Control of Dopant Distribution in Yttrium-Doped Bioactive Glass for Selective Internal Radiotherapy Applications Using Spray Pyrolysis

materials

Article Control of Dopant Distribution in Yttrium-Doped Bioactive Glass for Selective Internal Radiotherapy Applications Using Spray Pyrolysis

Abadi Hadush Tesfay 1, Yu-Jen Chou 2, Cheng-Yan Tan 1, Fetene Fufa Bakare 1, Nien-Ti Tsou 3 , E-Wen Huang 3 and Shao-Ju Shih 1,* 1 Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan; [email protected] (A.H.T.); [email protected] (C.-Y.T.); [email protected] (F.F.B.) 2 Department of Mechanical Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan; [email protected] 3 Department of Materials Science and Engineering, National Chiao Tung University, No. 1001, Tahsueh Road, HsinChu 300, Taiwan; [email protected] (N.-T.T.); [email protected] (E.-W.H.) * Correspondence: [email protected]; Tel.: +886-2-2730-3716

Received: 6 March 2019; Accepted: 22 March 2019; Published: 25 March 2019

Abstract: In this study, we demonstrate the fabrication of Y-doped bioactive glass (BG), which is proposed as a potential material for selective internal radiotherapy applications. Owing to its superior bioactivity and biodegradability, it overcomes the problem of yttrium aluminosilicate spheres that remain in the host body for a long duration after treatment. The preparation of Y-doped BG powders were carried out using a spray pyrolysis method. By using two different yttrium sources, we examine the change of the local distribution of yttrium concentration. In addition, characterizations of phase information, particle morphologies, surface areas, and bioactivity were also performed. The results show that both Y-doped BG powders are bioactive and the local Y distribution can be controlled.

Keywords: bioactive glass; Yttrium; electron microscopy; spray pyrolysis

1. Introduction Bioactive glass (BG) has been studied extensively since its first report by Hench et al. [1]. It was the first synthetic material to show a bone-bonding ability and has been successfully applied to various applications such as drug carriers, tooth fillers, and bone scaffolds [2–4]. Among these three applications, the development of drug carriers was the latest and is not mature yet. Therefore, in recent years, one popular application of drug carrier BG is selective internal radiation therapy (SIRT), which has been used for tumor tissue treatments [5–7]. The SIRT therapy is limited by the need to employ low doses of radiation to reduce damage to healthy tissues near the affected area [8], and so far the most common and popular material is yttrium aluminosilcate (YAS, Y2O3-Al2O3-SiO2) spheres [9,10]. The therapeutic use of Y microspheres was first prepared by Ehrhard et al. [11] and it has been used for more than 20 years owing to its advantage of high chemical stability and short half-life [12]. Since then, studies of Fe-doped, Tm-doped, and Er-doped YAS were reported [13,14]. However, these spheres have some serious drawbacks that need to be overcome; first, the YAS spheres are not biodegradable, and therefore, it will reside in the host for a long time and may cause damage after the end of the radioactive treatments [15]; second, the YAS spheres are biologically inactive and therefore do not establish a favorable interaction with the treated area [5]. Thus, Y-doped BG powders offer the merits of biodegradability and strong interaction with the treated tissues to become one of the potential candidates for SIRT applications [16].

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Although Y-doped BG powders have been applied for radioisotope vectors, only a few studies have been reported [5–7]. For example, Cacaina et al. prepared the Y-doped BG powders as radioisotope vectors using conventional glass melting process and studied its behavior in simulated body fluid (SBF) [17]. Since the 90Y isotope is the main radioactive source to kill tumors in the Y-doped BG powder, the position of Y in BGs has started to attract some attention: First, the environment of Y in BG has been studied by Christie et al. [6]. Then, in 2015, Tilocca built the ion exchange model to use a molecular dynamics simulation to discuss the structural configuration of Y in a BG matrix to influence the biodegrading properties [5]. Though Y distribution in BG has been studied by the above simulation works with the assumption of a homogenous distribution for Y [5,6], according to our previous studies, Y distribution of concentrations may be inhomogeneous and strongly correlates with the experimental parameters (e.g., heat treatment conditions [18] and precursor properties [19]). Since the β radiation emitted by Y has low penetrating power, for better radiation efficiency, it is essential to control the Y distribution. Therefore, in this study, Y-doped BG powders were prepared from two common Y precursors such as yttrium acetate (YAc) and yttrium nitrate (YN). In this study, pure BG powder and two Y-doped BG powders from YAc and YN salt were synthesized using spray pyrolysis (SP). Then, phase compositions, surface morphologies, inner structures, chemical compositions, and specific surface areas of powders were obtained using X-ray diffraction (XRD), scanning electron microscopy (SEM), focus ion beam (FIB), energy-dispersive X-ray spectroscopy (EDS), and the Brunauer–Emmet–Teller (BET) method, respectively. In addition, the local Y concentrations were obtained using several cross-sectional Y-doped BG particles. Finally, the bioactive tests were carried out and characterized using a Fourier transform infrared reflection (FTIR) spectrophotometer.

