Silicon (2023) 15:2493–2505

https://doi.org/10.1007/s12633-022-02207-3

REVIEW PAPER

A Review on Calcium Silicate Ceramics: Properties, Limitations,

and Solutions for Their Use in Biomedical Applications
Rasha A. Youness1 · Doha M. Tag El‑deen1 · Mohammed A. Taha2

Received: 28 September 2022 / Accepted: 27 October 2022 / Published online: 10 November 2022
© Springer Nature B.V. 2022

Abstract
The bone, being an essential tissue in the human body, not only protects the organs inside the body but also provides mechani-
cal support, haematopoiesis, mineral storage and mobility. Although bone may regenerate and heal itself, significant bone
defects caused by severe trauma, tumour removal, malignancy, or congenital diseases can only be corrected via bone grafting.
Bone biomaterials, also known as bone graft alternatives, have seen an increase in demand in recent years. Over 2 million
procedures are performed in the United States each year to restore damaged/fractured bones by grafting. The number of
patients in China with reduced limb function owing to bone abnormalities has risen to 10 million. Traditional bone defect
repair materials include autogenous bone, allogeneic bone, xenogeneic bone, decalcified bone matrix, bioceramics, and
metal materials, which are easily available and processed. Calcium silicate (Ca-Si) ceramic is among the most promising
bioceramics for these purposes due to their amazing characteristics such as bioactivity, biocompatibility and osteoinductiv-
ity. Unfortunately, its high biodegradation rate along with its poor strength represents major limitations that limit its use in
clinical applications significantly. In light of the above, this article briefly discussed the different types of bone substitute
materials, the properties of Ca-Si ceramic, the advantages, limitations and potential solutions to overcome these drawbacks
and its biomedical applications such as orthopedic, dental, wound healing and drug delivery.

Keywords Calcium silicate · Properties · Limitations · Solutions · Biomedical applications

1 Introduction Material science, in collaboration with biomedical sci-

ences, has facilitated the development of biomaterials that
While bone has the intrinsic ability to regenerate as part of help to regenerate or replace injured bone tissues. Biomate-
the healing process after an injury [1], it cannot regenerate rial is a material designed to interact with biological systems
tissue if the wound is bigger than the critical size defect [2]. in order to assess, treat, augment, or replace any body tissue,
In such conditions, numerous studies have shown the usage organ, or function [6]. Based on their sources, biomaterials can
of autologous and allogeneic transplantations. However, in be divided into natural and synthetic biomaterials [7]. Natural
autologous transplantation, complications such as scarring, biomaterials are substances that are naturally derived or have
disability and injury of donor site have been reported in up undergone chemical alterations to be employed in the produc-
to 20.6% of cases [3, 4]. In allograft transplantation, the bio- tion of scaffolds or other implants. Notably, they can be divided
logical and mechanical properties change during the sterili- into two categories based on the nature of their origin: protein-
zation and preservation process causing a loss of osteogenic based and polysaccharide-based natural biomaterials [8]. Exam-
and integration ability [5]. All these disadvantages lead to ples of natural biomaterials are collagen and chitosan [9]. In
development of biomaterials as bone replacements. fact, one can expect that each type has its own advantages and
disadvantages. One of the major advantages of using this type
of biomaterials is the lack/rarity of toxicity issues compared to
* Rasha A. Youness synthetic materials. Besides, they are bioactive, with specialised
[email protected] protein binding sites and other biochemical signals that could
1
Spectroscopy Department, National Research Centre, El help with a variety of physiological functions like cell adhesion,
Buhouth St, Dokki, 12622 Giza, Egypt cell to cell communication, and tissue regeneration [10]. Unfor-
2
Solid State Physics Department, National Research Centre, tunately, natural biomaterials are relativity unstable which may
El Buhouth St, Dokki, 12622 Giza, Egypt cause mechanical malfunction or premature decomposition.

