Hydroxyapatites enriched in silicon – Bioceramic materials for biomedical and pharmaceutical applications

Abstract

Hydroxyapatite (Ca10(PO4)6(OH)2, abbreviated as HA) plays a crucial role in implantology, dentistry and bone surgery. Due to its considerable similarity to the inorganic fraction of the mineralized tissues (bones, enamel and dentin), it is used as component in many bone substitutes, coatings of metallic implants and dental materials. Biomaterial engineering often takes advantage of HA capacity for partial ion substitution because the incorporation of different ions in the HA structure leads to materials with improved biological or physicochemical properties. The objective of the work is to provide an overview of current knowledge about apatite materials substituted with silicon ions. Although the exact mechanism of action of silicon in the bone formation process has not been fully elucidated, research has shown beneficial effects of this element on bone matrix mineralization as well as on collagen type I synthesis and stabilization. The paper gives an account of the functions of silicon in bone tissue and outlines the present state of research on synthetic HA containing silicate ions (Si-HA). Finally, methods of HA production as well as potential and actual applications of HA materials modified with silicon ions are discussed.

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Progress in Natural Science: Materials International
journal homepage: www.elsevier.com/locate/pnsmi
Review
Hydroxyapatites enriched in silicon –Bioceramic materials for biomedical
and pharmaceutical applications
Katarzyna Szurkowska, Joanna Kolmas
⁎
Medical University of Warsaw, Faculty of Pharmacy with Laboratory Medicine Division, Department of Inorganic and Analytical Chemistry, ul. Banacha1,
02-097 Warsaw, Poland
ARTICLE INFO
Keywords:
Hydroxyapatite
Silicon
Biomaterials
Ionic substitution
Bioceramics
ABSTRACT
Hydroxyapatite (Ca
10
(PO
4
)
6
(OH)
2
, abbreviated as HA) plays a crucial role in implantology, dentistry and bone
surgery. Due to its considerable similarity to the inorganic fraction of the mineralized tissues (bones, enamel
and dentin), it is used as component in many bone substitutes, coatings of metallic implants and dental
materials. Biomaterial engineering often takes advantage of HA capacity for partial ion substitution because the
incorporation of different ions in the HA structure leads to materials with improved biological or physico-
chemical properties. The objective of the work is to provide an overview of current knowledge about apatite
materials substituted with silicon ions. Although the exact mechanism of action of silicon in the bone formation
process has not been fully elucidated, research has shown beneficial effects of this element on bone matrix
mineralization as well as on collagen type I synthesis and stabilization. The paper gives an account of the
functions of silicon in bone tissue and outlines the present state of research on synthetic HA containing silicate
ions (Si-HA). Finally, methods of HA production as well as potential and actual applications of HA materials
modified with silicon ions are discussed.
1. Introduction
In terms of its global distribution, silicon (Si) is second only to
oxygen, accounting for approx. 26–29% of the earth's crust. It does not
occur in pure form in nature due to its high affinity for oxygen and
hydrogen. The most abundant silicon compound is silica or silicon
dioxide (SiO
2
). In the human body, silicon is one of the trace elements,
coming after zinc and iron [1,2]. The bioavailable forms of silicon
include silicic acids, as well as soluble sodium and potassium metasi-
licates (Na
2
SiO
3
,K
2
SiO
3
), which release orthosilicic acid in the
stomach in the presence of hydrochloric acid. In addition, silica gel
releases some orthosilicic acid upon contact with body fluids. The
serum concentration of silicon amounts to 10–30 µg/dL. This element
is present in all tissues, with the highest content found in connective
tissues, including the aorta, trachea, bones and skin. The concentration
of Si in the hair and fingernails ranges from 1 to 10 ppm, while that in
bones amounts to as much as 100–150 ppm dry weight [1–6]. Silicon
distribution in the body is linked to its biological activity, especially in
terms of the functions of connective tissues, and in particular bones.
Silicon has been found to affect the condition of the skin, hair and
fingernails, and has also been implicated in the prevention of athero-
sclerosis and Alzheimer's disease [2–4,6–9]. The most important
source of silicon for human is the diet (see Fig. 1).
2. The role of silicon in bone tissue
The role of silicon in the metabolism of bone tissue was first
discovered by Carlisle in her studies on animals [10–13]. In young
rodents, increased Si accumulation was found at sites of active miner-
alization of new tissue; the content of this element decreased with bone
maturation. A relationship was also found between the content of silicon
and calcium. Carlisle proved the significance of silicon to the process of
skeletal development in a month-long experiment on chicks fed low- and
high-silicon diets [11]. The animals fed diets supplemented with silicon
(in the form of Na
2
SiO
3
) gained more weight and exhibited normal
growth, while those deprived of a sufficient silicon intake revealed
significant anomalies of skeletal development (lower bone mineraliza-
tion and smaller size). Thus, silicon was shown to be an essential trace
element indispensable for normal skeletal development, especially in the
initial phase of bone formation. In addition, Schwarz reported the
presence of a bound form of silicon in some mucopolysaccharides:
hyaluronic acid, chondroitin 4-sulfate and heparan sulfate [14].
http://dx.doi.org/10.1016/j.pnsc.2017.08.009
Received 6 March 2017; Received in revised form 4 August 2017; Accepted 16 August 2017
Peer review under responsibility of Chinese Materials Research Society.
