Highly Bioactive Sol-Gel-Derived Borate Glasses

Highly Bioactive Sol-Gel-Derived Borate GlassesWilliam C. Lepry and Showan N. Nazhat*

Department of Mining and Materials Engineering, McGill University, Montreal, Quebec H3A 0C5, Canada

*S Supporting Information

ABSTRACT: Attributable to their low chemical durability,borate-based glasses have been demonstrated to convertrapidly to hydroxy-carbonated apatite (HCA), the inorganiccomponent of bone. However, the effect of sol-gel processingon the bioactivity of borate-based glasses has not beeninvestigated. In this study, the gel and glass forming abilities ofsix different borate-based glass formulations with boratecontent ranging from 36 to 61 mol % and based on apreviously studied four component melt-derived glass system[(46.1)B2O3−(26.9)CaO−(24.4)Na2O−(2.6)P2O5; mol %] were investigated. Compared to melt-quench, sol-gel processingfabricated nanoporous glass particles with at least 2 orders of magnitude greater values for specific surface areas and total porevolumes, which translated to dramatically higher aqueous interaction and ion release rates. Surprisingly, when immersed insimulated body fluid, HCA conversion was achieved in as little as 3 h for sol-gel derived borate based glasses, demonstrating a 25-fold increase in mineralization rate when compared to melt derived equivalents. The ability of the sol-gel derived borate-basedglasses to rapidly convert to bone-like HCA holds promise in numerous potential tissue engineering applications, including therepair and augmentation of mineralized tissues.

1. INTRODUCTION

Since their initial conception more than 45 years ago, bioactivesilicate-based glasses have been widely studied, of whichBioglass (“45S5”; (46.1)SiO2−(26.9)CaO−(24.4)Na2O−(2.6)P2O5, by mol %), has been in clinical use for more thantwo decades.1−4 Owing to their ability to release ions inphysiological environments, a layer of hydroxy-carbonatedapatite (HCA) is formed on the surface of bioactive glasses,which has been shown to promote bonding to bone tissue.However, as a consequence of the slow and incompletedissolution of silicate-based glasses, there has been a recentgrowth in interest in bioactive glasses based on other networkforming oxides (e.g., phosphates, borates).5,6 In particular, andattributable to their lower chemical durability, borate-basedglasses have been shown to undergo more rapid degradationand conversion to HCA when compared to silicate-basedglasses.7−12 Furthermore, although the excess release of boroncan be toxic,13 borate-based glasses have been demonstrated tosupport the proliferation and differentiation of stem cells, invitro.14−16 Numerous studies have also shown that these glassesare able to regrow bone with no toxicity, in vivo.17−19 Morewidely, borate-based glasses are being used as substrates to treatbone infection,20−22 in wound healing applications,23−26 as wellas neural substrates for axon growth.27

Although the majority of bioactive glasses are melt-quenchderived, the sol-gel process has demonstrated distinctadvantages, including increased surface area, nanoporosity,purity, and homogeneity, coupled with reduced processingtemperatures.28−31 In contrast to silicate-based sol-gels wherethe main network former is tetrahedrally coordinated [SiO4]resulting in a strongly interconnected network,32 in borate-

based glasses, the boron ion is typically trigonally coordinated,giving it a pseudo-three-dimensional character because the BO3network is more planar. However, it is also known that in manyborate-based glass systems, a fraction of the boron can be four-coordinated [BO4], which depends on the amount of alkalimetal present.33,34 Nevertheless, this combination of three- orfourfold coordination lowers the network connectivity (NC),which in turn reduces the chemical durability and increases thedissolution rate of the glasses.8 More importantly, this makesgel formation difficult, which may have resulted in the sol-gelprocessing of borate-based glasses being relatively poorlystudied. Notwithstanding this, the first sol-gel borate-basedglasses, fabricated by Tohge and colleagues,35 were typicallyeither two- or three-component systems often modified withalkali metals such as Na, K, and Li36,37 along with otherelements such as Si38 and Ti.39 Yet, studies regarding theirapplications are scarce.Today, borates are commonly added to increase the thermal

shock resistance of silicate-based glasses and used to producenonlinear optical materials (e.g., β-barium borate thin films)through the sol-gel method.40,41 For more biomedical focusedcompositions, boron has been used as a modifier in the sol-gelprocess42−44 and as the main component in a sol-gelprecipitation method.45 Recently, the addition of up to 20mol % borate was shown to improve the apatite-forming abilityof silicate-based glasses produced through a sol-gel process.46