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Based on this problem, scientists have invented synthetic bio- composite material in which organic and inorganic com-
materials to overcome the defects of natural biomaterials. As ponents make up 30 and 70%, respectively of bone tissue.
a result of this interest, many biomaterials have arisen, which HA is a mineral made of calcium phosphate, which is the
can be divided into four main classes; namely ceramics, metals, main inorganic component. However, collagen fibers and
polymers, and composites. Compared with natural biomaterials, noncollagenous proteins (NCPs) make up the majority of
synthetic biomaterials are simple and inexpensive to produce, the organic material [25]. It is important to note that HA
and show more stable and controllable mechanical, biodegra- mineral has two main functions: it strengthens the collagen
dation and physicochemical properties [11]. Because of these complex, increases the mechanical resistance of bones,
amazing benefits, bioceramics are commonly used in the field and provides calcium, phosphate, and magnesium ions for
of dentistry and bone replacement [9]. mineral homeostasis. It is common for smaller mineral
Bone substitute materials can be classified into three crystals to be destroyed during bone remodelling due to
groups: physicochemical reasons, and therefore it is not surpris-
ing that in osteoporosis, larger and more perfect crystals
a) Bioinert and biostable materials such as zirconia ­(ZrO2), remain within the matrix [26], which increases osteopo-
titania ­(TiO2) and alumina ­(Al2O3), in which its function rosis [27]. While the most abundant components of the
is to compensate for the defect without provoking the organic extracellular matrix (ECM) in bones are collagen
body immune system [12]. types I, III, and V. Collagens’ primary purposes are to
b) Bioactive osteoconductive materials such as calcium provide mechanical support and serve as a framework for
phosphates (Ca-Ps) materials like hydroxyapatite (HA) bone cells [28]. 90% of the collagen in bone tissue is type
which initiate a specific biochemical response at the I collagen, which assembles into triple helices of polypep-
interface, forming a strong bond between material and tides to create the collagen fibrils. The higher-order fibril
tissue to enhance bone repair [13]. bundles and fibres are constructed by these fibrils inter-
c) Bioresorbable osteoinductive materials such as bioactive acting with other collagenous and noncollagenous pro-
glasses (BGs), and composites of bioactive salts (Ca-Ps, teins (NCPs) [29]. Collagen types III and V are present in
calcium silicate, etc.) with polymers which have recently smaller amount and they control the fiber diameter and the
been designed to stimulate tissue regeneration by pro- process of fibrillogenesis of collagen type I [30]. Impor-
moting certain biological reactions at the molecular tantly, NCPs such as proteoglycan and glycoslated proteins
level [14]. comprise 10–15% of the total protein content of bones.
Interestingly, NCPs have multiple functions, including
It should be noted that biomaterials used in bone repair must coordinating interactions between cells and minerals in the
meet a huge number of requirements such as: biocompatibility, matrix, arranging the extracellular matrix and modulating
adequate mechanical and physical (density and porosity) char- the mineralization process [31].
acteristics [15, 16], and suitable osteoinduction, manageable Human bone is a living tissue that undergoes continual
bioactivity, and an acceptable degradation rate [14]. Compared bone resorption (release of calcium and phosphate from min-
with several biomaterials that have been studied for bone heal- eralized bone) and deposition (use of calcium and phosphate
ing and endodontic procedures, biodegradable ceramics are to form new bone) bearing in mind that primary bone cells
promising candidates for bone repair [17, 18]. In this sense, are osteogenic cells, osteoclasts, osteoblasts, osteocytes and
although HA has chemical characteristics similar to natural bone lining cells regulate this process [25]. This process
apatite and it can chemically interact with bone tissue promot- is called bone remodelling in which old bone is replaced
ing fast bone repair [19–21], experiments have shown that HA by new bone. Bone remodelling consists of three phases:
has a significantly slower dissolution rate which slows down (1) the beginning of bone resorption by osteoclasts, (2)
the rate of its interaction with surrounding bone tissue which the transition (or reversal period) from resorption to new
is considered one of its major drawbacks along with its high bone formation, and (3) bone formation by osteoblasts [31,
brittleness and limited mechanical stability, which hinders its 32]. This process occur through the coordinated actions of
use in the treatment of bone problems [22–24]. osteoclasts, osteoblasts, osteocytes, and bone lining cells,
which collectively form the transient anatomical structure
known as the basic multicellular unit (BMU) [33]. In view
2 Bone Composition and Properties of this fact, normal bone remodelling is essential for cal-
cium homeostasis, fracture repair, and skeletal adjustment
Bone accounts for the highest proportion of connective to mechanical stress [34]. However, an imbalance between
tissue mass in the body. Bone has multiple functions, bone formation and resorption leads to a number of bone
such as supporting the body, promoting motion, and stor- disorders. For instance, excessive bone loss and osteoporosis
ing minerals such as calcium and phosphate. Bone is a can be caused due to high resorption by osteoclasts without