2. Materials and Methods

2.1. Specimen Preparation First, pure BG powder was synthesized using spray pyrolysis based on the composition of 58S (60 mol% SiO2, 35 mol% CaO, and 5 mol% P2O5). The precursor solution was prepared by adding tetraethyl orthosilicate (TEOS, Si(OC2H5)4, 99.9 wt%, Showa, Tokyo, Japan), calcium nitrate tetrahydrate (CN, Ca(NO3)2·4H2O, 98.5 wt%, Showa, Tokyo, Japan), and triethyl phosphate (TEP, (C2H5)3PO4, 99.0 wt%, Alfa Aesar, Heysham, UK) into 60.00 g of ethanol with 1.60 g of 0.5 M diluted hydrochloric acid. The solution was then stirred at room temperature for 2 h to reach homogeneity. In addition, the precursor solutions of Y-doped BG powders were prepared by mixing an additional 10 wt% of yttrium source, either yttrium acetate (YAc, YC6H9O6, Sigma Aldrich, St. Louis, MO, USA) or yttrium nitrate (YN, YNO3O9·6H2O, 99.8%, Sigma Aldrich, St. Louis, MO, USA), into the pure precursor solution and stirred for 2 h as well. For the spray pyrolysis process, all precursor solutions were poured into an ultrasonic atomizer (KT-100A, King Ultrasonic, New Taipei, Taiwan) operating at a frequency of 1.67 MHz. The atomized droplets were led into a tube furnace (D110, Dengyng, New Taipei, Taiwan) with three different heating zones. The temperature of each zone was set at 250 ◦C, 550 ◦C, and 300 ◦C for preheating, calcination, and cooling, respectively. At the exit of the furnace, a high voltage of 16 kV was applied to charge the surface of the synthesized powders. The charged powders were then neutralized and condensed inside an earthed stainless steel electrostatic collector.

