A Review on Calcium Silicate Ceramics: Properties, Limitations, and Solutions for Their Use in Biomedical Applications

The bone, being an essential tissue in the human body, not only protects the organs inside the body but also provides mechanical 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 osteoinductivity. 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.


Introduction
While bone has the intrinsic ability to regenerate as part of the healing process after an injury [1], it cannot regenerate tissue if the wound is bigger than the critical size defect [2]. In such conditions, numerous studies have shown the usage of autologous and allogeneic transplantations. However, in autologous transplantation, complications such as scarring, disability and injury of donor site have been reported in up to 20.6% of cases [3,4]. In allograft transplantation, the biological and mechanical properties change during the sterilization and preservation process causing a loss of osteogenic and integration ability [5]. All these disadvantages lead to development of biomaterials as bone replacements.
Material science, in collaboration with biomedical sciences, has facilitated the development of biomaterials that help to regenerate or replace injured bone tissues. Biomaterial is a material designed to interact with biological systems in order to assess, treat, augment, or replace any body tissue, organ, or function [6]. Based on their sources, biomaterials can be divided into natural and synthetic biomaterials [7]. Natural biomaterials are substances that are naturally derived or have undergone chemical alterations to be employed in the production of scaffolds or other implants. Notably, they can be divided into two categories based on the nature of their origin: proteinbased and polysaccharide-based natural biomaterials [8]. Examples of natural biomaterials are collagen and chitosan [9]. In 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 synthetic materials. Besides, they are bioactive, with specialised protein binding sites and other biochemical signals that could help with a variety of physiological functions like cell adhesion, cell to cell communication, and tissue regeneration [10]. Unfortunately, natural biomaterials are relativity unstable which may cause mechanical malfunction or premature decomposition.

3
Based on this problem, scientists have invented synthetic biomaterials to overcome the defects of natural biomaterials. As a result of this interest, many biomaterials have arisen, which can be divided into four main classes; namely ceramics, metals, polymers, and composites. Compared with natural biomaterials, synthetic biomaterials are simple and inexpensive to produce, and show more stable and controllable mechanical, biodegradation and physicochemical properties [11]. Because of these amazing benefits, bioceramics are commonly used in the field of dentistry and bone replacement [9].
Bone substitute materials can be classified into three groups: a) Bioinert and biostable materials such as zirconia (ZrO 2 ), titania (TiO 2 ) and alumina (Al 2 O 3 ), in which its function is to compensate for the defect without provoking the body immune system [12]. b) Bioactive osteoconductive materials such as calcium phosphates (Ca-Ps) materials like hydroxyapatite (HA) which initiate a specific biochemical response at the interface, forming a strong bond between material and tissue to enhance bone repair [13]. c) Bioresorbable osteoinductive materials such as bioactive glasses (BGs), and composites of bioactive salts (Ca-Ps, calcium silicate, etc.) with polymers which have recently been designed to stimulate tissue regeneration by promoting certain biological reactions at the molecular level [14].
It should be noted that biomaterials used in bone repair must meet a huge number of requirements such as: biocompatibility, adequate mechanical and physical (density and porosity) characteristics [15,16], and suitable osteoinduction, manageable bioactivity, and an acceptable degradation rate [14]. Compared with several biomaterials that have been studied for bone healing and endodontic procedures, biodegradable ceramics are promising candidates for bone repair [17,18]. In this sense, although HA has chemical characteristics similar to natural apatite and it can chemically interact with bone tissue promoting fast bone repair [19][20][21], experiments have shown that HA has a significantly slower dissolution rate which slows down the rate of its interaction with surrounding bone tissue which is considered one of its major drawbacks along with its high brittleness and limited mechanical stability, which hinders its use in the treatment of bone problems [22][23][24].