⁎
Corresponding author.
E-mail address: joanna.kolmas@wum.edu.pl (J. Kolmas).
Progress in Natural Science: Materials International 27 (2017) 401–409
Available online 09 September 2017
1002-0071/ © 2017 Chinese Materials Research Society. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
MARK

The publications cited above provided a starting point for wider-
ranging research on the physiological functions of silicon in the
development of bone tissue [15–24]. Further experiments on animals
confirmed stimulating effects of silicon on bone formation. A study
involving ovariectomized female rats (an animal model reflecting a loss
of bone mass in postmenopausal women) showed that silicon supple-
mentation reduces the degree of bone resorption, while increasing bone
mineral density (BMD) [17]. In turn, a study examining female quarter
horses fed zeolite A (a natural source of silicon) found a correlation
between serum Si concentration and training distance to failure,
indicating enhanced mechanical bone strength [18].
Extensive cohort studies have been carried out to establish the
influence of silicon consumption by humans on BMD, which is
responsible for the mechanical strength of bone tissue and is used as
a diagnostic of osteoporosis. In the Framingham Offspring cohort
consisting of 2847 individuals aged 30–87, a positive correlation was
found between dietary silicon intake and BMD in males and preme-
nopausal women. Differences between groups with the highest and
lowest silicon intake (Si > 40 mg/day vs. < 14 mg/day, respectively)
amounted to as much as 10%. However, such a correlation was absent
in postmenopausal women, which suggests that the absorption and
distribution of silicon may be affected by sex hormone levels [19].
The Aberdeen Prospective Osteoporosis Screening Study (APOSS)
was conducted on perimenopausal and postmenopausal women aged
45–62 to elucidate the influence of dietary silicon intake on markers of
bone metabolism. The study groups differed in terms of the use of
hormone replacement therapy (HRT), whether currently or in the past.
In contrast to the previous study, higher silicon intake was found to
have a beneficial influence on BMD also in postmenopausal women,
but only those treated with HRT, which shows a possible favorable
interaction between silicon and estrogen (and especially estradiol)
levels [20].
Supplementation with choline-stabilized orthosilicic acid (ch-OSA)
in conjunction with calcium and vitamin D3 was evaluated in 136
osteopenic females (T-score < –1.5) by examining the effects of differ-
ent doses of ch-OSA on markers of bone formation and BMD. The
former included osteocalcin and procollagen type I N-terminal propep-
tide (PINP), while the resorption markers were deoxypyridinoline and
collagen type I C-terminal telopeptide. At 12 months, the study found
an increase in the bone formation markers, and in particular PINP,
which is consistent with the literature data concerning the mechanism
of action of Si [21].
Also experiments on tissue and cell cultures support a bone
formation role for silicon. Reffitt et al. [22],whoconductedextensive
research on collagen synthesis, studied in vitro the relationship
between orthosilicic acid concentration in the substrate and collagen
type I synthesis by several cell lines (human osteosarcoma cell line
MG-63, primary osteoblast-like cells derived from human bone
marrow stromal cells and an immortalized osteoblast precursor cell
line). The other measured parameters included collagen synthesis by
fibroblasts, proline hydroxylase activity, alkaline phosphatase activity
and osteocalcin production (reflecting osteoblast differentiation).
Silicon was added to the medium in the amount of 10, 20, or
50 μM. The effect of silicon on proline hydroxylase was also investi-
gated in the presence of its inhibitor. Collagen synthesis increased in
all cell lines, with the optimal silicon content being 20 μM. In turn,
alkaline phosphatase activity and osteocalcin synthesis were signifi-
cantly higher at a silicon concentration of 10 µM, which indicates
increased osteoblast differentiation; at the other studied concentra-
tions the results were less favorable. A stimulating effect of silicon on
collagen synthesis was not found in the presence of proline hydro-
xylase inhibitors, which suggests a mechanism of action involving
proline hydroxylase activity regulation [22].
Another study, involving co-cultures of human dermal fibroblasts
(HDF) and human umbilical vein endothelial cells (HUVEC), reported
a stimulating effect of silicate ions on angiogenesis [23]. It should be
noted here that adequate implant vascularization is prerequisite for the
normal functioning and development of new tissue. The application of
calcium silicate based material led to increased expression of vascular
endothelial growth factor (VEGF) as well as VEGFR 2 receptor, which
enhanced angiogenesis. Furthermore, it should be noted that VEGF
exerts a beneficial effect on the level of bone morphogenetic protein,
which regulates osteoblast growth and differentiation.
