Page 1of48 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/jbm.a.36061. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen Qingdao, Shandong Province, 266042, China China 266042, Province, Qingdao,Shandong MIUSA 48109, E mail: E mail: 1 Zhou,PhD Xianfeng Engineeri Tissue Bone and Orthopaedics in Silicates Acknowledgments: +1 330 972 5795 Phone: +1 330 972 7001 Fax: * 4 3 2 USA USA
from the University of Akron and the Ohio Research Research Ohio and the of Akron University the from Corresponding author: Corresponding Department of Biologic and Materials Sciences, Univ Sciences, andMaterials Departmentof Biologic Qingdao Engineering, and Science Polymer of School Akron, of Science,University Departmentof Polymer Integrated Bioscience Program and Department of Geo of Department and Program Bioscience Integrated
[email protected] Article
iaca spot a poie b NF M (0906817 DMR NSF by provided was support Financial 1, 2 1,
, , Zhang, Nianli PhD N.S. N.S. Journal ofBiomedicalMaterialsResearch:PartA
This article isprotected by copyright. All rights reserved.
4 , Steven Mankoci Steven ,
Scholar Program to Dr. Nita Sahai, PI. PI. Dr.Sahai, Nita to Program Scholar ersity of Michigan, Ann Arbor, Arbor, Ann Michigan, ersityof Akron, OH 44325, USA USA OH Akron, 44325, University of Science and Technology, Technology, and Science of University logy, University of Akron, OH 44325, 44325, OH Akron, of University logy, 1 , and Nita Sahai, PhD Sahai, and , Nita ng Materials Materials ng ), start up funds funds start up ), 1, 3,* 1,
oe ise niern apiain ad eet bre recent and applications engineering tissue bone being actively investigated as orthopaedic bone and bone orthopaedic as investigated actively being play important roles in promoting bone formation an formation bone promoting in roles important play mat bioactive silicon); (silica, silicate KEYWORDS: c of third generation design rational ideasfor the si of osteoinductivity the for mechanisms molecular not been fully understood and are controversial. He controversial. and are understood beenfully not propos the for mechanisms the However, engineering. osteoinductive factor. Natural silicate minerals an minerals silicate Natural factor. osteoinductive t binding of capable layer surface hydroxyapatite a Following the success of silicate based glasses as as glasses silicate based of success the Following ABSTRACT
Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 2 ell and gene affecting biomaterials. biomaterials. gene affecting ell and d silicate substituted hydroxyapatites are also also are hydroxyapatites silicate substituted d re, we review the potential roles of silicate for for ofroles silicate potential the review we re, bioactive materials, silicates are believed to to believed are silicates materials, bioactive lica. The goal of this article is to inspire new inspire to is article this of goal The lica. dental biomaterials for application in tissue in application for biomaterials dental erials; osteoblast; osteoclast; mechanism. mechanism. osteoclast; osteoblast; erials; d have therefore been considered to provide provide to considered been therefore have d akthroughs in identifying the cellular level cellular level the identifying in akthroughs bn a wl a ptnily en a pro a being potentially as well as bone o ed roles of silicate in these materials have have materials these in silicate of roles ed Page 2of48 Page 3of48 phosphate is not surprising as these ions constitut ions these as surprising not is phosphate en netgtd nldn mtl, lse, cerami glasses, metals, including investigated been f iiae n hs mtras r hglgtd alon highlighted are materials these in silicate of gla including biomaterials, silicate based of types biomateri orthopaedic of field the entered silicate pape this In works. silicate how and why understand level trace at occurs normally which silicate, also (calcium constituents chemical the only not include formation. tissue bone enhance and bone to bond can composi specific of glasses and Ceramics materials. actively promote desirable responses. To address th address To responses. desirable physi promote actively a present tissue, bone native of features the 1. Introduction Introduction 1. novel materials has shifted from bone tissue replac tissue from bone shifted has materials novel tissue of concept the of development the Since [3]. replacemen and repair bone involving treatments The
surgical procedures for implantation of prostheses prostheses of implantation for procedures surgical reliable of development the of result a as routine di damaged, of Replacement [1]. infection or trauma b where situations in and impaired, are turnover or os and disease, Paget’s imperfecta, osteogenesis as oe ise niern rqie bocie n oste and bioactive requires engineering tissue Bone
Accepted Article be bone regenerating or replacing of importance The Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 3 e the mineral phase of bone [7], but it is hard to to hard is it but [7], bone of phase mineral the e als and tissue engineering materials. Different Different materials. engineering tissue and als sses and ceramics are reviewed, and the roles roles the and reviewed, are ceramics and sses ement to tissue regeneration [4]. regeneration tissue to ement teoporosis in which normal bone development development bone normal which in teoporosis and affordable biomaterials and perfection of of perfection and biomaterials affordable and s in bone [5, 6]. The choice of calcium and and calcium of choice The 6]. [5, bone in s and subsequent rehabilitation of patients [2]. [2]. patients of rehabilitation subsequent and ese requirements, a variety of materials have have materials of variety a requirements, ese one is surgically removed because of severe severe of because removed surgically is one and phosphate) of natural bone mineral, but but mineral, bone natural of phosphate) and g with recent contradictory reports in the the in reports contradictory recent with g tions are considered to be bioactive as they they as bioactive be to considered are tions These formulations of ceramics and glasses glasses and ceramics of formulations These engineering, the emphasis on developing developing on emphasis the engineering, t have improved and saved countless lives countless saved and improved have t r, we first provide a brief history of how how of history brief a provide first we r, ochemical biomimetic environment, and and environment, biomimetic ochemical oinductive materials that mimic some of of some mimic that materials oinductive s plmr ad opsts f these of composites and polymers cs, comes clear in the cases of diseases such such diseases of cases the in clear comes seased or aged bone tissue has become become has tissue bone aged or seased
biological role in humans [5] and play an essential an play and [5] humans in role biological ppm in the liver, kidney, lungs and muscle, 100 ppm 100 muscle, and lungs kidney, liver, the in ppm SiO organism living all in found also is Si [8]. oxygen as 28% (about crust earth’s the in element abundant [15]. Lower levels of collagen were also observed i observed also were collagen of levels Lower [15]. co and wattle a of absence the as well as fractured thinne shorter, sockets), eye the around distortion c Si supplemented for g 116 of mass the to compared the weeks, 4 After metasilicate. sodium as Si mg/g mg/g 2 of content silicate low very a with corn and [1 chicks in performed were experiments deprivation bone the in sites calcification active at localized 2. Why silicate? silicate? Why 2. are presented. po can that mechanisms several Finally literatures.
oad ta o iel tihoerc A (Ca HAP stoichiometric ideal of that towards pr mineralization as limit detection the below fall (HAP hydroxyapatite stoichiometric in 1.67) = (Ca/P rat Ca/P when calcification bone of stages earliest tha observed Carlisle microanalysis, probe electron of study earliest The [13]. tissue connective other Silicon (Si) is the eighth most common element in t in element common eighth most the is (Si) Silicon 2
Accepted Articlepresent is Si [9 12]. exoskeleton their produce to Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 10 4 (PO r, and more flexible limb bones that were easily easily were that bones limb flexible more and r, Si in bone dates back to the early 1970s. Using Using 1970s. early the to back dates bone in Si s [5]. It has been proposed to play an important important an play to proposed been Ithas [5]. s ios are low (Ca/P = 0.7) compared to the ratio ratio the to compared 0.7) = (Ca/P low are ios tentially explain the biological roles of silicate silicate of roles biological the explain tentially o yug ie n rt. diinly Si Additionally, rats. and mice young of s average mass of Si deprived chicks was 76 g, 76 was chicks Si deprived of mass average t Si levels were highest (0.5 wt%) during the the during wt%) (0.5 highest were levels Si t or fed the same diet supplemented with 100 100 with supplemented diet same the fed or role in organisms such as diatoms that use that diatoms as such organisms in role n the cartilage of Si deficient chicks, but no but chicks, Si deficient of cartilage the n mb were reported in the Si deprived chicks chicks Si deprived the in reported were mb 4 cee, n te aP f oe increased bone of Ca/P the and oceeded, ). Subsequently, Si levels were observed to observed were levels Si Subsequently, ). in bone and 200 600 ppm in cartilage and and cartilage in ppm 200 600 and bone in 5] that were fed a diet consisting of casein casein of consisting diet a fed were that 5] ) hicks. Skull deformities (shorter skull and and skull (shorter deformities Skull hicks. he universe by mass, and the second most second most the and mass, by universe he various forms of silica or silicate) after after silicate) or silica of forms various 6 at a level of ~ 1 ppm in the serum, 2 10 2 10 serum, the in ppm 1 ~ of level a at (OH) 4 [4. hs S ws hw t be to shown was Si Thus, [14]. ) Page 4of48 Page 5of48 oe oue erae b 4% n nrae aias c animals untreated in 48% by decreased volume bone rmnpua wmn ih M dfeecs s ag a large as differences BMD with women premenopausal process of bone [19, 20] and may inhibit the physio the inhibit and20] may [19, processof bone orthopaedic implant materials. materials. orthopaedicimplant Si Hence, bone. of phases organic the and inorganic difference in the level of non collagenous proteins non collagenous of level the in difference
and the localization of Si is at the growing front growing the at is of Si localization andthe the with associated processes metabolic for element Si Therefore, cartilage. as such tissues connective role important potentially indicated findings these pigmen incisor of impairment and development enamel seb loss, hair rats, in Milne and Schwartz by study development and growth bone normal for required was significantly linked to bone mineral density (BMD) (BMD) density mineral bone to linked significantly differenc Furthermore, [20]. bone of matrix mineral remodeling bone in factor important an osteopontin, a to lead also animals ovariectomized in deficiency inhibitor an estradiol, or silicate aqueous either Si/day) and lowest levels (< 14 mg Si/day) of Si in Si of Si/day) mg 14 (< levels lowest and Si/day) A recent study using dietary Si supplementation in in supplementation Si dietary study using Arecent
In summary, Si appears to be required for the forma forthe berequired to appears Si Insummary, Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. Figure 1 Figure1 5 of bone. bone. of of the resorption activity of osteoclasts [19]. Si [19]. osteoclasts of activity resorption the of logical resorption process. process. logicalresorption [16, 17]. Carlisle Carlisle 17]. [16, orrhoea, loss of muscle tone, disturbances in in disturbances tone, muscle of loss orrhoea, development of bone and connective tissues, tissues, connective and bone of development o S i te omto o bn ad other and bone of formation the in Si of s take [21]. Si played a role in the remodeling remodeling the in role a played Si [21]. take has been incorporated in the design of many many of design the in incorporated been has may be categorized as an essential trace trace essential an as categorized be may ovariectomized mice showed that trabecular trabecular that showed mice ovariectomized es in dietary Si intake were positively and and positively were intake Si dietary in es , especially in anchoring osteoclasts to the to osteoclasts anchoring in especially , tion of bone and is associated with both the the both with associated andis of bone tion decrease in the concentration of plasma plasma of concentration the in decrease t l hp esrmn sts n e and men in sites measurement hip all at tation were observed [18]. Taken together,Taken [18]. observed were tation in higher animals (Fig. 1). In a similar similar a In 1). (Fig. animals higher in ompared to the groups which received received which groups the to ompared 1% ewe te ihs ( 4 mg 40 (> highest the between 10% s et alet . demonstrated that Si that demonstrated .