Bone Composition and Properties
Bone accounts for the highest proportion of connective tissue mass in the body. Bone has multiple functions, such as supporting the body, promoting motion, and storing minerals such as calcium and phosphate. Bone is a composite material in which organic and inorganic components make up 30 and 70%, respectively of bone tissue. HA is a mineral made of calcium phosphate, which is the main inorganic component. However, collagen fibers and noncollagenous proteins (NCPs) make up the majority of the organic material [25]. It is important to note that HA mineral has two main functions: it strengthens the collagen complex, increases the mechanical resistance of bones, and provides calcium, phosphate, and magnesium ions for mineral homeostasis. It is common for smaller mineral crystals to be destroyed during bone remodelling due to physicochemical reasons, and therefore it is not surprising that in osteoporosis, larger and more perfect crystals remain within the matrix [26], which increases osteoporosis [27]. While the most abundant components of the organic extracellular matrix (ECM) in bones are collagen types I, III, and V. Collagens' primary purposes are to provide mechanical support and serve as a framework for bone cells [28]. 90% of the collagen in bone tissue is type I collagen, which assembles into triple helices of polypeptides to create the collagen fibrils. The higher-order fibril bundles and fibres are constructed by these fibrils interacting with other collagenous and noncollagenous proteins (NCPs) [29]. Collagen types III and V are present in smaller amount and they control the fiber diameter and the process of fibrillogenesis of collagen type I [30]. Importantly, NCPs such as proteoglycan and glycoslated proteins comprise 10-15% of the total protein content of bones. Interestingly, NCPs have multiple functions, including coordinating interactions between cells and minerals in the matrix, arranging the extracellular matrix and modulating the mineralization process [31].
Human bone is a living tissue that undergoes continual bone resorption (release of calcium and phosphate from mineralized bone) and deposition (use of calcium and phosphate to form new bone) bearing in mind that primary bone cells are osteogenic cells, osteoclasts, osteoblasts, osteocytes and bone lining cells regulate this process [25]. This process is called bone remodelling in which old bone is replaced by new bone. Bone remodelling consists of three phases: (1) the beginning of bone resorption by osteoclasts, (2) the transition (or reversal period) from resorption to new bone formation, and (3) bone formation by osteoblasts [31,32]. This process occur through the coordinated actions of osteoclasts, osteoblasts, osteocytes, and bone lining cells, which collectively form the transient anatomical structure known as the basic multicellular unit (BMU) [33]. In view of this fact, normal bone remodelling is essential for calcium homeostasis, fracture repair, and skeletal adjustment to mechanical stress [34]. However, an imbalance between bone formation and resorption leads to a number of bone disorders. For instance, excessive bone loss and osteoporosis can be caused due to high resorption by osteoclasts without producing enough new bone by osteoblast to replace it [33]. Therefore, there must be a balance between bone resorption and formation which can be regulated by multiple factors such as chemokines, cytokines and hormones.

Types of Calcium Silicate as a Promising Biomaterial for Biomedical Applications
Calcium silicate (Ca-Si) is well recognized as the principal component of Portland cement in the construction field, although it has only been used as a biomaterial for about two decades. There are three types of Ca-Si, each with distinct Ca/ Si ratio: monocalcium silicate (MCS; CaSiO 3 ), dicalcium silicate (C 2 S; Ca 2 SiO 4 ), and tricalcium silicate (C 3 S; Ca 3 SiO 5 ), and pyrosilicate (C 3 S 2 ; Ca 3 Si 2 O 7 ). Moreover MCS exhibits three modifications. The high-temperature form, α-CaSiO 3 (pseudowollastonite), occurs rarely in nature whilst the two β-polymorphs, (parawollastonite) and (wollastonite), are more common [35]. The major components of Portland cement, C 2 S and C 3 S, are hydraulic and may be hydrated and hardened when combined with liquid phase. C 2 S is known to have five polymorphs, which are denoted by the symbols, α, α'H, α'L, β and γ. At room temperature, the γ form is stable and inert against hydration. The β form is unstable; however, at room temperature it possesses hydration action [36]. Ca-Si bioceramic is one of the most promising candidates for use in dentistry and orthopaedics due to its outstanding bioactivity [22]. Past studies have demonstrated that releasing of specific amounts of Si in microenvironment promote cellular adhesion and promote osteogenic differentiation of bone marrow mesenchymal stem cells [37][38][39]. Moreover, the Si ion has been associated to the upregulation of angiogenic factors gene expression [40]. Furthermore, phosphate ions in simulated body fluid (SBF) have also been observed to react with Ca ions on the surface of Ca-Si scaffolds, resulting in HA mineralization. This mineralization causes the surface to become hydrophilic, which improves the scaffold's capacity to adhere to living tissues [41]. Despite these amazing characteristics, the biomedical applications of Ca-Si ceramic are restricted by several limitations such as its brittle nature, weak strength and high degradation rate, which affects cell proliferation (because of high pH values) and induces premature bone decay before its ability to recover [37,42,43]. Also, Ca-Si's antibacterial activity is insufficient to successfully remove microorganisms from the implanted bone fracture [44].
One solution to solve the rapid biodegradation of Ca-Si is doping with additional materials, such as magnesium oxide (MgO), zinc oxide (ZnO) and ZrO 2 leading to the formation of diopside, akermanite, bredigite, monticellite, merwinite, serendibite, tremolite, hardystonite, and baghdadite [45]. Another solution to modify the composition is to prepare hybrid composites with the aim of improving the insufficient mechanical performance of Ca-Si. Among these materials that can be added to Ca-Si to prepare the desired hybrid composites are ceramics [46,47]; synthetic biopolymers such as poly(lactic-coglycolic acid), polycaprolactone and poly(L-lactide); and natural biological polymers, such as silk fibrin, chitosan and gelatine [48]. When compared to single phase Ca-Si, the composites often present enhanced mechanical characteristics as well as improved biocompatibility [49]. Finally, some metal oxides can be added to Ca-Si to enhance its antibacterial properties.

