong, Buk-gu, Daegu 702-701, Republic of KoreabDepartment of Chemical Engineering, College of Engineering, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia

a r t i c l e i n f o

Article history:Received 26 August 2010Received in revised form29 October 2010Accepted 6 November 2010Available online 13 November 2010

Keywords:MNPsOA/MAH-b-CD coatingPoly(NIPAAm)

* Corresponding author. Tel.: þ82 53 950 5630; faxE-mail address: psy@knu.ac.kr (S.-Y. Park).

0032-3861/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.polymer.2010.11.011

a b s t r a c t

This study has developed a novel route for the synthesis of the thermoresponsive core-shell nano-particles that consist of the magnetite core and the poly(N-isopropylacrylamide) (poly(NIPAAm) shell inaqueous medium. Magnetic nanoparticles (MNPs) were coated first with oleic acid (OA) and then vinylcarboxylic acid-b-cyclodextrin (MAH-b-CD). The OA-MNPs and the MAH-b-CD-MNPs showed mono-dispersion in n-hexane and aqueous medium, respectively. NIPAAms were successfully polymerized fromthe vinyl double bonds of the MAH-b-CD MNPs and cross-linked with N, N-methylenebisacrylamide(MBA) to make the stable thermoresponsive core-shell morphology with the MNP core and the poly(NIPAAm) shell (poly(NIPAAm)-MNP). The aqueous solutions dispersed with poly(NIPAAm)-MNPsshowed magnetic heating due to a superparamagnetic property, and the poly(NIPAAm) shell shrankabove its LCST temperature. The combination of these properties are potentially important in the tar-geted delivery of therapeutic agents in vivo, hyperthermic treatment of tumors, magnetic resonanceimaging (MRI) as a contrasting agents, tissue repair, immunoassay, cell separation, biomagnetic sepa-ration of biomolecules, etc.

� 2010 Elsevier Ltd. All rights reserved.

1. Introduction

In the past few years, considerable interest has been devotedtoward the design of new drug delivery systems [1] with an aim torelease drug at a controlled rate and desired time [2]. MNPshave shown great potential for use in biomedicine due to theirability to get close to biological entities such as cells, viruses,proteins, and genes with heating ability when exposed to a time-varying magnetic field [3]. Superparamagnetic MNPs with provedbiocompatibility [4], have attracted significant attention as drugcarriers in hyperthermia therapy [5], magnetic resonance imaging(MRI) as a contrasting agent, tissue repair, immunoassay, and cellseparation procedures [6]. Awide range of methods were proposedfor the synthesis of iron and iron-based MNPs. To produce MNPs inan aqueous medium considerable research has been done so far.Co-precipitation is a simple and suitableway to produce iron oxidesfrom aqueous salt solutions of Feþ2/Feþ3 by the addition of a baseunder inert atmosphere at room temperature or at elevatedtemperature. The size, shape, and composition of the magneticnanoparticles much depend on the type of salts used (e.g. chlorides,

: þ82 53 950 6623.

All rights reserved.

nitrates, sulfates) the Feþ2/Feþ3 ratio, the reaction temperature, thepH value and ionic strength of the media. With this synthesis, oncethe synthetic conditions are fixed, the quality of the magnetitenanoparticles is fully reproducible [7,8]. Barick et al. synthesizedaqueous stable amine functionalized Fe3O4 magnetic nanoparticlenanoassemblies (MNNAs) by a single step process [9]. Park et al.synthesized MNPs by modified high temperature thermal decom-position method [10]. Popovici et al. used a laser pyrolysis tech-nique to produce iron-based nanomaterials [11]. Choi et al.synthesizedMNPs by chemical vapor condensation and pyrolysis oforganometallic precursors of Fe(CO)5 [12]. Xiaomin et al. developeda one-step route for the preparation of MNPs by reduction of ironsalts with hydrazine hydrate in a strong alkaline solution [13]. Meraet al. synthesized MNPs by a colloidal method at room temperaturewithout the use of surfactants [14].