iatv cmoiin 4 w% SiO wt% (45 composition bioactive bone after implantation implantation after bone the bone material interface to be bonded (I bonded be to interface bone material the oncie ise ihn 0 as Bocie glass Bioactive days. 5 10 within tissue connective and, eventually, elicited the formation of a non ad formation the elicited and,eventually, ls cmoiin fo 4 2 t SiO wt% 40 52 from compositions glass 3.1 Silicate in bioactive glasses glasses bioactive in Silicate 3.1 biomaterials in Silicate 3. o bocie lse wt SiO with glasses bioactive for Inparticular [27]. composition glass bioactive the bonding The osteoconductive. are they specifically, promoted they because bioactive termed were glasses was deposited of bone, phase mineral the to similar than 60 wt% SiO wt% 60 than s to bond not did but bone with bond to time longer
When immersed in biological fluids, a layer of HAP HAP of layer a fluids, biological in immersed When named “Bioglassnamed melt derived four component glasses composed of SiO of composed glasses four component melt derived Henc 1970s, early the In substitutes. graft bone on The positive effect of Si on bone metabolism has ra has metabolism bone on Si effect of The positive Accepted(I of bioactivity Theindex Article
® 2 were biologically inert because they bonded neithe bonded they because inert biologically were ”. This was the first bioactive material, discovere material, bioactive first the was This ”. Journal ofBiomedicalMaterialsResearch:PartA n vivo in This article isprotected by copyright. All rights reserved. b ) is defined as the inverse of the time required fo required time of the inverse as the defined )is 2 ihu te ed o a eet t h tm o surge of time the at cement a for need the without otns f 55 w% wih odd o oh ot a soft both to bonded which wt%, 45 52 of contents John Wiley& Sons,Inc. 2 2. w% a, 45 t Na wt% 24.5 CaO, wt% 24.5 , 2 ae I have b Figure 2 Figure2 = 100/t= 6 , the most rapid rates of bonding were obtained obtained were bonding of rates rapid most the , herent fibrous interfacial capsule (Fig. 2) [29]. 2) [29]. capsule(Fig. herentinterfacial fibrous b on the glass surface. Therefore, these specific specific these surface.Therefore, glass the on h and his co workers discovered that specific specific that discovered co workers his and h oft tissue [28]. Glass compositions with more with compositions Glass [28]. tissue oft aus ayn fo 1. t 1. h most The 10. to 12.5 from varying values rate to existing bone tissue was specific to to specific was tissue bone existing to rate ised the interest of research groups working working groups research of interest the ised 0.5bb s otiig 56 w% SiO wt% 55 60 containing es a positive response from the tissue; more more tissue; the from response positive a 2 , CaO, Na CaO, , r yrxl abntd ptt (HCA) apatite carbonated hydroxyl or ). In the SiO the In ). 2 d in 1969 [30], and has found found has and [30], 1969 in d O and Pand O r to bone nor to soft tissues tissues soft to nor bone to r 2 2 CaO Na ad w% P wt% 6 and O 2 O r more than 50% of of 50% rmorethan 5 could bond with with bond could 2 O P 2 2 required a a required ry [22 26]. [22 26]. ry O 5 2 system, O d hard nd 5 was ) Page 6of48 Page 7of48 noprto o OH of incorporation phosph calcium a of formation and layer silica rich Si(OH) glass in a 4 week rat tibial implant [31]. implant rat tibial glassa 4 week in ult t showed which microscopy, leading via proven was mechanism respond, to begin cells then and layer, Colla surface. glass the with interact can moieties physi these After [32]). 3, (Fig. HCA form to layer the most successful materials to regenerate bone [2 regenerate to bone successful materials most the fie dental and orthopaedic the in applications many and differentiation. anddifferentiation. pr ionic released the of concentrations the slowly, SiO % wt 52 than more with to bond rapidly dissolve that glasses Only diagram. rep 2 Fig. that noted was it Thus, differentiation. respon cell of rates the to compared dissolution of
an amorphous SiO amorphous an of repolymerization and condensation (iii) groups; xhne f Na of exchange immerse glasses bioactive silicate based of surface The behavior of glasses of different compositional compositional different glassesof of The behavior Clark and Hench [31] first proposed a detailed sequ detailed a proposed first [31] Hench and Clark 4
Accepted Article with glass the in bridges Si O Si of hydrolysis by +
n Ca and 2 rich surface layer; (iv) migration of Caof migration (iv) layer; surface rich n CO and Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 2+ n h gas ih H with glass the in 2 bond to bone but not to soft tissue. For glasses t glasses For tissue. soft to not but bone to bond 3 2 rm h slto ad usqet rsalzto o crystallization subsequent and solution the from John Wiley& Sons,Inc. Figure 3 Figure3 7 + oducts are too low to promote cell proliferation proliferation cell promote to low too are oducts in solution; (ii) release of soluble silicate as as silicate soluble of release (ii) solution; in resents kinetic boundaries and is not a phase phase a not is and boundaries kinetic resents 2]. gen molecules are incorporated in the HCA HCA the in incorporated are molecules gen surface silanols with soluble silicate to form to silicate soluble with silanols surface ate (CaP) rich layer on the glass surface; (v) (v) surface; glass the on layer rich (CaP) ate lds. Even today it is considered to be one of of one be to considered is it today Even lds. soft tissue (Region E in Fig. 2) and glasses glasses and 2) Fig. in E (Region tissue soft ranges was explained on the basis of the rate rate of the basis the on explained rangeswas i smltd oy li (B) () rapid (i) (SBF): fluid body simulated in d ses such as attachment, proliferation and and proliferation attachment, as such ses ence of reactions occurring reactions of ence cal chemical reactions occur, biological biological occur, reactions cal chemical imately to bone growth. The bonding bonding The growth. bone to imately he interface between bone and bioactive bioactive and bone between interface he 2+ and POand the formation of surface silanol silanol surface of formation the 4 3 to the surface through the the through surfacethe to hat dissolve too too dissolve hat in vitro in te Ca P the f at the the at
phosphate (Ca phosphate silicate substitute as such substitutes, graft bone eff made have groups research some metabolism, bone j in occur reactions the which in glasses bioactive bone gla bioactive A Class elicited. response biological (i.e., are only osteoconductive). Note that these “ these that Note osteoconductive). only are (i.e., s more dissolve materials bioactive B class whereas ar (i.e., responses intracellular and extracellular However, synthetic HAP exhibits limited ability to to ability limited exhibits HAP synthetic However, bioceramics phosphate calcium in Silicate 3.2 BFig. 2. in Aand regions crystal size, and morphology of the bone mineral. I mineral. bone the of morphology and size, crystal by mineral bone of activity biological the in roles substit These [37]. levels wt%) 1 (< trace at occur K, Na,Mg, as such aselements aswell wt%, 8 to up minera bone in exist substitutions Various [36]. OH but compound, stoichiometric a not is bone in found tiss bone new for space creating in factor limiting does and insoluble relatively is HAP stoichiometric
The authors also defined two classes of bioactivity of classes two defined also authors The
Synthetic stoichiometric HAP has been utilized exte utilized been has HAP stoichiometric Synthetic n vivo in n rbi mdl te epne a tk svrl d several take may response the model; rabbit a in 3
(PO Accepted Article
4 ) 2 , TCP) , [39]. Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 8 A” and “B” classes are not to be confused with confused be to not are classes “B” and A” d HAP [38] and silicate substituted tricalcium tricalcium silicate substituted and [38] HAP d e both osteoconductive and osteoinductive), osteoinductive), and osteoconductive both e influencing the solubility, surface chemistry, chemistry, surface solubility, the influencing utions in the apatite structure play important important play structure apatite the in utions ue formation [35]. Additionally, the mineral mineral the Additionally, [35]. formation ue l, in particularly, carbonate anion is found at found is anion carbonate particularly, in l, Sr, Zn, Ba, Cu, Al, Fe, F, Cl, and Si that can can that Si and F, Cl, Fe, Al, Ba, Zn,Cu, Sr, nspired by the positive effects of silicate on on silicate of effects positive the by nspired form an osteoconductive bond with existing with bond osteoconductive an form lowly and elicit only extracellular responses responses extracellular only elicit and lowly based on the glass compositional range and and range compositional glass the on based not degrade significantly, which can be a a be can which significantly, degrade not exhibits variable deficiencies in Ca, P and P Ca, in deficiencies variable exhibits nsively as a skeletal replacement material. material. replacement skeletal a as nsively orts to develop silicate containing CaP as CaP silicate containing develop to orts sses dissolve rapidly and induce both both induce and rapidly dissolve sses s a e mnts 3] Moreover, [34]. minutes few a ust y [3 we cmae to compared when [33] ays Page 8of48 Page 9of48 crystal lattice (Fig. 4, [40, 41]). The amount of s of amount The 41]). [40, 4, (Fig. lattice crystal a comparative study, new bone formation was also ob also was formation bone new study, comparative a incorporati the with improved was significantly HAP sufficient to yield significant improvements in the in improvements significant yield to sufficient am small However, [42]. wt% 1.6 to 0.1 from ranging (Si HAP) HAP Silicate substituted 3.2.1 o pr HP 2. ± . %. diinly te perc %) 7.3 com ± (59.8 Si HAP forgreater significantly the Additionally, %). 6.5 ± (22.0 HAP pure for ± (37.5 Si HAP for ingrowth bone of percentage The granula wt%) (0.8 Si HAP and HAP both between space Moreover, [44]. cells osteoblast like human tran of expression the and proliferation osteoblast with agreement in also are findings These culture. pr cell the was higher the wt%), 1.6 to (up content proliferation cell in and n vitro in g phases apatite new of that to similar morphology, surf new a developed Si HAP contrast, In unchanged. sur the weeks, five for SBF in immersed were Si HAP
(3 (4,5 dimethylthiazol 2 yl) 2,5 diphenyltetrazoli me by determined was proliferation Cell [40]. (HOC) In Si HAP, silicate anions (SiO anions silicate Si HAP, In
Accepted non cytot is Si HAP that showed tests culture cell Article Journal ofBiomedicalMaterialsResearch:PartA in vitro in This article isprotected by copyright. All rights reserved. compared to pure HAP [43]. For example, when pure pure when example, For [43]. HAP pure to compared 4 4 ) substitute phosphate anions (PO anions phosphate substitute ) John Wiley& Sons,Inc. Figure 4 Figure4 in vivo in 9 ilicate is incorporated with only a limited values values limited a only with incorporated is ilicate sforming growth factor beta (TGF β) mRNA in in mRNA (TGF β) beta factor growth sforming um bromide) assay. The higher the silicate silicate the higher The assay. bromide) um studies indicated that the early bioactivity of of bioactivity early the that indicated studies formation of a new layer of hydroxyapatite hydroxyapatite of layer new a of formation rown on bioactive glasses [43]. Additionally, Additionally, [43]. glasses bioactive on rown oliferation from the first day to one week of of week one to day first the from oliferation pared to HAP (47.1 ± 3.6 %) [45]. %) 3.6 [45]. ± (47.1 paredHAP to the observed effect of zeolites in promoting promoting in zeolites of effect observed the on of silicate ions into the HAP structure. In structure. HAP the into ions of silicate on asuring the mitochondrial activity via MTT MTT via activity mitochondrial the asuring ace HAP phase with acicular and plate like plate like and acicular with phase HAP ace served directly on the surfaces and in the the in and surfaces the on directly served 5.9 %) was significantly greater than that that than greater significantly was %) 5.9 r implants in a white rabbit model [45]. model rabbit white a in implants r nae f oeipat oeae was coverage bone/implant of entage ounts (0.5 and 1 wt%) are apparently apparently are wt%) 1 and (0.5 ounts face of pure HAP remained almost almost remained HAP pure of face oxic to human osteosarcoma cells cells osteosarcoma human to oxic 4 3 ) directly in the apatite apatite the in directly ) HAP and and HAP