Diopside
Diopside (CaMgSi 2 O 6 ) is calcium and magnesium silicate. It has a chemical composition that is similar to Ca-Si and Ca 2 MgSi 2 O 7 [50]. Nakajima et al. [51] produced CaMgSi 2 O 6 ceramics for use as biomaterial, and observed that it could form apatite in SBF and could closely bind to bone tissue when implanted in rabbits. Studies have shown that the CaMgSi 2 O 6 scaffolds have a mechanical strength that is similar to that of human sponge bone (0.2-4 MPa) [52]. Also, the compressive strength of CaMgSi 2 O 6 scaffolds only decreased by 30% after 14 days of soaking in SBF, compared to a 54 and 60% decline in the strength of BG and Ca-Si scaffolds, respectively [53]. These reveal that CaMgSi 2 O 6 scaffolds have improved mechanical strength as well as mechanical stability, implying that they are preferable to traditional bioceramics in bone regeneration applications [52]. Despite a weight loss of only 2% after 28 days of soaking, CaMgSi 2 O 6 scaffolds in SBF solution maintained a sustained Si ion release, demonstrating that the CaMgSi 2 O 6 scaffolds are degradable in biological environments. After soaking for 28 days, CaMgSi 2 O 6 scaffolds lose less weight than Ca 2 MgSi 2 O 7 (18%) [54] and Ca-Si (26%) [50], implying that CaMgSi 2 O 6 scaffolds, can be used when a controlled slow degradation rate is desirable [55]. Moreover, the high dissolution rate causes the pH to be in the range of 7.4-7.6, indicating a better environment for in vitro bone cell culture [52].

Akermanite
Akerminate, Ca 2 MgSi 2 O 7 , is calcium and magnesium silicate. Lately, akermanite has attracted a high interest because of its desirable mechanical characteristics and controllable degradation rate [55]. Wu et al. [50,56] studied the bioactivity of Ca 2 MgSi 2 O 7 by soaking the akermanite in SBF. After ten days of immersion in SBF, the surface layer formed a HA film. In a recent article, the rate of Ca 2 MgSi 2 O 7 dissolution was investigated where the ability to deposit apatite on the ceramic surface was improved by the increased dissolving rate of Ca 2 MgSi 2 O 7 over CaMgSi 2 O 6 . The surface morphology of Ca 2 MgSi 2 O 7 has a substantial impact on biological characteristics, Ca 2 MgSi 2 O 7 with rougher surfaces being related to increased apatite production and subsequent bone formation [57]. According to a recent study, Ca 2 MgSi 2 O 7 bioceramics also had distinct dual functionalities of osteogenesis/angiogenesis stimulation in vitro and in vivo, it also represses osteoclastic activity to promote bone reconstruction and when exposed to osteoporosis, it has superior bone repair ability [58].

