Materials Science and Engineering C 35 (2014) 245–252
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Review
Bioactive behavior of silicon substituted calcium phosphate basedbioceramics for bone regeneration
Ather Farooq Khan a,⁎, Muhammad Saleem a, Adeel Afzal a,b,c,⁎⁎, Asghar Ali c,Afsar Khan d, Abdur Rahman Khan d
a Interdisciplinary Research Centre in Biomedical Materials, COMSATS Institute of Information Technology, Defence Road, Off Raiwind Road, Lahore 54000, Pakistanb Affiliated Colleges at Hafr Al-Batin, King Fahd University of Petroleum and Minerals, P.O. Box 1803, Hafr Al-Batin 31991, Saudi Arabiac Research and Development Unit, ALAM Medix, Lahore 54000, Pakistand Depatment of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
⁎ Corresponding author. Tel.: +92 111 001 007x829.⁎⁎ Correspondence to: A. Afzal, Affiliated Colleges at Hafof PetroleumandMinerals, P.O. Box 1803, Hafr Al-Batin 31720 3426x1675.
Bone graft substitutes are widely used for bone regeneration and repair in defect sites resulting from aging, dis-ease, trauma, or accident. With invariably increasing clinical demands, there is an urgent need to produce artifi-cial materials, which are readily available and are capable of fast and guided skeletal repair. Calcium phosphatebased bioactive ceramics are extensively utilized in bone regeneration and repair applications. Silicon is often uti-lized as a substituent or a dopant in these bioceramics, since it significantly enhances the ultimate properties ofconventional biomaterials such as surface chemical structure, mechanical strength, bioactivity, biocompatibility,etc. This article presents an overviewof the silicon substituted bioceramics,whichhave emerged as efficient bonereplacement and bone regeneration materials. Thus, the role of silicon in enhancing the biological performanceand bone forming capabilities of conventional calcium phosphate based bioceramics is identified and reviewed.
composed of collagen, and calcium phosphate [1,2]. The presence ofcalcium phosphates distinguishes bone from other hard tissues likeshell, chitin and enamel [3]. The biological functions of bone include: pro-tection of soft tissues and sensitive organs, e.g., by the rib framework or bythe skull; physical support for the mechanical action of tissues, e.g., themuscles’ contraction and the lungs’ expansion; and calcium homeostasis[4]. One of themajor structural constituents of bone is calcium phosphatethat is similar to hydroxyapatitewith calcium to phosphatemolar ratio of5: 3 (1.67) and chemical formula of Ca10(PO4)6(OH)2 [5,6]. On the other
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hand, the control of bonemetabolism is a function of the cellular compo-nents of bone, which work in sync and are responsible for the mainte-nance and repair function as well [7].
Silicon (Si) is widely recognized as an essential component of differ-ent types of biomaterials such as bioactive ceramics in skeletal therapies[8]. In general, it is utilized as a substituent or in combination with avariety of other materials for filling bone defects. It imparts severaldistinguishing features to various types of bioceramics enhancing theirin vivo biological performance. Thus, silicon embraces a vast and anemerging field of research to address bone regeneration and repair.Before presenting a review of recent literature on silicon substitutedbioceramics, it is important to understand the structure of bone in detailin order to comprehend how the complex process of bone regenerationoccurs, when fractures heal.
1.1. The structure of bone
Bone can be classified basically as a nanocomposite material. Hy-droxyapatite forms the major portion of the mineral component ofbone [9,10]. The protein part is composed mainly of collagen (althoughother proteins are also involved in development and maintenance ofthe tissue, as discussed later). Collagen is intrinsically a fibrous protein.This is reflected by the main quality it imparts to bone tissue, that is,flexibility. This is in paradox to the rigidity provided by hydroxyapatitenanocrystals, which are embedded in the collagen matrix. However,instead of being bound directly to collagen the mineral crystals arebound through non-collagenous proteins, which also provide sites forcellular attachment [11,12].
