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DOI 10.1007/s12633-015-9291-x
ORIGINAL PAPER
Synthesis, Characterization and In Vitro Biological
Evaluation of Sol-gel Derived Sr-containing
Nano Bioactive Glass
S. Solgi1·M. Khakbiz1·M. Shahrezaee2·A. Zamanian3·M. Tahriri4,5,6 ·
S. Keshtkari7·M. Raz6·K. Khoshroo5·S. Moghadas8·A. Rajabnejad1
Received: 9 February 2015 / Accepted: 16 March 2015
© Springer Science+Business Media Dordrecht 2015
Abstract In this study, bioactive glass of the type SiO2–
CaO–SrO–P2O5was obtained by the sol-gel processing
method and the effects of SrO/CaO substitution on the in
vitro biological properties of the synthesized glasses were
evaluated. The obtained bioactive glasses were character-
ized by X-ray diffraction (XRD), Fourier transform infrared
spectroscopy (FTIR), scanning electron microscopy (SEM),
thermal gravimetric analysis (TGA), differentioal scanning
caloremetry (DSC) and Brunauer, Emmett and Teller (BET)
M. Tahriri
m-tahriri@sina.tums.ac.ir
1Faculty of New Science and Technologies, University
of Tehran, Tehran, Iran
2Orthopedic Surgery Department, AJA University of Medical
Science, Tehran, Iran
3Nanotechnology and Advanced Materials Department,
Materials and Energy Research Center, Karaj, Iran
4Iranian Tissue Bank & Research Center, Tehran University
of Medical Sciences (TUMS), Tehran, Iran
5Dental Biomaterials Department, School of Dentistry, Tehran
University of Medical Sciences (TUMS), Tehran, Iran
6Biomaterials Group, Faculty of Biomedical Engineering,
Amirkabir University of Technology, Tehran, Iran
7School of Medicine, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
8Ceramic Department, Materials and Energy Research Center,
Karaj, Iran
analyses. The effects of various glass compositions on pro-
liferation and differentiation of osteoblastic cells were also
evaluated. The results showed that incorporation of Sr in
the obtained glass network did not result in any structural
alteration due to the similar role of SrO compared with that
of CaO. In vitro experiments with human osteosarcoma cell
lines (MG-63) indicated that bioactive glass incorporating 5
mol % in the composition revealed optimal cell proliferation
and alkaline phosphatase (ALP) activity. Our results ascer-
tained this material to be non-toxic and compatible for the
proposed work in segmental defects in the rabbit model in
vivo.
Keywords Bioactive glass ·Strontium ·Sol-gel ·
Osteoblastic cell
1 Introduction
Bioactive glasses have been clinically useful for more than
ten years as bone repair materials or fillers on account of
their ability to bond to living bone and their good bioactiv-
ity, biodegradability and osteoconductivity [1–5].
Hench and Polak labeled the bioactive materials as third
generation biomaterials, following the first generation of
bioinert materials, and the second generation of more inter-
active materials such as bioactive ceramics and biodegrad-
able polymers. In the pursuit for the new generation of
materials, bioactive glasses with various compositions hold
promise [6].
The sol-gel process is a consummate technique to attain
compositional and structural control. The process, a sub-
stitute for traditional melt quenching for bioactive glasses,
involves conversion of monomers into a colloidal solution
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(sol), typically composed of metalorganic and metal salt
precursors which act as the precursor for an integrated net-
work (gel) of either discrete particles or network polymers
[7–9]. Compared with melt-synthesized bioactive glasses
(BGs), sol-gel-synthesized BGs are prepared at lower tem-
peratures and have superior compositional control. More-
over, sol-gel-derived BGs are more easily acquired with the
combination of biodegradability and bioactivity [10,11].
In vitro studies in simulated body fluid (SBF) and in vivo
analysis in animal models reveal that sol-gel processed BGs
are more degradable (as depicted by the amount of residual
glass) and bioactive (as depicted by the apatite forma-
tion) than BGs synthesized by conventional melt methods
[12–15].
The ability of BGs to bond to bone comes from the
formation of a bone-like apatite layer [hydroxyl carbon-
ate apatite (HCA)] on their surfaces, which interacts with
collagen fibrils of damaged bone to form a bond [16].
The sequence of events leading to bonding of BGs to
the bone includes protein adsorption, incorporation of col-
lagen fibrils, attachment of bone progenitor cells on the
surface of BGs after formation of the HCA layer fol-
lowed by cell differentiation, excretion of bone extracellular
matrix and its mineralization. The HCA layer also pro-
vides a surface appropriate for osteogenic cell attachment
[4,17,18].