Bredigite
Bredigite, Ca 7 Mg(SiO 4 ) 4 , is a member of calciummagnesium silicates with an orthorhombic structure. Ca 7 Mg(SiO 4 ) 4 , in comparison to Ca 2 MgSi 2 O 6 and Ca 2 MgSi 2 O 7 , has superior bioresorbability and bioactivity due to its increased Ca ion content [59]. The compressive strength of Ca 7 Mg(SiO 4 ) 4 scaffolds was higher than that of TCP scaffolds, with values of 0.233 and 0.05 MPa, respectively. However, there are two fundamental disadvantages to using Ca 7 Mg(SiO 4 ) 4 scaffolds in bone tissue engineering. One is Ca 7 Mg(SiO 4 ) 4 's high resorption rate, which results in a high Ca 2+ concentration, metabolic alkalosis, and thus an unfavourable cellular response [60]. Second problem is like a lot of bioceramics, its lack of mechanical strength, which is insufficient for bone regeneration [61]. One of the solutions to these disadvantages is coating Ca 7 Mg(SiO 4 ) 4 with poly (lactic-co-glycolic acid; PLGA). A study reported that the Ca 7 Mg(SiO 4 ) 4 -10%PLGA scaffold is the best scaffold for bone regeneration, with good mechanical strength, pore interconnectivity and cytocompatibility [59].

Monticellite
Monticellite, (CaMgSiO 4 ), is a member of calcium-magnesium silicate.  (SiO 4 ) 2 )-implanted rats showed significantly greater new bone growth and material breakdown after 2 and 8 weeks compared to the HA-implanted group. In addition, the newly generated bone tissue entered the centre of (Ca 3 Mg(SiO 4 ) 2 ) implants 8 weeks after implantation, which resulted in substantially higher degradation of (Ca 3 Mg(SiO 4 ) 2 ). According to in vivo findings, (Ca 3 Mg(SiO 4 ) 2 ) have good bioactivity and can, thus, promote bone progenitor cells to proliferate and differentiate more than HA [64].

Serendibite (CaMg 3 Si 3 O 10 )
Serendibite is a rare silicate mineral that has been found only a little over a dozen times in the world. Its complex composition includes calcium, magnesium, aluminium, silicon, boron, and oxygen. It is formed in the triclinic crystal system and it can be found in a variety of high-temperature, high-pressure conditions as a metasomatic product [65]. The lowest temperature at which it is generated is close to 500 °C, at a pressure of about 1000 MPa. With rising temperature, the pressure range in which it can be generated broadens, and at 700 °C it can be formed in a pressure range of at least 100 to 2000 MPa [66]. Due to the above reasons of difficulty in preparing this type of Ca-Si ceramic along with its rarity, one can expect that no biomedical applications for it are recorded.

Tremolite (Ca 2 Mg 5 Si 8 O 24 )
Tremolite is silicate of magnesium which is monoclinic in structure with ideal formula Ca 2 Mg 5 Si 8 O 24 . Tremolite is one of the most common amphibole species which are a complex assemblage of minerals that have variable composition and extensive elemental substitutions. Tremolite is found in the fibrous form (i.e., characterized by crystals/particles consisting of fibres with length > 5 μm, width < 3 μm) [67]. Tremolite is an indicator of metamorphic grade since at high temperatures it converts to diopside by reaction (1 tremolite + 3 calcite + 2 quartz = 5 diopside + 3 CO 2 + 1 H 2 O). A series of SEM photos from the experiment show that diopside selectively nucleates and develops topotactically on tremolite. A simplified scheme that consists of three processes is used to model the mechanism of the forward reaction. In each process, the formation, transport, and incorporation of (1) the Ca-, (2) the Mg-, and (3) the Si-bearing species in the fluid (water) in response to the dissolution of tremolite and crystallisation of diopside are described. Using the dependence of the overall-reaction rate on the surface area of the reactants, it was experimentally determined that process (dissolution of tremolite, transport of the Mg-bearing species in the fluid and crystallization of diopside) will be rate-limiting in most cases where metamorphism occurs in an internally controlled system at high temperature and at high ratios of fluid to solids [68].

Calcium zinc Silicates (Hardystonite; Ca-Zn-Si)
Hardystonite (Ca 2 ZnSi 2 O 7 ) is a Ca-rich silicate bioceramic that was created by introducing Zn into the Ca-Si oxide system in order to improve chemical stability [69]. Among many bioceramics, Ca 2 ZnSi 2 O 7 demonstrated a greater potential to form apatite as well as a suitable degradation rate [52,70], Xiong et al. [71] investigated the dissolving rate of Ca-Si bioceramics containing Ca and Si ions, and found that porous layers containing Zn lowered the dissolution rate while having no negative impact on osteogenic cell adhesion or apatite production on the scaffold surface.
Studies have shown that Ca 2 ZnSi 2 O 7 implants in a rabbit's damaged femur had a greater rate of healing and enhance rate of osteogensis when compared to β-tricalcium phosphate. They have also shown that these scaffolds have no toxicity [72]. Ca 2 ZnSi 2 O 7 ceramics also have been reported to stimulate cellular attachment, and to promote proliferation and differentiation of cells more than calcium silicate. Moreover, when Ca 2 ZnSi 2 O 7 interact with human osteoblast-like cells, it promotes expression of osteocalcin and collagen type I and alkaline phosphatase [53,73]. Although Ca 2 ZnSi 2 O 7 ceramic exhibits good mechanical performance, its compressive strength can be further improved by incorporating CaMgSi 2 O 6 up to 12.5 wt% into the matrix, but the additional amount (25 wt%) lowered compressive strength. Interestingly, adding CaMgSi 2 O 6 to the Ca 2 ZnSi 2 O 7 scaffold can considerably improve the biological properties [74,75].