MNPs generates heat via magnetic hysteresis loss, Neel-relaxa-tion, andBrown-relaxationwhenexposed to avaryingmagneticfield[7] whereas thermally-responsive polymers can collapse or expandon heating [15]. Combining MNPs with thermally-responsive poly-mers represents an important class of composite responsivematerialwith potential applications in biomedical fields, such asmicro fluidicdevices [16], pulsatile drug release systems [17e20], bioadhesionmediators [21,22] and motors/actuators and hyperthermia, etc.,

M. Omer et al. / Polymer 52 (2011) 91e9792

[23e25]. Poly(NIPAAm) collapses when the temperature increasesabove its LCST temperature. The phase transition in poly(NIPAAm) isdue to theamphiphilicnatureof themonomerunit itself. Thebalancebetween the hydrogen bonding interactions (between the hydro-philic eC]O and eNH groups) and the hydrophobic interactions(between pendant isopropyl groups) is instrumental in stabilizingpoly(NIPAAm) [26]. Themajor problem associatedwithMNPs is thatthey are usually dispersed in organic media. Not many studies havebeen reported in the literature on the synthesis of MNPs dispersiblein aqueousmedium. Topotentially useMNPs inbiomedicalfields andto understand their implications, it is essential to develop a genericsynthetic routewhich can transferMNPs fromanorganic phase to anaqueous-phase.

The present work has developed a novel route for the synthesisof the aqueous-phase dispersible MNPs coated with the thermor-esponsive polymer poly(NIPAAm). It is believed that this novelroute for the synthesis of the thermoresponsive core-shell MNPs inaqueous medium (Scheme 1) will prove a potential step forward inthe use of these core-shell MNPs in robust controlled drug delivery[27], tissue repair, immunoassay, cell separation, biomagneticseparation of biomolecules, etc.

2. Experimental

2.1. Preparation of poly(NIPAAm)-MNPs

Ferric chloride hexahydrate (FeCl3$6H2O), ferrous chloride tet-rahydrate (FeCl2$4H2O), sodium hydroxide (NaOH), oleic acid (OA),maleic anhydride (MAH), benzene, n-hexane, N, N-dimethylformamide (DMF), acetone (C3H6O), trichloromethane (CHCl3)potassium persulfate (KPS) were purchased from Duksan�.b-cyclodextrin (b-CD), N-isopropylacrylamide (NIPAAm) and N,N-methylenebisacrylamide (MBA) were purchased from SigmaAldrich�. KPS and NIPAAm were recrystallized from water anda benzene/n-hexane (3:6 v/v) mixture, respectively. All the otherchemicals were of analytical-reagent grade and were used asreceived. Magnetites were synthesized using the chemical co-precipitation method. Calculated amounts of FeCl2$4H2O andFeCl3$6H2O in grams were dissolved into deionized water. A three-

Scheme 1. Schematic for the preparation of the thermoresponsive MNPs coated withOA, MAH-b-CD and poly(NIPAAm) in sequence.

necked flask was charged with 100 mL of 2 mol L�1 NaOH solution.The solution of Feþ2/Feþ3 was added dropwise to the NaOH solutionand themixture solutionwas vigorously stirred over a period of 2 h.The resulting MNPs were washed repeatedly with deionized water,dried in a vacuum oven at 50 �C for 12 h, and stored in glass vials.