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producing enough new bone by osteoblast to replace it [33]. composition is to prepare hybrid composites with the aim
Therefore, there must be a balance between bone resorption of improving the insufficient mechanical performance of
and formation which can be regulated by multiple factors Ca-Si. Among these materials that can be added to Ca-Si
such as chemokines, cytokines and hormones. to prepare the desired hybrid composites are ceramics
[46, 47]; synthetic biopolymers such as poly(lactic-co-
glycolic acid), polycaprolactone and poly(L-lactide);
3 Types of Calcium Silicate as a Promising and natural biological polymers, such as silk fibrin, chi-
Biomaterial for Biomedical Applications tosan and gelatine [48]. When compared to single phase
Ca-Si, the composites often present enhanced mechani-
Calcium silicate (Ca-Si) is well recognized as the principal cal characteristics as well as improved biocompatibility
component of Portland cement in the construction field, [49]. Finally, some metal oxides can be added to Ca-Si
although it has only been used as a biomaterial for about two to enhance its antibacterial properties.
decades. There are three types of Ca-Si, each with distinct Ca/
Si ratio: monocalcium silicate (MCS; ­CaSiO3), dicalcium sili-
cate ­(C2S; ­Ca2SiO4), and tricalcium silicate (­ C3S; ­Ca3SiO5), 4 Possible Solutions to the Defects of Ca‑Si
and pyrosilicate ­(C3S2; ­Ca3Si2O7). Moreover MCS exhibits Ceramic
three modifications. The high-temperature form, α-CaSiO3
(pseudowollastonite), occurs rarely in nature whilst the two 4.1 Doping with Metal Oxides as a Solution
β-polymorphs, (parawollastonite) and (wollastonite), are more for the High Biodegradability of Ca‑Si
common [35]. The major components of Portland cement,
­C2S and C ­ 3S, are hydraulic and may be hydrated and hardened 4.1.1 Diopside
when combined with liquid phase. C ­ 2S is known to have five
polymorphs, which are denoted by the symbols, α, α’H, α’L, Diopside ­(CaMgSi2O6) is calcium and magnesium silicate.
β and γ. At room temperature, the γ form is stable and inert It has a chemical composition that is similar to Ca-Si and
against hydration. The β form is unstable; however, at room ­Ca2MgSi2O7 [50]. Nakajima et al. [51] produced ­CaMgSi2O6
temperature it possesses hydration action [36]. ceramics for use as biomaterial, and observed that it could
Ca-Si bioceramic is one of the most promising candi- form apatite in SBF and could closely bind to bone tissue
dates for use in dentistry and orthopaedics due to its out- when implanted in rabbits. Studies have shown that the
standing bioactivity [22]. Past studies have demonstrated ­CaMgSi2O6 scaffolds have a mechanical strength that is simi-
that releasing of specific amounts of Si in microenviron- lar to that of human sponge bone (0.2–4 MPa) [52]. Also, the
ment promote cellular adhesion and promote osteogenic compressive strength of C­ aMgSi2O6 scaffolds only decreased
differentiation of bone marrow mesenchymal stem cells by 30% after 14 days of soaking in SBF, compared to a 54
[37–39]. Moreover, the Si ion has been associated to the and 60% decline in the strength of BG and Ca-Si scaffolds,
upregulation of angiogenic factors gene expression [40]. respectively [53]. These reveal that C
­ aMgSi2O6 scaffolds have
Furthermore, phosphate ions in simulated body fluid (SBF) improved mechanical strength as well as mechanical stability,
have also been observed to react with Ca ions on the sur- implying that they are preferable to traditional bioceramics
face of Ca-Si scaffolds, resulting in HA mineralization. This in bone regeneration applications [52]. Despite a weight loss
mineralization causes the surface to become hydrophilic, of only 2% after 28 days of soaking, ­CaMgSi2O6 scaffolds in
which improves the scaffold’s capacity to adhere to liv- SBF solution maintained a sustained Si ion release, demon-
ing tissues [41]. Despite these amazing characteristics, the strating that the C
­ aMgSi2O6 scaffolds are degradable in bio-
biomedical applications of Ca-Si ceramic are restricted by logical environments. After soaking for 28 days, C­ aMgSi2O6
several limitations such as its brittle nature, weak strength scaffolds lose less weight than C ­ a2MgSi2O7 (18%) [54] and
and high degradation rate, which affects cell proliferation Ca-Si (26%) [50], implying that C ­ aMgSi2O6 scaffolds, can be
(because of high pH values) and induces premature bone used when a controlled slow degradation rate is desirable [55].
decay before its ability to recover [37, 42, 43]. Also, Ca-Si’s Moreover, the high dissolution rate causes the pH to be in the
antibacterial activity is insufficient to successfully remove range of 7.4–7.6, indicating a better environment for in vitro
microorganisms from the implanted bone fracture [44]. bone cell culture [52].
One solution to solve the rapid biodegradation of
Ca-Si is doping with additional materials, such as mag- 4.1.2 Akermanite
nesium oxide (MgO), zinc oxide (ZnO) and Z ­ rO2 leading
to the formation of diopside, akermanite, bredigite, mon- Akerminate, ­Ca2MgSi2O7, is calcium and magnesium sili-
ticellite, merwinite, serendibite, tremolite, hardystonite, cate. Lately, akermanite has attracted a high interest because
and baghdadite [45]. Another solution to modify the of its desirable mechanical characteristics and controllable