2.2. Characterization First, an X-ray diffractometer (XRD, D2 Phaser, Bruker, Karlsruhe, Germany) with Cu-Kα radiation was used to obtain the phase compositions using a collection angle that ranged from 20◦ to 80◦. Next, the morphologies of all BG particles were examined using a scanning electron microscope (SEM, JSM-6500F, JEOL, Tokyo, Japan). To get reliable average particle sizes, more than 300 particles were measured from several SEM images for each specimen. In addition, a constant-volume adsorption apparatus (Novatouch LX2, Quantachrome Instruments, Boynton Beach, FL, USA) was operated Materials 2019, 12, 986 3 of 8 Materials 2019, 12, x FOR PEER REVIEW 3 of 8 at −196 ◦C to obtain nitrogen adsorption and desorption isotherms. The speciﬁc surface areas of operated at −196 °C to obtain nitrogen adsorption and desorption isotherms. The specific surface pure BG powder and Y-doped BG powders were computed using the BET method. At last, for the areas of pure BG powder and Y-doped BG powders were computed using the BET method. At last, characterization of inner structure and Y distributions, the cross-section specimens were prepared by for the characterization of inner structure and Y distributions, the cross-section specimens were focused ion beam (FIB, Quanta 3D FEG, FEI, Hillsboro, OR, USA) and the atomic compositions of each prepared by focused ion beam (FIB, Quanta 3D FEG, FEI, Hillsboro, OR, USA) and the atomic specimen were examined using energy dispersive spectroscopy (EDS, Oxford Instruments, Abingdon, compositions of each specimen were examined using energy dispersive spectroscopy (EDS, Oxford UK) analysis. Instruments, Abingdon, UK) analysis. 2.3. In Vitro Bioactivity Test 2.3. In Vitro Bioactivity Test The in vitro bioactivity tests of all BG powders were carried out using the SBF which has an ionic The in vitro bioactivity tests of all BG powders were carried out using the SBF which has an ionic concentration similar to human plasma [20]. The test specimens were prepared by immersing the concentration similar to human plasma [20]. The test specimens were prepared by immersing the powders in SBF solution a solid to liquid ratio of 1 mg to 5 mL and were held at 37 ◦C for 6 h. The powders in SBF solution a solid to liquid ratio of 1 mg to 5 mL and were held at 37 °C for 6 h. The resulting powders were washed three times with acetone and de-ionized water and dried for a day in resulting powders were washed three times with acetone and de-ionized water and dried for a day an oven at 70 ◦C. Finally, FTIR spectra were used to conﬁrm the bioactivity of each specimen. in an oven at 70 °C. Finally, FTIR spectra were used to confirm the bioactivity of each specimen. 3. Results 3. Results Figure1 shows the XRD patterns of pure and Y-doped BG powders prepared using SP. First, for the pureFigure BG 1 powder, shows the no XRD distinct patterns diffraction of pure peaks and canY-doped be observed BG powders from theprepared XRD pattern using SP. with First, only for a broadthe pure band BG existingpowder, between no distinct 20◦ diffractionto 40◦. The peaks result can suggests be observed that the from structure the XRD of purepattern BG with powder only isa amorphous.broad band existing Meanwhile, betwee bothn 20° Y-doped to 40°. BG The powders result suggests from YAc that and the YN structure precursors of pure show BG similar powder XRD is patternsamorphous. as the Meanwhile, pure BG powder,both Y-doped indicating BG powders that all spray-pyrolyzedfrom YAc and YN BG precursors and Y-doped show BGsimilar powders XRD werepatterns synthesized as the pure successfully BG powder, with indicating a glassy phase.that all spray-pyrolyzed BG and Y-doped BG powders were synthesized successfully with a glassy phase.

Figure 1. XRD patterns of pure BG powder, YAc-derived BG powder and YN-derived BG powder. Figure 1. XRD patterns of pure BG powder, YAc-derived BG powder and YN-derived BG powder. For the observation of surface morphologies and particle sizes, Figure2 shows the SEM images of pureFor and the Y-doped observation BG powders. of surface It canmorphologies be seen from and Figure particle2a thatsizes, the Figure pure 2 BG shows powder the SEM exhibited images a sphericalof pure and morphology Y-doped BG for powders. all particles, It can which be isseen the fr typicalom Figure particle 2a that morphology the pure forBG the powder spray exhibited pyrolysis processa spherical [21]. morphology Meanwhile, for it can all alsoparticles, be seen which from is Figure the typical2b,c that particle both Y-doped morphology BG powders for the fromspray YAcpyrolysis and YNprocess precursors [21]. Meanwhile, have a similar it can surfacealso be seen morphology. from Figure In 2b,c addition, that both statistical Y-doped measurements BG powders offrom particle YAc sizesand ofYN all sprayprecursors pyrolyzed have BG a powderssimilar weresurface calculated morphology. based onIn theaddition, SEM images. statistical The measurements of show particle that sizes the averageof all spray particle pyrolyzed size of BG pure powders BG powder were calculated was 0.99 ±based0.40 onµm, the while SEM Y-dopedimages. The BG powdersmeasurements from YAcshow and that YN the salts average were 0.94particle± 0.39 size and of pure 0.89 ±BG0.34 powderµm, respectively. was 0.99 ± 0.40 On theµm, other while hand, Y-doped the BET BG data powders showed from that YAc the speciﬁcand YN surface salts were areas 0.94 of pure ± 0.39 BG powder,and 0.89 YAc ± 0.34 derived µm, Y-dopedrespectively. BG powder,On the andother YN-derived hand, the Y-dopedBET data BG showed powder that were the 4.65 spec±ific0.07, surface 4.42 ± areas0.08, andof pure 10.08 BG± 0.12powder, m2/g, YAc respectively, derived Y-doped which indicatesBG powder, the YN-derivedand YN-derived Y-doped Y-doped BG powder BG powder exhibited were the4.65 highest ± 0.07, 2 speciﬁc4.42 ± 0.08, surface and area10.08 compared ± 0.12 m /g, with respectively, the pure BG which powder indicates and YAc-derived the YN-derived Y-doped Y-doped BG powder. BG powder exhibited the highest specific surface area compared with the pure BG powder and YAc-derived Y- doped BG powder.