Calcium Zirconium Silicates (Baghdadite; Ca-Zr-Si)
Baghdadite, (Ca 3 ZrSi 2 O 9 ), is a calcium zirconium silicate mineral. Because of its biocompatibility and good mechanical strength, zirconium (Zr) has been widely used as a biomaterial in the fabrication of implants and prosthetic devices, particularly in bone and dental applications [76,77]. Roohani et al. [78] were the first to develop Ca 3 ZrSi 2 O 9 -based porous scaffolds to treat critical size bone defects. After 12 weeks, radiographic images of rabbit radial bone defects revealed that implanted Ca 3 ZrSi 2 O 9 scaffolds had greater bone ingrowth and complete bridging than TCP/HA scaffolds. Histological analyses revealed that bone grew within the pores of Ca 3 ZrSi 2 O 9 scaffolds, as opposed to TCP/HA, where bone grew between the ulna bone and the scaffold. In vitro cell viability studies with human bone osteosarcoma cells (Saos-2) demonstrated that Ca 3 ZrSi 2 O 9 -based scaffolds do not cause cytotoxicity when compared to a control group cultivated on tissue culture plastic [79]. In addition to enhanced cell viability and proliferation, when human primary osteoblasts cells were cultivated on Ca 3 ZrSi 2 O 9 instead of TCP/HA, the expression of osteopontin, osteocalcin, bone sialoprotein, and RUNX2 genes was increased [80]. The summary of the doped Ca-Si ceramics is listed in Table 1.

Ca-Si Ceramic-Based Nanocomposites as a Solution to Poor Mechanical Properties
It is known that bioactive ceramics have the ability to generate nano-sized carbonated hydroxyapatite (CHA) both in vivo and after treatment in SBF solution [81][82][83][84]. As a result, they show osteoconductivity property [85][86][87]. Unfortunately, the poor fracture toughness and high elastic modulus compared to that of human bone are the main limitations of their widespread use in clinical applications. In this context, the synthetic polymer provides one of the most important solutions to this serious issue, thanks to its great fracture toughness, malleability, and regulated biodegradability. However, it causes severe inflammations in vivo and exhibits no osteoconductivity at all. Based on this fact, its use as a bone grafting material is highly limited. In order to acquire good CHA forming capability, acceptable mechanical and biodegradable qualities, the combination of the two materials is desired [88]. The HAPEX® is a representative composite which is composed of micron-sized bioactive HA particles and synthetic polyethylene matrix [89]. It has been used to create ossicular replacement prosthesis with success [90]. However, when blending ceramic and polymer phases, numerous issues have been discovered resulting from various wetabilities. Phase separation, which happens at the interface of the two phases because the synthetic polymer is typically hydrophobic while the ceramic is hydrophilic, is one issue. This phase separation weakens the mechanical properties of the composite. The bioactive ceramic particles' poor level of dispersion in the polymer matrix is 1 3 another issue. Nanocomposite has been created to address these two issues, and it can reduce phase separation and increase dispersion [91].
There have been numerous studies over the past few decades to create new polymer/ceramic nanocomposites for the potential use as a bone grafting material. The biodegradable one is poly(-caprolactone)/Ca-Si nanocomposite [92][93][94][95][96]. While non-degradable ones are poly(methylmethacrylate; PMMA)/Ca-Si [97,98], poly(dimethylsiloxane; PDMS)/Ca-Si [99], PDMS/ Ca-Si/ TiO 2 [100][101][102], poly(tetrametylene oxide; PTMO)/Ca-Si [103,104], PTMO/TiO 2 [104], PTMO/Ca-Si/TiO 2 [105] nanocomposites. Besides, adding various polymer ratios to Ca-Si ceramics can improve the tensile strength and fracture toughness [106]. Therefore, making a nanocomposite with polymer could improve mechanical characteristics of Ca-Si ceramics and produce flexible implant. However, in vivo inflammations or responses to foreign bodies have been observed [88]. One example of biodegradable nanocomposite is poly (e-caprolactone; PCL)/ baghdadite nanocomposite. PCL is one of the most widely used commercially accessible biodegradable polymers that are frequently employed in biomedical applications [97]. However, one of the problems that prevents its usage in bone regeneration is its lack of bioactivity [107,108]. Using dip-coating techniques, a highly porous baghdadite-PCL composite scaffold with open and linked pores was effectively created. The nanobaghdadite scaffold's compressive strength was increased from 0.18 to 0.41 MPa, and its achieved porosity was 80% mainly due to PCL-coating. Additionally, PCL-coating significantly contributes to the reinforcement and toughening of the composite scaffold [79].