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degradation rate [55]. Wu et al. [50, 56] studied the bioactiv- of ­CaMgSiO4, a decrease in cell viability happens. There is
ity of ­Ca2MgSi2O7 by soaking the akermanite in SBF. After no significant variation in the ALP test when incubation time
ten days of immersion in SBF, the surface layer formed a HA changes. However, when the concentration of the C ­ aMgSiO4
film. In a recent article, the rate of ­Ca2MgSi2O7 dissolution was increased, we noticed a modest drop in ALP activity [62].
was investigated where the ability to deposit apatite on the
ceramic surface was improved by the increased dissolving rate 4.1.5 Merwinite ­(Ca3Mg(SiO4)2)
of ­Ca2MgSi2O7 over ­CaMgSi2O6. The surface morphology of
­Ca2MgSi2O7 has a substantial impact on biological charac- The mineral merwinite (­ Ca3Mg ­(SiO4)2) is a member of the
teristics, ­Ca2MgSi2O7 with rougher surfaces being related to CaO-MgO-SiO2 system. It has an orthosilicate structure and
increased apatite production and subsequent bone formation a melting point more than 1450 °C. Because ­(Ca3Mg(SiO4)2)
[57]. According to a recent study, ­Ca2MgSi2O7 bioceramics is similar to ­CaMgSi2O6 in composition, it is both mechani-
also had distinct dual functionalities of osteogenesis/angiogen- cally strong and bioactive. Studies shown that ­(Ca3Mg(SiO4)2)
esis stimulation in vitro and in vivo, it also represses osteoclas- bending strength, fracture toughness, and Young’s modulus
tic activity to promote bone reconstruction and when exposed are 151 MPa, 1.72 MPa ­m1/2, and 31 GPa, respectively, which
to osteoporosis, it has superior bone repair ability [58]. are similar to those of the cortical bone. When immersed in
SBF, ­(Ca3Mg(SiO4)2) caused the development of an apatite-
4.1.3 Bredigite like layer on its surface. On the (­ Ca3Mg(SiO4)2) surface, osteo-
blasts adhered and spread, and the extract from its dissolution
Bredigite, ­C a 7 Mg(SiO 4 ) 4 , is a member of calcium- markedly stimulated osteoblast cell development [63].
magnesium silicates with an orthorhombic structure. In vivo, ­(Ca3Mg(SiO4)2) is successfully implanted in rat
­C a 7 Mg(SiO 4 ) 4 , in comparison to C ­ a 2 MgSi 2 O 6 and femoral defect model. ­(Ca3Mg(SiO4)2)-implanted rats showed
­Ca2MgSi2O7, has superior bioresorbability and bioactivity significantly greater new bone growth and material breakdown
due to its increased Ca ion content [59]. The compressive after 2 and 8 weeks compared to the HA-implanted group. In
strength of C­ a7Mg(SiO4)4 scaffolds was higher than that of addition, the newly generated bone tissue entered the centre of
TCP scaffolds, with values of 0.233 and 0.05 MPa, respec- ­(Ca3Mg(SiO4)2) implants 8 weeks after implantation, which
tively. However, there are two fundamental disadvantages resulted in substantially higher degradation of ­(Ca3Mg(SiO4)2).
to using C­ a7Mg(SiO4)4 scaffolds in bone tissue engineering. According to in vivo findings, (­ Ca3Mg(SiO4)2) have good bio-
One is C­ a7Mg(SiO4)4’s high resorption rate, which results in activity and can, thus, promote bone progenitor cells to prolif-
a high C­ a2+ concentration, metabolic alkalosis, and thus an erate and differentiate more than HA [64].
unfavourable cellular response [60]. Second problem is like
a lot of bioceramics, its lack of mechanical strength, which 4.1.6 Serendibite ­(CaMg3Si3O10)
is insufficient for bone regeneration [61]. One of the solu-
tions to these disadvantages is coating ­Ca7Mg(SiO4)4 with Serendibite is a rare silicate mineral that has been found only a
poly (lactic-co-glycolic acid; PLGA). A study reported that little over a dozen times in the world. Its complex composition
the ­Ca7Mg(SiO4)4-10%PLGA scaffold is the best scaffold includes calcium, magnesium, aluminium, silicon, boron, and
for bone regeneration, with good mechanical strength, pore oxygen. It is formed in the triclinic crystal system and it can
interconnectivity and cytocompatibility [59]. be found in a variety of high-temperature, high-pressure con-
ditions as a metasomatic product [65]. The lowest temperature
4.1.4 Monticellite at which it is generated is close to 500 °C, at a pressure of
about 1000 MPa. With rising temperature, the pressure range
Monticellite, ­(CaMgSiO4), is a member of calcium-magnesium in which it can be generated broadens, and at 700 °C it can be
silicate. By immersing monticellite in the 2X SBF solutions formed in a pressure range of at least 100 to 2000 MPa [66].
for 10 days, the crystalline HA phase occurs in urea-derived Due to the above reasons of difficulty in preparing this type
­CaMgSiO4, while the amorphous apatite phase occurs in of Ca-Si ceramic along with its rarity, one can expect that no
other fuel-derived materials. This finding suggests that when biomedical applications for it are recorded.
­CaMgSiO4 samples are subjected to physiological condi-
tions, they have the ability to trigger apatite production. Pure 4.1.7 Tremolite ­(Ca2Mg5Si8O24)
­CaMgSiO4 demonstrates improved bioactivity within 10 days.
Previous research has shown that after 15 days of immersion Tremolite is silicate of magnesium which is monoclinic in
in SBF, HA deposition on the C ­ aMgSiO4 surface occurs. For structure with ideal formula C
­ a2Mg5Si8O24. Tremolite is one
the pure ­CaMgSiO4 sample, cell viability and alkaline phos- of the most common amphibole species which are a complex
phatase (ALP) tests were performed on MG-63 cell lines. The assemblage of minerals that have variable composition and
test results showed that up to a concentration of 50 mg/mL extensive elemental substitutions. Tremolite is found in the

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fibrous form (i.e., characterized by crystals/particles consisting mechanical strength, zirconium (Zr) has been widely used
of fibres with length > 5 μm, width < 3 μm) [67]. Tremolite is as a biomaterial in the fabrication of implants and pros-
an indicator of metamorphic grade since at high temperatures thetic devices, particularly in bone and dental applica-
it converts to diopside by reaction (1 tremolite + 3 calcite + 2 tions [76, 77]. Roohani et al. [78] were the first to develop
quartz = 5 diopside + 3 ­CO2 + 1 ­H2O). A series of SEM photos ­Ca3ZrSi2O9-based porous scaffolds to treat critical size
from the experiment show that diopside selectively nucleates bone defects. After 12 weeks, radiographic images of rab-
and develops topotactically on tremolite. A simplified scheme bit radial bone defects revealed that implanted ­Ca3ZrSi2O9
that consists of three processes is used to model the mecha- scaffolds had greater bone ingrowth and complete bridg-
nism of the forward reaction. In each process, the formation, ing than TCP/HA scaffolds. Histological analyses revealed
transport, and incorporation of (1) the Ca-, (2) the Mg-, and that bone grew within the pores of ­Ca3ZrSi2O9 scaffolds,
(3) the Si-bearing species in the fluid (water) in response to as opposed to TCP/HA, where bone grew between the ulna
the dissolution of tremolite and crystallisation of diopside bone and the scaffold. In vitro cell viability studies with
are described. Using the dependence of the overall-reaction human bone osteosarcoma cells (Saos-2) demonstrated
rate on the surface area of the reactants, it was experimentally that ­Ca3ZrSi2O9-based scaffolds do not cause cytotoxicity
determined that process (dissolution of tremolite, transport of when compared to a control group cultivated on tissue cul-
the Mg-bearing species in the fluid and crystallization of diop- ture plastic [79]. In addition to enhanced cell viability and
side) will be rate-limiting in most cases where metamorphism proliferation, when human primary osteoblasts cells were
occurs in an internally controlled system at high temperature cultivated on C
­ a3ZrSi2O9 instead of TCP/HA, the expression
and at high ratios of fluid to solids [68]. of osteopontin, osteocalcin, bone sialoprotein, and RUNX2
genes was increased [80]. The summary of the doped Ca-Si
4.1.8 Calcium zinc Silicates (Hardystonite; Ca‑Zn‑Si) ceramics is listed in Table 1.