To obtain the OA-modified MNPs (OA-MNPs), calculatedamounts of MNPs were sonicated in deionized water for 1 h. 13 mLof OA per gram of MNPs were added dropwise into the MNP-dispersed in water at 80 �C over the course of 2 h under vigorousmechanical stirring and nitrogen atmosphere. After modification,the MNPs were extracted into n-hexane and washed repeatedlywith first water and then ethanol to remove the unreacted OAs [28].The introduction of MAH in b-CD was performed according to thereported method as follows [29]. A 5.68 g of b-CD (0.005 mol) wasdissolved in 30 mL DMF, and then 4.90 g of MAH (0.05 mol) wasadded to it. The solutionwas heated at 80 �C under vigorous stirringfor 10 h.When the reactionwas completed, the solutionwas cooledat room temperature and 30mL of trichloromethanewere added toit. White precipitates of MAH-b-CD were filtered, washed threetimes with acetone, dried in a vacuum oven at 40 �C for 24 h, andstored in a glass vial. For the coating of the OA-MNPs with MAH-b-CD (MAH-b-CD-MNPs), equal volumes of the OA-MNPs n-hexanesolution (2 wt %) and the MAH-b-CD aqueous solution (2 wt %)were mechanically stirred at room temperature for 48 h. TheOA-MNPs were transferred into the MAH-b-CD aqueous solution tomake the MAH-b-CD-MNPs (the details will be discussed in theResults and discussion section) [30]. The MAH-b-CD-MNP powderswere obtained by drying the aqueous part of the phase-separatedn-hexane/water solution. TheMAH-b-CD-MNPs were used to makethe thermoresponsive core-shell MNPs that consist of the magne-tite core and the poly(NIPAAm) shell (poly(NIPAAm)-MNPs) [31] byusing a precipitation polymerizationmethod in the presence of KPS(as an initiator) and MBA (as a cross-linker) under nitrogen atmo-sphere at 70 �C [32]. The mixture was cooled to room temperatureand diluted with distilled water. The poly(NIPAAm)-MNPs wereisolated from the solution by placing a magnet below the reactionvial. This process was repeated several times to remove theunreacted NIPAAm monomers and the separated poly(NIPAAm)chains from the MNPs.

2.2. Characterization

FT-IR spectra were obtained with a Nicolet-560 spectrometer onKBr pellets. X-ray diffraction (XRD) patterns of the MNPs wererecorded using an X-ray diffractometer (D/max-Ra, Rigaku, Japan)with Cu-Ka radiation at 42 kV and 109 mA. The crystal size of MNPswas calculated using a Scherrer’s equation (Eq.(1)) where b is thewidth of the peak at half maximum intensity of a specific (hkl)diffraction peak in radians, K is a constant of 0.9, l is thewavelengthof the incident X-ray, q is the half angle between the incident anddiffracted beams (2q), and L is the crystallite size.

L ¼ Klbcos q

(1)

Different sizes (diameter) of magnetic nanoparticles i.e., 8.6,10.7, and 14.9 nm were obtained as mentioned in the Table 1 byusing the Scherrer’s equation along with their saturation magne-tization (Ms) and coercivity (Hc). The magnetic properties of thesynthesized MNPs were measured by using a lakeshore 7400vibrating-sample magnetometer (VSM) at room temperature. Themorphologies of the as-synthesized MNPs, the OA-MNPs, theMAH-b-CD-MNPs, and the poly(NIPAAm)-MNPs were studiedusing transmission electron microscopy (TEM, JEM-1OOCX, JEOL,Japan) with an accelerating voltage of 80 kV. Samples for TEMwere

Table 1Crystal size and magnetic properties of S1, S2, and S3 determined from X-ray andVSM. Particle size along with their standard deviation of OA coated, MAH-Beta-CDand PNIPAAm coated MNPS is given. Ms is saturation magnetization, the values forcoercivity (Hc) (unit is Oersted (Oe) in cgs system and Amperes per meter (A/m) in SIsystem) are given.

Sample Feþ2

(M)Feþ3

(M)Particlesize (nm)

Standarddeviation (sd)

Ms(emu.g�1)

Hc (Oe)

S1 0.05 0.1 8.6 e 67.0 53.57S2 0.1 0.2 10.7 e 67.0 57.40S3 0.5 1.0 14.9 e 80.0 74.69OA coated MNPs e 36.0 16 e

MAH-Beta-CDMNPs

e 66.0 18 e

PNIPAAm-MNPs e 87.0 33 e

M. Omer et al. / Polymer 52 (2011) 91e97 93

prepared by dispersing the MNPs in acetone at a very diluteconcentration, dropping the dispersed solution on the carbon-coated copper grid, and then evaporating it. Poly(NIPAAm) wasnegatively stained with phosphotungstic acid in order to make thepolymer part visible (Negative staining solution was prepared bydissolving 0.1 g (1 wt%) of sodium phosphotungstate (PTA) powderto 10mL of distilled water in a shell vial). The pH of the solutionwasadjusted to 7.2e7.4 with the 0.1 N NaOH. The particle size of theOA-MNPs, MAH-b-CD-MNPs, and poly(NIPAAm)-MNPs weremeasured by taking into consideration upto two hundred (200)particles each from OA-MNPs, MAH-b-CD-MNPs, and poly

Fig. 1. (a) FT-IR spectra, (b) X-ray diffraction patterns, and (c) magnetization curves of the S1is the magnetic field strength.