Today, researchers demonstrate that ionic dissolution
products from BGs have an important role in their in vitro
and in vivo behaviors. The control of ion release from BGs
is an attractive approach to improve the biological capabil-
ity [19–21]. Ionic dissolution products from BGs have been
known to stimulate angiogenesis, osteogenesis, and vascu-
larization. In order to the obtained therapeutic effects of
active metal ions and to enhance the biological performance
of the BGs toward a specific host response, new concepts
have been introduced to establishing active metal ions into
the glass network [22–24].
The strontium (Sr) ion is an important source of interest
in recent years benefiting patients agonizing from osteo-
porosis, as it suppresses osteoclast activity [25,26]. Sr is one
of the alkaline earth metals and like Ca is a bone-seeking
agent [25]. The biological influences of Sr are related to its
chemical similarity to group 2 periodic table elements such
as Ca. Owing to its bone-seeking characteristic, Sr accu-
mulates to a high degree in bone, can displace Ca in hard
tissue metabolic processes and at high concentrations inter-
feres with normal bone development [22–27]. Therefore, an
effective way to deliver a steady supply of strontium ions in
such patients is incorporation of Sr in BGs. The increasing
interest in Sr-containing BGs has resulted in a multiple-fold
increase in the number of scientific reports in this field in
recent years [28–30].
In this study, we describe the sol-gel synthesis and
characterization of Sr-containing bioactive glasses (with Sr
concentration of 0, 5 and 10 mol %) based on this quaternary
system. Moreover, in vitro biological investigations were
conducted by culturing osteosarcoma cells on the prepared
bioactive glasses to identify the role of Sr concentration in
the BG composition on the cell proliferation and level of
alkaline phosphatase activity.
2 Experimental Procedure
2.1 Materials
Triethyl phosphate (TEP) (product NO. 8211410100) and
tetraethyl orthosilicate (TEOS) (product NO. 8006580250)
were obtained from Merck chemical Co. and were employed
as phosphate precursor and silica precursor, respectively.
Calcium nitrate tetrahydrate Ca(NO3)2.4H2O (product NO.
1021210500) and strontium nitrate Sr(NO3)2(product NO.
1078720250 ) were also purchased from Merck chemical
Co. and were employed as the alkaline-earth metal sources.
All commercially available solvents and reagents were of
analytical grade with no further purification.
2.2 Synthesis of BGs
The BGs were sol-gel synthesized by changing the
Ca2+/Sr2+ratio in a glass composition. Sr is substituted for
Ca with a ratio of 0, 5 and 10 mol %.
At first 2 M nitric acid was mixed with distilled water
with the volume ratio of 1:6 and stirred for 5 min. Then,
tetraethyl orthosilicate and triethyl phosphate with the molar
ratio of 1:12 were added into the water/acid solution, respec-
tively and stirred at ambient temperature for 1 h. Subse-
quently, calcium nitrate and strontium nitrate were added to
the obtained solution and stirred at 50 ◦Cinordertodis-
solve the nitrate salt and attain a homogeneous solution. The
obtained sols were sealed and kept at 37 ◦Cfor7daysto
complete the gelation process. The samples were dried at
70 ◦C and 140 ◦C for 24 h, respectively and, heated at
800 ◦C for 3 h to remove the residual nitrate and organic
substances.
2.3 Characterization of BGs
2.3.1 X-ray Diffraction Analysis
To detrmine the crystal structure of the synthesized BGs,
X-ray diffraction (XRD) patterns were used at ambient tem-
perature using an INEL Equinox3000 (Cu-Ka radiation)
operating at a voltage of 40 kV and current of 30 mA.
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Synthesized BGs were examined in the 2θangle range of
10–80◦.
2.3.2 FTIR Analysis
Infrared spectroscopy was conducted using a Fourier
transform infrared (FTIR) Nicolet USA operating in the
wavenumber range of 400–4000 cm−1andemployedinthe
transmission mode to obtained the chemical composition of
the synthesized BGs.
2.3.3 Scanning Electron Microscopy (SEM)
A scanning electron microscope (SEM Philips XL30)
equipped with an energy dispersive X-ray spectrometer
(EDS) was employed to evaluated the morphology and
chemical composition of the synthesized BGs.
2.3.4 Transmission Scanning Microscopy (TEM)
The morphology of precipitates was observed by TEM
(CM200-FEG-Philips). Carbon coated 200 mesh copper
grids were dipped in a dilute suspension of the precipi-
tate. The particles were deposited onto the support grids by
deposition from a dilute suspension in ethanol.