Hardystonite ­(Ca2ZnSi2O7) is a Ca–rich silicate bioceramic 4.2 Ca‑Si Ceramic‑Based Nanocomposites

that was created by introducing Zn into the Ca–Si oxide as a Solution to Poor Mechanical Properties
system in order to improve chemical stability [69]. Among
many bioceramics, ­Ca2ZnSi2O7 demonstrated a greater It is known that bioactive ceramics have the ability to gen-
potential to form apatite as well as a suitable degradation erate nano-sized carbonated hydroxyapatite (CHA) both
rate [52, 70], Xiong et al. [71] investigated the dissolving in vivo and after treatment in SBF solution [81–84]. As
rate of Ca-Si bioceramics containing Ca and Si ions, and a result, they show osteoconductivity property [85–87].
found that porous layers containing Zn lowered the dissolu- Unfortunately, the poor fracture toughness and high elastic
tion rate while having no negative impact on osteogenic cell modulus compared to that of human bone are the main
adhesion or apatite production on the scaffold surface. limitations of their widespread use in clinical applications.
Studies have shown that C ­ a2ZnSi2O7 implants in a rab- In this context, the synthetic polymer provides one of the
bit’s damaged femur had a greater rate of healing and enhance most important solutions to this serious issue, thanks to
rate of osteogensis when compared to β-tricalcium phosphate. its great fracture toughness, malleability, and regulated
They have also shown that these scaffolds have no toxicity biodegradability. However, it causes severe inflammations
[72]. ­Ca2ZnSi2O7 ceramics also have been reported to stim- in vivo and exhibits no osteoconductivity at all. Based
ulate cellular attachment, and to promote proliferation and on this fact, its use as a bone grafting material is highly
differentiation of cells more than calcium silicate. Moreo- limited. In order to acquire good CHA forming capabil-
ver, when ­Ca2ZnSi2O7 interact with human osteoblast-like ity, acceptable mechanical and biodegradable qualities,
cells, it promotes expression of osteocalcin and collagen type the combination of the two materials is desired [88]. The
I and alkaline phosphatase [53, 73]. Although C ­ a2ZnSi2O7 HAPEX® is a representative composite which is com-
ceramic exhibits good mechanical performance, its com- posed of micron-sized bioactive HA particles and syn-
pressive strength can be further improved by incorporating thetic polyethylene matrix [89]. It has been used to create
­CaMgSi2O6 up to 12.5 wt% into the matrix, but the additional ossicular replacement prosthesis with success [90]. How-
amount (25 wt%) lowered compressive strength. Interestingly, ever, when blending ceramic and polymer phases, numer-
adding ­CaMgSi2O6 to the ­Ca2ZnSi2O7 scaffold can consider- ous issues have been discovered resulting from various
ably improve the biological properties [74, 75]. wetabilities. Phase separation, which happens at the inter-
face of the two phases because the synthetic polymer is
4.1.9 Calcium Zirconium Silicates (Baghdadite; Ca‑Zr‑Si) typically hydrophobic while the ceramic is hydrophilic, is
one issue. This phase separation weakens the mechanical
Baghdadite, (­ Ca3ZrSi2O9), is a calcium zirconium sili- properties of the composite. The bioactive ceramic par-
cate mineral. Because of its biocompatibility and good ticles’ poor level of dispersion in the polymer matrix is

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Table 1  Summary of types of doped Ca-Si ceramics

Types of doped Ca-Si ceramicas Examples Chemical formula Main findings in vivo and in vitro

Calcium magnesium silicates (Ca-Mg-Si) Diopside CaMgSi2O6 • It has better mechanical strength and stability than that of cal-
cium silicate.
• It can be used when a controlled slow degradation rate is
required.
• In vitro culture, it provide a neutral PH which decreases chance
of bacterial infection and it supports human osteoblast cell adhe-
sion and differentiation similar to hydroxyapatite.
Akermanite Ca2MgSi2O7 • It is known for its good mechanical properties and degradation
rate
• Its surface morphology plays an important role in apatite forma-
tion as rough surfaces increase apatite production
• Has dual functionalities of osteogenesis/angiogenesis stimula-
tion in vitro and in vivo
• Remarkably more than TCP, it encourages the proliferation and
differentiation of bone marrow-derived mesenchymal stromal
cells.
Bredigite Ca7Mg(SiO4)4 • It contains higher calcium ions so it has greater bioactivity and
bioresorbability.
• Its compressive strength is higher than TCP
• Bredigite coated with poly (lactic-co-glycolicacid) showed best
results as a bone scaffold.
Monticellite CaMgSiO4 • In 2X SBF, Urea-derived monticellite features the crystalline
HA phase, whereas other fuel-derived minerals feature the amor-
phous apatite phase.
• It has the capacity to promote osteoblastic activity within a
given concentration range.
Merwinite Ca3Mg(SiO4)2 • It has bending strength and fracture toughness similar to cortical
bone.
• In vivo, it promote bone progenitor cells to proliferate and dif-
ferentiate more than HA and has better degradation that HA
Serendibite CaMg3Si3O10 • It is a rare silicate mineral
• It can be found in a variety of high-temperature, high-pressure
conditions
Tremolite Ca2Mg5Si8O24 • Tremolite is one of the most common amphibole species
• Tremolite is an indicator of metamorphic grade since at high
temperatures it converts to diopside
Calcium zinc silicates (Ca-Zn-Si) Hardystonite Ca2ZnSi2O7 • It, more effectively, stimulates osteogenic differentiation of
mesenchymal stem cells derived from human bone marrow than
TCP.
• It stimulates osteoblast-like cells to differentiate, and express
genes important for bone formation.
• To further improve the mechanical properties of hardystonite,
diopside can be added to it.
Calcium zirconium silicates (Ca-Zr-Si) Baghdadite Ca3ZrSi2O9 • It exhibits strong cytocompatibility and attachment of osteo-
blasts, osteoclasts, and endothelial cells.
• Bone can grew within the pores of ­Ca3ZrSi2O9 scaffolds oppo-
site to TCP/HA
• In cell culture it can increase expression of osteopontin, osteoc-
alcin and RUNX2 genes.