imtras ln o i cnucin ih biodegr a with conjunction in or alone biomaterials eas te SiO the because surface ions and the leaching process. Thus, SBF re SBF Thus, process. leaching the and ions surface high concent of microstructure porous that indicate wt% 8.1 of surface the on time same the in attained afte HAP by covered partially was Si α TCP wt% 2.23 ion silicate increasing an with increased Si α TCP stoichiom to compared degradation mediated cell and exhibit (Si α TCP) α TCP substituted Silicate [51]. omd ny t eprtrs ihr hn ,0 º. B ºC. 1,200 than higher temperatures at only formed
3.2.2 Silicate substituted TCP (Si TCP) (Si TCP) TCP Silicate substituted 3.2.2 factors of different sum asa beconsidered should Ther fact. this of consequence a be would formation SiO (XPS spectroscopy photoelectron X ray by confirmed bone implant the at layer HAP new the of deposition increas Si HAP the in boundary grain ordered less a HAP, pure to Compared [42]. size grain the decrease decrease could which site, hydroxyl the at disorder HAP [46]. The substitution of SiOof substitution The [46]. HAP rate dissolution higher the to due be may This HAP. Bone remodeling around the implant also occurred fa occurred also implant the around remodeling Bone TCP occurs as alpha (α TCP) and beta (β TCP) crysta (β TCP) beta and (α TCP) alpha as occurs TCP 4 4 Accepted Article SiO polymeric a in than rather group,
4 4
ru i peeetal sbtttd y PO by substituted preferentially is group Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 4 4 for POfor John Wiley& Sons,Inc. 4 3 in the HAP lattice yields tetrahedral distortion a distortion yields tetrahedral lattice HAP the in 2 om 5] Te rsne f SiO of presence The [50]. form 10 at different levels. levels. different at ed enhanced bone apposition, bone in growth bone apposition, bone enhanced ed substitution [53]. In particular, the surface of surface the particular, In [53]. substitution the stability of the apatite structure and also also and structure apatite the of stability the ached super saturation with respect to HAP HAP to respect with super saturation ached s of the Si HAP implants compared to pure pure to compared implants Si HAP the of s interface [46 49]. Furthermore, Si has been been has Si Furthermore, [46 49]. interface the smaller grain size and the formation of of formation the and size grain smaller the dbe oye, uh s oylclc acid polyglycolic as such polymer, adable Si α TCP. The results were interpreted to to interpreted were results The Si α TCP. efore, the mechanism of the silicate action action silicate the of mechanism the efore, es the solubility and affects the timing of of timing the affects and solubility the es ain iTP epd h dsouin of dissolution the helped Si TCP ration ) to exist as an isolated tetrahedral silicate, silicate, tetrahedral isolated an as exist to ) etric counterparts [52]. The bioactivity of of bioactivity The [52]. counterparts etric oth phases can be used as orthopaedic orthopaedic as used be can phases oth r one week, and complete coverage was was coverage complete and week, one r ster when silicate was incorporated into into incorporated was silicate when ster l polymorphs, and the α TCP phase is is phase α TCP the and polymorphs, l 4 3 Te faster The . 4 n vitro in 4 s important, is apatite apatite nd nd Page 10of48 Page 11of48 CaO and P and CaO 3.3 Bioactive silicate ceramics ceramics silicate Bioactive 3.3 applicatio non load bearing in defects bone filling ne te rd nm Actifuse name trade the under man are materials Si HAP Single phase applications.
Actifuse in a short time and accelerated the deposition of H of deposition the accelerated and time short a in formed a surface HAP layer, when immersed in SBF an SBF in immersed when layer, HAP surface a formed ht CaO SiO that SiO any adverse effects, such as inflammation. as inflammation. such effects, anyadverse imp the of None [55]. 5) (Fig. tissue bone lamellar replaced were and years 2 after resorbed completely scaffold the of 10–20% only that found authors The manufactured commercially by Millenium Biologix Cor Biologix Millenium by commercially manufactured compared to 3, 5 wt% Si TCP [54]. The result was al was result The [54]. Si TCP wt% 5 3, to compared f was bioactivity) greatest (the layer HAP thickest another long term term long another celldifferentia enhanced mesenchymal matrix the in with α TCP silicate doped 1% containing cement the It was long believed that in order to be bioactive, be to order in that believed long was It Currently, two different silicate substituted CaPs CaPs silicate substituted different two Currently, 2 did not form a HAP layer. This seemed to indicate indicate to seemed This layer. HAP a form not did TM 2 and Skeliteand O 5 2 , which are the main components of the HAP. However HAP. the of components main the are which ,
lse fe o P of free glasses Accepted Article
in vivo in TM Journal ofBiomedicalMaterialsResearch:PartA are both prepared in microporous scaffold and/or g and/or scaffold microporous in prepared both are This article isprotected by copyright. All rights reserved. study, the performance of Si TCP implant was inves was implant Si TCP of performance the study, TM 2 O S tblzd as opsd rmrl o Si α TCP of primarily composed CaPs Si stabilized . 5 s el s hs cnann vr sal mut of amounts small very containing those as well as John Wiley& Sons,Inc. Figure 5 Figure5 11 ns. ns. glasses and glass ceramics must contain both both contain must glass ceramics and glasses AP [53]. In contrast, Camire Camire contrast, In [53]. AP lanted bioceramics were reported to produce produce to reported were bioceramics lanted tion and osteoblast activity in rabbits [54]. In [54]. rabbits in activity and osteoblast tion ormed on the surface of 1 wt% Si TCP, Si TCP, wt% 1 of surface the on ormed pure α TCP indicated that silicate presence presence silicate that indicated α TCP pure remained after 1 year. The scaffolds were were scaffolds The year. 1 after remained so supported by by supported so fcue cmecal b Aaeh Ltd. Apatech by commercially ufactured d interestingly, CaO P interestingly, d poration under the trade name Skelitename trade the under poration are used in clinical bone substitute substitute bone clinical in used are that bioactive materials can be obtained obtained be can materials bioactive that by newly formed highly mineralized highly mineralized newly formed by , Ohura Ohura , in vivo in ranules intended for for intended ranules et alet study. Comparing Comparing study. 2 O tigated in sheep. sheep. in tigated 5 et alet . [56] observed [56] . glasses free of of free glasses . found the the found . P are are 2 O TM 5 . . ,
bonds much more susceptible to hydrolysis than the the than hydrolysis to susceptible more much bonds bioactivity. bioactivity. ih tan soitd ih h S i od angles bond Si O Si the with associated strain high these observations, some silicate ceramics such as as such ceramics silicate some observations, these chains. This results in the greater solubility and and solubility greater the in results This chains. polymorph) temperature high a (pseudowollastonite, SBF CaSiO
ikd o om iiae his Fg 6. h silica The 6). (Fig. chains silicate form to linked CaSiO with compositions based on the CaO SiO the on based compositions with CaSiO whi structures, crystal different but stoichiometry “silicate 3 rings”, whereas α CaSiO whereas 3 rings”, “silicate ale tm pit fr β CaSiO for points time earlier elcmn. h to oyops f CaSiO of polymorphs two The replacement. ih h slct rns n can rsetvl, is respectively, chains and rings silicate the with bioactive in sites defect “3 rings” the to similar temperature polymorph). Both CaSiOBoth polymorph). temperature 3.3.1 CaSiO 3.3.1 eosrtd ht h to CaSiO two the that demonstrated n h 19s e z ad owres eosrtd the demonstrated co workers and Aza De 1990s the In n vitro in 3 3 3 tre iiae erhda r cvlnl bne v bonded covalently are tetrahedra silicate three , in cell culture medium [68]. Soluble silicate conc silicate Soluble [68]. medium culture cell in of kinetics the studied we group, our In 67]. [66, 3
Accepted Article bone living to bond and Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 3 hn o α CaSiO for than 3 John Wiley& Sons,Inc. is made up of corner sharing silicate tetrahedral tetrahedral silicate corner sharing of up made is 3 3 phases are promising candidate materials for bone bone for materials candidate promising are phases phases can form a surface HAP layer after exposure after layer HAP surface a form can phases n viv in 2 system rather than on CaO P on than rather system o [57 63]. Subsequently, numerous other studies studies other numerous Subsequently, [57 63]. o 12 glasses [64, 65]. The negative charge associated associated charge negative The 65]. [64, glasses 3 ae dnia ceia cmoiin and composition chemical identical have ch can affect their bioactive properties. In β In properties. bioactive their affect can ch lcrsaial blne b Ca by balanced electrostatically islto rt o β CaSiO of rate dissolution e 3rns srcue on i β CaSiO in found structure “3 rings” te 3 CaSiO n h “ ig” f β CaSiO of “3 rings” the in more stable Si O Si bonds in the α CaSiO the in bonds Si O Si stable more , consistent with the higher solubility and and solubility higher the with consistent , n α CaSiOand entrations peaked at higher levels and levels higher at peaked entrations 3 islto o te β CaSiO the of dissolution have been tested for their potential potential their for tested been have a onrsaig xgn t form to oxygens corner sharing ia iatvt o β CaSiO of bioactivity 2 3 O wlatnt, low a (wollastonite, 5 . Taking into account account into Taking . 3 oprd o α to compared 3 ae these makes 2+ os The ions. covalently covalently 3 n α and 3 to to is 3 3
Page 12of48 Page 13of48 but cell proliferation increased once lower steady lower once increased proliferation cell but bone with lamellar structure similar to native bone native to similar structure lamellar with bone
the bone in contact with the surface of the β CaSiO the of surface the with contact in bone the direct contact with the β CaSiO the with contact direct observ Histological [71]. tibias rat into implanted reasonβ CaSiO that versus structure three ring the of rate dissolution cytotoxic. In our Inour cytotoxic. demonst experiments These evaluated. been have [70] were achieved [67, 68]. 68]. [67, achieved were nefc [1 7] T ipoe h osteointegration the improve To 72]. [71, interface caus has this cases, multiple In unchanged. remains only place take usually materials these and tissue released from β CaSiOfrom released 3.3.2 Silicate ceramic composites composites ceramic Silicate 3.3.2 growing interface. the at wasstill tahet n is blt t afc otols beh osteoblast affect to ability its and attachment implants). When bioactive materials are implanted implanted are materials bioactive When implants). osteointe implant is problems outstanding important n vivoIn The cytotoxicity of β CaSiO of cytotoxicity The Despite the success of various silicate based mater silicate based various of success the Despite
Accepted smal which in conducted been also have experiments Article
in vitro in