(NIPAAm)-MNPs, determined their diameters and then find outtheir mean value (diameter) in nm along with the standard devi-ation as presented in Table 1. TGA thermograms were obtained ina nitrogen atmosphere at a heating rate of 10 �C/min between 25 �Cand 600 �C using a TA 4000/Auto DSC 2910 System. The inductionheating was measured with HF Induction Heater at 293 kHz and2.5 kW with 4 mL and 2 g/L solutions in which the weight of theMNPs from TGA results were considered for calculating theconcentration of the solutions in the case of the organic materialcoatedMNPs such as the OA-MNP and the poly (NIPAAm)-MNP. Thehydrodynamic radius (Rh) of the poly(NIPAAm)-MNPs wasmeasured with a dynamic light scattering (DLS) method (ELS-8000,Photal Otsuka electronics) at a wavelength of 632.8 nm (heliumneon laser) from 22 �C to 68 �C with an increment of 2 �C. Theconcentration of the poly(NIPAAm)-MNP solution was 0.06 wt%,and the sample was sonicated before DLS measurement.

3. Results and discussion

3.1. Preparation of MNPs

The MNPs were synthesized with different Feþ2/Feþ3 ratios asgiven in Table 1. The Feþ2/Feþ3 ratios of S1, S2, and S3 inmol L�1 (M)are 0.05/0.1, 0.1/0.2, and 0.5/1, respectively (As Fe3O4 can besynthesized by a molar ratio of 1:2 of ferrous and ferric salts,therefore, same ratio (1:2) has been kept for the concentration of

, S2 and S3 MNPs at room temperature where Ms is the saturation magnetization and H

Fig. 2. (a) FT-IR spectra of the (I) OA, (II) the OA-MNPs, (III) the b-CD, (IV) the MAH-b-CD, and (V) the poly(NIPAAm)-MNPs, (b) FT-IR spectra of coated particles zoomed from 800 to1800 cm�1 (c) the schematic, and (d) the digital image of the phase transfer of S3 MNPs from an organic phase to an aqueous-phase.

M. Omer et al. / Polymer 52 (2011) 91e9794

Feþ2 and Feþ3). Fig. 1a shows the FT-IR spectra of the synthesizedMNPs. As-synthesized MNPs showed bands at 570 and 630 cm�1

corresponding to the absorption bands of the FeeO bond in thecrystalline lattice, indicating that MNPs were successfully synthe-sized [33]. Fig. 1b represents the XRD patterns of the S1, S2, and S3with seven strong Bragg diffraction peaks, which can be indexed as(220), (311), (400), (422), (511), (440), and (533) of magnetite(Fe3O4) in a cubic phase [34]. The crystal size of MNPs calculatedfrom the most intense (311) peak increased with an increase in theFeþ2/Feþ3M ratio (Table 1). Due to concentration effects the particlesize has increased, also the same concentration ratio (1:2) has beenkept throughout the synthesis of MNPs as Molar ratio for Feþ2 andFeþ3 is also same as 1:2. Fig. 1c illustrates the magnetization curvesof the S1, S2, and S3. The saturation magnetization (Ms) increasedwith an increase in the crystal size of the particles. The

Fig. 3. TEM micrographs of (a) OA-MNPs, (b) MAH-b-CD-MNPs, and (c) poly(NIPAAm)-MNMNPs and poly(NIPAAm)-MNPs in distilled water. The dispersed samples were dropped(NIPAAm)-MNPs were stained with phosphotungstic acid.

undetectable hysteresis and coercivity suggests that the synthe-sized MNPs have superparamagnetic properties. The S3 MNPsshowed higher Ms compared to S1 and S2, therefore, S3 MNPs wereused in this article.