another issue. Nanocomposite has been created to address nanocomposite [92–96]. While non-degradable ones
these two issues, and it can reduce phase separation and are poly(methylmethacrylate; PMMA)/Ca-Si [97, 98],
increase dispersion [91]. poly(dimethylsiloxane; PDMS)/Ca-Si [99], PDMS/ Ca-Si/
There have been numerous studies over the past few TiO2 [100–102], poly(tetrametylene oxide; PTMO)/Ca-Si
decades to create new polymer/ceramic nanocompos- [103, 104], PTMO/TiO2 [104], PTMO/Ca-Si/TiO2 [105]
ites for the potential use as a bone grafting material. nanocomposites. Besides, adding various polymer ratios to
The biodegradable one is poly(-caprolactone)/Ca-Si Ca-Si ceramics can improve the tensile strength and fracture

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Silicon (2023) 15:2493–2505 2499

toughness [106]. Therefore, making a nanocomposite with and E. coli. Although these samples have good antibacterial
polymer could improve mechanical characteristics of Ca-Si effects against S. aureus and S. epidermidis, they have no
ceramics and produce flexible implant. However, in vivo antibacterial effects, whatsoever, on E. coli. It is significant
inflammations or responses to foreign bodies have been to note that the investigated specimens exhibit roughly twice
observed [88]. One example of biodegradable nanocompos- as much antibacterial activity against S. epidermidis as they
ite is poly (e-caprolactone; PCL)/ baghdadite nanocompos- do against S. aureus [47].
ite. PCL is one of the most widely used commercially acces- When examining the silver (Ag)-doped C ­ aSiO3, antimi-
sible biodegradable polymers that are frequently employed crobial assay demonstrated an antibacterial activity against
in biomedical applications [97]. However, one of the prob- two potential sources of infection in wound healing, such
lems that prevents its usage in bone regeneration is its lack as E. coli and S. aureus. ­CaSiO3 that has been doped with
of bioactivity [107, 108]. Using dip-coating techniques, ­Ag+ significantly inhibited both pathogens, and the diameter
a highly porous baghdadite-PCL composite scaffold with of the inhibition zone was shown to grow as the quantity
open and linked pores was effectively created. The nano- of ­Ag+ doping increased [113]. Moreover, the agricultural
baghdadite scaffold’s compressive strength was increased waste derived ­CaSiO3 doped with ­Cu+/Cu2+ demonstrated
from 0.18 to 0.41 MPa, and its achieved porosity was 80% good resistance to P. aeruginosa and E. coli. The inhibi-
mainly due to PCL-coating. Additionally, PCL-coating sig- tion zone diameter (IZD) of C ­ aSiO3 with 5.0% CuO ranged
nificantly contributes to the reinforcement and toughening between 22 and 30 mm. Other with a 3.0% CuO content
of the composite scaffold [79]. Another example is β-CS/ displayed a moderate IZD, i.e. 20 mm. Both C ­ aSiO3 and
poly (1, 8 Octanediol-co-Citrate; POC) nanocomposite. The Cu-CaSiO3 were found to inhibit microbial growth; however,
most remarkable feature of this composite is the promising the minimum concentration of Cu- ­CaSiO3 particles was
mechanical capabilities which can overcome the drawback sufficient to stop the growth of both the bacterial strains E.
in the mechanical properties of β–(Ca-Si). The bending and coli and S. aureus. The rupture of the bacterial cell wall and
compressive strengths of 60 β-(Ca-Si)/40 POC (%), which other cellular components is caused by copper metal accu-
are 176.11 ± 13.51 MPa and 84.25 ± 9.35 MPa, respectively, mulation [114, 115]. Therefore, it is suspected that the Cu
are noticeably greater than those with a smaller proportion and Si ions interacted with the bacterial membrane and hin-
of β-(Ca-Si). Additionally, this kind of composite is suffi- dered its growth by mechanically damaging the membrane.
ciently flexible to be used in the machining or moulding of The improved antibacterial action is mediated by the Cu ions
fixation devices, such as bone screws [109]. that adhere to bacterial DNA, either inhibiting replication or
interacting with sulfhydryl groups, which stimulate bacte-
4.3 Doping with Metal Oxides as a Solution for Low rial growth, it was also reported that the Cu-CaSiO3 inhibits
Antibacterial Activity of Ca‑Si significantly the growth of Gram + bacterial strains [116].