However, to date, a multicomponent glass with borate as the

Received: May 7, 2015Revised: June 12, 2015

Article

pubs.acs.org/cm

© XXXX American Chemical Society A DOI: 10.1021/acs.chemmater.5b01697Chem. Mater. XXXX, XXX, XXX−XXX

network forming oxide has not been made using sol-gelprocessing, and the effect of sol-gel processing on thebioactivity of such borate based glasses has not yet beeninvestigated.Herein, the creation of bioactive sol-gel derived borate-based

glasses (SGBGs) has been attempted for the first time. The geland glass forming abilities of six different SGBG formulationswith borate content ranging from 36 to 61 mol %, based on apreviously studied four component melt-derived boronsubstituted 45S5 glass (“45B5”),8,47 were investigated. Theeffect of sol-gel processing and composition on the glassnanoporous properties were analyzed. Furthermore, in order toinvestigate the reactivity and bioactivity of SGBGs, theiraqueous interactions, ion release, and mineralization insimulated body fluid (SBF) were characterized.

2. EXPERIMENTAL SECTIONMaterials. Boric acid (≥99.5%), monosodium phosphate

(>99%), sodium carbonate (≥99.5%), calcium carbonate(≥99%), and anhydrous ethanol were all purchased fromSigma-Aldrich (Canada). Triethyl phosphate (>99.8%) andsodium methoxide (25 wt % in methanol) were obtained fromFisher Scientific (Canada). Calcium methoxyethoxide (20% inmethoxyethanol) was purchased from Gelest (U.S.A.).Sol-Gel Processing. All materials were used as received and

all sol-gel processing took place within a nitrogen gas purgedglovebox. Boric acid was first added to anhydrous ethanol in awatch-glass-covered Teflon beaker, and magnetically stirred at40 ± 3 °C to aid dissolution. Once the solution was clear,triethyl phosphate, calcium methoxyethoxide, and sodiummethoxide were added in a dropwise manner at 30 minintervals. After the final addition, the solution was mixed for afurther 30 min or until the viscosity was too high for any furtherstirring. The sol was then cast into polypropylene vials, sealed,and stored at 37 °C for further gelation and aging. After 10days, the gels were removed and placed in crystallization dishesand dried in air at room temperature for 1 day, followed byoven drying at 120 °C for a further 2 days. Table 1 gives theinvestigated SGBG compositions.

To investigate the effect of calcination temperature on theproperties of the SGBGs, calcination of the as-made particleswere carried out in air at 400, 450, 500, 550, and 600 °C. Alltemperatures were reached at a heating rate of 3 °C/min,followed by a 2 h dwell time, and then furnace cooled.Following calcination, the particles were ground and sieved toisolate a particle size fraction of 25−75 μm and stored in adesiccator until analysis. A melt-derived borate glass (“45B5”),equivalent to B46, was generated through melt-quenching, aspreviously described.8 Here, boric acid, monosodium phos-

phate, sodium carbonate, and calcium carbonate werethoroughly dry mixed and placed in a Pt crucible then heatedat 1100 °C for 2 h with intermediate stirring to ensurehomogeneity. The melt was then rapidly quenched betweentwo steel plates and the resultant glass was ground to 25−75μm particles.

Particle Characterization. The particle size (D50) of thesieved glass powders was determined using a Horiba LA-920(ATS Scientific Ink., Canada). The specific surface area of thecalcined powders (400 °C, n = 3) sieved to 25−75 μm weremeasured with nitrogen gas adsorption and desorptionisotherms collected with a Micromeritics TriStar 3000(Micromeritics Instrument Corporation, U.S.A) gas sorptionsystem. Specific surface area (SSA) values were determinedfrom the isotherm with the Brunauer−Emmett−Teller (BET)method.48 The Barrett−Joyner−Halenda (BJH) method,49

using the adsorption isotherms, provided the average porewidth and pore volume values.

Thermal Analysis. Differential scanning calorimetry wasperformed with a Jupiter STA 449 (Netzsch, Germany) using30 mg of calcined glass powder in a Pt crucible under flowingargon purge. Analysis was carried out between 50 and 1000 °Cat a heating rate of 10 °C/min and the output was used tocalculate glass transition and crystallization temperatures (Tgand Tc, respectively).