Apart from collagen and hydroxyapatite, internally the bone consistsof anionic and cationic substitutions: mainly carbonates up to 8 wt.%,magnesium and sodium up to 0.5 and 0.8 wt.% (i.e., on trace level)respectively, while it contains zinc, fluorine, chlorine, strontium, potas-sium, and silicon on ultra-trace level [13]. The presence of all theseelements provides a readily available source of inorganic nutrients ofgreat metabolic significance. Importantly, the amount of Si varies withage and sex of the individual [14]. The overall composition of bonesignificantly varies with the type of bone as well. The whole corticalbone contains 9% water, 22% organic, and 69% inorganic constituents[15].
It is important tomention the presence of cellular matrix in bones toprovide a complete overview of bone structure. The bone cells canbe characterized and distinguished according to the functions theyperform. These cells are named: osteoblasts, osteoclasts, osteocytes,osteoprogenitor cells, and bone lining cells [16]. The osteoprogenitorcells are also ‘bone precursor cells’. The primary task of bone formationis undertaken by the osteoblasts. Osteocytes are the mature bone cells.These are essential in the transport of minerals between the bone andthe blood. The transfer ofminerals in and out of bone tissue is a functionof the bone lining cells, which are also important in responding tohormones, and this ultimately cascades into the activation of osteoclasts[16].
1.2. Bone engineering
Tissue engineering and regenerative medicine endeavor the combi-natorial effect of functional cells and bioactive scaffolds used to con-struct and to revive diseased or damaged tissue such as bone fromengineered biomaterials [17,18]. The most active class of biomaterialsfor modern bone regeneration applications is the bioceramics such ashydroxyapatite and tricalciumphosphates. Tenacious bonds are formedwith the natural bone when bioactive inorganic materials react withphysiological fluids by forming bone like bioceramic layers, whichescort the orthopedic patient to fixation of bone tissue and effectivebiological interaction with the materials' surface [12,19]. The favorableintercellular and extracellular responses stimulate rapid bone regenera-tion, and the reason for this activity is the reactions on the bioactive
material's surface, which in turn stimulate the discharge and the tradeof critical amount of soluble ions, e.g., Si, Ca, P, and Na ions. To realizeeffective bone regeneration, the biomaterial should have some charac-teristic properties in terms of its biosorption, bioactivity and moreimportantly spacemaintainability, which is key to its mechanical stabil-ity during the bone healing process [12,17].
Various bone regeneration and skeletal repair strategies emergedduring the last few decades showing the promise and potential of thisfield [20,21]. Thus, bones and hard tissues, which have been damagedor lost as a result of some distressing disease or aging, can be successful-ly regenerated or repaired. Autografts used for the treatment of bonedefects have certain limitations likemorbidity of donor sites and inade-quate supply [22,23]. Alternatively, allografts are expensive and couldincrease the risk of disease transmission [22–24]. Artificial or syntheticbone grafts, on the other hand, are ideal bone substitute materialseven though the clinical success of these synthetic grafts could not beachieved [25]. Bioactive scaffolds, a product of biomedical engineering,can be used to heal diseased and/or damaged tissues [26,27]. Oneof the most fascinating biomaterials are calcium phosphate basedbioceramics such as hydroxyapatite and tricalcium phosphates, whichare cytocompatible and bioactive materials [28,29]. This paper presentsa state of the art review of biological activity of the Si substitutedbioceramics that are developed and used for bone regeneration andrepair applications. The effects of Si substitution on bone formationand related biological properties of bioceramics are discussed.
2. Silicon in bone regeneration and repair
Silicon is an essential nutrient [30,31]. Carlisle in 1970s [32]identified the abnormal bone formation due to deficiency of Si thatwas later confirmed by Schwarz [19,33], who recognized it as thecrosslinking agent in the connective tissues along with its importanceto vascular health. It has been reported that bone and muscles bonddirectly to the Si containing bioceramics having improved bioactivitydue to presence of Si [34]. Si is found not only to promote collagentype I synthesis and osteoblast differentiation, but also to facilitatebone repair at the wounded site [34,35]. According to other reports,bone mineralization requires the smallest amount of soluble Si[36,37]. Si provides stability to biological apatite, yet imparts sufficientreactivity to allow the growth of nanocrystallites in vivo [38].
