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Application of Trace Element Strontium-Doped Biomaterials in the Field of Bone Regeneration

Rui Zhao , Xiao Yang , Xiangdong Zhu , Xingdong Zhang

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (4) : 533 -542.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (4) : 533-542 DOI: 10.7536/PC200537
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Application of Trace Element Strontium-Doped Biomaterials in the Field of Bone Regeneration
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Abstract

Clinical studies have confirmed that strontium ranelate can inhibit osteoporosis by improving bone formation and reducing bone resorption. These effects are partly mediated by the effect of strontium on bone metabolism. Trace element strontium can promote osteogenesis as well as angiogenesis. To date, the research on strontium-doped composites is increasing in orthopaedic related field. The current article mainly reviews the main action mechanisms of strontium on bone tissue, including the validated and potential mechanisms, as well as the detailed biological interaction between strontium and bone. This article also focuses on different strontium-doped biomaterials applied in the local bone tissue repair, especially for the osteoporotic bone regeneration. We hope that this review would shed light on the rationale for further application of strontium in bone repair.

Contents:

1 Introduction

2 Action mechanism of strontium

2.1 Effect of strontium on osteogenesis

2.2 Effects of strontium on osteoclastogenesis

2.3 Effects of strontium on angiogenesis

3 Strontium doped bone repair materials

3.1 Strontium-doped bone cement

3.2 Strontium-doped calcium phosphate bioceramic

3.3 Strontium-doped bioactive glass

3.4 Bioactive coating of strontium-doped composite

3.5 Other strontium-doped multiphase composites

4 Conclusion and outlook

Graphical abstract

Keywords

strontium / bone regeneration / strontium ranelate / osteoporosis / biomaterials

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Rui Zhao, Xiao Yang, Xiangdong Zhu, Xingdong Zhang. Application of Trace Element Strontium-Doped Biomaterials in the Field of Bone Regeneration. Progress in Chemistry, 2021, 33(4): 533-542 DOI:10.7536/PC200537

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1 Introduction

The importance of trace elements in maintaining natural bone health has been well documented, and elements such as lithium, zinc, magnesium, manganese, silicon, and strontium have been shown to promote bone formation or angiogenesis[1]. Strontium (Sr), as an essential trace element in the human body, belongs to the same group as Calcium (Ca) in the periodic table of elements, and its physiological function is closely related to bone formation. 99% of Strontium (36-140 mg/kg) in the body is deposited in the femur, lumbar spine and ilium[2]. However, the total amount of strontium in bone is less than that of calcium, accounting for only 0.035% of the calcium content. Strontium can promote the proliferation of preosteoblasts, osteoblast differentiation, bone matrix mineralization and inhibit the differentiation of osteoclasts[3]. Among them, strontium ranelate is the most widely used strontium salt drugs in clinic, which can promote bone formation, inhibit bone resorption, improve bone quality and reduce the incidence of fracture, and can be used for the treatment of postmenopausal osteoporosis[4]. Compared with Alendronate, strontium ranelate has a more significant therapeutic effect in elderly patients with osteoporosis. It was also found that systemic strontium ranelate injection could promote fracture healing in osteoporotic animals[5]. However, long-term use of strontium ranelate can cause adverse reactions such as diarrhea, headache, nausea and allergy, and the European Medicines Agency limited the indication of strontium ranelate to the treatment of severe osteoporosis in 2013.It also points out that the use of strontium can lead to an increased risk of myocardial infarction, thromboembolic events and serious skin reactions[6].
Therefore, researchers imagine that the use of bone materials that can locally release strontium at the fracture site may avoid the adverse reactions caused by systemic injection of strontium ranelate and hopefully accelerate fracture healing. In recent years, many studies have confirmed that a series of strontium-containing biomaterials, such as strontium-doped calcium phosphate bioactive ceramics, bioactive glass and bone cement, have the ability to accelerate bone formation in the surrounding host[7,8]. Studies have further found that strontium as an additive to bone repair materials can also effectively act on host bone with osteoporosis and enhance the healing ability of autologous bone[9,10]. However, it has not yet been determined how strontium released locally stimulates new bone formation and through which signaling pathways it acts on surrounding osteoblasts and osteoclasts. In this paper, the mechanism of strontium in bone metabolism and the recent research progress of strontium-doped bone repair materials are reviewed, in order to provide a reference for the application of strontium in bone repair.