3 is more bioactive than α CaSiO than more bioactive is 3 is initially cytotoxic towards human mesenchymal s mesenchymal human towards cytotoxic initially is Journal ofBiomedicalMaterialsResearch:PartA experiments, we found that a high concentration of concentration high a that found we experiments, This article isprotected by copyright. All rights reserved. 3 3 [69], and the suitability of the material as a sub a as material the of suitability the and [69], implants after only 3 weeks. After twelve weeks im weeks twelve After weeks. 3 only after implants John Wiley& Sons,Inc. Figure 6 Figure6 13 the chain silicate structure, which may be the the be may which structure, silicate chain the on their surfaces, while the bulk of the material material the of bulk the while surfaces, their on state soluble silicate concentrations (~ 80 ppm) ppm) 80 (~ concentrations silicate soluble state ations showed the new bone was growing in in growing was bone new the showed ations avior at a distance from the material surface surface material the from distance a at avior . At twelve weeks of implantation, new bone bone new implantation, of weeks twelve At . ed a harmful shear stress at the bone implant the at stress shear harmful a ed 3 , the scaffold must have a high degree of of degree high a have must scaffold the , n vivo in 3 ials for bone replacement, one of the most most the of one replacement, bone for ials . appeared to be progressively replaced by by replaced progressively be to appeared rated that β CaSiO that rated gration (ingrowth of new bone into the the into bone new of (ingrowth gration , the interactions between the bone bone the between interactions the , clnes f β CaSiO of cylinders l 3 were not significantly significantly not were silicate (> 120 ppm) ppm) 120 (> silicate tem cells (hMSCs), (hMSCs), cells tem stratum for cell for stratum plantation 3 were were
pseudomorphic transformation of α TCP into apatite apatite into of α TCP transformation pseudomorphic phosphate of the SBF, leading to the precipitation precipitation the to leading SBF, the of phosphate porosity [73]. However, ceramics and bioactive glas bioactive and ceramics However, [73]. porosity according to the reaction: reaction: accordingthe to Bioeutectic n B [3. hn h β CaSiO the When [63]. SBF in
eeoig pru HPlk structure HAP like porous a developing eetd o Ca for detected s the into and interface the from away solution SBF exchange of two H two of exchange ceramics as synthetic bone scaffolds [29, 74]. 74]. [29, scaffolds bone assynthetic ceramics drawback This ceramics. of brittleness inherent the fo inadequate are properties mechanical macroscopic ec wt te Ca the with react following Immediately 8.9. to increase to interface laye silica amorphous surface a of formation the in eeoe t ades hs ocr. Bioeutectic concern. this address to developed The silicate and excess Ca excess and silicate The A wide variety of ceramic ceramic, ceramic polymer ceramic polymer ceramic ceramic, of variety wide A ®
Accepted Articleβ CaSiO bioactive of consists 2+
ocnrto i slto. o ot f h Ca the of most So solution. in concentration + 2+ from the SBF for one Ca one for SBF the from 6HPO n OH and Journal ofBiomedicalMaterialsResearch:PartA 3Ca This article isprotected by copyright. All rights reserved. 4 2 3 + 10Ca 2+ (PO , which were not involved in the reaction, migrated reaction, the in involved not were which , os rsn i te ofnd hnes 6] A a r a As [63]. channels confined the in present ions 4 3 ) via reacted it SBF, the with contact in came phase 2 + Ca John Wiley& Sons,Inc. 2+ + 8OH 2+ n situ in 3 +2OH and resorbable α TCP, and presents a high reactivi high a presents and α TCP, resorbable and 2+ Ca 14 from β CaSiOfrom ® when they are implanted into a living body. body. living a into implanted are they when is one such composite, which is capable of of capable is which composite, such one is Ca r and also caused the pH at the material/SBF material/SBF the at pH the caused also and r hs ecin te C lmla satd to started lamellae TCP the reaction, this occurred according to the reaction: reaction: the to occurredaccording olution. However, a large increase was not not was increase large a However, olution. 10 ses are formed as porous scaffolds, so the the so scaffolds, porous as formed are ses seriously limits the clinical relevance of of relevance clinical the limits seriously laigbaig plctos eas of because applications loading bearing r of HAP on the surface of the material material the of surface the on HAP of (PO and glass ceramic composites have been been have composites glass ceramic and 10 4 (PO ) 6 (OH) 3 4 (Fig. 7a). This exchange resulted resulted exchange This 7a). (Fig. ) 6 2+ (OH) 2 must have reacted with the the with reacted have must + 6H 2
2 O through the the through esult, a a esult, an ion ion an ty ty Page 14of48 Page 15of48 thermo gravimetric analyses (TGA) and Nand (TGA) analyses thermo gravimetric concentration Si OH The factor. important an be to HAP for sites nucleation as act may groups silanol prope structural and textural compositional, the of mesopo three the of behaviors different The MCM 41. M for required were days 60 while SBF, in immersion dev SBA 15 8). (Fig. 78] [77, MCM 41 and materi Materials) type Amorphous Barbara (Santa SBA 15 as such h studies Bioactivity [77]. regeneration tissue for sil surface inner and nm 2 90 of range the in sizes quartz or glasses silica dense on not but SBF, with
3.4 Bioactive porous silica silica Bioactive 3.4 porous of bone. replacement o cnetain f iao gop ( groups silanol of concentration low areas with the bone [75]. Thus, Bioeutectic Thus, [75]. bone the with areas inte the towards migrated osteoblasts The implants. mineralized fully new a showed results The tibiae. spectroscopy (Fig. 7b). 7b). spectroscopy(Fig. by detected as P, in decrease a and Ca, in increase In 1992, Li 1992, In For i increase large a in resulted reaction overall The in vivo in studies, Bioeutectic studies,
Acceptedalet Article
. reported the formation of HAP on silica gels when gels silica on HAP of formation the reported . Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. ® implants were inserted into the critical size defe size critical the into inserted were implants John Wiley& Sons,Inc. ca 22 ml iH m SiOH mmol 2.2 . 2 adsorption measurements. MCM 41 showed a rather rather a showed MCM 41 measurements. adsorption Figure 7 Figure7 ® ceramic could be satisfactorily used for repair or repair for used satisfactorily be could ceramic 15 ave been carried out on porous silica materials, materials, silica porous on out carried been ave anol, have been shown as bioactive materials bioactive as shown been have anol, inductively coupled plasma atomic emission emission plasma atomic coupled inductively rface and colonized the surface at the contact contact the at surface the colonized and rface layer. The silanol group concentration seems seems concentration group silanol The layer. te. s led mnind bv, surface above, mentioned already As rties. [76]. The mesoporous silica, having pore pore having silica, mesoporous The [76]. CM 48, a HAP layer did not form at all on on all at form not did layer HAP a CM 48, rous materials were explained on the basis the on explained were materials rous bone growing in direct contact with the the with contact direct in growing bone per unit surface area was determined by by determined was area surface unit per n Si concentration in the SBF, a small small a SBF, the in concentration Si n eloped a HAP layer after 30 days days 30 after layer HAP a eloped 2 al), MCM 48 (Mobil Crystalline Crystalline (Mobil MCM 48 al), cmae t SA1 ( SBA 15 to compared ) the gels were in contact contact in were gels the cts of rabbits’ rabbits’ of cts ca. 12.7 12.7
erdd atr hn arsae i ( Si macroscale than faster degraded mmol SiOH m SiOH mmol could degrade. The experiments showed that freshly that showed experiments The degrade. could wh wafer, Si polished Unlike [79]. Si bulk of areas top on growth HAP induce could film Si microporous 3.5 Bioactive porous silicon silicon Bioactive 3.5 porous hs rsls rvd ht i hdae, i tef c itself Si hydrated, if that, proved results These both with devices microscale for appealing it make surface to vol large a has which MacPSi, especially an differentiation growth, osteoblast supporting in an MesPSi than better performed MacPSi Furthermore, HAP nucleation kinetics on SBA 15 compared to MCM 4 to SBA 15 compared on kinetics nucleation HAP may which nm), (3.6 MCM 41 and nm) (3.6 MCM 48 with showed SBA 15 nucleation. HAP faster and diffusion bigge Usually, account. into taken also were silica textural The MCM 41. in bioactivity of absence the [82], Si wafers can be rendered highly bioactive. bioactive. highly rendered be can wafers Si [82], electrochemical or [79] (nano etching) wet etching hemo poor has it because [80] polymers and ceramics promis a considered been never has Si semiconductor microstructur suitable with layers poly Si hydrated irpru S isl hs en hw t b bioactiv be to shown been has itself Si Microporous
Accepted Article 2 ) and MCM 48 ( MCM 48 and ) Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. ca . 12.9 mmol SiOH m SiOH mmol 12.9 . John Wiley& Sons,Inc. ca . 1 µm, MacPSi) in cell culture medium [82]. [82]. medium culture cell in MacPSi) µm, 1 . Figure 8 Figure8 16 ould become an important tissue compatible tissue compatible important an become ould PSi, summary, In function. their sustaining d ich do not degrade in cell medium, porous Si porous medium, cell in degrade not do ich etching techniques in HF based electrolytes electrolytes HF based in techniques etching ad oe cesbe oe wl fvr ion favor will pores accessible more and r and structural properties of the mesoporous the of properties structural and ume ratio and flexible surface chemistry, chemistry, surface flexible and ratio ume etched mesoscale Si ( Si mesoscale etched compatibility [81]. However, with simple simple with However, [81]. compatibility e induced HAP deposits. However, the the However, deposits. HAP induced e of the porous Si and even on neighboring neighboring on even and Si porous the of drug delivery and scaffolding functions. functions. scaffolding and drug delivery Si) porous nanoscale nm, 15 (< NanPSi d the largest pore size (8.8 nm) compared nm) (8.8 size pore largest the n vitroIn ing biomaterial compared to numerous numerous to compared biomaterial ing 2 e [79]. Similar to bioactive ceramics, ceramics, bioactive to Similar [79]. e 8 and MCM 41. and MCM 41. 8 ). This could be one reason to explain explain to reason one be could This ). have been responsible for the faster faster the for responsible been have studies in SBF showed that that showed SBF in studies ca . 50 nm, MesPSi) MesPSi) nm, 50 . Page 16of48 Page 17of48 biomaterial, and could potentially have widespread widespread have potentially could and biomaterial, hntp [, 58] Smlry te islto pr dissolution the Similarly, 85 87]. [2, phenotype differentiation the ultimately, and, proliferation etr ilgcl rpris n oe ise enginee tissue bone in properties biological better concentration range of silicate and Caand silicate of range concentration control ultimately, and, cells precursor osteogenic
(cell proliferation and differentiation). The inorg The differentiation). and proliferation (cell mater silicate of bone) to bonds that layer surface etc or at least silanol surface sites. So the apparent the So sites. surface silanol orleast at resul hydration the that note However, engineering. cells (Table 1). These genes encode transcription o transcription encode genes These 1). (Table cells up or activate could products dissolution these of changes at the surface that eventually lead to a ch a lead to eventually that changessurface the at materials the in Si of presence the that a suggested discussion and reports the on Based counterparts. 4. The controversial roles of silicate silicate of roles controversial The 4. Therefore, an “active role” was claimed that silica that claimed was role” an“active Therefore, form the influence also and process, resorption the proliferation osteoblast on effects dose dependent h sinii cmuiy iey cet te stateme the accepts widely community scientific the Yet, the role of silicate may go beyond the simple simple the beyond go may silicate of role the Yet, After almost 50 years of development of silicate ba of development of years 50 almost After