X-ray Diffraction. X-ray diffraction (XRD) diffractogramsof the glasses were analyzed with a Bruker D8 Discover X-raydiffractometer (Bruker AXSS Inc., U.S.A) equipped with a CuKα (λ = 0.15406 nm) target set to a power level of 40 mV and40 mA. Using an area detector, three frames of 25° werecollected from 15−75 2θ (deg) and merged in post-processing.Phase identification was carried out using X’Pert HighscorePlus (PANalytical, Netherlands).

Attenuated Total Reflectance Fourier TransformInfrared Spectroscopy. Attenuated total reflectance Fouriertransform infrared (ATR-FTIR) spectroscopy was carried outusing a Spectrum 400 (PerkinElmer, U.S.A) between 4000 and650 cm−1 with a resolution of 4 cm−1 using 64 scans persample. All spectra were baseline corrected and normalized tothe total area surface area under absorption bands usingSpectrum software (PerkinElmer, U.S.A).

Nuclear Magnetic Resonance. Solid state 11B nuclearmagnetic resonance (NMR) was used to examine the structureof the glasses. 11B NMR spectra were recorded on an Agilent/Varian VNMRS300 spectrometer with a 11B frequency of 96.2MHz. Approximately 2000 accumulations for each spectra wereobtained by applying a 90 deg pulse of microseconds every 8 swith proton decoupling.

Dynamic Vapor Sorption. In order to investigate theaqueous interactions of SGBGs, their vapor sorption wasexamined using a DVS Intrinsic (Surface Measurement SystemsLtd., U.K.), which measures mass changes (±0.1 μg) undercontrolled humidity and temperature. Approximately 5 mg ofSGBG particles was placed in an aluminum pan and insertedinto a chamber at 37 ± 0.05 °C. Two methods of analysis werecarried out: (1) the relative humidity (RH) was increasedstepwise at 5% RH up to 90% RH then decreased back down to0% RH while the relative mass change was measured whenequilibrium was reached or after maximum of 4 h; (2) the glassparticles were directly exposed to 90% RH for 6 h and then to0% RH for a further 6 h.

Inductively Coupled Plasma Optical Emission Spec-trometry. Release of boron, calcium, sodium and phosphorus

Table 1. Glass Compositions

composition (mol %) composition (wt %)

glass ID B2O3 CaO Na2O P2O5 B2O3 CaO Na2O P2O5

B36 36.2 31.9 28.9 3.0 38.6 27.4 27.4 6.6B41 41.1 29.4 26.6 2.8 43.6 25.2 25.2 6.1B46 46.1 26.9 24.4 2.6 48.6 22.9 22.9 5.6B51 51.1 24.4 22.1 2.4 53.6 20.7 20.7 5.1B56 56.1 21.9 19.8 2.2 58.6 18.4 18.4 4.6B61 61.3 19.3 17.5 1.9 63.6 16.2 16.2 4.145B5 46.1 26.9 24.4 2.6 48.6 22.9 22.9 5.6

Chemistry of Materials Article

DOI: 10.1021/acs.chemmater.5b01697Chem. Mater. XXXX, XXX, XXX−XXX

B

ions from glass powders in deionized water (DIW) at a 1.5 mg/mL ratio, were quantified using an inductively coupled plasma−optical emission spectrophotometer (ICP-OES, ThermoScientific iCAP 6500, U.S.A). Aliquots of 10 mL were filteredthrough a 0.2 μm nylon filter and stored in a 15 mL falcon tube,to which 4% (w/v) nitric acid (Fisher Scientific, Canada) wasadded. NIST standards were used as calibration values. The pH

of the DIW solution was measured at each time point using anAccumet XL20 pH meter (Fisher Scientific).

Scanning Electron Microscopy. Scanning electronmicroscopy (SEM) was used to investigate the morphologicalproperties of the glass powders. Samples were sputter coatedwith Au/Pd and analysis was performed with an Inspect F50Field Emission Scanning Electron Microscope (FEI Corpo-

Figure 1. An overview of the sol-gel process; (i) mixing of precursor materials, (ii) casting and aging, (iii) gel monoliths at day 10, (iv) drying, and(v) post calcination at 400 °C (scale bars =1 cm). (iii) Demonstrates the scaling up possibilities with these gels in larger containers.

Figure 2. Effect of calcination temperature on SGBG structure. XRD diffractograms of calcined glasses indicate the amorphous characteristics by thepresence of two broad humps. Crystallization of the glasses was initiated at higher calcination temperatures and was dependent on SGBGcomposition. All SGBG compositions crystallized at 600 °C.