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(a()a ) (b) (b) (c) (c)

FigureFigure 2. SEM 2. 2. SEMSEM micrographs micrographs micrographs of ( ofa of) (pure (aa)) pure pure BG BG powder, BG powder, powder, (b) (YAc, (bb)) YAc, YAc, and and and (c) YN( (cc)) YN YNderived derived derived Y-doped Y-doped Y-doped BG BG BGpowders. powders. powders.

Next,Next, the the compositional compositional analysis analysis analysis of pureof of pure pure and and and Y-doped Y-doped BG BG powders powders was was carried carried out out using using EDS EDS andand the the resulting resulting spectra spectra are are shown shown in Figurein Figure 3. 3Excluding3.. ExcludingExcluding the thethe peak peakpeak at at0.275at 0.2750.275 eV, eV,eV, which whichwhich corresponds correspondscorresponds to the C-Kα1 edge from the carbon paste, all BG powders showed peaks of O-Kα1, Si-Kα1, P-Kα1, to theto the C-K C-Kα1 edgeα1 edge from from the the carbon carbon paste, paste, all allBG BG powders powders showed showed peaks peaks of O-Kof O-Kα1,α Si-K1, Si-Kα1,α P-K1, P-Kα1,α Ca-1, Ca- Ca-Kα , and Ca -Kβ at 0.519, 1.746, 2.039, 3.670, and 4.007 KeV, respectively. Moreover, Y-Kα and KαK1,α and1, and 1Ca Ca -K β-K1 βat1 0.519,at 0.519,1 1.746, 1.746, 2.039, 2.039, 3.670, 3.670, and and 4.007 4.007 KeV, KeV, respectively. respectively. Moreover, Moreover, Y-K Y-Kα1 αand1 and 1Y- Y- Y-Kβ edges were observed from both YAc- and YN-derived Y-doped BG powders. In addition, Si, KβK1 edgesβ1 edges1 were were observed observed from from both both YAc- YAc- and and YN-derived YN-derived Y-doped Y-doped BG BG powders. powders. In addition,In addition, Si, Si,Ca, Ca, ± ± ± andandCa, P concentrations andP concentrations P concentrations were were computed were computed computed to beto be58.35 to 58.35 be ± 58.35 1.56, ± 1.56, 31.331.56, 31.33 ± 31.331.17, ± 1.17, and 1.17,and 10.31 10.31 and ± 0.76 10.31 ± 0.76 at% at%0.76 for for the at% the pure for pure the ± ± ± BGBGpure powder; powder; BG powder; meanwhile, meanwhile, meanwhile, Si, Si,Ca, Ca, P, Si, andP, Ca,and Y P,concentrationsY andconcentrations Y concentrations were were 59.58 59.58 were ± 4.55, ± 59.58 4.55, 24.12 24.124.55, ± 2.50, ± 2.50, 24.12 7.16 7.16 ± 0.76,2.50, ± 0.76, and 7.16 and ± ± ± ± 9.149.140.76, ± 2.36 ± and 2.36 at% 9.14 at% for for the2.36 the YAc-derived at% YAc-derived for the YAc-derivedBG BG powder powder and BG and powder52.05 52.05 ± 1.83, and± 1.83, 52.0529.71 29.71 ± 0.97,1.83, ± 0.97, 11.17 29.71 11.17 ± 1.06, 0.97,± 1.06, and 11.17 and 7.05 7.05 1.06,± ± ± 0.380.38and at% at% 7.05 for for the 0.38the YN-derived YN-derived at% for the BG YN-derivedBG po wder.powder. The BGThe results powder. results indicate indicate The resultsthat that both indicateboth pure pure and that and Y-doped both Y-doped pure BG andBG powders powders Y-doped werewereBG successfully powders successfully were synthesized synthesized successfully with with synthesized their th eirgiven given with precursor precursor theirgiven concentrations. concentrations. precursor concentrations.