It is suggested that particularly in bone and cartilage, Si might playan essential role in connective tissue metabolism [37,39,40]. Hench[41] reported that wear and tear in the proliferation and the operationof bone forming cells due to osteoporosis and osteopenia are associatedwith the loss of biological availability of Si. Furthermore, bone cellsmultiply much faster in the presence of soluble Si in culture as demon-strated by Keeting et al. [42] with the help of zeolite A — Si containingparticulate material. These studies evidently reveal the enormouspotential of Si inclusion in the biomaterials' lattice intended at re-generating hard tissues. Recent studies show that regular siliconconsumption in diet is positively related to skeletal health, especiallywith the density of cortical bone, which is dependent on the estrogens'availability [43,44].
For the efficient biological interactions and attachment of bone withthe bioceramic surface, Si substitution plays a key role. However, onecannot find standard design criteria at present, when it comes tomechanical properties of bioactive materials (scaffolds) that are to beutilized for bone repair especially if these materials are used for defectsrelated to load bearing capability. A bioactive material needs to imitatethe structure, morphology, and function of bone so that surroundingtissues can readily assimilate with them [25,26]. The inconsistency inmechanical properties and architecture of the bone together with vari-ances in nourishing state, physical activity, i.e., mechanical load andfunctioning, health status, and age of every patient puts biomedicalmaterial scientists in a challenging position to design and fabricate bio-active ceramics for specific defect sites [45]. In the following section, we
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review the type and performance of various Si substituted calciumphosphate based bioceramics.
3. Si substituted bioceramics
Calcium phosphate based bioceramics are renowned for their suc-cessful biomedical applications and have been used as implantablebone regeneration materials owing to their close structural and func-tional resemblance with the inorganic component of bone [46,47].The most abundant phase of calcium phosphate in bone mineral ishydroxyapatite that is highly insoluble, while the more soluble andimmature calcium phosphates are found only at the cortical, endosteal,subperiosteal, and Haversian surfaces [48]. Table 1 presents type,composition, and formulae of various calcium phosphate phases foundin bone mineral [48–50]. Since Si substitution plays an important rolein enhancing the biological performance of these calcium phosphates,we evaluate different Si substituted calcium phosphate bioceramics inthis section for a brief overview of the advantages and applications ofthese bioceramics in bone regeneration.
3.1. Si substituted hydroxyapatite
Hydroxyapatite – a calcium phosphate based bioceramic – is amongthemost efficient biomaterials to prepare implantable scaffolds for boneaugmentations [47,51,52]. Because of the soaring demand for artificialbiomaterials to support, regenerate, and-or replace bone skeleton andhigh frequency of the existing medical implants' failure, a great deal ofexploratory and applied research focuses on the design of implantablebioceramics and improvising the interaction at the implant–tissueinterface [51]. This is done considering the fact that the implant shouldresorb in concert with the natural restorative process [53]. Hydroxyap-atite has gained importance as an artificial bone substitute and dentalfilling material due to its structural similarity with bone mineral andits excellent biocompatibility with hard and soft tissues [38,54–56].
However, the biological apatite differs from synthetic hydroxyapatitein different aspects such as stoichiometry, composition, and crystallinity.The stoichiometric hydroxyapatite does not have sufficient capacity toform an interface with existing bone and to stimulate or promote thedevelopment of new bone. In addition, it is not bioresorbable and isretained by the body as a permanent fixture that is vulnerable to failurein the long-run [57]. Another disadvantage of using hydroxyapatiteimplants is that its reactivity with the natural bone tissue and boneforming cells is very low along with the slower rate of bone appositionand integration [58].