Mladenovićet al. [24] examined the influence of silicon on the
activity of osteoclasts, which are responsible for bone tissue resorption.
Experiments on murine bone marrow showed inhibited osteoclast
synthesis.
3. Silicon-substituted apatites as bone replacement
materials
In clinical practice, silicon has been incorporated in a variety of
biomaterials, mostly in the form of bioglasses and porous silica. These
materials typically exhibit very good osseointegration capacity and
rapid bioapatite generation on their external surfaces. The external
regions of the biomaterial become hydrated, releasing silicate; this
leads to high osteoblast activity and differentiation, as well as acceler-
ated synthesis of collagen type I [16,25,26]. The possibility of
incorporating silicate ions into the hydroxyapatite structure was
extensively explored, amongst others, by Gibson et al. [27].
For many years now, HA has been used in reconstructive surgery
due to its considerable similarity to the inorganic fraction of bone
tissue, enamel, dentin and cementum, making it a biocompatible and
non-toxic material. The crystallographic structure of HA enables partial
substitution of calcium, orthophosphate and hydroxyl ions. Also
biological apatite exhibits different patterns of substitution, due to
which its actual composition is variable. In general, bioapatite is a
calcium- and hydroxyl-deficient carbonate hydroxyapatite containing a
range of ionic impurities, such as Na
+
,K
+
,Mg
2+
,Zn
2+
, HPO
42-
, SiO
44-
,
Cl
-
and F
-
[25,26,28–31].
Since the 1990s, ion substitution in hydroxyapatite, and especially
partial substitution of PO
43-
with SiO
44-
, has been widely applied in
biomaterial engineering, largely due to the ease of this process [25,26].
According to the mechanism proposed by Gibson [27], when
orthosilicate ions (SiO
44-
) substitute phosphate ions (PO
43-
), hydroxyl
Fig. 1. Main sources of silicon for humans.
K. Szurkowska, J. Kolmas Progress in Natural Science: Materials International 27 (2017) 401–409
402

groups are released to create vacancies compensating for the charge
difference (see Fig. 2):
Ca
10
(PO
4
)
6
(OH)
2
+ x SiO
44-
→Ca
10
(PO
4
)
6−x
(SiO
4
)
x
(OH)
2−x
+xPO
43-
+
xOH
-
According to this mechanism, the value of x must be in the range of
0≤x≤2.
It should be noted that such a substitution mechanism, as well as
the difference in ionic radii, affect the crystal lattice parameters in
modified HA [32,33]. The crystals become much smaller and exhibit a
lower degree of crystallinity [25,26,33,34]. The process gives rise to an
extensive hydrated surface layer surrounding the core of HA crystals.
Tetravalent orthosilicate ions replacing trivalent orthophosphate ions
in that layer affect the overall charge on the surface of crystals.
Importantly, a more negative charge has been found to enhance the
biological activity of apatite [35]. The incorporation of silicates into the
HA structure also modifies its thermal stability, solubility and mechan-
ical properties [26,36,37].
Many silicated hydroxyapatites have been synthesized with up to
5 wt% Si (approx. 1.7 mol of Si/1 mol of HA); some authors have
suggested that the incorporation of 1 mol of Si per 1 mol of HA is
optimal for thermal stability and phase purity [38,39]. It should be
noted that depending on Si content and synthesis method, the obtained
samples may exhibit different phase decomposition patterns, with the
most frequently found impurities being α- and β-TCP (especially
following high-temperature treatment), CaO, as well as amorphous
silica.
The properties of silicon-substituted hydroxyapatite have been
investigated in numerous in vitro and in vivo studies.
3.1. In vitro studies
As mentioned previously, several studies have demonstrated that
silicon is essential for normal bone growth and development. Briefly,
silicon exposure has been shown to result in the enhanced production
of collagen type I and glycosaminoglycans in bone and cartilage cells
[16]. Moreover, recent in vitro studies [40] have revealed the mechan-
ism behind the stimulation of human mesenchymal stem cell (HMSC)
osteoblastic differentiation by orthosilicic acid. Taking into considera-
tion the crucial role of Si in bone tissue growth, it is not surprising that
silicon-substituted hydroxyapatites feature in high bioactivity.
Laboratory in vitro studies enable the preliminary evaluation of
bioactivity, osteogenic activity and screening for cytotoxicity.
Si-substituted hydroxyapatites exhibit an improved formation of a
surface apatite layer, compared with unsubstituted HA [41–43].In
addition, Gibson et al. [41] proved that Si-HA increased the metabolic
activity of human osteosarcoma (HOS) cells. Moreover, Balas et al. [42]
showed that materials containing monomeric silicate ions exhibit higher
bioactivity than samples with polymeric silicates. The research per-
formed by Botelho et al. [43] revealed that human osteoblasts are
affected by silicon incorporated into the HA crystals. It should be noted
that increasing protein production, together with a high content of
osteoblast markers (alkaline phosphatase and osteocalcin), was ob-
served, especially in the experiments with 0.8 wt% Si-HA. Recent studies
performed by Honda et al. [44] have confirmed these results.