Acceptedproven been have glasses bioactive from released .) Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 2+ [2]. Xynos Xynos [2]. bioactivity of Si is most likely related to silica. to likely related most is of Si bioactivity 17 anic dissolution products (Si(OH) products dissolution anic ange of the biological response [83]. [83]. response angeof biological the ials and may include influences on cell activity activity cell on influences include may and ials te can affect bone cell metabolism [5]. [5]. metabolism cell bone cante affect regulate seven families of genes in osteogenic osteogenic in genes of families seven regulate f numerous proteins that control the cell cycle, cell the control that proteins fnumerous ts in the formation of a surface layer of silica silica of layer surface a of formation the in ts and differentiation, osteoclast formation and formation osteoclast differentiation, and oducts from Si TCP were reported to have have to reported were Si TCP from oducts cell differentiation [84, 85] at a specific specific a at 85] [84, differentiation cell et al.et of cells towards the mature osteoblastic osteoblastic mature the towards cells of cause chemical, physical, or topographical topographical or physical, chemical, cause to o te xrclua mti [2 88]. [52, matrix extracellular the of ation osteoconductivity (the ability to form HAP HAP form to ability (the osteoconductivity t ta slct usiue mtras have materials silicate substituted that nts sed biomaterials as orthopaedic implants, implants, orthopaedic as biomaterials sed to influence and control the cell cycle of of cycle cell the control and influence to applications in biomedicine and tissue tissue and biomedicine in applications bove, a passive mechanism has been been has mechanism passive a bove, ring compared to their silicate free silicate free their to compared ring discovered that critical concentrations concentrations critical that discovered 4 , Ca , 2+ , PO,
4 3 ,
basal diet may all have contributed to the inter ex the to contributed have all may diet basal ae o te islto pout o bocie glas bioactive of products dissolution the on based which suggested a structural role (stabilization of (stabilization role structural a suggested which tr mRNA increasing by production I Col increased in Increasing concentrations of H of concentrations Increasing
enhance the dissolution of CaP and whether silicate whether and CaP of dissolution the enhance [83] review critical a in Therefore, studies. these s for required silicate levels the or concentrations bone long weight bearing a in resorption material animals, Si source and route of administration, as as administration, of route and source Si animals, the of duration as such conditions, experimental in S by and [15] Carlisle by reported results dramatic growi in silicate of essentiality the investigating dissolved only than rather solution multicomponent natural bone mineralization might bemight over evaluated naturalmineralization bone times less Ca less times also been doubted because most of the arguments to to arguments the of most because doubted been also sili of roles the Furthermore, level. therapeutic a demonstrated not to dissolve dissolve to not demonstrated (H oee, oe rus ae hlegd hs concepts these challenged have groups some However, To address these concerns, Reffitt Reffitt concerns, these address To 4 SiO 4 ) addition to MG63 osteosarcoma cells increased col increased cells osteosarcoma MG63 to addition )
Accepted Article2+ and 100 times less phosphate ions than in serum [8 serum in than ions phosphate less times 100 and Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. in vitro in 4 SiO 4 (0 50 µM) in primary human osteoblast cells also r also cells osteoblast human primary in µM) (0 50 John Wiley& Sons,Inc. et alet during more than two weeks in a solution containin solution a in weeks two than more during . [96] showed that 10 µM and 20 µM orthosilicic aci orthosilicic µM 20 and µM 10 that showed [96] . Table 1 Table1 18 therapeutic effects were not determined in any of in determined not were effects therapeutic cate to activate or up regulate genes in cells had had cells in genes up regulate or activate to cate ng animals [90 94] have failed to reproduce the the reproduce to failed have [90 94] animals ng perimental variance [95], the role of silicate in in silicate of role the [95], variance perimental collagen) or a metabolic role (a co factor for for co factor (a role metabolic a or collagen) well as overall nutritional compositions of the the of compositions nutritional overall as well chwarz and Milne [18]. Although differences differences Although [18]. Milne and chwarz in Si CaPs can be released released be can Si CaPs in . . experiment, age, gender and species of the the of species and gender age, experiment, , it was questioned whether silicate could could silicate whether questioned was it , anscription or mRNA stabilization [97, 98], [97, stabilization mRNA or anscription silicate. Moreover, some recent studies studies recent some Moreover, silicate. support the active roles of silicate were were silicate of roles active the support heep model [55], but silicate release release silicate but [55], model heep ses/ceramics, which result in a a in result which ses/ceramics, lagen type I (Col I) levels 1.75 fold. 1.75 fold. I)levels (Col I type lagen . In one study, Si HAP was was Si HAP study, one In . 9]. An 9]. in vivo in in vivo in study showed showed study and attain attain and esulted esulted g 10 10 g d Page 18of48 Page 19of48 atce my ed o ey ifrn physicochemica different very to lead may particles process (Fig. 9) is stimulatory to osteoblast diffe osteoblast to stimulatory is 9) (Fig. process prolyl hydroxylase) for silicate [95]. H [95]. silicate for hydroxylase) prolyl inhibition of osteoclastogenesis of RAW264.7 pre os RAW264.7 of osteoclastogenesis of inhibition system, co culture chamber Boyden a using By (OPG). to reported was sponges, in skeleton siliceous the outcomes. biological positive these for responsible silicate not that possible is it Therefore, [106]. hexagonal silica nanoparticles with size about 100 100 about size with nanoparticles silica hexagonal
resorption resorption [101] differentiation and proliferation, activity, repo been has silicate soluble Recently, 100]. [99, o of indicators are which phosphatase, alkaline and roles of silicate. ofroles silicate. authors recognized, subtle changes in charge, shape charge, in changes subtle recognized, authors tmlts uohgsm asml [0] Atog s Although [105]. assembly autophagosome stimulates kinase protein activated mitogen the of stimulation caveo a through cells the enter could nanoparticles osteoclasti promote but formation bone osteoblastic (NF κB), cells B activated of light chain enhancer anta can diameter) in nm (50 nanoparticle silica of di osteoblast on effects stimulatory potent mediate oe eety slc (SiO silica recently, More
Accepted Articlevitro in
[102]. However, none of these studies attempted to attempted studies these of none However, [102]. Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 2 nnprils 13 ad aoltlt [0] were [104] nanoplatelets and [103] nanoparticles ) John Wiley& Sons,Inc. 4 SiO 4 also increased the gene expression of osteocalcin osteocalcin of expression gene the increased also 19 rted to enhance the human osteoblast metabolic metabolic osteoblast human the enhance to rted rentiation and mineralization. However, as the the as However, mineralization. and rentiation fferentiation. It was shown that a specific size size specific a that shown was It fferentiation. u, h nn ie sld atce cud be could particles solid nano sized the but, gonize the activation of nuclear factor kappa factor nuclear of activation the gonize a signal transduction pathway that can inhibit inhibit can that pathway transduction signal a nm did not show any bioactive effect effect bioactive any show not did nm , size, and/or surface chemistry of these silica silica these of chemistry surface and/or size, , and inhibit osteoclast formation and bone bone and formation osteoclast inhibit and lae mediated endocytosis, which triggers the the triggers which endocytosis, lae mediated Biosilica, the inorganic scaffold that forms forms that scaffold inorganic the Biosilica, steogenic differentiation and mineralization mineralization and differentiation steogenic (MAPK) ERK1/2 (p44/p42) pathway and and pathway (p44/p42) ERK1/2 (MAPK) teoclasts was due to the increased level of of level increased the to due was teoclasts induce the expression of osteoprotegerin osteoprotegerin of expression the induce rsoss f el [0] Fr example, For [103]. cells of responses l some research groups concluded that the the that concluded groups research some c bone resorption [103]. These silica silica These [103]. resorption bone c till not completely understood, this this understood, completely not till determine the mechanistic mechanistic the determine shown to to shown in vitro in
proliferation of hMSCs and mHSCs in normal growth m growth normal in mHSCs and hMSCs of proliferation eo 2 M S eit peoiaty s ooei Si monomeric as predominantly exists Si mM, 2 below osteoclast formation by antagonizing NF κB signalin NF κB antagonizing by formation osteoclast for mechanism a acti established studies our Therefore, RANKL) induced (or TNFα decrease to shown were
sebat, hra Si(OH) whereas osteoblasts, su anti miR 146a by function miR 146a of Inhibition osteoclast differentiation (Fig. 10, [107]). [107]). (Fig. 10, differentiation osteoclast c which OPG, by bound be may (RANKL) ligand kappa B silic to exposure after osteoblasts by released OPG ground breaking studies are showing that silicate n silicate that showing are studies ground breaking behavior cell affecting in size) nm Si(OH) M 19. eo ti cnetain or tde sho studies our concentration, this Below [109]. mM p to polymerize to tendency the has but pH, neutral os hmtpitc tm el (HC) 18. t th At [108]. (mHSCs) cells stem hematopoietic mouse (hM cells stem mesenchymal human of differentiation microRNA 146a (miR 146a) was significantly up regul significantly was (miR 146a) microRNA 146a analys microarray microRNA differential [108]. mechanisms, differentiation osteoclast repressing while specific gene transcription and protein expression. protein and transcription gene specific The above discussion suggests an active role for di for role active an suggests discussion above The s of effects the investigated have we group, our In 4
Acceptedpr by resorption bone and formation bone regulated Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 4 ramn cutrce ti ihbto ad promote and inhibition this counteracted treatment John Wiley& Sons,Inc. n vitro in by specific molecular biology pathways These These pathways biology molecular specific by 20 Furthermore, both miRNA 146a and Si(OH)and miRNA 146a both Furthermore, ot only promotes osteogenic differentiation of of differentiation osteogenic promotes only ot silicate to promote osteogenesis and suppress and osteogenesis promote to silicate ate. The receptor activator of nuclear factor factor nuclear of activator receptor The ate. olysilicate at Si concentration above ~ 2 3 3 2 ~ above concentration Si at olysilicate g via miR 146a (Figure 11). 11). (Figure gmiR 146a via ssolved silicate and silica nanoparticles (50 (50 nanoparticles silica and silicate ssolved ppressed osteogenic differentiation of pre of differentiation osteogenic ppressed e ta slbe Si(OH) soluble that wed To elucidate the possible molecular molecular possible the elucidate To ated in bone cells treated with Si(OH) with treated cells bone in ated SCs) and osteoclastic differentiation of of differentiation osteoclastic and SCs) edium. More interestingly, we found the the found we interestingly, More edium. e physiological pH and concentrations concentrations and pH physiological e es were applied. Results showed that that showed Results applied. were es (OH) an abolish RANKL function to inhibit inhibit to function RANKL abolish an oluble silicic acid on osteogenic osteogenic on acid silicic oluble omoting osteoblastic gene program program gene osteoblastic omoting vation of NF κB in bone cells. cells. bone in NF κB of vation 4 Ti Si(OH) This . 4 s nhre at uncharged is 4 stimulates the the stimulates osteoblast d 4 4 . .