Doping with Metal Oxides as a Solution for Low Antibacterial Activity of Ca-Si
It is recognized that infections that develop as a result of implanting biomaterials into injured human body parts are a major factor in patient morbidity and the occurrence of acute and chronic infections as a result of the development of biofilm [110]. Therefore, improving antibacterial activity of Ca-Si ceramics when implanted in human body is critical for patient health. When studying antibacterial viability of Zn substituted calcium zirconium silicate, i.e. baghdadite over E. coli and S. aureus bacterial strain, results showed that adding ZnO to baghdadite reduces the viability of E. coli and S. aureus bacteria. When the proportion of ZnO is increased, the bacterial viability of S. aureus bacteria decreases up to 26.78% by increasing percentage of ZnO, while that of E. coli bacteria decreases up to 37.16% when compared to pure baghdadite. Debate exists over ZnO's antibacterial mechanism [111]. According to some experts, the antibacterial properties of ZnO are caused via hydrogen peroxide production and Zn 2+ ion leaching into medium [112]. In another study, the antibacterial activity of sintered TiO 2 /ZrO 2 /Ca-Si nanocomposites samples was examined against Gram + and Gram − microorganisms such as S. aureus, S. epidermidis, and E. coli. Although these samples have good antibacterial effects against S. aureus and S. epidermidis, they have no antibacterial effects, whatsoever, on E. coli. It is significant to note that the investigated specimens exhibit roughly twice as much antibacterial activity against S. epidermidis as they do against S. aureus [47]. When examining the silver (Ag)-doped CaSiO 3 , antimicrobial assay demonstrated an antibacterial activity against two potential sources of infection in wound healing, such as E. coli and S. aureus. CaSiO 3 that has been doped with Ag + significantly inhibited both pathogens, and the diameter of the inhibition zone was shown to grow as the quantity of Ag + doping increased [113]. Moreover, the agricultural waste derived CaSiO 3 doped with Cu + /Cu 2+ demonstrated good resistance to P. aeruginosa and E. coli. The inhibition zone diameter (IZD) of CaSiO 3 with 5.0% CuO ranged between 22 and 30 mm. Other with a 3.0% CuO content displayed a moderate IZD, i.e. 20 mm. Both CaSiO 3 and Cu-CaSiO 3 were found to inhibit microbial growth; however, the minimum concentration of Cu-CaSiO 3 particles was sufficient to stop the growth of both the bacterial strains E. coli and S. aureus. The rupture of the bacterial cell wall and other cellular components is caused by copper metal accumulation [114,115]. Therefore, it is suspected that the Cu and Si ions interacted with the bacterial membrane and hindered its growth by mechanically damaging the membrane. The improved antibacterial action is mediated by the Cu ions that adhere to bacterial DNA, either inhibiting replication or interacting with sulfhydryl groups, which stimulate bacterial growth, it was also reported that the Cu-CaSiO 3 inhibits significantly the growth of Gram + bacterial strains [116].