2 Action mechanism of strontium

Although strontium has a positive effect on bone regeneration, its mechanism of action is not yet clear. It is believed that strontium and strontium ranelate have similar modes of action, both promoting bone formation and slowing bone resorption[11,12]. With the degradation of the material, strontium ions are slowly released, and a microenvironment rich in strontium ions is formed locally at first. In vivo experiments, Thormann et al observed the release of strontium in strontium-doped calcium phosphate cement by time-of-flight secondary ion mass spectrometry (TOF-SIMS), and found that there was a higher concentration of strontium at the bone-implant interface, which was the main reason for the promotion of bone formation in the strontium-doped group[9]. Pharmacological studies have shown that strontium can activate a variety of signaling pathways in osteoclasts or osteoblasts, mainly including the activation of Ca-sensing receptor (CaSR), which leads to the activation of phospholipase Cβ and inositol 1,4,5-trisphosphate, the release of intracellular calcium ions, the activation of MAPK-ERK1/2 and Wnt/NFATc signaling, and then promotes the proliferation and differentiation of osteoblasts, thus exerting its pharmacological effects[12,13]. Currently, the most studied cellular mechanisms include CaSR, a G-protein-coupled receptor (GPCR) located in bone cells, which has been considered to be related to bone remodeling in recent years[14]. It has been shown that CaSR can bind to Ca2+ and homologous Sr2+ to control key cellular functions, such as cell growth, differentiation and apoptosis[15,16]. Strontium can also affect osteoclast production and resorptive activity by disrupting the actin cytoskeleton in the closed areas and fold edges of mature osteoclasts[17]. The effects of strontium on osteoblasts and osteoclasts were dose-dependent[3]. In addition, strontium-doped materials may involve the interaction of strontium with other components in the material, thus affecting bone regeneration.

2.1 Effect of strontium on osteogenesis

At present,many studies have confirmed that strontium can promote the proliferation and differentiation of osteoblasts,induce the high expression of alkaline phosphatase(ALP),osteocalcin(OCN)and bone sialoprotein(BSP),and promote the mineralization of bone matrix and the formation of calcium nodules[18,19]。 in recent years,In vitro studies have further found that strontium ranelate can promote the proliferation and differentiation of osteoblasts on the one hand,and promote the osteogenic differentiation of adipose-derived stem cells on the other hand by activating CaSR pathway[20]。 At the same time,strontium can down-regulate the expression of Wnt inhibitor sclerostin,further enhance the signal transduction ofβ-catenin in bone,increase the expression of osteogenic factors in cells,promote the maturation and differentiation of osteoblasts,and increase bone formation[11,21]。 Peng et al.Found in 2009 That strontium ranelate can promote the osteogenic differentiation of bone marrow mesenchymal stem cells(MSCs)by enhancing the expression of several genes(BSP,OCN and ALP,etc.)that regulate different osteogenic stages and matrix maturation.This process is mediated by Ras/MAPK signaling pathway,and then up-regulates the expression of Runx2(runt-related transcription factor 2),which promotes the differentiation of MSCs into osteoblasts[22]。 in 2013,it was reported that BMP-2/Smad pathway was also involved In osteoblastic differentiation of rat MSCs induced by strontium[23]。 in addition,In 2017,Jia et al.Found that strontium regulates the expression of Setd2 by activating MAPK pathway,thereby promoting ERK phosphorylation,generating positive feedback and stimulating osteoblast MG63 to differentiate into osteoblasts[24]。
In vitro studies also confirmed that strontium-doped materials can promote the proliferation and differentiation of preosteoblasts and osteoblasts(fig.1)[25]。 For example,Hao et al.Found that strontium-doped nano-hydroxyapatite can promote the adhesion and proliferation of osteoblasts,thereby increasing the formation of extracellular mineralized matrix[26]。 Compared with the pure material group,strontium-doped submicron bioactive glass can promote the expression of osteoblast-related factors ALP,osteopontin(OPN)and OCN in mouse bone marrow mesenchymal stem cells(mMSCs),which may be due to the synergistic effect of strontium-activated NFATc signaling pathway and silicate-activated Wnt/β-catenin signaling pathway[27]。 In 2014,Zhang et al.prepared mesoporous bioactive glass(Sr-MBG)scaffolds with strontium substitution degrees of 5,10 and 20 mol%by three-dimensional printing technology.Sr-MBG scaffolds can promote the proliferation,ALP activity and matrix mineralization of osteoblasts MC3T3-E1[28]。 It was found that there was no significant difference in proliferation and ALP activity of MC3T3-E1 cells on these scaffolds with different degrees of substitution.Liu et al.Prepared calcium polyphosphate(SCPP)scaffolds with strontium substitution of 1,2,5,8 and 10 mol%,and found that SCPP materials could promote the proliferation and differentiation of osteoblasts ROS17/2.8[29]。 Under the effect of low concentration of strontium,cell proliferation increased with the increase of strontium concentration in a dose-dependent manner,and 8 mol%SCPP showed the best proliferation effect.the mRNA expression of vascular endothelial growth factor(VEGF)and basic fibroblast growth factor(bFGF)in SCPP group was higher than that in control group,and 8 mol%SCPP was the best.Therefore,the concentration of strontium released by 8 mol%SCPP is close to the optimal dose of strontium to promote cell proliferation and the expression of osteoblast-related factors。