The answer to such problems lies in Si substitution of the stoi-chiometric hydroxyapatite that effectively overcomes some of theseproblems [59–61], as discussed below. For instance, Patel et al. [62]compared in vivo behavior of pristine and Si substituted hydroxyapatitegranules, and demonstrated that the bioactivity of hydroxyapatite isconsiderably improved by the inclusion of silicate ions into its lattice.In an in vitro study by Gibson et al. [63], it is observed that Si substitutedhydroxyapatite increases themetabolic activity of human osteosarcomacells. In a series of experiments, Botelho et al. [64,65] revealed that the
Table 1Different phases of calcium orthophosphate based bone mineral in order of decreasingacidity, decreasing solubility, and increasing thermodynamic stability [48,49].
a Boanini et al. [50] reported Ca/P molar ratio: 1.2–2.2 for ACP.
adhesion of humanosteoblasts in Si substituted hydroxyapatite culturesis substantially enhanced. The human osteoblasts are influenced by theabundance of Si in hydroxyapatite lattice and their effectiveness de-pends on the degree of Si substitution. It is shown that the abundanceof osteoblast markers expressed by 0.8 wt.% Si substituted apatite ishigher than that expressed by 1.5 wt.% Si substituted apatite [64].
It is found that compared to the stoichiometric apatite, the osteo-blast cell activity is significantly enhanced by substitution of phosphate(PO4
3−) ions with silicate (SiO44−) ions in hydroxyapatite [66,67]. A
recent study by Tian et al. [68] indicated that Si substitutes the phos-phate ion sites in the stoichiometric hydroxyapatite structure formingSiO4
4− ions. It is also suggested that the negative charge of a SiO44− ion
that substitutes a PO43− ion is stabilized by the formation of a hydroxide
(HO−) ion vacancy [69], that can be expressed in the general formula ofa Si substituted hydroxyapatite as: [Ca10(PO4)6 − x(SiO4)x(OH)2 − x].Botelho [70] first verified that an increase in Si content in the hydroxy-apatite lattice results in enhanced bioactivity leading to faster apatiteformation. On the other hand, it has been shown that if Si substitu-tion increases above 2 wt.%, the hydroxyapatite starts to destabilizeand α-tricalcium phosphate (α-TCP) is formed [71].
Additionally, Si substituted hydroxyapatite plays an important rolein osteointegration of implants as demonstrated by both in vivo andin vitro biological response studies [58,62,72,73]. Hing et al. [73]highlighted the effects of Si level on rate, quality, and progression ofbone healing within Si substituted porous hydroxyapatite scaffolds.They observed that bone healing process is sensitive to Si level in thefemoral intercondylar notch of New Zealand's white rabbits. It wassuggested that an optimal response can be obtained with 0.8 wt.% Sisubstituted hydroxyapatite by examining its effect on the activity ofbone forming and resorbing cells [73].
Honda et al. [74] demonstrated that Si content influences theosteoblastic cells proliferation and morphology, as shown in Fig. 1, sug-gesting that there is an optimal Si content for cell culture. A number ofrecent studies on Si substituted hydroxyapatite [74–80] also claim thatSi inclusion improves the biological activity of hydroxyapatite and thatit proves to be a better alternate to conventional hydroxyapatite forbone regeneration applications. However, the mechanism by which Siimproves osteoconductivity of hydroxyapatite is still not clear. At pres-ent, several explanations can be considered such as a change in surfacechemistry and/or surface topography of a silicated hydroxyapatite[81,82]. Further studies are therefore required to identify the correctmechanisms operating behind the positive influence of Si substitutionon the biological response of bioceramics, especially hydroxyapatite.Moreover, it is yet doubtful that superior biological behavior of Sisubstituted hydroxyapatite is related to its physical and chemical charac-teristics, which also demands further investigations.