(a) (a) (b) (b) (c) (c)

FigureFigureFigure 3. EDS 3. 3. EDSEDS spectra spectra spectra of (ofa of) (pure (aa)) pure pure BG BG BGpowder, powder, powder, (b) ( (YAc,bb)) YAc, YAc, and and (c) (YN c) YN derived derived Y-doped Y-doped BG BGBG powders. powders.powders.

Then,Then, Figure Figure 4 shows 44 showsshows the thethe SEM SEMSEM images imagesimages of ofofFIB-pr FIB-preparedFIB-preparedepared cross-section cross-sectioncross-section specimens specimensspecimens with withwith insets insetsinsets of ofof theirtheirtheir as-prepared as-prepared as-prepared state. state. state. By By Byexamining examining examining more more more than than than 20 20particles 20 particles particles within within within each each each BG BG BGpowder, powder, powder, it can it can be be seen seen fromfromfrom Figure Figure 4a 44athata thatthat the thethe pure purepure BG BGBG particles particlesparticles exhibited exhibitedexhibited an an aninner innerinner solid solidsolid structure. structure.structure. In Inaddition, addition, YAc-derived YAc-derived Y-dopedY-doped BG BG particles particles (Figure (Figure 4b) 44b) b)showed showedshowed the thethe same samesame inner innerinner solid solidsolid structure structurestructure as asasthe thethe pure purepure BG BGBG particles. particles.particles. However,However, for for the the YN-derived YN-derived Y-doped Y-doped BG BG particle particles,particles, twos, two morphologies morphologies of ofsolid solid and and hollow hollow were were observedobserved as asshown shown in inFigure Figure 4c,d. 44c,d.c,d. Furthermore, Furthermore,Furthermore, the thethe local locallocal Y YconcentrationsY concentrationsconcentrations of ofofeach eacheach specimen specimenspecimen were werewere recordedrecorded and and shown shown in inFigure Figure 5.5 5.The. TheThe result resultsresults shows showshow that thatthat for forfor the thethe YAc-derived YAc-derivedYAc-derived powder powderpowder (■ (),( ■the),), thethe Y Y Y concentrationconcentration increased increased increased from from from the the thecenter center center (7.11 (7.11 (7.11 ± 1.09 ± ±1.09%)1.09%) %)to theto the to edge the edge (11.16 edge (11.16 (11.16± 1.36%). ± 1.36%).± 1.36%). Meanwhile Meanwhile Meanwhile the the YN- YN- the derivedderivedYN-derived powder powder powder (●) ( ●showed) showed (•) showed a consistent a consistent a consistent distribution distribution distribution of aroundof around of around 7% 7% for for 7%the thefor whole whole the wholeparticle. particle. particle.

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(a) (b)

(c) (d) (c) (d) Figure 4. SEM images of focused ion beam-prepared cross-sectional solid particles of (a) pure BG FigureFigure 4. 4.SEM images of focused ion beam-prepared cross-sectional solid particles of (a) apure BG powder, (b) YAc,SEM and images (c) YN of derived focused Y-doped ion beam-prepared BG powders. cross-sectional (d) Cross solid sectional particles hollow of ( ) pure particle BG of YN- powder,powder, (b)( YAc,b) YAc, and and (c) YN (c) YNderived derived Y-doped Y-doped BG powders. BG powders. (d) Cross (d) Crosssectional sectional hollow hollow particle particle of YN- of derivedderived YN-derivedY-doped Y-doped powder. Y-doped powder. powder.

Figure 5. Mean Y concentration distributions of YAc- and YN-derived Y-doped BG powders.