Page 20of48 Page 21of48 presence of other dissolved ions along with silicat with along ions dissolved other of presence
upeet o ra otoooi, dsae hc r which disease a osteoporosis, treat to supplement exampl For drug. a like acts silicate soluble which but substitutes graft bone as simply not considered biomateria silicate based Thus, [102 105]. activity differentiat osteoclastic suppresses also but hMSCs Funds. Biomaterials St the and Funds “Start Up” Akron of University the Acknowledgements: size. nanoparticlesof specific active an for evidence of body growing a to adding of results The etc. biomateirals silica containing dose effe surfaces, biomaterial solid of effect the co experimental in differences of because mechanism ex effect an whether resolving in arose Controversy Summary 5. women in common is which and resorption, formation The effect of silicate on bone formation has long b long has formation bone on silicate of effect The
Accepted Article N.S. gratefully acknowledges financial support by by support financial acknowledges gratefully N.S. Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. Figure 11 Figure11 Figure10 Figure 9 Figure9 21 cts of dissolved silicate released from various various from released silicate dissolved of cts e, the effects of truly dissolved silicate versus versus silicate dissolved truly of effects the e, ion of mHSCs and osteoclast bone resorption resorption bone osteoclast and mHSCs of ion more carefully designed recent studies are are studies recent carefully designed more een recognized and debated in the literature. the in debated and recognized een r, fetvl, rg eiey ytm in systems delivery drug effectively, are, ate of Ohio for the Ohio Research Scholar Research Ohio the for Ohio of ate , Si(OH)e, esults due to an imbalance between bone bone between imbalance an to due esults ists and, if so, is it by a passive or active active or passive a by it is so, if and, ists s ht ees slbe iiae a be can silicate soluble release that ls after menopause and older men [21, 95]. 95]. [21, oldermen and aftermenopause role of dissolved silicate and solid silica silica solid and silicate dissolved of role nditions, cell types and animal models, models, animal and types cell nditions, 4 could be used as a nutritional nutritional a as used be could NSF DMR 0906817, 0906817, DMR NSF
acids, and muhicarboxylic acids: potential role in in Acta 2004;68:227 37. Cosmochim role potential acids: muhicarboxylic and acids, sil of shifts NMR 29Si of Calculation N. Sahai [12] Soil in Metals of Heavy Reactivity andHydrological E the in Interactions Silicon Organic N. Sahai [11] Relat Inorg2002;41:748 56. Chem Synthesis. and Shifts Ro NMR Complexes: Silicon−Polyalcohol 29Si Hypercoordinated JA. Tossell N, Sahai [10] 53. biomineralizati silica in complexes serine silicate NMR and energies Formation JA. Tossell N, Sahai [9] 2006;44:48 55. elements chemical of Abundances A. Yaroshevsky [8] 1959;238:789. of Dynamics Chemical The MW. Newman WF, Newman [7] Geochem2006;64:283 313. O for Biomaterials Silicate N. Sahai M, Cerruti [6] Nutr J andhealth. bone Silicon R. Jugdaohsingh [5] Biomedical LL, Hench Third Generation JM. Polak [4] engineering.Scienc Langer Tissue J. Vacanti R, [3] J glass. LL.Hench of bioactive design Genetic [2] 2009;25:1 Prog Biotechnol strategies. drugdelivery engi tissue Bone KC. Popat TT, Ruckh JR, Porter [1] Reference
Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 22 on. Geochim Cosmochim Acta 2001;65:2043 Acta Cosmochim Geochim on. Eur Ceram Soc 2009;29:1257 65. 2009;29:1257 65. EurSoc Ceram e 1993;260:920 6. e1993;260:920 6. rthopaedic and Dental Implants. Rev Mineral Mineral Rev Implants. Dental and rthopaedic Health Aging 2007;11:99 110. 2007;11:99 110. Aging Health 539 60. 539 60. nvironment and in Organisms. Geochemical Geochemical Organisms. in and nvironment s: CRC Press; 2003. Press; CRC s: icate complexes with carbohydrates, amino amino carbohydrates, with complexes icate neering: a review in bone biomimetics and and biomimetics bone in review a neering: Materials. Science 2002;295:1014 7. 2002;295:1014 7. Science Materials. chemical shifts calculated for putative putative for calculated shifts chemical biological silica utilization. Geochim Geochim utilization. silica biological le in Sol−Gel and Biogenic Silica Silica Biogenic and Sol−Gel in le n h Erhs rs. ece Int Geochem crust. Earth’s the in v Saiiis acltd for Calculated Stabilities ive oe iea. m Md Sci Med J Am Mineral. Bone Page 22of48 Page 23of48 bioactivity of CaO–MgO–SiO2 P2O5 sol gel glasses.pd sol gel of CaO–MgO–SiO2 P2O5 bioactivity
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Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 28 silicate minerals. Nature 1993;366:253 6. 1993;366:253 6. Nature minerals. silicate ence of pseudowollastonite ceramic. J Biomed J ceramic. pseudowollastonite of ence 2013;1:1101 10. 2013;1:1101 10. ter Sci: Mater Med 2003;14:33 8. Mater 2003;14:33 8. Med terSci: terfaces. Biomaterials 2005;26:5763 70. 2005;26:5763 70. Biomaterials terfaces. mics: Past, present and for the future. J Eur J future. the for and present Past, mics: 4322 41. 4322 41. oceramic materials. Bol Soc Esp Ceram V Ceram Esp Soc Bol materials. oceramic ferentiation of human mesenchymal stem stem mesenchymal human of ferentiation Aaie C5P43H Nceto at Nucleation (Ca5(PO4)3OH) Apatite f and stereochemical match for apatite apatite for match stereochemical and Sahai N. Effects of pseudowollastonite pseudowollastonite of Effects N. Sahai esenchymal stem cells. Biomaterials Biomaterials cells. stem esenchymal e Aza PN, De Aza S, et al. In vitro vitro In al. et S, Aza De PN, Aza e z S Shedr J e a. Indirect al. et YJ, Schneider S, Aza WL, Sahai N. Crystal structures of of structures Crystal N. Sahai WL, terial scaffolds and osteogenesis. osteogenesis. and scaffolds terial , Arnold GW. Leaching and and Leaching GW. Arnold , Page 28of48 Page 29of48 polymer/inorganic composite scaffolds for bone tiss bone for scaffolds composite polymer/inorganic based ordered mesoporous materials: medical applica medical materials: mesoporous basedordered
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Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 29 Am Ceram Soc 1992;75:2094 7. 1992;75:2094 7. Soc Ceram Am ue engineering. Biomaterials 2006;27:3413 Biomaterials engineering. ue er 2007;19:921 4. er2007;19:921 4. Mater Chem 2006;16:26 31. J tions. tion through nanoetching techniques. Adv Adv techniques. nanoetching through tion . . aterials. Solid State Sci 2005;7:983 9. 2005;7:983 9. Sci State aterials.Solid a I, Gonzalez Calbet JM. Revisiting silica Revisiting JM. Gonzalez Calbet I, a . Bioeutectic® Ceramics for Biomedical Biomedical for Ceramics Bioeutectic® . , Nakamura T, et al. Apatite Formation Formation Apatite al. et T, Nakamura , , González Calbet JM, Vallet Regí M. M. Vallet Regí JM, González Calbet , ano to Microscale Porous Silicon as a as Silicon Porous Microscale to ano oeia Ipat plctos Ann Applications. Implant iomedical es – A critical view. Biomaterials Biomaterials view. critical A – es iodegradable and bioactive porous porous bioactive and iodegradable In vivo Evaluation. Materials Materials Evaluation. vivo In archant R, Desai T, et al. al. et T, Desai R, archant
tmlts sebat unvr n ehne bn fo bone enhances and turnover osteoblast stimulates LD, Buttery JJ, Batten MVJ, Hukkanen ID, Xynos [85] 2000;3:313 23. Innovations MaterRes Bio LDK. Buttery ID, Xynos JM, Polak LL, Hench [84] Elem Res 1994;42:151 64. 1994;42:151 64. Res Elem and germanium of Effects F. Nielsen C, Seaborn [93] Res Trace Elem Biol diets. fedturkeyssemipurified bioavailability Silicon X. Jia H, Kayongo Male [92] 1991;70:1390 402. Sci Poult Chickens. Dietary of Effects Some HM. EDWARDS MA, ELLIOT [91] 1991;121:201 7. Nutr chickens.J silic dietary of Effect HM. Edwards MA, Elliot [90] v In A2003;66A:364 MaterBiomed Res J hydroxyapatites. M. Vallet Regí J, Pérez Pariente F, Balas [89] biocer Si TCP in silicon 2004 Queen’s University of Kingston: characterization. role The A. Pietak [88] 2001;55:151 7. MaterBiomed Res ioni the with treatment following osteoblasts human Pol LL, Hench LDK, Buttery AJ, Edgar ID, Xynos [87] B Biochem Synthesis. and Protein Expression IImRNA Osteobl Human of Proliferation Increase Dissolution Pol LL, Hench LDK, Buttery AJ, Edgar ID, Xynos [86] Ti engineering.Calcif for tissue bone applications
Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 30 ssue Int 2000;67:321 9. Int2000;67:321 9. ssue 1999;67:173 86. 1999;67:173 86. . . c products of Bioglass® 45S5 dissolution. J J dissolution. 45S5 Bioglass® of products c studies in young rapidly growing rats and and rats growing rapidly young in studies asts and Induce Insulin like Growth Factor Factor Growth Insulin like Induce and asts on on growth and skeletal development in in development skeletal and growth on on silicon on bone mineralization. Biol Trace Trace Biol mineralization. bone on silicon 75. 75. iophys Res Commun 2000;276:461 5. 2000;276:461 5. Commun Res iophys ak JM. Ionic Products of Bioactive Glass Glass Bioactive of IonicProducts JM. ak Hench LL, Polak JM. Bioglass ®45S5 ®45S5 Bioglass JM. Polak LL, Hench itro bioactivity of silicon substituted silicon substituted of bioactivity itro active materials to control cell cycle. cycle. cell control to materials active rmation rmation k M Gn xrsin rfln of profiling Gene expression JM. ak amics: a material and biological biological and material a amics: Aluminum and Silicon on Broiler Broiler on Silicon and Aluminum n vitro in ipiain and implications : Page 30of48 Page 31of48
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based nanoparticles stimulate bone forming osteobla bone forming stimulate nanoparticles based islc i te sepoeei/AK rto n hum in ratio osteoprotegerin/RANKL the in biosilica Hum of Differentiation Osteogenic for Nanoplatelets
[104] Gaharwar AK, Mihaila SM, Swami A, Patel A, Sa A, Patel A, Swami SM, Mihaila AK, Gaharwar [104] Nanot Nanomed vivo. density in mineral bone enhance M, Yamaguchi CE, Camalier S W, Ha GR, Jr Beck [103] i andresorption bone formation osteoclast inhibits Shahabi B, Willman A, Johansson Ž, Mladenović [102] 1979. and biochemistry. solubility, silica: of chemistry The RK. Iler [109] 2016;39: Acta Biomater activation. NF κB antagonize differentiatio osteoblast stimulates Si(OH)4, acid, Zh P, Ustriyana S, Mankoci FM, Moussa X, Zhou [108] 2010;31:7716 25. [107] Wiens M, Wang X, Schröder HC, Kolb U, Schloßm U, Kolb HC, Schröder X, Wang M, Wiens [107] 2005;19:2014 6. FASEBJ celltracking. stem hu in nanoparticles mesoporous of labeling cellular W H, Chen S C, Hsu B S, Ko Y, Hung D M, Huang [106] Nano2014;8:5898 910. ACS an Autophagy of Stimulation through Differentiation Sili Bioactive GR. Beck MN, Weitzmann S W, Ha [105] 2013;25:3329 36.