Furthermore, the increased expression of RUNX2, the marker gene
responsible for osteoblast development and maturation, was observed,
which could suggest that silicon induces osteoblasts differentiation [44].
Aminian et al. [33] evaluated the biological activity of Si-HA
samples, in vitro, by soaking them in simulated body fluid (SBF), as
well as by conducting experiments on osteoblast cells. HA substituted
with 0.8 wt% or 1.5 wt% Si exhibited lower crystallinity and, by the
same token, increased sample solubility. Silicated samples were found
to possess higher bioactivity than pure HA, reflected in faster nuclea-
tion and growth on the surface of specimens immersed in SBF, in
addition to enhanced osteoblast proliferation. Better results were
obtained for the 0.8% sample (see Fig. 3), perhaps due to the fact that
its Si content was similar to that of human bones (< 1%).
Tian et al. [45] synthesized apatites containing up to 2 wt% Si,
which were subsequently soaked in SBF to investigate their in vitro
activity. Needle-like crystals started to emerge on the sample surface as
early as 4 days after treatment, which indicates the material's con-
siderable potential for bioactivity.
The studies involving human osteoblast-like cells have proven that
Si substitution in HA crystals improves cells adhesion [46]. Similar
Fig. 2. Scheme of silicate substitution into the HA crystal.
K. Szurkowska, J. Kolmas Progress in Natural Science: Materials International 27 (2017) 401–409
403

results have been obtained by Thian et al. [47]. The authors produced
thin Si-HA coatings up to 4.9 wt% Si on titanium implants.
Biocompatibility was determined in human osteoblast-like cells. Si-
HA was found to stimulate cell adhesion, proliferation and differentia-
tion to a higher degree than stoichiometric HA. It should be noted that
a high Si content involved the dissolution of coatings that was too fast,
while cell adhesion was hindered. The optimum level of Si was then
determined as 2.2 wt% [48].
Palard et al. [34] examined the relationship between silicon content
and biological activity in silicated hydroxyapatite ceramics (Si-HA).
Samples containing between 0 and 1 mol of Si per 1 mol of HA (0–
2.73 wt% Si) were prepared via aqueous precipitation method. The
obtained powders, containing up to 0.6 mol of Si, were subsequently
sintered and studied in vitro in human osteoblast cells. Powder X-ray
diffraction showed thermal decomposition to α-TCP and Ca
2
SiO
4
at >
1150 °C, and to Ca
10
(PO
4
)
4
(SiO
4
)
2
at > 1250 °C. It was found that the
higher the Si content, the more readily the material decomposes at high
temperature. However, no differences in osteoblast proliferation and
viability between the HA and Si-HA samples were reported from in
vitro experiments.
The effect of Si-HA on the differentiation of mononuclear cells in
osteoclasts has also been studied. Botelho et al. [49] showed that Si-HA
improved the differentiation of osteoclasts by comparing with pure HA.
This may be explained by the faster dissolution of Si-HA and the higher
release of calcium and phosphates into the medium.
By contrast, Matesanz et al. [50] proved that nanocrystalline Si-HA
delayed the differentiation of osteoclasts and decreased their resorptive
activity. Recent studies by Casarrubios et al. [51] have revealed that the
nanocrystallinity of the Si-HA materials is essential, as it affects the
bone cell/apatitic material interface and results in a loss of cell
anchorage and osteoclast apoptosis.
3.2. In vivo studies
The use of implants in living organisms allows for better observa-
tion of the systemic effects of the treatment, enabling close examination
of interactions between the material and the surrounding tissue.
The first in vivo studies on Si-HA materials were produced by Patel
et al. [52,53], who implanted sintered Si-HA granules into the femoral
condyle of female rabbits and sheep. The results indicated a signifi-
cantly higher bioactivity of Si-HA, compared with unsubstituted HA
prepared under the same conditions.
Porter et al. [54] studied the solubility of HA containing up to
1.5 wt% Si in vivo. Samples were prepared by the precipitation method
with silicate ions derived from silicon acetate. The resulting precipi-
tates were processed by mechanical sieving into granules, which were
subsequently inserted into defects drilled into the femoral condyles of
sheep. Samples were taken after 6 and 12 weeks following implanta-
tion. The results confirmed that increased bioactivity of Si-HA was
linked to its higher solubility, according to the dissolution–reprecipita-
tion theory. Locally increased concentrations of calcium, phosphorus
and silicon ions stimulated the deposition of biological apatite on the
surface of ceramic implants [54,55]. The solubility of samples, which
increased with silicon content, was much greater than that of the
stoichiometric compound [55].