3.2. Si substituted tricalcium phosphates (TCPs)
Tricalcium phosphate (TCP) – another valuable form of calciumphosphate based bioceramics – is also extensively investigated forapplications in bone grafting and as a coating material for metallic pros-theses and implants thanks to its good biocompatibility and osteocon-ductive properties [83–85]. TCP exists in two phases: β-Ca3(PO4)2 andα-Ca3(PO4)2 [86]. The characteristic feature of TCP is that the molarratio of calcium to phosphate is 3:2 (1.5), see Table 1. The β-form ofTCP is thermodynamically stable at room temperature, and its stabilityranges between 25 °C and 1120 °C; while α-TCP is thermodynamicallystable between 1140 and 1470 °C (i.e., α-TCP is metastable below1120 °C) [87].
These TCPs have long been used as a temporary support for regener-ated bone and as a bone cement [88]. According to recent reports[83,89–91], β-TCP is an efficient bioresorbable ceramic used widely asa bone substitute material, whereas α-TCP is the major constituent ofbioactive pastes applied as bone filling materials, thus it is so called ascalcium phosphate cement. The α-form of TCP has higher solubility
Fig. 1.Morphological changes of osteoblastic (MC3T3-E1) cells on Si substituted hydroxyapatite ceramics. The osteoblastic cells were cultured for 2 days on (A) polystyrene plate;(B) hydroxyapatite (0 wt.% Si); (C) 0.8 wt.% Si substituted hydroxyapatite; and (D) 1.6 wt.% Si substituted hydroxyapatite. These cells were stainedwith DAPI (Dojindo, Japan) for nuclei andAlexa Fluor® 594-labeled phalloidin (Invitrogen, Carlsbad, CA) for F-actin at 20 °C for 1 h. Bars indicate 200 μm. Arrows show the spindle-shaped cells and asterisks indicate shrinkage cells.Reprinted with permission from Honda et al. [74], copyright (2012) Springer.
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than β-TCP that leads to an accelerated degradation [92,93]. However,the β-form shows an optimal reactivity with the surrounding tissues ascompared to α-TCP [94]. Ruan et al. [95] described that α-TCP has self-setting ability which is one of the basic requirements of the biomedicalmaterials of ear ossicle and dentals.
Furthermore, the dissolution rate of TCP in biological fluid is fasterthan hydroxyapatite and it is believed to reinforce biological proper-ties of hydroxyapatite [96–98]. These findings are now leading theway to commercial availability of bone graft substitutes based onhydroxyapatite/β-TCP composites. Silicon, as described earlier, furtherstrengthens the physicochemical attributes of calcium phosphatesresulting in enhanced biological performance [77,99–101]. Song et al.[102], for instance, developed Si substituted biphasic calcium phosphate(BCP, composed of hydroxyapatite and β-TCP), which was proficient infaster formation of a new apatite phase on the surface interacting withphysiological fluids as compared to pristine BCP. Furthermore, theyillustrated that Si substitution positively affects the degree of dissolutionof BCP powders in Hanks' balanced salt solution (HBSS).
In the last few years, intensive research efforts have been focusedon the development of silicate ion substituted α-TCP bioceramics toimprove osteogenesis, rate of resorption, and mechanical strength ofα-TCP [103,104]. Si containing α-TCP blocks were developed for bonegraft applications and their osteointegration ability was examined rabbittibiae using histological, histomorphometric, and micro-computed to-pography (micro-CT) techniques [105]. The results indicated new bonegrowth in direct contact with the α-TCP block. It was found that siliconpresence in the block graft enhanced the stability and osteointegrationof the α-TCP. Silicon doped α-TCP blocks also exhibited improvedmesenchymal cell differentiation and increased osteoblastic activity ascompared to pristine α-TCP [105]. None of the implanted bioceramicswere reported to produce any adverse effects such as inflammation.
Thus, these Si substituted α-TCP ceramics are excellent candidates forbone regeneration [46].
Camiré et al. [106] evaluated the biological effects of substituting 1, 3,or 5 wt.% Si in α-TCP. They observed the formation of an apatite layersimilar to natural bone on the surface of set cements that was thickestfor 1 wt.% Si substituted TCP. These results were supported by in vivostudies,whichmanifested that 1 wt.% Si dopedα-TCP increasedmesen-chymal cell differentiation and bioactivity of osteoblasts as comparedto pure α-TCP. Fig. 2 shows the images of the interface between bonetissue and 1 wt.% Si doped α-TCP, and the percentage of bone contacton the material.