3.2. Structure of MNPs

Fig. 2a shows the FT-IR spectra of the OA, the OA-MNPs, theb-CD, the MAH-b-CD, and the Poly(NIPAAm)-MNPs. The FT-IRspectrum of the OA showed bands at2924, 2854, 3500, 1708, 1453and 1285 cm�1, which were attributed to the asymmetric CH2 andsymmetric CH2 stretching, OeH in plan bending, and C]O and CeOstretch [35]. The OA-MNPs spectrum showed bands at 2922, 2852,1187 cm�1 and reduced band at 3500 cm�1 as well as the MNPbands (the absorption bands of the FeeO bond, Fig. 1a) at 570 and

Ps. The samples were prepared by dispersing OA-MNPs in n-hexane and MAH-b-CD-on to a graphite coated copper grid and the solvent was allowed to evaporate. Poly

Fig. 4. TGA thermograms of the MNPs, the OA-MNPs and the poly(NIPAAm)-MNPs.

M. Omer et al. / Polymer 52 (2011) 91e97 95

630 cm�1. The shift in the bands to the lower wave numbers 2922,2852 and 1187 cm�1, the reduction of 3500 cm�1 and broadening of1453 cm�1 bands might be attributed to the fact that OA moleculesin the adsorbed state were subject to the field of solid surface andthat hydrocarbon chains in the monolayer surrounding the MNPSwere in closed-packed crystalline state [35]. The results confirm

Fig. 5. (a) The temperature changes of the MNP (in 1 M HNO3), the OA-MNP (in hexane), atime, (b) digital images of poly (NIPAAm)-MNPs in aqueous solution (I) without and (II) withwater.

that OA chemisorbed onto the surface of the MNPs, although theconsistent C]O stretching band at 1712 cm�1might be due to someuncoated OAmolecules [36]. In the spectra of b-CD and MAH-b-CD,the eOH band at 3200 cm�1 in b-CD was shifted to 3500 cm�1 inMAH-b-CD as a result of the introduction ofMAH [29]. The intensityof the eCH2OeH vibration band around 2900 cm�1 in b-CD wasreduced in MAH-b-CD due to the nucleophilic reaction of thehydroxyl oxyen in eCH2OeH groups with the carbonyl carbon ofMAH [37]. New eCOOH and C]O stretching bands at 2560 and1720 cm�1, respectively, also appeared in MAH-b-CD. The shiftofeOH band, the reduction in intensity of theeCH2eOH stretchingbands, and the appearance of new eCOOH and C]O bands in thespectrum of MAH-b-CD confirmed the successful synthesis ofMAH-b-CD. The FT-IR spectrum of the poly(NIPAAm)-MNP showedthe characteristic poly(NIPAAm) bands (at 3300 cm�1 (broadsecondary NH amide), 2971-2861 cm�1 (CH group in isopropylgroup), 1649 cm�1 (strong C]O amide), 1541 cm�1 (strong NHamide II), 1458 cm�1 (eCH2 scissoring vibration), 1385 cm�1 (eCH3bending vibration), 1365 cm�1 (CeH bending vibration), and1170 cm�1 (bending vibration)) as well as the characteristichydrolyzed MAH (∼1707 cm�1) and the FeeO bands (570 cm�1). Allthese bands confirmed the successful synthesis of poly(NIPAAm)-MNP. Fig. 2 shows the schematic (Fig. 2b) and the digital image(Fig. 2c) of theMNPs in the n-hexane/watermixture solution beforeand after mechanical stirring during which the yellowish colorgradually disappeared from the top n-hexane layer, then theaqueous layer became yellowish, and finally the bottom layerended up as a translucent suspension. This phase transfer did not

nd the poly(NIPAAm)-MNP (in water) in the oscillating magnetic field as a function ofmagnet, and (c) hydrodynamic radii of the poly (NIPAAm)-MNPs dispersed in distilled

M. Omer et al. / Polymer 52 (2011) 91e9796

occur in a control experiment without MAH-b-CD, indicating thatthe MAH-b-CD formed an inclusion complex with the OA, and thehydrophilic groups in the b-CD made the b-CD-MNPs hydrophilicand dispersible in aqueous medium [30].