Table 2. Glass Textural and Thermal Properties: Average Median Diameter D50, Specific Surface Area SSA, Average Pore Widthand Average Pore Volume As Well As Glass Transition Temperature Tg and Crystallization Temperature Tc

ID D50 (μm) SSA (m2/g) pore width (nm) pore volume (cm3/g) Tg (°C) Tc (°C)

B36 34.7 54.9 ± 7.7 32.8 ± 2.0 0.42 ± 0.06 431 474B41 34.6 71.8 ± 8.3 33.2 ± 1.9 0.65 ± 0.11 441 510B46 43.8 93.8 ± 8.2 28.9 ± 0.7 0.74 ± 0.05 453 525B51 33.7 114.2 ± 14.9 32.9 ± 1.0 0.94 ± 0.18 474 579B56 38.8 121.0 ± 12.9 29.6 ± 0.4 0.98 ± 0.11 485 632B61 47.1 138.4 ± 11.8 29.0 ± 0.7 1.18 ± 0.12 484 63945B5 44.1 0.238 ± 0.017 34.0 ± 8.6 0.00089 ± 0.00006 473 531

Figure 3. Characterization of calcined SGBGs. (a) ATR-FTIR spectra of the SGBGs calcined at 400 °C and 45B5 indicate typical borate bondingmodes. (b) 11B MAS NMR of the SGBGs calcined at 400 °C including 45B5. (c) Glass forming ability as indicated by the trend of the differencebetween Tc and Tg versus NC. Compositions with higher borate content were more likely to form a glass, as demonstrated by the increase in thedifference between Tc and Tg.



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ration, U.S.A.) at 10 kV. To determine HCA conversion, energydispersive spectroscopy (EDS) using an attached EDAX and aTEAM EDS Analysis System was performed at 20 kV on 8unique glass surface areas to determine the Ca/P ratio at the 6h and 7 days time points.Bioactivity. The in vitro mineralization of the glasses was

examined using Kokubo’s SBF (pH 7.4).50 Glass powder wasadded to sterile 50 mL falcon tubes containing SBF at a 1.5mg/mL ratio and stored at 37 ± 1 °C. Twice per day, the vialswere gently agitated in order to prevent agglomeration.Mineralization of the glasses was examined at 6-h, 1-day, 3-day, and 7-day time points when the powders were gentlyrinsed twice with DIW then twice with ethanol, dried overnightat room temperature, and then dried in an oven at 60 °C for 1day. The pH of the SBF solution was measured at each timepoint using an Accumet XL20 pH meter (Fisher Scientific).

3. RESULTS AND DISCUSSIONSol-Gel Processing. Figure 1 provides an overview (using

B46) of the sol-gel process. During this process, boric acid was

dissolved in ethanol, which created excess water, thus allowingfor hydrolysis and polycondensation reactions, and eventuallyleading to the gelling of the precursor materials. A schematic ofthis proposed network formation is presented in Supporting

Information Figure S1. All compositions formed a gel, asqualitatively confirmed by placing the storage vials upside downand noting no flow. The viscosity of all compositions increasedpost-mixing, and sol formation was initiated almost immedi-ately, except for B36, which exhibited two distinct phases; abottom precipitate layer, and a clear gel layer similar to theother compositions (Supporting Information Figure S2).Monolithic gels also formed in larger containers (Figure 1iii)demonstrating the scalability of this process. Upon monolithdrying, as-made particles were generated, as often observedwith nonsilicate-based sol-gel systems.35,42 XRD diffractogramsof the as-made glass particles displayed two broad humpsindicating their amorphous and homogeneous nature, exceptfor B36, which displayed a number of minor peaks, attributableto a precipitate phase (Supporting Information Figure S2).XRD diffractograms of SGBGs calcined at different temper-

atures indicated their progressive crystallization with temper-ature, with low borate content glasses crystallizing at lowertemperatures (Figure 2). All SGBGs underwent crystallizationwhen calcined at 600 °C, with the majority resulting in a formof Na−Ca−B phase, indicating the successful incorporation ofthe precursors into the glass network during processing. It wasalso found that glasses with higher sodium content tended tocrystallize at lower temperatures; an effect previously observedin sol-gel derived silicate-based glasses.39 This was corroboratedby ATR-FTIR spectroscopy, which showed sharp, doubletpeaks at increased calcination temperatures, indicatingcrystallization (Supporting Information Figure S3).