FigureAt last, 5.Figure MeanFigure 5. MeanY 6 concentration shows Y concentration the FTIR distributions distributionsspectra for of examining YAc-YAc- and and YN-derivedthe YN-derived in vitro Y-doped bioactivity. Y-doped BG powders. TheBG powders.results confirmed that both pure and Y-doped BG powders were bioactive due to the presence of the P–O bondingAt that last, formed. Figure To6 shows determine the FTIRthe bioactivity spectra for of examiningeach specimen, the ain ratio vitro ofbioactivity. peak intensities The were results Atcomputed conﬁrmedlast, Figure from that the 6 both FTIRshows pure spectra andthe Y-doped[22,23],FTIR whichspectra BG powders will for be discussedexamining were bioactive in the the duefollowing in to vitro the paragraph. presence bioactivity. of the P–OThe results confirmedbonding that thatboth formed. pure and To determine Y-doped the BG bioactivity powders of eachwere specimen, bioactive a ratio due of to peak the intensities presence were of the P–O bondingcomputed that formed. from theTo FTIRdetermine spectra [22the,23 bioactivity], which will of be discussedeach specimen, in the following a ratio paragraph.of peak intensities were computed from the FTIR spectra [22,23], which will be discussed in the following paragraph.

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(a) (b)

FigureFigure 6. FTIR 6. FTIR spectra spectra of pure of pure BG BG powder, powder, and and YAc- YAc- and and YN-derived YN-derived Y-doped Y-doped BG BG powders: powders: (a) ( abefore) before andand (b) ( bafter) after immersion immersion in inSBF SBF solution solution for for 6 h. 6 h.

4. 4.Discussion Discussion TheThe first first issue issue to todiscuss discuss is isthe the SP SP formation formation mechanism mechanism of ofthe the BG BG powders. powders. Previous Previous studies studies havehave demonstrated demonstrated that that there there are are two two main main format formationion mechanisms mechanisms for for the the spray spray pyrolysis pyrolysis method, method, whichwhich are are “one-particle-per-drop” “one-particle-per-drop” and and “gas-to-particle” “gas-to-particle” [24]. [24 Based]. Based on on the the observation observation of ofthe the SEM SEM imagesimages shown shown in inFigure Figure 2,2 both, both pure pure and and Y-do Y-dopedped BG BG powders powders exhibited exhibited a asingle single morphology morphology of of sphericalspherical particles particles with with no no nanosized nanosized particles particles formed. formed. This This indicates indicates that that all all spray spray pyrolyzed pyrolyzed BG BG powderspowders followed followed the the formation formation mechanism mechanism of of“one-particle-per-drop.” “one-particle-per-drop.” Next,Next, the the inner inner structures structures of ofall all BG BG powders powders were were examined examined using using FIB-prepared FIB-prepared cross-section cross-section specimens.specimens. During During a a spray spray pyrolysispyrolysis system,system, the the precursor precursor droplets droplets go throughgo through three three stages stages of thermal of thermaltreatments treatments of solvent of solvent evaporation, evaporation, solute solute decomposition, decomposition, and and particle particle calcination calcination to form to form the the final finalparticles. particles. Factors Factors influencing influencing the innerthe inner structure struct areure suggestedare suggested to be to evaporation be evaporation rates ofrates the of solvent, the solvent,solubilities, solubilities, and melting and melting temperature temperature of precursors of precursors [25,26]. For[25,26]. the pureFor the BG pure powders, BG powders, the inner the solid innerstructure solid wasstructure observed was (Figureobserved4a) due(Figure to the 4a) high due solubilities to the high and solubilities high melting and temperatures high melting of temperaturesprecursors, theof precursors, precursor droplets the precursor followed droplets the “volume followed precipitation” the “volume mechanism, precipitation” which mechanism, precipitated whichhomogenously precipitated during homogenously the SP [27 during]. By addingthe SP [27] YAc,. By which adding also YAc, has which a high also melting has a temperaturehigh melting of ◦ temperature285 C[28] of into 285 the °C precursor [28] into solution,the precursor it follows solution, the same it follows formation the same mechanism formation as pure mechanism BG powders as pureand BG hence powders results and in ahence solid results structure in a (Figure solid 4strub).cture However, (Figure for 4b). the However, precursor for ofYN, the aprecursor low melting of ◦ YN,temperature a low melting of 88 temperatureC[29] will of let 88 the °C solutes [29] will on let the the surface solutes of on the the droplets surface melt of the during droplets the solventmelt duringevaporation the solvent stage evaporation and trap the stage solvent and in trap the centerthe solvent [27]. Thus,in the acenter solid shell[27]. willThus, be a formed solid shell and will result bein formed the hollow and particleresult in (Figure the hollow4d). Meanwhile, particle (Figure the surface 4d). areaMeanwhile, of the YN-derived the surface Y-doped area of BG the powder YN- derivedwas about Y-doped two timesBG powder higher was than about the other two times powders, high verifyinger than the its other inner powders, structure verifying was hollow. its inner structureNext, was the hollow. local Y distributions in Y-doped BG powders were discussed. Considering the movement of ionsNext, may the belocal assisted Y distributions by the diffusion in Y-doped of water, BG the mobilitypowders ofwere ions discussed. can therefore Considering be related tothe the movementsolubilities of ofions the may precursor. be assisted In this by study, the diffusion solubilities of water, of YAc the and mobility YN precursors of ions can in water therefore were be 100 relatedand 1550 to the g/L, solubilities respectively, of the at aroundprecursor. room In this temperature study, solubilities [30,31]. In of this YAc case, and the YN acetate precursors groups in of waterthe YAcwere precursor 100 and dissolved1550 g/L, betterrespectively, in the solution,at around leading room Ytemperature ions to distribute [30,31]. closer In this to thecase, droplet the acetatesurface. groups In contrast, of the YAc owing precursor to the dissolved high solubility better ofin the solution, YN precursor, leading the Y ions to will distribute distribute closer more to evenlythe droplet throughout surface. the In particle. contrast, During owing the to calcinationthe high solubility stage, Y willof the precipitate YN precursor, simultaneously the ions will in the distributewhole particle. more evenly YN-derived throughout Y-doped the BG particle. particles During will therefore the calcination have local stage, Y distribution Y will precipitate dispersed simultaneouslyhomogenously in in the the whole whole particle. particle. YN-derived Y-doped BG particles will therefore have local Y distributionAt last, dispersed the in vitro homogenouslybioactivity in tests the werewhole carried particle. out and examined using FTIR spectra. To determineAt last, the bioactivityin vitro bioactivity of each specimen,tests were a ca ratiorried of out peak and intensities, examined I1 /Iusing2, were FTIR computed spectra. fromTo −1 determinethe FTIR the spectra bioactivity [22,23], of where each spec I1 isimen, the intensity a ratio of of peak P–O intensities, bending vibration I1/I2, were around computed 567cm from[32 the,33 ] −1 FTIRand spectra I2 is the [22,23], intensity where of the I1 is Si–O–Si the intensity bending of P–O vibration bending at 482vibration cm [around34,35]. This567cm value−1 [32,33] correlates and I2 to is thethe amountintensity of of hydroxyapatite the Si–O–Si bending (HA) formed, vibration i.e. theat 482 higher cm−1 the [34,35]. I1/I2 ratio,This value the larger correlates amount to ofthe HA amount of hydroxyapatite (HA) formed, i.e. the higher the I1/I2 ratio, the larger amount of HA was