Accepted Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 32 polymerization, colloid and surface properties, properties, surface and colloid polymerization, n vitro. Acta Biomater 2014;10:406 18. 2014;10:406 18. Acta Biomater vitro. n man mesenchymal stem cells: implication for implication cells: stem mesenchymal man sts, suppress bone resorbing osteoclasts, and osteoclasts, bone resorbing suppress sts, n in vitro by upregulating miR 146a to to miR 146a upregulating by vitro in n 192 202. 192 202. an Mesenchymal Stem Cells. Adv Mater Mater Adv Cells. Stem Mesenchymal an d Direct Association with LC3 and p62. p62. and LC3 with Association Direct d echnol 2012;8:793 803. 2012;8:793 803. echnol ang N, Abdelmagid S, et al. Orthosilicic al. et S, Abdelmagid N, ang K, Björn E, Ransjö M. Soluble silica silica Soluble M. Ransjö E, Björn K, an osteoblast like cells. Biomaterials Biomaterials cells. osteoblast like an nt S, Reis RL, et al. Bioactive Silicate Silicate Bioactive al. et RL, Reis S, nt acher U, Ushijima H, et al. The role of of role The al. et H, Ushijima U, acher Li Y, Lee J K, et al. Bioactive silica Bioactive al. et J K, Lee Y, Li a aoatce Pooe Osteoblast Promote Nanoparticles ca Chien C L, et al. Highly efficient efficient Highly al. et C L, Chien Page 32of48 Page 33of48 bone is mainly deposited on its external surface. A surface. external its on deposited mainly is bone permission [37]. The Royal 2012, Society. Copyright [37]. permission &Wiley Sons, John 2005, Copyright [29]. permission ec ad owres fo a iatv melt prepare bioactive a from co workers, and Hench 3 months, the cross sectional shape of the implant implant the of shape cross sectional the months, 3 sacr sheep of tibiae the in implanted scaffolds TCP Figure 3.Figure FIGURECAPTIONS usiue hsht ain (PO anion phosphate substitute Figure 2. 2. Figure 1. Figure Figure 5. 5. Figure IO Copyright 2012, [41]. permission Reproducedwith tissue soft the collagen, to adhere curves) (dashed n and forming non glass a is D Region implantation. complete are C region in those implanted; when them ine are glass bottle and window as such B region in vitro composition a have that glass ceramics and Glasses Figure 4. 4. Figure was fed a diet with low levels of silicate (2 mg/g) of silicate levels low with adiet wasfed levels high with diet a fed was left the to chicken and in vivo in Schematic illustration of the reaction sequence le sequence reaction the of illustration Schematic Gross cross section (top panels) and contact micror contact and panels) (top section cross Gross Beneficial effect of silicate on bone is illustrate is bone on silicate of effect Beneficial Bioactive regions in the CaO SiO the in regions Bioactive
Accepted Si and HA pure of lattices the of diagram Schematic Article . Compositions inside the dashed line also bond to bond also dashedline the inside Compositions . Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 4 3 i te ptt cytl atc abi t a limite a to albeit lattice crystal apatite the in ) John Wiley& Sons,Inc. 2 Na 33 of silicate (100 mg/g) while the one to the right right the to one the while mg/g) (100 silicate of . (Photo: Carlisle, 1972) 1972) Carlisle, (Photo: . 2 O system. All glasses contain 6% wt of Pof wt 6% contain glasses All system. O t 6 months, the loss of the central canal of the the of canal central the of loss the months, 6 t ificed at 3, 6 and 24 months after surgery. At At surgery. after months 24 and 6 3, at ificed falling inside region A develop HAP both both HAP develop A region inside falling
on bonding region. Glasses within region E E region within Glasses region. on bonding is still recognizable and the newly formed newly formed the and recognizable still is Inc. rt and a fibrous capsule is formed around around formed is capsule fibrous a and rt P Publishing Ltd. Publishing P component of bone. Reproduced with with Reproduced bone. of component d by these four week old chickens. The The chickens. old four week these by d ly dissolved at 10 30 days following following days 10 30 at dissolved ly CaO SiO d ading to HCA formation according to to according formation HCA to ading adiographs (bottom panels) of Si α of panels) (bottom adiographs soft tissues. The compositions compositions tissues.The soft H. iiae nos (SiO anions Silicate HA. 2 glass. Reproduced with with Reproduced glass. d extent. extent. d 2 O 4 4 in in 5 ) .
panels: O = red, Si = blue, Ca = green. green. = Ca = blue, Si O= red, panels: permission [105]. Amer by Copyright published 2014, [105]. permission y oh C ad 6, eutn i te omto of formation the in resulting p62, and LC3 both by
Figure 7. 7. Figure ifrnit t otoye ad iig el. P c OPG cells. lining and osteocytes to osteoblasts differentiate in OPG of expression enhances Biosilica Figure 6. 6. Figure Liebert,Inc. Mary Ann 2006, Copyright shows bar Scale (arrows). detected be can fragments is phase implant the months, 24 At pores. inner the f implant both of result a as occurs implant hollow Figure 9Figure C [77]. permission with Reproduced d. and 60 30 15, 8Figure Reproduce byElsevier published 1997, Copyright modification. SBF. in immersion after material eutectic iue 10Figure uohg i ncsay o otols differentiati osteoblast for necessary is autophagy t to I form LC3β of processing the for necessary is depend pathway transduction signal a triggers which inter are Nanoparticles differentiation. osteoblast . SEM micrographs and EDS spectra of SBA 15, MCM 48 SBA 15, of spectra EDS and micrographs SEM . . Schematic representing the intrinsic biological e biological intrinsic the representing Schematic . Schematic representation of the first stages (a) an (a) stages first the of representation Schematic Pooe efcs f islc o otolss ost osteoblasts, on biosilica of effects Proposed .
Accepted Article β CaSiO of structure crystal the of Schematic Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc. 34 he activated form II. Nanoparticles are bound bound are Nanoparticles II. form activated he ragmentation and new bone formation within within formation bone new and ragmentation nalized by caveolae mediated endocytosis, endocytosis, caveolae mediated by nalized markedly reduced, and very few and sparse sparse and few very and reduced, markedly Ltd. ent on ERK1/2. This stimulation of ERK1/2 of stimulation This ERK1/2. on ent opyright 2006, The Royal Society. Society. The Royal opyright2006, on and mineralization. Reproduced with with Reproduced mineralization. and on 5 mm. Reproduced with permission [55]. permission with Reproduced mm. 5 utrcs aiu efcs f AK, a RANKL, of effects various ounteracts ican Chemical Society. Society. icanChemical . Osteoblasts have the potential to to potential the have Osteoblasts . 3 wt priso [3 wt slight with [63] permission with d uohgsms Te tmlto of stimulation The autophagosomes. ffects of silica based nanoparticles on on nanoparticles silica based of ffects n α CaSiO and d final stage (b) of HAP formation in formation HAP of (b) stage final d eoclasts, and their progenitors. progenitors. their and eoclasts, and MCM 41 materials at 0, 0, at materials MCM 41 and 3 . Legend for atoms in in atoms for Legend . Page 34of48 Page 35of48 permission [106]. Else by Copyright published 2014, [106]. permission differentiation and inhibit osteoclast differentiat osteoclast inhibit and differentiation
yoie ht nue peotols mtrto and maturation pre osteoclast induces that cytokine Copyright 2016, published by Elsevier Ltd. Ltd. byElsevier published 2016, Copyright remode bone in role potential a implies which 146a, iue 11 Figure transcription gene for osteoclast precursor differe precursor osteoclast for gene transcription in also NF κB of deactivation This differentiation. transcri master the Runx2, of activation in results act reduce to miR 146a endogenous of expression the enter the cell through Na+ HCOthrough cell the enter
Accepted Article Si(OH) .