Experiments on sheep were continued by studying biological apatite
precipitation and collagen fibre generation [56]. The procedures of
sample preparation, implant insertion and timing were similar to those
stated above. The apatite crystals, which arose at the interface between
the bone and 1.5% Si-HA, were better spatially ordered than those
found on the surface of pure HA. Furthermore, organized collagen
fibrils were found at the Si-HA–bone interface (see Fig. 4). These
results were consistent with the dissolution–reprecipitation theory.
Bone remodelling proceeded at a faster rate in the case of Si-HA than
pure HA, which suggests good osteoconductive properties in this
modified apatite.
Hing et al. [57] investigated the relationship between the silicon
content of implantation material and the rate of bone tissue healing.
Samples containing up to 1.5 wt% Si, obtained by the precipitation
method, were used to make porous scaffolds, which were then inserted
into defects drilled into the femurs of New Zealand White rabbits.
Samples for histological analysis were taken after 1, 3, 6 and 12 weeks
following implantation to evaluate new tissue apposition and the rate of
healing at the implantation site. Silicon was found to have a beneficial
effect on the rate of generation of new bone tissue and the degree of
mineralization; the best biological response was obtained for 0.8% Si-HA.
Silicon-substituted HA, prepared from cuttlefish bones, was sub-
jected to both in vitro and in vivo studies [58]. The granules containing
Si were found to induce faster bone healing in the in vivo rabbit
calvarial defect model. In turn, rat calvarial defects were successfully
Fig. 3. SEM images of cell attachment on surface of specimens: (a) phase pure HA (b) Si-HA with 0.8 wt% Si (c) Si-HA with 1.5 wt% Si [33].
K. Szurkowska, J. Kolmas Progress in Natural Science: Materials International 27 (2017) 401–409
404

treated with Si-HA scaffolds containing a bone morphogenetic protein-
2-related peptide [59]. In order to improve the bioactivity of titanium
implants, Zhang et al. [60] coated titanium with Si-HA. 2 and 4 weeks
following implantation into the rabbit femur, Si-HA-coated Ti was
found to induce a higher bone development rate and a significantly
better bioactivity with respect to HA-coated Ti.
3.3. The major methods of synthesis
3.3.1. The precipitation method
This is the most frequently used method of synthesizing both pure
and silicate-substituted hydroxyapatite [25,34,36,38,39,54–57,61–63].
A precipitate is produced as a result of combining aqueous solutions
containing calcium, orthophosphate and silicate ions (see Fig. 5).
Calcium nitrate or hydroxide are typically used as a source of Ca
2+
,
ammonium hydrogen phosphate or orthophosphoric acid supply
phosphorus ions, while silicon acetate or tetraethylorthosilicate
(TEOS) [Si(OC
2
H
5
)
4
] provide silicon ions. The reaction medium should
be basic (approx. pH 9–11), which may be adjusted by the addition of
ammonia. The important steps of the process include precipitate aging
followed by filtering and repeated washing with distilled water to
remove water-soluble reaction products. The resulting precipitate is
then dried and can be subjected to further thermal treatment (sintering
at > 600 °C) or microwave treatment [61]. Precipitation may be con-
ducted at ambient temperature or upon heating. Some authors used an
argon atmosphere to prevent the incorporation of carbonates from the
air [34,38,39]. On the other hand, Palard et al. [39] reported a
beneficial effect of carbonates on Si substitution. It should be noted
that straightforward synthesis by precipitation leads to fine crystalline
single-phase hydroxyapatite.
3.3.2. The sol-gel method
This method consists of a transition from a colloidal solution of
reagents (sol) to a gel (see Fig. 6)[25,63,64]. Balamurugan et al. [64]
produced a series of implants containing up to 5 wt% Si. In the first
step they hydrolyzed triethyl phosphate (a source of phosphorus),
which was then combined with TEOS (a source of silicon).
Subsequently, Ca(NO
3
)
2
was slowly added under stirring. The obtained
sol was aged and dried to remove the solvent and gaseous byproducts.
The resulting material could be subjected to further thermal treatment.
3.3.3. The hydrothermal method
Hydrothermal reactions are conducted in aqueous media at high
temperature and high pressure, often in an autoclave. This technique
usually results in HA with high degrees of crystallinity and good
dispersion (low tendency for agglomeration). The obtained crystals
usually assume an elongated shape, but different morphologies can be
generated by manipulation of reaction conditions [25,33,63,65,66].
Aminian et al. [33] produced hydroxyapatite substituted with up to
1.8 wt% Si in a hydrothermal reaction conducted at 200 °C for 8 h. The
precursors were Ca(NO
3
)
2
, (NH
4
)
3
PO
4
/(NH
4
)
2
HPO
4
and
Si(OCH
2
CH
3
)
4
(TEOS), and polyethylene glycol to improve particle
dispersion. A similar reaction was carried out by Tang et al. [65], who
incorporated up to 4 wt% Si in HA. The obtained samples exhibited
phase purity, and only calcining at 1000 °C led to partial decomposi-
tion to TCP. A combination of hydrothermal and solvothermal treat-
ments (the latter in acetone) was used by Kim et al. [66] to transform
natural coral into porous hydroxyapatite containing up to 0.19 wt% Si.