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was formed which represents higher bioactivity. Following Figure6, the resulting I 1/I2 values of the pure BG powder, and YAc- and YN-derived Y-doped BG powders were computed to be 0.32, 0.44, and 0.53, respectively, indicating the order of bioactivity was pure BG powder < YAc-derived Y-doped BG powder < YN-derived Y-doped BG powder, similar to the measured surface areas.

5. Conclusions In this study, both pure and Y-doped BG powders were successfully synthesized using spray pyrolysis method. The composition analysis shows that the local Y distributions were controlled by the addition of YAc and YN, while the particles’ morphologies and surface areas were also observed. At last, both Y-doped BG powders were conﬁrmed to be bioactive with the formation of HA after immersing in the SBF for 6 h. Thus, it can be concluded that Y-doped BG powders can be a potential candidate for the effective treatment of cancerous cells in selective internal radiotherapy applications.

Author Contributions: Data curation, A.H.T., C.-Y.T. and F.F.B.; Formal analysis, Y.-J.C.; Funding acquisition, S.-J.S.; Project administration, S.-J.S.; Writing—original draft, A.H.T. and Y.-J.C.; Writing—review & editing, N.-T.T. and E.-W.H. Funding: This research was funded by the Ministry of Science and Technology of Taiwan (Grant Numbers of MOST 105-2221-E-011-034, 106-2221-E-011-049 and 107-2218-E-009-003) and from the Tokushima University and National Taiwan University of Science and Technology (Gran Numbers of TU-NTUST-106-01). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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