In a recent study,Mostafa et al. [78] demonstrated that the bioactivityof Si substituted calcium phosphate ceramics increased in a systematicway with an increasing silicate ion substitution. The surface of ceramicswith 2.23% Si substitution was partially covered with apatite layer afteroneweek,while ceramicswith 8.1% Si substitutionwere completely cov-ered with apatite in the first week. They concluded that the porous mi-crostructure of high-concentration Si substituted ceramics helps thedissolution of surface ions and the leaching process, thus allowing simu-lated body fluids to reach super-saturation in a short time and accelerat-ing the deposition of apatite layer. However, the higher value of Si mayalso mean a higher level of cytotoxicity of the Si substituted TCP, asreported by Douard et al. [101]. Thus, it is important to monitor the tox-icity of such compositions.
4. Role of silicon in biological performance of bioceramics
Porter [107] discussed in detail the mechanism of bone bonding tocalcium phosphate based bioceramics. It is believed that bone-to-bioceramics bonding follows the proposed dissolution–reprecipitationmechanism of apatite nucleation [107]. According to this theory, the
Fig. 2. Images from 2-week specimens: (a) the interface between tissue and calcium deficient hydroxyapatite (CDHA, i.e., α-TCP in this case) with pre-osteoblasts laid on the material;(b) osteoblasts with newly formed bone on 1% Si substituted α-TCP (1% Si-CDHA). Original magnification: 40×. (c) Bone contact percent on the material interface as a function of time.Adapted with permission from Camiré et al. [106], copyright (2005) Wiley Periodicals, Inc.
Fig. 3. Time course of the implanted tibia in the animal sacrificed 2 years after surgery: (a–b) Post-surgery; (c) 1.5 months; (d) 4 months; (e) 4.5 months; (f–g) 7.5 months;(h–i) 13.5 months; and (j) 20.5 months. Subperiosteal bone formation is detectable at 1.5 months when some plate bowing is also evident and becomes progressively moreprominent at 4 months when newly formed bone and implant integration were judged to be consolidated enough to remove the plate. The implant reduced progressivelywith time to be extremely rarefied and not easily recognizable at 20.5 months.Reprinted with permission from Mastrogiacomo et al. [121], copyright (2006) Mary Ann Liebert, Inc.
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dissolution of calcium and phosphate ions from the bioceramic surfaceincreases their concentration locally leading to the precipitation of bio-logical apatite heterogeneously on the surface of proteins present closeto the bioceramic coating or directly on itself, i.e., the surface of coating[108–110]. Subsequently, more proteins and osteoblasts are absorbedon the modified bioceramic surface promoting cell adhesion and boneformation [111–113]. However, Porter [107] concluded that dissolutionof bioceramic implant is not a prerequisite for osteointegration to occur,though it accelerates nucleation of biological apatite.
As discussed earlier, the degree of bone apposition and in-growth isprofoundly influenced by the Si content and optimal response of boneforming and bone resorbing cells is obtained at 0.8 wt.% Si [73]. In gener-al, bone tissue bonds directly to bioceramic surface either by establishinga non-collagenous transition layer composed of biological apatite[114–116], or in consequence of the direct apposition of proteins, e.g.,collagen fibrils [117–119]. It is believed that the apposition of non-collagenous transition layer on bioceramic surface is associated withthe intrinsic solubility of calcium phosphate phases in it [107,115].Thus, relatively soluble calcium phosphate phases such as α- or β-TCPcould enhance bone-to-bioceramic bonding and bone apposition.