The precursors were (NH
4
)
2
HPO
4
and silicon acetate, while the coral
was a source of Ca
2+
ions and determined the three-dimensional
structure of the resulting elements.
Fig. 4. TEM micrographs of the bone/1.5 wt% Si-HA interface at 12 weeks in vivo. (a) Fibrous structures with the appearance of calcified collagen aligned parallel to the implant. (b)
Crystallites, predominantly with plate-like appearance, aggregated into nodular aggregates (a) adjacent to and separated from the Si-HA grains. (c) Collagen fibrils aligned both parallel
(ls) and perpendicular (ts) to the implant surface. (d) Collagen fibrils aligned perpendicular (ts) to the implant surface and overlaying the synthetic Si-HA grains. Black arrows indicate
regions of interface where collagen fibrils overlay the synthetic Si-HA grains [56].
K. Szurkowska, J. Kolmas Progress in Natural Science: Materials International 27 (2017) 401–409
405

3.3.4. The mechanochemical method
This is a simple and economical method of synthesis proceeding
between solid reactants ground in ball or vibration mills, which can be
used on an industrial scale. In the dry variant, the reaction proceeds
without a solvent, while in the wet variant the reaction is carried out in
an aqueous phase. Mechanochemical treatments can be conducted at
ambient temperature as friction between the reagents creates local
high-temperature spots enabling the reaction to occur [25,45,67].
A detailed mechanochemical process of Si-HA production was
described by Chaikina et al. [67], who used Ca(H
2
PO
4
)
2
·H
2
Oor
CaHPO
4
, CaO and amorphous silica. Single-phase Si-substituted
hydroxyapatite was obtained after as little as 30 min of reaction in a
ball mill.
Tian et al. [45] conducted mechanochemical synthesis using
Ca(OH)
2
, (NH
4
)
2
HPO
4
and TEOS. The reagents were mixed in aqueous
medium in a ball mill for 12 h. The resulting mixture was filtered,
washed and dried, and the powders were sintered at 900 °C.
3.3.5. Spark plasma sintering
This treatment is usually applied in thermal processing of pre-
viously obtained HA powder to produce dense blocks. Powder particles
are transiently heated by spark discharges between them, due to which
the material becomes uniformly sintered. The strong electrical field
arising between the particles makes them collide with each other and
enables chemical reactions. Plasma sintering is superior to traditional
furnace sintering in that the treatment is much shorter, as it lasts only
several minutes. Furthermore, this technology decreases the risk of
contamination and the formation of excessively coarse grain [68].
Spark plasma sintering was successfully used to incorporate orthosili-
cate ions into the HA structure by combining amorphous silica with HA
obtained by precipitation treatment. Sintering at 1000 °C for 3 min led
to dense Si-HA blocks with a small secondary β-TCP phase [69].
3.3.6. Solid-state synthesis
In this method, the reagents are mixed, compacted, and then
sintered at high temperature for a prolonged time. Boyer et al. [70]
and Leshkivich et al. [71] described the synthesis of apatites sub-
stituted with not only silicates, but also sulfates, lanthanum and
fluorine. There is no available literature on solid-state synthesis of
apatites substituted solely with silicate ions. In a previous project, the
present authors developed a method for solid-state synthesis of Si-HA.
Substrates containing Ca, P and Si were ground in a ball mill and the
resulting mixture was compacted and sintered in an appropriate
temperature cycle. This novel method is the subject of a patent
application (no. P.411636).
3.4. Applications in medicine and pharmacology
Apatite powders produced with one of the methods presented in
Section 3.3 are usually subjected to further treatment and sintering to
obtain, e.g., dense compacts shaped to fit a particular bone defect.
Granules are also frequently applied. More advanced implants, known
as scaffolds, not only serve as supports, but also enable better
connectivity between the implant and bone due to the porous structure
of the former. In addition, a porous biomaterial undergoes a more
rapid resorption and is more readily replaced by regenerated bone
tissue than dense elements. On the other hand, the more porous the
material, the lower its mechanical strength, and so highly porous
biomaterials may be either applied at sites which are not subjected to
high loads or used in conjunction with other robust materials [72,73].
The most common methods of scaffold production involve:
–Burning out the porogen (pore-forming agent) –a mixture of Si-HA
and porogen is ground in a mill, pressed and sintered at high
temperature; the porogen burns out creating pores with sizes
Fig. 5. Scheme of Si-HA synthesis via standard precipitation method.
Fig. 6. Scheme of Si-HA synthesis via sol-gel method.