2.3.5 Thermal Gravimetric Analysis (TGA) and Differential
Scanning Calorimetery (DSC)
Simultaneously thermal analysis (STA) generally refers to
the simultaneous application of thermogravimetry (TGA)
and differential scanning calorimetry (DSC) to one and
the same sample in a single instrument. A thermoanalyzer
(STA; Polymer Laboratories PL-STA 1640) that started
from room temperature up to ∼1000◦C with the heating
rate of 10◦C /min was used to record the conventional
thermoanalytical curves.
2.3.6 Specific Surface Area Measurement
The specific surface area (SSA) of the powder of the sam-
ples was measured by the nitrogen adsorption technique
known as the Brunauer, Emmel and Teller (BET) method.
Nitrogen adsorption–desorption isotherms at −196 ◦Cwere
obtained using a Micromeritics ASAP 2020 Analyzer.
2.4 Biological Evaluation
2.4.1 MTT Assay
The cell viability of the synthesized BGs was deter-
mined using MTT (3-(4, 5dimethylthiazol-2-yl)-2,
5-diphenyltetrazolium bromide) assay. At first, cells were
seeded on to 96 well plates at a density of 1×104cells per
well and were incubated under standard culturing condi-
tions. The cells were incubated on the BGs for 7 and 14
days. After the incubation, the medium was seperated and
the media containing 10 % of MTT solution was added.
Then, the plates were incubated at 37 ◦C for 4 h. The
medium was then separated and 100 µl of solubilization
buffer (Triton-X 100, 0.1N HCl and isopropanol) were
added to each well to dissolve the formazan crystals, which
have been produced because of the activity of living cells in
MTT solution. The absorbance of the lysate was recorded
in a microplate reader at a wavelength of 570 nm.
2.4.2 Alkaline phosphatase
Alkaline phosphatase (ALP) is an enzyme whose produc-
tion signifies proliferation and differentiation of osteoblasts.
An ALP assay kit was used to measure ALP activity accord-
ing to the manufacturer’s protocol (Biocat, Heidelberg,
Germany). Briefly, human osteosarcoma cell lines (MG-63)
were seeded in 24-well cell culture plates at a density of
1×104cells/cm2. The glass samples (n =5) were placed in
the wells. Three wells in the absence of glass samples were
used as negative controls. The plates were incubated for 7
and 14 days at 37 ◦C in humidified air with 5 % CO2. Then,
the supernatant of each well was removed and the cell layer
was rinsed twice with PBS, homogenized with 1 ml Tris
buffer, and sonicated for 4 min on ice. Aliquots of 20 ml
were incubated with 1ml of a p-nitrophenyl phosphate solu-
tion at 30◦C for up to 5 min. Cellular alkalinephosphate
activity was determined by the conversion of p−nitrophenyl
phosphate to p-nitrophenol, and monitored by following
absorption at 405 nm, and conversion to enzyme activ-
ity was made using the p-nitrophenol standard absorption
curve.
3 Results and Discussion
3.1 XRD Analysis
XRD patterns of the synthesized BGs are given in Fig. 1.
As can be observed, the prepared bioactive glasses have
amorphous structure but by incorporation of strontium to
the bioactive glass structures some new broad and weak
peaks are seen that could be related to presence of strontium
compounds like SrCO3(JCPDS No. 05-0418) and Sr2Si2O4
(JCPDS No. 38-0271). Also, the diffraction maximum of
the amorphous phase shifted to smaller 2θvalues when the
strontium content in the bioactive glasses increased. This
phenomenon could be due to enhancement in the average
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Fig. 1 XRD patterns of the
synthesized bioactive glasses
spacing in the bioactive glass structure with regard to the
larger size of Sr ions relative to Ca ions. Furthermore, with
increasing Sr content in the prepared glasses, crystallinity
has decreased.
3.2 3.2. FTIR Analysis
FTIR analysis was conducted to evaluate the structure of the
prepared bioactive glasses. The main infrared bands in the
FTIR spectra were located at: 500, 605, 850, 1135, 1485 and
3685 cm−1wavenumber (see Fig. 2). The band positioned
at 500 cm−1is related to PO43−. Bands located at 1135
cm−1are related to the Si-O-Si group and the band located
at 605 cm−1is related to the Si-O group. The differences
in the FTIR spectra are seen in the range of 1565–1375
cm−1. This range could be related to carbonate group for-
mation arising from the reaction of bioactive glass with CO2
of the atmosphere. Addition of strontium in the bioactive
glass enlarges the structure of the glass due to the difference
between strontium and calcium ion size. It is noticeable that
the formation of the strontium/calcium carbonate with addi-
tion of strontium to the structure of the bioactive glass is
because of the expansion of the glass network that enhances
the permeation of the carbonate [31].