Fig. 3 shows the TEM micrographs of the dispersed OA-MNPs inn-hexane, b-CD-MNPs and poly(NIPAAm)-MNPs in distilled water.The narrowly distributed mean diameters and standard deviationvalues of OA-MNPs, b-CD-MNPs and poly(NIPAAm)-MNPs calcu-lated from TEM are tabulated in Table 1. OA-MNPs (Fig. 3a) andb-CD-MNPs (Fig. 3b) showed mono-dispersion in n-hexane anddistilled water, respectively although some aggregations betweensynthesized poly(NIPAAm)-MNPs were observed. This aggregationcould happen during the evaporation of the solvent on the TEMgrids although there were also possibilities of the aggregated formduring the synthesis. A similar morphology for the polymer-coatedMNPs was reported by Wang et al. [38].

Fig. 4 shows the TGA thermograms of the MNPs, the OA-MNPs,and the poly (NIPAAm)-MNPs. The MNPs did not show anyweight loss whereas the OA-MNPs and the poly(NIPAAm)-MNPsshowed step-wise weight loss as temperature increased. Theweight losses of the OA-MNPs at ∼250 and ∼350 �C might be dueto the thermal degradations of the free (1.35 mg) and coated OAs(2.86 mg), respectively and those of the poly(NIPAAm)-MNPsat ∼220 and ∼350 �C might be due to the thermal degradations ofthe MAH-b-CD inclusion complex (0.71 mg) and the poly(NIPAAm) (1.59 mg), respectively [39,40]. These results alsoindicate the successful polymerization of poly(NIPAAm) onto theMNP surface.

3.3. Properties of MNPs

Fig. 5a shows the temperature changes of the MNP (in 1 MHNO3), the OA-MNP (in hexane), and the poly(NIPAAm)-MNP (inwater) in the oscillating magnetic field as a function of time. Thetemperature linearly increased initially and then saturated as timeincreased further. The temperature increase in the solutions indi-cates that the MNP particles have an ability of magnetic heatingwhen exposed to an alternating magnetic field [7,41]. The saturatedtemperatures of the MNPs, the OA-MNPs, and the poly(NIPAAm)-MNPs solutions were 65, 49, and 52 �C, respectively. The decreaseof the saturation temperatures of the OA-MNPs and the poly(NIPAAm)-MNPs solutions as compared to that of the MNP mightbe due to low electrical conductivity of the organic shell (OA andpoly(NIPAAm)) [42]. Fig. 5b shows the reversible attraction of thepoly(NIPAAm)-MNPs toward a magnet. The poly(NIPAAm)-MNPswere homogeneous dark brown without magnet (Fig. 5b(I)).However, the poly(NIPAAm)-MNPs were attracted toward themagnet when it was close to the wall of the vial (Fig. 5b(II)) indi-cating a superparamagnetic property for the poly(NIPAAm)-MNPs.Superparamagnetic and magnetic heating properties of the poly(NIPAAm)-MNPs are critical for their applications in biomedical[43] and bioengineering fields, because they prevent MNPs fromaggregation and enables them to redisperse when the magneticfield is removed [44]. Fig. 5c shows the thermoresponsive behaviorof the poly(NIPAAm)-MNPs. The decrease in the hydrodynamicradii (Rh) happened at ∼34 �C (LCST temperature of poly(NIPAAm))[45]. The decrease in radius at elevated temperature was due to theincreased hydrophobicity of the poly(NIPAAm) segments, whichled to the collapse of polymer chains and shrinkage of the gelnetwork. Thus, this result indicates that the method developed inthis article might be one of the novel ways of synthesizing a ther-moresponsive poly(NIPAAm)-MNPswhich showsmagnetic heatingby MNPs in the core causing the shrinkage of the poly(NIPAAm)chains in the shell.

4. Conclusion

This study has successfully preparedMNPs via a co-precipitationmethod in order to attach the poly(NIPAAm) chains on the MNPs tomake the thermoresponsive core-shell MNPs. The MAH-modifiedb-CD where b-CD made an inclusion complex with OA which wasfirst coated on MNP was introduced. The double bonds of the MAHin (MAH-b-CD) initiated the polymerization of NIPAAm and thepoly (NIPAAm) chains in the shell were cross-linked with MBA. It istheorized that this novel approach for the preparation of theaqueous-dispersible thermoresponsive MNPs could be a stepforward in their use in the fields of biomedical and bioengineering.

Acknowledgements

This work was supported by the National Research Foundationof Korea Grant (2010-0014822) funded by the South KoreanGovernment.

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