K. Szurkowska, J. Kolmas Progress in Natural Science: Materials International 27 (2017) 401–409
406

dependent on the degree of substrate fineness (see Fig. 7A) [72–74].
–Addition of a foaming agent –Si-HA is suspended in a porogen,
which decomposes at high temperature to gaseous species; the
foamed suspension is then dried (see Fig. 7B) [57,72,73,75].
–Rapid prototyping with 3D printing –enables precise design of
various shapes and sizes of scaffolds containing well-interconnected
porous systems to enable effective bone ingrowth and angiogenesis
[76].
Si-substituted apatite materials may also be used as coatings on
metallic elements [25,28]. Such a combination is particularly beneficial
in the case of titanium implants, which exhibit high mechanical
strength, while an outer apatite coating improves their osseointegration
potential. Si-HA coatings can be produced by magnetron sputtering
[47], electrochemical deposition [77,78], or direct Si-HA precipitation
on an implant immersed in a suitable solution [79]. In turn, Rau et al.
[80] produced a coating of Si-HA (1.4 wt% Si) by means of pulsed laser
deposition. This technique results in dense layers characterized by a
high degree of crystallinity and improved strength properties (amor-
phous HA more easily dissolves). Temperature manipulation during
treatment may be used to control the roughness of the coating to
enhance osteoblast adhesion and bioapatite precipitation. An in vitro
investigation of biological activity indicated that the material induced
calcium phosphate precipitation (similarly as it is the case with
biological apatite in tissues).
Silicated hydroxyapatite may also be applied in hybrid materials, in
which the silicon-containing phase is combined with an organic
fraction (e.g., polysaccharides) [28,81]. Such materials are character-
ized by superior degradability and connectivity with bone tissue as
compared to pure ceramics. A good example here is a composite
containing hydroxyapatite, silica and chitosan developed by Grandfield
et al. [78], which can be electrophoretically deposited in a thin layer.
Importantly, in addition to biocompatibility and chemical stability,
chitosan exhibits antibacterial activity and favorable mechanical prop-
erties. Another example of a hybrid material is a combination of HA
with silica and collagen synthesized by Heinemann et al. [82].
In addition to its roles as a mechanical support and osseointegra-
tion stimulator, considerable attention has been given to the applica-
tion of Si-HA in therapeutic drug delivery systems gradually releasing
pharmaceutical substances. In this respect, mesoporous silica (rather
than SiO
44-
ions) may be incorporated into the apatite crystalline
lattice, as it increases the specific surface area of the resulting elements,
enabling the attachment of greater amounts of a drug. Furthermore, Si-
HA scaffolds may be used as sites of attachment of peptides, as in the
work of Manzano et al. [76], who experimented with osteostatin (a
pentapeptide associated with parathyroid hormones which stimulates
osteogenesis). Si-HA was obtained by a precipitation method and
contained 0.3 mol of Si per 1 mol of HA, with TEOS being the source
of silicon. The scaffolds were made by 3D printing. Osteostatin was
attached to the scaffolds by adsorption or covalent bonding (confirmed
by chemical analysis), and was then gradually released. In an in vitro
study of osteoblast activity and differentiation in MC3T3-E1 murine
cells, both bound and adsorbed peptides revealed stimulating activity.
In turn, Lasgorceix et al. [83] used Si-HA as a substrate for adsorbing
insulin, which had been shown to alleviate inflammatory response and
stimulate osteoblast proliferation and differentiation. The obtained
samples were investigated both in vitro and in vivo.
Substituted hydroxyapatite may be also incorporated in dental
materials. Chadda et al. [84] developed acrylate-based hydroxyapa-
tite-filled and silica/hydroxyapatite-filled composite resins, which were
found to be non-toxic and highly biocompatible.
Sych et al. [85] successfully used hydroxyapatite substituted with
2 wt% and 5 wt% Si as a delivery system for rifampicin, an antibiotic
with proven activity against tuberculosis, leprosy and bacterial osteo-
myelitis. The presence of silicon in HA increased the porosity and
specific surface area of the material, enhancing its loading capacity.
Samples were immersed in an alcohol solution of the antibiotic for
36 h, after which time the solvent was evaporated. Release kinetics was
studied in 0.9% NaCl solution. Huang et al. [86] used a composite
consisting of hydroxyapatite and mesoporous silica to deliver alendro-
nate, a bisphosphonate preventing bone resorption by osteoclasts and
stimulating bone formation by osteoblasts. The composite was im-
mersed in an alendronate solution for 24 h and then dried. The authors
studied drug release as well as the in vitro bioactivity of the composite
using bone marrow mesenchymal stem cells BM-MSC. The cytotoxicity
of mesoporous silica decreased as a result of its incorporation into HA.