Dental and Orthopaedic Applications
(Ca-Si)-based ceramics main function is the ability to use in repairing hard tissue texture, bone scaffolds, bone cements, or implant coatings. It has been demonstrated that (Ca-Si)based ceramics exhibit good biological and advantageous mechanical qualities that are similar to human bone tissue. In comparison to C 2 S and C 3 S, MCS is the most studied for uses in bone repair and regeneration [117]. Siriphannon et al. [118] showed that wollastonite had a quicker rate of carbonated hydroxyapatite (CHA) formation than other bioactive glass ceramics. De Aza et al. [119] studied the morphology and chemistry of the interface between the Ca-Si implant and surrounding bone in the femora condyle of rats and found that the wollastonite implant appeared to function as a physical support as cells with osteoblastic abilities were found to migrate and develop. Xue et al. [120] implanted wollastonite coatings in dog muscle and cortical bone marrow with the aim of studying the bioactivity of these coatings and discovered that the presence of these coatings effectively form apatite layer. Moreover, Xu et al. [121] assessed the resorption and bone regenerative potential of CaSiO 3 porous scaffolds in rabbit calvarial defect model. The results showed that CaSiO 3 has bigger bone regenerative ability and a much higher resorption rate when compared to porous TCP.
CaMgSi 2 O 6 scaffolds promoted MC3T3-E1 cells to differentiate, mineralize, and interact with ALP activity. Additionally, it was related to the angiogenesis and adhesion of human aortic endothelial cells (hAECs) and the L-929 fibroblast cell lines, respectively. Furthermore, it was effectively implanted in vivo in the mandible of a monkey and the jaw bone of rabbit and could promote formation of new bones [122]. Ca 2 MgSi 2 O 7 was found to promote the growth of human CaMgSi 2 O 6 derived stem cells (hASCs) and human bone marrow stromal cells (hBMSC) and hAECs, it enhances the angiogenesis and osteogenesis of hAECs and promotes, through extracellular signal-released kinase signalling pathway, the differentiation of hASCs in new Zealand rabbits [123]. Moreover, Ca-Si ceramics can be widely used for filling tooth defects, thanks to their outstanding properties [124,125].
In the last ten years, the mineral trioxide aggregate (MTA) has made its way into the area of dentistry, namely within conservative and endodontic treatments. It can be observed that MTA is a hydrophilic and biocompatible endodontic cement that promotes healing and osteogenesis. It is made up of a powder of fine trioxides (tricalcium oxide, silicon oxide, bismuth oxide) and other hydrophilic particles (tricalcium silicate, tricalcium aluminate, which are responsible for the chemical and physical features of this aggregate) that hardens when exposed to moisture [126]. In response to this information, MTA is one of the most extensively utilised bioceramic materials as fillers for root canal therapy [127]. Additionally, studies have shown that MTA functions to activate signalling molecules for intercellular processes, resulting in osteoinductive effects on tooth pulp tissues and peripheral root tissues [128]. It is used in endodontic treatments, such as pulp capping, pulpotomy, perforation repair and apexification [129]. At the exposed pulp after pulp capping, MTA speeds up the production of reparative dentine [130]. Earlier research has demonstrated that MTA increased pulp cells' in vitro odontogenic differentiation [131]. MTA may directly interact with the apical papilla tissue during apexification, promoting the development of hard tissue in developing permanent teeth [132]. Unfortunately, despite MTA being a promising material in endodontic treatment, MTA is not commonly used due to its long setting time; namely at least 2-5 h. Therefore, despite the fact that the MTA is frequently utilised in patients with extensive gum bleeding, the performance of its sealing for bleeding patients is greatly diminished by the long curing duration [133].
Tricalcium silicate-based (TCS-based) cements are hydraulic bioactive materials widely used as endodontic cements in dentistry and as bone substitutes in orthopedics.
There are several commercial TCS-based cements available with slight variations in the composition and manufacturing technique. Biodentine and ProRoot White MTA (WMTA) are two TCS-based cements with outstanding clinical performance in dentistry. Without causing cell death, human dental pulp stem cell absorbs the Ca 2+ produced from TCSbased biomaterials. When human dental pulp stem cells were stimulated with TCS-based cements, the increased Biodentine-linked Ca 2+ load resulted in changed intracellular Ca 2+ dynamics, which in turn led to differential gene expression, cellular differentiation, and mineralization potential [134].