It is recognized that infections that develop as a result of

implanting biomaterials into injured human body parts are 5 Applications of Calcium Silicate
a major factor in patient morbidity and the occurrence of
acute and chronic infections as a result of the development of 5.1 Dental and Orthopaedic Applications
biofilm [110]. Therefore, improving antibacterial activity of
Ca-Si ceramics when implanted in human body is critical for (Ca-Si)-based ceramics main function is the ability to use in
patient health. When studying antibacterial viability of Zn repairing hard tissue texture, bone scaffolds, bone cements,
substituted calcium zirconium silicate, i.e. baghdadite over or implant coatings. It has been demonstrated that (Ca-Si)-
E. coli and S. aureus bacterial strain, results showed that based ceramics exhibit good biological and advantageous
adding ZnO to baghdadite reduces the viability of E. coli and mechanical qualities that are similar to human bone tissue.
S. aureus bacteria. When the proportion of ZnO is increased, In comparison to ­C2S and ­C3S, MCS is the most studied for
the bacterial viability of S. aureus bacteria decreases up to uses in bone repair and regeneration [117]. Siriphannon et al.
26.78% by increasing percentage of ZnO, while that of E. [118] showed that wollastonite had a quicker rate of carbon-
coli bacteria decreases up to 37.16% when compared to pure ated hydroxyapatite (CHA) formation than other bioactive
baghdadite. Debate exists over ZnO’s antibacterial mecha- glass ceramics. De Aza et al. [119] studied the morphology
nism [111]. According to some experts, the antibacterial and chemistry of the interface between the Ca-Si implant and
properties of ZnO are caused via hydrogen peroxide pro- surrounding bone in the femora condyle of rats and found
duction and ­Zn2+ ion leaching into medium [112]. In another that the wollastonite implant appeared to function as a physi-
study, the antibacterial activity of sintered T
­ iO2/ZrO2/Ca-Si cal support as cells with osteoblastic abilities were found to
nanocomposites samples was examined against Gram + and migrate and develop. Xue et al. [120] implanted wollastonite
Gram − microorganisms such as S. aureus, S. epidermidis, coatings in dog muscle and cortical bone marrow with the aim

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2500 Silicon (2023) 15:2493–2505

of studying the bioactivity of these coatings and discovered There are several commercial TCS-based cements available
that the presence of these coatings effectively form apatite with slight variations in the composition and manufacturing
layer. Moreover, Xu et al. [121] assessed the resorption and technique. Biodentine and ProRoot White MTA (WMTA)
bone regenerative potential of ­CaSiO3 porous scaffolds in rab- are two TCS-based cements with outstanding clinical per-
bit calvarial defect model. The results showed that ­CaSiO3 has formance in dentistry. Without causing cell death, human
bigger bone regenerative ability and a much higher resorption dental pulp stem cell absorbs the ­Ca2+ produced from TCS-
rate when compared to porous TCP. based biomaterials. When human dental pulp stem cells were
CaMgSi2O6 scaffolds promoted MC3T3-E1 cells to differ- stimulated with TCS-based cements, the increased Bioden-
entiate, mineralize, and interact with ALP activity. Addition- tine-linked ­Ca2+ load resulted in changed intracellular ­Ca2+
ally, it was related to the angiogenesis and adhesion of human dynamics, which in turn led to differential gene expression,
aortic endothelial cells (hAECs) and the L-929 fibroblast cell cellular differentiation, and mineralization potential [134].
lines, respectively. Furthermore, it was effectively implanted
in vivo in the mandible of a monkey and the jaw bone of rabbit 5.2 Wound Healing
and could promote formation of new bones [122]. ­Ca2MgSi2O7
was found to promote the growth of human C ­ aMgSi2O6 Wound healing is a complex biological process involving
derived stem cells (hASCs) and human bone marrow stromal ­Ca2+ that regulates blood coagulation, proliferation of cells,
cells (hBMSC) and hAECs, it enhances the angiogenesis and inflammation and cell remodelling [135]. Although ceramic-
osteogenesis of hAECs and promotes, through extracellular based biomaterial tended to concentrate more on hard tissue
signal-released kinase signalling pathway, the differentiation of regeneration, focus has switched to soft tissue regeneration
hASCs in new Zealand rabbits [123]. Moreover, Ca-Si ceram- due the ability of bioactive ions to regulate the fate of stem
ics can be widely used for filling tooth defects, thanks to their cells and the interaction with their microenvironment [136].
outstanding properties [124, 125]. Silica ­(SiO2), a key component of ceramics, promotes angi-
In the last ten years, the mineral trioxide aggregate (MTA) has ogenesis and collagen synthesis, which improves soft tissue
made its way into the area of dentistry, namely within conserva- regeneration [137]. The signalling process for wound healing
tive and endodontic treatments. It can be observed that MTA is a is positively mediated by other ceramic calcium components
hydrophilic and biocompatible endodontic cement that promotes acting as a secondary messenger [134]. Furthermore, it has
healing and osteogenesis. It is made up of a powder of fine tri- been discovered that calcium supports the normal homeostasis
oxides (tricalcium oxide, silicon oxide, bismuth oxide) and other of skin. In recent studies calcium silicate has established its
hydrophilic particles (tricalcium silicate, tricalcium aluminate, interaction with soft tissues [138]. The ionic dissolution of
which are responsible for the chemical and physical features of Si and Ca ions caused by the exposure of ­CaSiO3 to an aque-
this aggregate) that hardens when exposed to moisture [126]. In ous environment has been shown to drive cell differentiation,
response to this information, MTA is one of the most extensively vascularization of endothelial cells (ECs), and fibroblast cell
utilised bioceramic materials as fillers for root canal therapy regeneration [139]. By boosting vascular endothelial growth
[127]. Additionally, studies have shown that MTA functions to factor (VEGF) and basic fibroblast growth factor, the ­CaSiO3
activate signalling molecules for intercellular processes, resulting has been shown to increase angiogenesis (bFGF). However,
in osteoinductive effects on tooth pulp tissues and peripheral root ­CaSiO3 has many disadvantages including porosity, poor
tissues [128]. It is used in endodontic treatments, such as pulp strength and possibility of microbial infections. Microbial
capping, pulpotomy, perforation repair and apexification [129]. infections slow down the healing process and also cause more
At the exposed pulp after pulp capping, MTA speeds up the pro- deterioration of the injury. Accordingly, the occurrence of
duction of reparative dentine [130]. Earlier research has dem- microbial infections can be significantly reduced by doping
onstrated that MTA increased pulp cells’ in vitro odontogenic ­CaSiO3 with metal ions having excellent antimicrobial effect
differentiation [131]. MTA may directly interact with the apical such as ­Zn2+, silver ­(Ag+), copper ­(Cu2+), cerium ­(Ce3+),
papilla tissue during apexification, promoting the development of and titanium ­(Ti4+). Among these metal ions, Zn is known
hard tissue in developing permanent teeth [132]. Unfortunately, to encourage the growth of soft tissues. Tetrahydra of Zn (O,
despite MTA being a promising material in endodontic treat- OH)4 plays a significant role in binding into the silicate anion
ment, MTA is not commonly used due to its long setting time; synthesis, which increases the stability of the ceramic, hence it
namely at least 2–5 h. Therefore, despite the fact that the MTA is mostly involved with epidermal formation [140, 141].
is frequently utilised in patients with extensive gum bleeding,
the performance of its sealing for bleeding patients is greatly 5.3 Drug Delivery
diminished by the long curing duration [133].
Tricalcium silicate-based (TCS-based) cements are Recently, Ca-Si ceramic materials have received a lot of atten-
hydraulic bioactive materials widely used as endodontic tion from researchers around the world for their use in drug
cements in dentistry and as bone substitutes in orthopedics. delivery purposes. Drug molecules having carboxyl group