4 mediated regulation of NF κB via miR 146a in bone bone in miR 146a via NF κB of regulation mediated Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 3 co transporter (NBC 1). Within the cell Si(OH) cell the Within (NBC 1). co transporter John Wiley& Sons,Inc. 35 ion by antagonizing NF κB activation via miR via activation NF κB antagonizing by ion ntiation. Thus, Si(OH) Thus, ntiation. ption factor necessary for osteoblast precursor precursor osteoblast for necessary factor ption vier Ltd. vier hibits the expression of NFATc1, the key key the NFATc1, of expression the hibits ivation of NF κB. The inhibition of NF κB of inhibition The NF κB. of ivation osteoclast activation. Reproduced with with Reproduced activation. osteoclast ig Rpoue wt priso [108]. permission with Reproduced ling. 4 can stimulate osteoblast osteoblast stimulate can el. Si(OH) cells. 4 can induce can 4 may may
published by Elsevier Ltd.Elsevier bypublished islto pout o bocie lse. Reproduc glasses. bioactive of products dissolution 1. Table N xlso earpoenEC 300 ERCC repairproteinexclusion DNA 240 400 recombinationandsynthesis, repair DNA 400 350 KCyclin ATF-4factor transcription cAMP-dependent 500 (CDKN1A)1 inhibitor kinaseCyclin-dependent proteinaseregulatory subunit26S 6A (CCND1)G1/S-specific D1 cyclin growth-relatedc-myc-responsiveRCL gene regulatorscycle cell factorsTranscriptionand nui-iegot atrI IFI) 300 160 (IGF-II)IIInsulin-like factorgrowth 450 cytokinesand factorsGrowth Deoxyribonuclease(DnaseII) II subunit; (regulatory) smallproteinaseCa-dependent 230 200 Defender(DAD-1) againstcell death 1 regulatorsApoptosis subunit(RFC38)kDa Replication 38 factor C High-mobility-group(HMG-1)protein homologprotein mutL
Accepted Article acti osteoblasts human primary in genes of Families Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved.
John Wiley& Sons,Inc.
36
d ih emsin 2. oyih 2008 Copyright [2]. permission with ed clan 410 calpain
ae o u-euae b ionic by up-regulated or vated Activation (%)Activation 200 300 Up-regulation (%) Up-regulation Up-regulation (%)Up-regulation Activation (%)Activation
36
Page 36of48 Page 37of48
Dual specificitynitrogen-activatedDual kinaseprotein kinas (MAPKAP 2 proteinkinasekinase-activated MAP moleculestransductionSignal 700 (V-CAM1)adhesionprotein-1 cellprecursor Vascular 200 precursoreceptor-1 fibroblast factor N-sam;growth 1Fibronectin integrin subunit;beta receptor beta hematopoeticantigenprecursor formCD44 receptorssurfaceantigensand Cell (VEGF)precursorfactorgrowth endothelial Vascular factorgrowth Bone-derived MCSF) (CSF1 factor Macrophage-specificstimulatingcolony oepoegya Ipeusr eoi 200 270 Accepted 22 200 proteoglycanprecursor; IIBone decorin (MI) 2 TIMP 370 Metalloproteinaseinhibitorprecursor1)(TIMP1 metalloproteinase 2) (MMPMatrix 2 metalloproteinase14) precursor Matrix (MMP 14 compoundsmatrix Extracellular ADP-ribosylationfactor1 Article
Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. John Wiley& Sons,Inc.
37
200 2 300 r 200 ) 600 2) e 200 ;
220 260 Activation (%)Activation Activation (%)Activation Activation (%)Activation 600 0
37
the left was fed a diet fed a left withthe high was levels silicat of
AcceptedFigureBeneficial 1. silicate effectof bone is on Article Journal ofBiomedicalMaterialsResearch:PartA lowCarlisle,silicate levels of (Photo: (2 mg/g). This article isprotected by copyright. All rights reserved. 80x48mm (300 x 300 DPI) (300 30080x48mm DPI) x John Wiley& Sons,Inc. e (100 mg/g) while the one to the right was fed a d fed mg/g)a was while e(100 right the to one the illustrated by these four-week old chickens. The ch The illustratedbythesefour-week old chickens.
1972)
icken to ietwith Page 38of48 Page 39of48
Compositions insideCompositions line dashed the so bondto also Figure 2. Bioactive regions in the CaO-SiO2-Na2O FigureCaO-SiO2-Na2O the regions sy Bioactive 2. in and bottle glass are inert and a fibrousbottle iscapsuleinert a are and glass and bondingregion region. cur (dashed within Glasses E are completelyare following 10-30 days dissolved at im glass-ceramics that have a compositionhave a glass-ceramicsthat insi falling
AcceptedReproduced bone. with permission[29]. Copyright 20 Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 80x58mm (300 x 300 DPI) (300 30080x58mm DPI) x John Wiley& Sons,Inc. formed around them when implanted; when them formed around in those region ft tissues. The compositions The asin tissues. region ft wi such B ves) adhere to collagen, the soft tissueves) collagen,adherecomponent to soft the plantation. Region non-glass is a non D forming and plantation. stem.6% Glasses wtAll glassescontain P2O5. an of
de region A develop in both vitro A HAP in vivo.de region and 05, John Wiley & Sons, Wiley John Inc. 05, Sons, &
ndow ndow C C of of - d
Figure 3. Schematic illustration Figurereactionse the Schematic of 3.
Accepted bioactive co-workers,melt-preparedfroma CaO-SiO2 Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 119x63mm (300119x63mm 300DPI) x John Wiley& Sons,Inc. 2012, The Royal Society. Royal Society. The 2012, quence according formation leadingHench HCA to to
glass. Reproduced glass. with permission[37]. Copyright
and and Page 40of48 Page 41of48
phosphate anion (PO43- anion phosphate
Accepteddiagram Figurelattices purethe Schematic of of 4. Article )in lattice crystal limitealbeit apatite the a to Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. [41]. Copyright 2012, IOP Publishing [41].IOP Copyright 2012, Ltd. 60x85mm (300 x 300 DPI) (300 30060x85mm DPI) x John Wiley& Sons,Inc.
HA and Si-HA. HA Si-HA. (SiO44-) Silicatesubstituteand anions d extent. Reproduced with permission Reproduced dextent.
phase is sparse markedly phase very reduced, fewand and cross sectional shape of the the of cross sectional shape implantis still recog scaffolds implanted scaffolds in tibiae the sheep of sacrific its external surface. At 6 months,6loss the the of At itsexternal surface. both implant fragmentation implantw bonenewboth fragmentation formation and Figuresectioncont cross Gross (top panels)5. and
AcceptedReproduced mm. with permission[55]. Copyright 2006 Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 140x108mm(300 300DPI) x John Wiley& Sons,Inc. nizable and the newly formed the and bone is mainlydeposit nizable ed at 3, 6 and 24months surgery. after and 6 months 3 3, edAt at centralhollow the of implant acanal res as occurs fragmentsbe shows detected bar can (arrows).Scale
act Si α of microradiographs TCP (bottompanels) ithinimplant the inner24months, the pores. At , Mary Ann Liebert, Inc. AnnLiebert, Mary , Inc.
ult of ed on , the the , 5 Page 42of48 Page 43of48
Acceptedcrystal the of β C of structureFigure Schematic 6. Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. red, Si = blue, Ca = green. = red,blue, = Si Ca 80x59mm (300 x 300 DPI) (300 30080x59mm DPI) x John Wiley& Sons,Inc. aSiO3 α CaSiO3. and forLegendatoms in = panels: O
material after immersion in SBF. Reproduced immersionmaterialSBF. after with pe in
Accepted Articlerepresentation first the Figureof sta Schematic 7. Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 150x50mm (300150x50mm 300DPI) x John Wiley& Sons,Inc. published byElsevier Ltd. ges (a) and final stage (b) of HAP ges(a) (b) finalHAP stage in of eutformation and rmission [63] with slight modification. Copyright 1 [63] rmission with slight modification.
ectic 997, 997, Page 44of48 Page 45of48
Acceptedmicrographs of spectra EDS Figure SEM SBA-15 and 8. Article d. Reproduced d. [77]. Copyright 2006, with permission Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 140x117mm(300 300DPI) x John Wiley& Sons,Inc.
, MCM-48 60, MCM-41 materials30 and 15, MCM-48 and 0, at The Royal Society.
formation of autophagosomes. of stimulationformation aut of The transduction pathway dependent pathway stimERK1/2. This transduction on Figure 9. Schematic representing FigureSchematic 9. intrinsic the biol differentiation. Nanoparticles are internalizedare differentiation. Nanoparticles by mineralization. Reproduced withmineralization.permission Reproduced [105]. C
Acceptedform Nanoparticles activated the to I formII. LC3β Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 80x102mm (30080x102mm 300DPI) x John Wiley& Sons,Inc. Society. Society. caveolae mediated endocytosis, which triggers sig which endocytosis, a caveolae mediated ogical effects of silica based of effects ost ogicalon nanoparticles
ophagy is necessary forisosteoblast necessary ophagy differentiation
are bound by both LC3 and p62, and LC3 byboth bound resultingare in the ulation of ERK1/2 of ulation processingforis the necessary o opyright 2014, published by American Chemical Chemical published 2014, opyright byAmerican
eoblast nal nal and and f f Page 46of48 Page 47of48
FigureProposed biosilicaosteobl 10. of effects on expression of OPG in osteoblasts. Osteoblasts have Osteoblasts expressionin osteoblasts. OPG of cells. OPG counteracts various a RANKL, cells.counteracts of effects OPG
AcceptedReproduced activation. osteoclast with permission [ Article Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 80x65mm (300 x 300 DPI) (300 30080x65mm DPI) x John Wiley& Sons,Inc. asts, osteoclasts, and theirosteoclasts, and asts, Biosilica progenitors. cytokinematuration and induces pre-osteoclast that
the the li and potential osteocytes differentiate to to
106]. Copyright 2014, publishedCopyright 2014, 106]. byElsevier Ltd.
enhances enhances ning
the master transcription master factor the forosteo necessary endogenous miR 146a to reduce activation of NF κB. of activation endogenousmiR 146a reduce to Thus, stimulate Si(OH)4Thus, can differentiatosteoblast also inhibits the expression of NFATc1, the key trakey the inhibits also NFATc1, of expression the Figurevia regulationSi(OH)4 mediated 11. NF κB of NF κB activation miR 146a, via implieswhich NF κB pote a
Acceptedco transporter Na+ HCO3 through Within th (NBC 1). Article permissionpublished 2016, [108]. Copyright byElse Journal ofBiomedicalMaterialsResearch:PartA This article isprotected by copyright. All rights reserved. 99x88mm (300 x 300 DPI) (300 30099x88mm DPI) x John Wiley& Sons,Inc. blast precursor blast deactivation This differentiation. ion and inhibit ionand byantag differentiation osteoclast nscriptiongene precursor forosteoclast differenti
TheRuresults of in inhibition activation NF κB of miR 146a in bone cells. Si(OH)4 may entermiR 146a cell the in may bone cells. Si(OH)4 ntialrole with in bone remodeling. Reproduced ecell induce expression the Si(OH)4 can of vier Ltd. Ltd. vier
of NF of onizing ation. ation. nx2, nx2, κB κB
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