The drug was released from the composite over a period of more than
30 days, in contrast to 5 days for pure silica. A similar study was
conducted by Zhu et al. [87] on a different bisphosphonate, namely
zoledronic acid, deposited on Kirschner wires (used to fix bone
fractures) by immersion for 3 days. The wires were precoated by
plasma spraying with pure HA or HA containing mesoporous silica. In
situ drug delivery was supposed to prevent undesirable resorption of
bone tissue and stimulate fracture healing. The study was conducted in
vitro on an osteoclast cell line to observe cell proliferation and
resorption activity. The incorporation of mesoporous silica increased
the specific surface area of the sample 10-fold, enabling an 8-fold
increase in adsorbed bisphosphate as compared to pure HA. Similarly
to the previously reported study, HA released almost all the drug over 3
days, while the hybrid material led to a very gradual release process.
It should be noted that silicon-substituted HA materials have also
been applied in regenerative medicine. An example of a commercial
preparation is Actifuse™(ApaTech Ltd.) [25], a synthetic porous bone
implant material consisting of HA with 0.8 wt% silicate ions (which is
an optimum concentration according to the literature). The high
porosity of this implant material makes it similar to cancellous bone;
its interconnected pores play a key role in osseointegration enabling the
ingrowth of the newly formed bone tissue as well as the delivery of the
nutrients necessary for osteogenesis. Actifuse™is available as 3D
scaffolds, porous granules (with a diameter of 1–5 mm), and an
applicator with paste (which reduces treatment invasiveness and
facilitates defect filling).
4. Other silicate-based biomaterials
Given the biological activity as discussed above, silicon can be
regarded as a component of many biomaterials other than hydroxya-
patite. Among the most examined silicate-based biomaterials are
Fig. 7. Methods of scaffold production: burning out the porogen (A); addition of a
foaming agent (B).
K. Szurkowska, J. Kolmas Progress in Natural Science: Materials International 27 (2017) 401–409
407

bioactive glasses, such as 45S5 Bioglass®[88,89], which was one of the
first artificial materials used to regenerate natural bone. 45S5 Bioglass®
was invented in the late 1960s and has been in clinical use since 1985.
It is composed of 45 wt% SiO
2
, 24.5 wt% Na
2
O, 24.5 wt% CaO and 6 wt
%P
2
O
5.
The unique feature of bioactive glass is that it creates a strong
chemical bond with the host bone by rapid formation of HA on its
surface. The material is highly bioactive due to the release of
orthosilicic acid, as well as calcium and phosphate ions, which
subsequently participate in apatite formation [89]. Bioactive glass
stimulates the proliferation and differentiation of osteoblasts, collagen
secretion and production of bone morphogenetic proteins [88–91].
Silicate bioceramics represent another group of silicon-based
biomaterials with various chemical compositions, physicochemical
properties and bioactivity. They are mainly oxides containing SiO
2
,
such as wollastonite CaSiO
3
(CaO and SiO
2
), akermanite Ca
2
MgSi
2
O
7
(MgO, CaO and SiO
2
) or dicalcium silicate Ca
2
SiO
4
(CaO and SiO
2
).
The dissolution of silicate bioceramics causes ionic interactions be-
tween the implant and the surrounding tissue. Released ions mediate
in the precipitation of biological apatite, as well as cause biological
activity, such as the stimulation of osteoblasts or stem cells [92–95].
Silicon substitution can also be found in other calcium phosphates,
namely, α- and β-TCP, which exhibit an accelerated degradation rate in
contrast to hydroxyapatite. The introduction of silicate ions into these
materials may significantly enhance their biological activity [96–100].
Indeed, silica-based gel and mesoporous silica are biomaterials with a
large surface area, which allows them to adsorb and then locally release
drugs into bone tissue (see also 3.4). Besides regenerative medicine,
they are widely used in the pharmacy within oral drug delivery systems
[101–104]. Recent developments of silicon-based biomaterials have
focused on silicon nitride, which is used in orthopaedics. It is
characterized by high mechanical strength, making it a suitable
material for hip and knee joint replacements or to promote bone
fusion in spinal surgery [105,106].
5. Summary
Silicon is an essential element necessary for normal development of
bone tissue. It stimulates osteoblast activity and differentiation as well
as the synthesis of collagen type I, a fundamental component of the
organic bone matrix. These properties of silicon are also used in the
development of biomaterials and bone implants. Synthetic Si-substi-
tuted hydroxyapatites are promising ceramic materials characterized
by high degrees of bioactivity and biocompatibility. Furthermore,
continued research is underway to develop di- and multi-substituted
apatites containing not only silicon, but also other ions (e.g., magne-
sium, strontium, fluorine) which have beneficial effects on the process
of bone regeneration.
Acknowledgments
Authors would like to thank Medical University of Warsaw for the
financial support (FW23/N/17). This work was supported by the
National Science Center (Poland) within project “Synthesis and physi-
cochemical and biological analysis of crystalline calcium phosphates
substituted with various ions”; UMO-2016/22/E/ST5/00564.
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