Properties of Calcined SGBGs. Because all SGBGsremained amorphous post calcination at 400 °C, thistemperature was chosen in this study to investigate theproperties of the various glasses. Calcination at this temperatureyielded glass particles of high SSA and large pore volume values(Table 2). There was an increase in these parameters with anincrease in glass borate content, indicating that the low boratecontent glasses underwent greater extents of densification atlower temperatures, likely leading to their earlier crystallization(Supporting Information Figure S4a).51 In contrast, the averagepore width remained consistent, which can be attributed to theuniform processing conditions. Compared to the melt-derived45B5, the SSA and total pore volume of B46 were ∼400 and∼800 times greater, respectively. On the other hand, anincrease in the calcination temperature of B46 led to a decreasein these parameters (Supporting Information Figure S4b).Thermal analysis of the calcined SGBGs indicated that therewas an increase in both Tg and Tc with an increase in glassborate content and corroborated their crystallization trendsobserved through XRD. Previously, it has been shown that theaddition of B2O3 increased the Tg of phosphate-based glasses.52

ATR-FTIR spectroscopy was used to analyze the bondingregions of the calcined SGBGs (Figure 3a). The three mainregions associated with borate-based glasses were present at850−1200 cm−1 (BO stretching of BO4 units), 1200−1500cm−1 (BO stretching of BO3 units), and a band at ∼720cm−1 attributable to the BOB bending of BO3 units, whichwas more defined in lower borate content glasses.53−55 With adecrease in glass borate content, the broad band between ∼942and ∼1000 cm−1, attributable to the BO linkages ofBO4,

52,56−58 formed a defined shoulder peak at ∼870 cm−1,which is characteristic of the BO stretching of boroxoal ringsas observed in the B36 to B51 range of the SGBGs. Acomparison of the spectra of 45B5 and B46 indicated that both

Figure 4. Reactivity through vapor adsorption. (a) Stepwise increase in% RH, with adsorption (solid line) and desorption (dashed line),indicating that lower borate content glasses experienced higher % masschanges. (b) Direct exposure to 90% RH showing a rapid increase inmass. The rate and extent of mass change were dependent on SGBGcomposition and increased with a decrease in glass borate contentsuggesting greater extents of reactivity.



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glasses were of analogous structures as they displayed similarpeaks.

11B MAS NMR spectroscopy provided geometrical informa-tion on the borate unit (Figure 3b). All calcined SGBGsexhibited a large, sharp peak near 0 ppm, which can be

attributed to 11B nuclei occupying a relatively symmetric site inthe chemical structure. The small broadening to the right of thispeak, as seen in B46−B61, may be due to 11B in less symmetricsites. B36, B41, and B61 showed greater broadening on the leftside, which may indicate 11B in asymmetric sites (i.e., BO3) or

Figure 5. SGBG ion release. (a) Boron, (b) calcium, (c) sodium, and (d) phosphorus ion release in DIW as measured through ICP-OES.

Figure 6. Mineralization in SBF solution. ATR-FTIR spectra before and after immersion in SBF for 6 h, 1 day, 3 days, and 7 days. The bendingmode (ν3) of PO4

3− at ∼1020 cm−1, which is characteristic of apatite formation, was observed at the 6 h time point and became more defined atlonger times in SBF.



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the same amount but in sites of less symmetry. The resonanceassociated with BO4 was quite narrow located in a chemicalshift range of 0 and −11 ppm due to its small quadrupolecoupling constant. Conversely, BO3 has a stronger quadrupoleinteraction and produces a more broad resonance between 14and 18 ppm. Furthermore, when 11B occupies a state of lowsymmetry, the relaxation times are relatively short (100 ms)due to its quadrupole nucleus. The glasses analyzed in thisstudy required an 8 s delay between pulses, which suggestedthat the 11B were in a state of high symmetry and likely to betetrahedrally coordinated, supporting the ATR-FTIR spectra.A plot of the relationship between NC (Supporting