3.3 SEM Observations
The morphology of the synthesized bioactive glasses was
investigated using SEM. We observed that the synthesized
bioactive glass powders have irregular shape and heteroge-
neous surfaces including random-sized particles with sharp
edges and voids among them (see Fig. 3). Also, no signifi-
cant change in particle shapes is recognizable with variation
of SrO percentage.
Fig. 2 The FTIR spectra of the
synthesized bioactive glasses
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Fig. 3 SEM micrographs of the synthesized bioactive glasses : (A)
SrO 0 %, (B) SrO 5 %, (C) SrO 10 %
3.4 TEM Observations
Fig. 4shows TEM micrographs of the prepared bioactive
glasses. TEM examination showed the spherical shape of
the synthesized bioactive glass nanoparticles. The diameter
of the nanoparticles mainly ranged from 40 to 60 nm.
3.5 Specific Surface Area Measurement
The specific surface area of the synthesized glasses is
summarized in Table 1. The results determined that incorpo-
ration of SrO into the glass composition causes an increase
Fig. 4 TEM micrograph of the synthesized bioactive glass for SrO
5%sample
in specific surface area that is related to the SrO concentra-
tion. The ionic radius of Ca is 1.00 ˚
A whereas it is 1.13 ˚
A
for the Sr ion. When smaller ions in radius are replaced with
larger ones, a stress-induced network is produced, causing
a powder with reduced particle size and increased specific
surface area.
3.6 Thermal Analysis
The weight loss from the TGA occurred in three stages
(Fig. 5). The first mass loss occurred between 50 ◦Cand
150 ◦C, corresponding to an endothermic curve in the DTA
at 150 ◦C. This is associated with the removal of physi-
cally adsorbed water. More weight loss commenced from
the end of the first weight loss (250 ◦C) until about 545 ◦C
and might be correlated to an exothermic peak in the DSC
curve, and is most likely due to the loss of organics (i.e.
alkoxy group). The third drop in mass occurred from the
end of the second weight loss (545 ◦C) until around 580
◦C, with a well-defined sharp endothermic peak at 565 ◦C.
This endothermic peak is due to the elimination of the resid-
ual nitrates introduced as metal nitrate in the preparation of
the sol. Also, the result from the TGA and DSC allowed
us to set the temperature of 700 ◦C for stabilization of the
sample.
Table 1 Specific surface area of various prepared bioactive glasses
Sample SrO 0 % SrO 5 % SrO 10 %
Specific surface
area (m2/g) 64 80.4 97.6
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Fig. 5 STA curves of various
bioactive glasses synthesized via
sol–gel process
Fig. 6 Cell proliferation of
MG-63 osteosarcoma cells
proliferated on the synthesized
bioactive glasses and control
sample after incubation for 7
and14days
Fig. 7 ALP activity analysis for
MG-63 osteosarcoma cells
grown on the synthesized
bioactive glasses after
incubation for 7 and 14 days
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3.7 Biological Evaluation
3.7.1 MTT Assay
Compared with the control sample, the cell viability cul-
tured on the synthesized bioactive glasses was higher (0 and
5 % SrO). This phenomenon ascertained there are no sig-
nificant toxic leachables in the synthesized bioactive glass
(see Fig. 6). The prepared bioactive glasses not only have
the effect of toxicity on the cells, but also they boost the
performance of cell growth and proliferation in the sample
containing 5 mol % of strontium.
3.7.2 ALP Activity
ALP is a well-defined marker for proliferation and dif-
ferentiation of osteoblasts on its expression during osteo-
genesis. ALP activity for MG-63 osteosarcoma cells is
reported for each composition after 7 and 14 days of
incubation. ALP activity analysis for MG-63 osteosar-
coma cells grown on the prepared bioactive glass along
with negative control after different incubation time is
giveninFig.7. The results showed that after 7 and
14 days of incubation, the ALP activity of the Sr con-
taining bioactive glasses was higher than for the control
group. Furthermore the sample containing 5 mol % of
strontium showed optimum ALP activity after 14 days of
incubation. These results ascertained the osteoconductiv-
ity of prepared bioactive glass compared to the control
sample that proves its potential for use in bone tissue
engineering.
4 Conclusions
In conclusion, the SiO2–CaO–P2O5–SrO quaternary glass
system has been successfully synthesized by the sol-
gel method. In vitro experiments with osteosarcoma cells
revealed that bioactive glass incorporating a limited amount
of strontium (5 mol %) in the composition stimulated bone
cell production of alkaline phosphatase. This research ascer-
tained that the synthesized bioactive glass is a biocompatible
material for ongoing osteogenic studies in segmental defects
in the rabbit model in vivo.
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