Although, it is well known that hydroxyapatite is not completelyresorbable or biodegradable [120], Mastrogiacomo et al. [121] demon-strated that Si substituted TCP scaffolds are resorbable in vivo as com-pared to stoichiometric hydroxyapatite. Fig. 3 shows the sequentialradiographic images of long bone defects in sheep filled with resorbableSi substituted TCP bioceramics. The animal (sheep) achieved completefunctional recovery of the treated limb [121]. On the other hand,in vitro studies demonstrate specific interactions between bioceramicand cells taking place on the surface of Si substituted bioceramics.Both Si substituted hydroxyapatite and TCP promote the proliferationof osteoclast cells and reveal sufficient resorption of the bioceramic byosteoclasts [62,65,122]. Si substituted bioceramics also exhibit im-proved osteogenesis of osteoblast-like cells with corresponding in-crease in formation of new bone [64,123].
According to Porter [107], Si substitutedhydroxyapatite has relative-ly smaller grain size and less-ordered grain boundaries as comparedto stoichiometric hydroxyapatite. This increases the solubility of Sisubstituted hydroxyapatite thus affecting both the morphology andthe kinetics of biological apatite deposited at the interface of bone andbone graft [119,124]. Evidently, these findings conclude that the disso-lution of Si substituted bioceramic accelerates reprecipitation aroundimplant surface and bone formation. Porter et al. [119], however, re-vealed that carbonate substituted hydroxyapatite is even more solublethan silicon substituted hydroxyapatite, but it shows reduced bioactivi-ty as compared to Si substituted hydroxyapatite. Consequently, it issilicon itself that plays a key role in promoting bone formation or itscontrolled release during the dissolution of bioceramic implant that isnecessary for optimum bone apposition [107].
A substantial evidence of the effect of silicon substitution and/ordoping in a material on osteogenesis is presented by Pabbruwe et al.[125]; who utilized Si to dope alumina – a biologically inert ceramic –in order to investigate its influence on bone apposition and in-growth,cell differentiation, osteogenesis, and remodeling as compared to un-doped alumina. They observed that at low doping (0.5 mol% Si), thebio-inert ceramic stimulates cellular activity at the bone–ceramicinterface, while osseous remodeling is enhanced at higher doping(5 mol% Si) [125]. This study supports the primary role of Si in resorp-tion, tissue in-growth, and osteogenesis through a direct chemicalmechanism. According to Pietak et al. [126], the release of aqueous Sicomplexes to the extracellular matrix may well be an additional factorto promote biological activity of Si substituted bioceramics.
5. Concluding remarks
This article reviews the bioactive behavior of silicon substitutedcalcium phosphate based bioceramics that are widely used for bone
regeneration and repair applications. These calcium phosphate basedbioceramics include hydroxyapatite and tricalcium phosphates (α- andβ-TCP). The role of Si in enhancing the biological performance of the cal-cium phosphate based bioceramics, for instance: osteogenesis, differen-tiation and proliferation of osteoblasts, bone apposition, and in-growthas well as cytotoxicity, is discussed. A few examples of the Si substitutedbioceramic-to-bone cell interactions, bone apposition on the surface of Sisubstituted bioceramics, and sequential bioresorption of Si substitutedbioceramics are also shown. We conclude that Si plays a biologicallysignificant role in bone regeneration and repair. Si substituted calciumphosphates increase biological activity by accelerating the precipita-tion of a biologically equivalent hydroxyapatite. These Si substitutedbioceramics stimulate and promote the biomimetic precipitation eitherby increasing the dissolution of the bone graft or through controlledrelease of silicon and its aqueous complexes, which synergistically leadto enhanced biological activity and performance of synthetic bone grafts.Although, several possiblemechanisms are hypothesized to comprehendthe biological effects of silicon, the conclusive evidence to support theseprocesses is rare and the specific role of silicon in enhancing osteogenesisremains vague. Therefore, more work is required to understand Siinduced chemical, structural, and-or morphological modifications of cal-cium phosphates, the mechanism and kinetics of Si release from thebioceramic, and the biomolecular processes that may catalyze boneapposition around Si substituted bioceramics.
Acknowledgements
AA gratefully acknowledges the financial support providedby the Higher Education Commission (HEC) of Pakistan under theStart-Up Research Grants Program and the National Research Programfor Universities (NRPU).
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