Information) and the difference between Tc and Tg of eachglass composition, demonstrated a linear correlation (R2 =0.9384; Figure 3c). An increase in the difference between Tc

and Tg provides a good estimate of the tendency of the glass toremain amorphous,59,60 which was used to predict the glassforming ability of the SGBGs. As verified by XRD and ATR-FTIR (Figure 2 and Supporting Information Figure S3,respectively), glasses with higher borate content remainedamorphous at higher calcination temperatures and suggestedthat these compositions favored glass formation.SGBG Aqueous Interactions and Ion Release. Attribut-

able to their relatively lower chemical durability, borate-basedglasses have been shown to undergo more rapid dissolutionwhen compared to silicate-based glasses.8,61 In this study, DVSwas used to investigate the immediate aqueous interactions of

SGBGs as an indicator of their reactivity and potentialsolubility, by gravimetrically measuring their sorption anddesorption of water vapor at different RH values.62 Under astepwise increase in RH, the % mass change for all SGBGs wassimilar up to 60% RH, above which there was a significantincrease in mass (Figure 4a). The mass change at 90% RHcorrelated with glass composition with the lower borate contentglass, B36, resulting in ∼74% increase compared with ∼36% forB61. Upon decreasing RH, desorption mainly occurredbetween 90 and 55% RH, and the final mass change at 0%RH ranged between 19.5 and 23.7%, which correlated withSGBG composition. With regard to the melt-derived 45B5,there was no mass change up to 65% RH, above which therewas a gradual increase up to ∼11% at 90% RH. Desorption in45B5 mainly occurred between 90 and 65% RH reaching a finalmass change of ∼3%.Under the direct exposure of SGBGs to 90% RH, there was

an immediate rapid increase in mass within the first 2 h that wasfollowed by a slower rate of increase up to 6 h (Figure 4b). Therate and extent of mass change (∼58 to ∼41%) were dependenton SGBG composition, and increased with a decrease in glassborate content suggesting greater extents of reactivity. Uponimmediately lowering the RH to 0%, there was a rapid decreasein mass with lower borate content glasses indicating greaterextents of final % mass change. In contrast to SGBGs, the directexposure of 45B5 to 90% RH resulted in ∼11% mass increase at6 h, and was less than that of B46 (∼48%). In addition, beyond

Figure 7. Mineralization in SBF solution. XRD diffractograms before and after immersion in SBF for 6 h, 1 day, 3 days, and 7 days. Characteristichydroxyapatite (“•” JCPDS 9-0432) peak formation initiated at the 6 h time point and became more defined at longer times in SBF. B36 indicated acalcite peak (“□” JCPDS 5-0586).



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the first 2 h, 45B5 experienced a relatively linear rate of % massincrease, similar to that experienced by melt-derived silicate63

and phosphate-based glasses.62

Therefore, reactivity, as indicated by vapor sorption, wasfound to be highly dependent on SGBG composition, whereatomic and molecular structures play prominent roles in thechemical durability of multicomponent glasses31,64 and can berelated to NC.

65,66 It is likely that in the case of lower boratecontent glasses, the fewer boron units resulted in more terminalgroups, specifically OH¯, which were more prone to aqueousinteraction and resulted in higher extents of mass change. Thisis particularly relevant to sol-gel derived glasses as theseterminal groups are not fully removed during drying andcalcination.31 On the other hand, the role of SGBG texturalproperties (SSA and pore volume) were prominent as B46 and45B5 experienced drastically different % mass changes.ICP-OES measurements up to day 7 in DIW revealed the

release of all four SGBG components (Figure 5). There wererapid rates of release of boron and sodium ions, which weredependent on borate and soda contents in the SGBGs,respectively. Beyond the 6 h time point, boron and sodiumion concentrations remained constant, indicating their fullrelease. Interestingly, although the release rates of calcium andphosphorus ions were also rapid within the first 6 h, the extentsof the release of these ions was inversely related to glasscomposition. Furthermore, beyond the 6 h time point, there

was a concomitant decrease in the concentrations of these ionsin solution that was presumably due to their complexing. Therates of ion release from the SGBGs were supported by changesin DIW pH, rapidly increasing within the first 6 h, thenstabilizing at a constant value, which suggested full ion release(Supporting Information Figure S5a).The ion release profiles from SGBGs were distinct from

those of the melt derived 45B5, which demonstrated a slower,more gradual release rate, where by day 3, the concentration ofboron ions in solution reached a similar level to that of B46achieved after 6 h. Sodium ion release was also higher in 45B5,which may be due to the lower release of boron ions, leading toa more basic solution, as previously reported.8 The higherextent of sodium ion release resulted in higher pH values, evenwith the significantly lower textural properties of the melt-derived 45B5. Furthermore, the release of calcium ions from45B5 displayed a contrasting trend to that of B46, where afterthe 6 h time point, it steadily increased in concentration andeventually stabilized at day 3. The extent of phosphorus ionrelease from 45B5 was found to be at least 10-fold lower whencompared to B46.