Wound Healing
Wound healing is a complex biological process involving Ca 2+ that regulates blood coagulation, proliferation of cells, inflammation and cell remodelling [135]. Although ceramicbased biomaterial tended to concentrate more on hard tissue regeneration, focus has switched to soft tissue regeneration due the ability of bioactive ions to regulate the fate of stem cells and the interaction with their microenvironment [136].
Silica (SiO 2 ), a key component of ceramics, promotes angiogenesis and collagen synthesis, which improves soft tissue regeneration [137]. The signalling process for wound healing is positively mediated by other ceramic calcium components acting as a secondary messenger [134]. Furthermore, it has been discovered that calcium supports the normal homeostasis of skin. In recent studies calcium silicate has established its interaction with soft tissues [138]. The ionic dissolution of Si and Ca ions caused by the exposure of CaSiO 3 to an aqueous environment has been shown to drive cell differentiation, vascularization of endothelial cells (ECs), and fibroblast cell regeneration [139]. By boosting vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, the CaSiO 3 has been shown to increase angiogenesis (bFGF). However, CaSiO 3 has many disadvantages including porosity, poor strength and possibility of microbial infections. Microbial infections slow down the healing process and also cause more deterioration of the injury. Accordingly, the occurrence of microbial infections can be significantly reduced by doping CaSiO 3 with metal ions having excellent antimicrobial effect such as Zn 2+ , silver (Ag + ), copper (Cu 2+ ), cerium (Ce 3+ ), and titanium (Ti 4+ ). Among these metal ions, Zn is known to encourage the growth of soft tissues. Tetrahydra of Zn (O, OH) 4 plays a significant role in binding into the silicate anion synthesis, which increases the stability of the ceramic, hence it is mostly involved with epidermal formation [140,141].

Drug Delivery
Recently, Ca-Si ceramic materials have received a lot of attention from researchers around the world for their use in drug delivery purposes. Drug molecules having carboxyl group (COOH) or hydroxyl (OH) group, such as ibuprofen, aspirin, and amoxicillin, can be efficiently adsorbed by surface-bound Ca 2+ cations. Materials made of Ca-Si have a wide range of uses; for instance, Ca-Si functions in cosmetic compositions as an absorbent, bulking agent, and opacifying agent [142]. In 1998, 132 formulations containing Ca-Si were reported to the U.S. Food and Drug Administration (FDA), of which 30% were face powders. Besides, Ca-Si is mentioned in the OTC Active Ingredient Status Report as an external analgesic and skin protectant [143]. A study showed that by using ciprofloxacin as the model drug, sodium calcium silicate in SBF medium was used to test the scaffolds' capacity for drug release. The bioceramic composite showed sustained drug release capability based on the release profile [144]. One of benefits of Ca-Si-based drug delivery systems is long drugrelease time (usually weeks) which can greatly extend a drug's therapeutic efficacy. Another benefit of these systems is the pH-responsive drug release capability of calcium silicatebased drug delivery systems, which can serve as an excellent platform for targeted drug administration [145].

Conclusion
It is perfectly acceptable to consider that bone can regenerate naturally as part of the healing process following injury, but if the wound is larger than the critical size defect, it cannot. Based on the above, biomaterials that aid in bone tissue regeneration or replacement have been made possible thanks to material science's partnership with biomedical sciences. A biomaterial can be defined as a substance created to work with biological systems to diagnose, treat, improve upon, or replace any organ, tissue, or bodily function. One of the most promising biomaterials that help in the bone regeneration is calcium silicate (Ca-Si) ceramic, thanks to its amazing bioactivity property. Unfortunately, the use of Ca-Si ceramic in biomedicine is constrained by a number of factors, including its brittleness, weakness, and high rate of degradation, which affects cell proliferation. Furthermore, the antibacterial effectiveness of Ca-Si is insufficient to effectively eliminate germs from the implanted bone fracture. In response to these challenges, researchers around the world have offered hopeful solutions. Firstly, doping Ca-Si with some oxides such as magnesium oxide (MgO), zinc oxide (ZnO) and zirconium oxide (ZrO 2 ) in order to improve its weak biodegradability and antibacterial effect. Second, adding polymers to Ca-Si ceramic to enhance its low mechanical properties. Based on these precious experiences, Ca-Si is expected to be used in various biomedical applications including dental and orthopedic applications, wound healing purposes and drug delivery systems.

Author Contributions
The manuscript was written by the contributions of all authors. All authors approved the final version of the manuscript. Rasha A. Youness-Presenting the idea of research and contributing to writing and reviewing the manuscript. Doha M. Tag El-deen-Collecting scientific materials and contributing to writing the manuscript. Mohammed A. Taha-Contributing to writing and reviewing the manuscript.
Funding Open access funding provided by The Science, Technology& Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

Data Availability
The data and materials are available of this article.

Conflict of Interest
The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Consent for Publication
The authors agree to publish this article in its current form.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated 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 permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.