13
Silicon (2023) 15:2493–2505 2501

(COOH) or hydroxyl (OH) group, such as ibuprofen, aspirin, Author Contributions The manuscript was written by the contri-
and amoxicillin, can be efficiently adsorbed by surface-bound butions of all authors. All authors approved the final version of the
manuscript. Rasha A. Youness- Presenting the idea of research and
­Ca2+ cations. Materials made of Ca-Si have a wide range of contributing to writing and reviewing the manuscript. Doha M. Tag
uses; for instance, Ca-Si functions in cosmetic compositions El-deen- Collecting scientific materials and contributing to writing the
as an absorbent, bulking agent, and opacifying agent [142]. manuscript. Mohammed A. Taha- Contributing to writing and review-
In 1998, 132 formulations containing Ca-Si were reported ing the manuscript.
to the U.S. Food and Drug Administration (FDA), of which Funding Open access funding provided by The Science, Technology&
30% were face powders. Besides, Ca-Si is mentioned in the Innovation Funding Authority (STDF) in cooperation with The Egyp-
OTC Active Ingredient Status Report as an external analge- tian Knowledge Bank (EKB).
sic and skin protectant [143]. A study showed that by using
Data Availability The data and materials are available of this article.
ciprofloxacin as the model drug, sodium calcium silicate in
SBF medium was used to test the scaffolds’ capacity for drug Declarations
release. The bioceramic composite showed sustained drug
release capability based on the release profile [144]. One of Conflict of Interest The manuscript was written through the contribu-
benefits of Ca-Si-based drug delivery systems is long drug- tions of all authors. All authors have approved the final version of the
manuscript. The authors declare that they have no known competing
release time (usually weeks) which can greatly extend a drug’s financial interests or personal relationships that could have appeared to
therapeutic efficacy. Another benefit of these systems is the influence the work reported in this paper.
pH-responsive drug release capability of calcium silicate-
based drug delivery systems, which can serve as an excellent Consent to Participate
platform for targeted drug administration [145].

6 Conclusion

It is perfectly acceptable to consider that bone can regen-

erate naturally as part of the healing process following Consent for Publication The authors agree to publish this article in
injury, but if the wound is larger than the critical size its current form.
defect, it cannot. Based on the above, biomaterials that
aid in bone tissue regeneration or replacement have been Open Access This article is licensed under a Creative Commons Attri-
made possible thanks to material science’s partnership bution 4.0 International License, which permits use, sharing, adapta-
with biomedical sciences. A biomaterial can be defined tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
as a substance created to work with biological systems provide a link to the Creative Commons licence, and indicate if changes
to diagnose, treat, improve upon, or replace any organ, were made. The images or other third party material in this article are
tissue, or bodily function. One of the most promising included in the article’s Creative Commons licence, unless indicated
biomaterials that help in the bone regeneration is cal- otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
cium silicate (Ca-Si) ceramic, thanks to its amazing bio- permitted by statutory regulation or exceeds the permitted use, you will
activity property. Unfortunately, the use of Ca-Si ceramic need to obtain permission directly from the copyright holder. To view a
in biomedicine is constrained by a number of factors, copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
including its brittleness, weakness, and high rate of deg-
radation, which affects cell proliferation. Furthermore, References
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