Bioactivity in SBF. The bioactivity of the various SGBGswas investigated up to day 7 in SBF. ATR-FTIR spectroscopyindicated that carbonated-apatite was initiated in as little as 6 hfor all SGBGs, through the formation of a strong band at∼1020 cm−1 along with shoulders at ∼961 and 1062 cm−1,which are characteristic of the bending modes ν1 and ν3 ofPO4,

3−67 respectively (Figure 6). In addition, the broad bandsat ∼1470 and ∼1421 cm−1 can be attributed to the stretchingmode (ν1) and (ν3) of CO3

2−, respectively,68,69 whereas theweak band at ∼1640 cm−1 is due to the bending mode (ν2) ofwater.70,71 The sharp peak at 870 cm−1 also indicates thebending mode (ν2) of CO3

2− as is commonly associated withcarbonated-apatite.68,69 However, this peak was also observedin the as-made SGBGs (Figure 3a), particularly in lower boratecontent glasses as the BO stretching of boroxol rings,suggesting a combination of both structural forms. An increasein exposure time to SBF corresponded with these peaksbecoming sharper and more defined, indicating the progressivecrystallization of HCA. While higher borate containing SGBGspresented more defined phosphate peaks at earlier time points,the spectra at day 7 indicated smaller carbonate peaks.XRD analysis confirmed apatite formation in 6 h as indicated

by the appearance of peaks at ∼25 and ∼32° 2θ; characteristicof hydroxyapatite (“•”, JCPDS 9-0432) where higher boratecontent glasses indicated more defined peaks (Figure 7). At day1, all SGBGs displayed more prominent broad apatite peaks,which may indicate the formation of nanometer-sized orpartially crystallized HCA.8 On the other hand, B36 showed theformation of a calcite phase (“□”, JCPDS 5-0586), attributableto its higher lime content, along with the lower NC, likelyresulting in calcite forming terminal groups. Furthermore, andin line with that observed in DIW, the increase in the pH ofSBF solution corresponded with glass borate content, thusfavoring HCA formation (Supporting Information Figure S5b).Indeed, the conversion mechanism of borate-based glasses tohydroxyapatite is thought to be similar to that of Bioglass 45S5,but without the formation of an SiO2 rich layer.8,54 It has beendescribed that in the case of borate-based glasses, an HCA isinitially formed on the outer glass surface which thencontinually reacts toward its center, causing a reduction involume, until full conversion has taken place.54 This has beenattributed to the relatively rapid release of BO3

3− and Na+ ions,

Figure 8. Morphological characterization of B46 and 45B5 as afunction of time in SBF. The initial textured surface of the calcinedB46 increased in roughness with time in SBF. As-made 45B5demonstrated a smooth surface that became rougher with time in SBF.EDAX of B46 at 6 h indicated a Ca/P ratio of 1.6, closely resemblingthat of hydroxyapatite. EDAX of both glasses at day 7 indicated similarCa/P ratios.



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whereas the remaining Ca2+ and PO43− ions from the glass

migrate to the surface and react with similar ions in the SBFsolution leading to formation of an amorphous calcium-phosphate layer that eventually crystallizes into HCA. Withthe SGBG formulations investigated in this study, it is proposedthat a similar mechanism of conversion occurs, yet at asignificantly more rapid rate compared to melt-derived glasses,attributable to their significantly higher textural properties andrapid ion release rates. Therefore, in order to further examinethe effect of sol-gel processing on the bioactivity of borate-based glasses, the rates of mineralization of B46 and 45B5 weredirectly compared. Figure 8 shows the SEM micrographs ofthese glasses as a function of time in SBF (SupportingInformation Figure S6 shows the SEM micrographs of allglasses at more extensive time points in SBF). Attributable tosol-gel processing, the surface of calcined B46 exhibited arough, nanoporous texture,31 corroborating the textural proper-ties in Table 2. In contrast, 45B5 displayed a relatively smooth

surface appearance, typical of melt-derived glasses. However,surface roughness in both glasses became more apparent withtime in SBF, as has been previously observed in borate-basedglasses.54,72 EDAX analysis of B46 after 6 h in SBF indicatedthe rapid formation of an apatite-like calcium-phosphate layer,with a Ca/P ratio approaching that of HCA (1.60 ± 0.01). Thiswas in contrast to 45B5, where the Ca/P ratio at the 6 h timepoint was more reflective of the glass composition. However, byday 7 in SBF, a comparable Ca/P ratio was observed in bothglasses.ATR-FTIR spectroscopy of the glasses at earlier time points

in SBF indicated that HCA-like formation was achieved in aslittle as 0.5 h in B46, compared to 3 days in the case of 45B5(Figure 9). Furthermore, XRD diffractograms showed thatHCA formation was initiated after 3 h for B46, compared to 3days for 45B5. This demonstration of the highly bioactivenature of SGBGs is unprecedented and can be attributed totheir ability to release greater extents of phosphate ions, thus

Figure 9. Mineralization rates of B46 and 45B5 in SBF solution. (a) ATR-FTIR spectra demonstrated that B46 rapidly (in 0.5 h) converted tocarbonated-apatite compared to 45B5 (3 days). (b) XRD diffractograms indicated typical hydroxyapatite peak formation (“•” JCPDS 9-0432) after 3h for B46 compared with 3 days for 45B5.



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favoring rapid HCA formation in SBF. Indeed, in assessing thebioactivity of melt-derived borate-based glasses, numerousstudies have utilized either 0.02 or 0.2 M K2HPO4solution,61,72−75 which provide supraphysiological concentra-tions of phosphate ions (20 and 200 fold higher compared tothat in SBF, respectively) to enable calcium-phosphateformation and the eventual conversion to hydroxyapatite.8 Asa comparison to SBF, this study also investigated themineralization of B46 and 45B5 in 0.02 M K2HPO4. It wasfound that apatite formation initiated within 6 h in both glasses,indicating that K2HPO4 artificially promoted rates ofmineralization in melt-derived borate-based glasses (SupportingInformation Figure S7). Therefore, although the use of SBF inassessing in vitro bioactivity has been questioned,76 it can beregarded as more representative than K2HPO4 solution.In terms of potential uses for the repair and augmentation of

mineralized tissues (bones and teeth), a rapid mineralizationrate may be desirable as it can potentially lead to faster tissuerepair. However, a compromise may be necessary betweenrapid rates of ion release and biological responses. To this end,and as has been demonstrated with silica-based glassescombined with the sol-gel processing, numerous parameterscan be easily adjusted to alter the properties and chemicaldurability of the glasses, ultimately leading to the controlrelease of therapeutically relevant ions for targeted healing andrepair.31 This will be the subject of further research includingthe role of higher borate containing glasses in regulatingmineralization as well as cellular and tissue responses in vitroand in vivo.

4. CONCLUSIONSHighly bioactive borate-based glasses have been created using anovel sol-gel processing route. All glasses remained amorphousafter calcination at 400 °C and demonstrated nanoporositythrough high specific surface areas and large pore volumes.Reactivity and ion release from the sol-gel derived glasses werefound to be composition dependent. Furthermore, the onsetmineralization of all SGBG compositions occurred within 3 h inSBF, demonstrating at least a ∼25 fold increase in bioactivityrate relative to melt-derived borate-based glasses. The ability ofthe SGBGs to rapidly convert to bone-like HCA holds promisefor the repair and augmentation of mineralized tissues. Futurework will investigate the effect of these glasses on cellularfunctions as well as the role of other ionic doping for a broaderpotential range of tissue engineering, antibacterial, and woundhealing applications.

■ ASSOCIATED CONTENT*S Supporting InformationDetails on gel network formation, a visual overview of gelation,XRD of the as-made glasses, ATR-FTIR at higher calcinationtemperatures, pH, SEM, bioactivity using a K2HPO4 solution aswell as the effect of calcination temperature on weight loss,specific surface area, and pore volume. The SupportingInformation is available free of charge on the ACS Publicationswebsite at DOI: 10.1021/acs.chemmater.5b01697.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected] authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

This study was supported by Canada NSERC, Quebec MEIE,CFI and McGill University Faculty of Engineering HatchFaculty Fellowship for S.N.N. W.C.L. is also supported by theMcGill Engineering Doctoral Award. Drs. Kristian Waters andFred Morin are gratefully thanked for use of the DVS andNMR, respectively.

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Highly Bioactive Sol-Gel-Derived Borate Glasses