2.2 Effect of strontium on osteoclast

Osteoclasts can be activated by a variety of factors,including proinflammatory cytokines,advanced glycation end products,stress,aging,and acute phase tissue response after implantation of biomaterials[30]。 Therefore,the local inflammatory Cytokines interleukin-1(IL-1),interleukin-6(IL-6)and tumor necrosis factor(TNF-α),which are mainly produced by macrophages,can lead to the recruitment and activation of osteoclasts at the bone implant interface.cytokines released by inflammation and aging can stimulate the expression of receptor activator of the nuclear factor kappa B ligand(RANKL)in osteoblasts,which helps to recruit and activate osteoclasts and lead to bone loss.Strontium ranelate has been found to regulate osteoclast apoptosis by activating CaSR and PI3K/Akt signaling pathways,amplifying the Wnt/β-catenin signaling cascade,and enhancing the regulation of RANKL/RANK bone resorption signaling pathways[3,31]。 Strontium can also promote the production of osteoprotegerin(OPG),which binds to RANKL and inhibits RANKL-induced osteoclast production,thereby inhibiting bone resorption[32]。 Liu et al.Found that strontium ranelate significantly prevented inflammatory osteolysis induced by titanium particles by inhibiting osteoclast formation,and significantly inhibited bone resorption and the production of tartrate-resistant acid phosphatase(TRAP)positive cells[33]。 the inhibitory effect of strontium ranelate on osteoclastogenesis is related to the stimulation of OPG expression,the inhibition of RANKL expression and the decrease of TNF-αand IL-1βsecretion。
It was found that strontium-substituted submicron bioactive glass(Sr-SBG)could moderately regulate the inflammatory state,promote the osteogenesis of mMSCs,and inhibit the differentiation of macrophages RAW264.7 cells into osteoclasts[34]。 Consistent with the in vitro results,in vivo studies also demonstrated that strontium incorporation reduced the immune response of the material,thereby promoting bone regeneration.Similarly,strontium-substituted calcium phosphate cement(Sr-CPC)as well as the pure material can combine with osteoclast precursors to form multinucleated osteoclast-like cells.However,Sr-CPC can reduce the activity of osteoclast-related enzymes TRAP,carbonic anhydrase II(CAII)and connexin 43(Cx43),alter the actin cytoskeleton,and significantly reduce their resorption by osteoclasts,but does not inhibit osteoclast formation[35]。 Consistent with previous studies,the inhibitory effect of calcium silicate ceramics(CS)and strontium-substituted calcium silicate(SrCS)ceramics on osteoclasts was manifested by OPG stimulation and RANKL down-regulation,but the inhibitory effect of CS only appeared in the early stage of culture,and the inhibitory effects of SrCS were stronger and more lasting[36]。 However,Thormann et al.Found that in metaphyseal bone defects of osteoporotic rats,the expression of TRAP was increased in the strontium-doped calcium phosphate cement implantation group[37]。 Consistent with this study,we found an increase in the number of TRAP-positive cells in the strontium-doped calcium phosphate whisker ceramic implant group compared with the whisker calcium phosphate ceramic implant group,indicating that osteoclast formation was activated[38]。 It is speculated that strontium-doped calcium phosphate materials can promote bone formation in vivo because the release of strontium accelerates the process of local bone remodeling。

2.3 Effect of strontium on angiogenesis

The ability of biomaterials to promote angiogenesis plays an important role in wound healing and tissue regeneration[39]。 strontium ranelate can promote angiogenesis by activating PI3K/AKT/mTOR signaling pathway,up-regulate VEGF and Ang-1 angiogenic gene expression,and immunostaining shows that strontium ranelate treatment group has higher intensity of CD31 and Vwf(markers of endothelial cells),so strontium also has the effect of promoting vascularization(Figure 2)[40]。 in addition,it was found that low-dose strontium doped calcium polyphosphate could promote the expression of VEGF and bFGF In osteoblasts and promote angiogenesis[29]。 Other studies have shown that the expression of VEGF and Matrix metalloproteinase 2(MMP-2)protein in strontium-doped calcium polyphosphate is higher than that in non-strontium-doped calcium polyphosphate,so it has the effect of inducing angiogenesis[41]。 Zhao et al implanted strontium-doped micro-nano bioactive glass(SrBGM)into rat skull for one week,and found that silicon,calcium,phosphorus and strontium ions released by material degradation could significantly increase the polarization trend of macrophages from M1 type to M2 type,and promote the expression of anti-inflammatory related cytokines.the expression of CD31 can promote the secretion of platelet-derived growth factor-BB(PDGF-BB)by macrophages,which is beneficial to the formation and maturation of blood vessels[39]。 Recently,our research team also found that strontium-doped whisker-based calcium phosphate ceramics,compared with whisker-based calcium phosphate ceramics,showed high expression of a class of osteoblast-related angiogenic proteins(CD31/Emcn)and vascular-like structures at the edge of the scaffold after one week of implantation[38]。

3 Strontium-doped bone repair material

Clinically, bone defects are often associated with osteoporosis and osteochondroarthritis.Strontium can not only promote bone formation and angiogenesis, but also reduce the adipogenic differentiation of MSCs and promote cartilage regeneration. For example, Peng et al observed in vitro that strontium can increase the osteogenic potential of MSCs and reduce their adipogenic potential[42]. Fournier et al. Have demonstrated that strontium can promote the proliferation of human multipotent mesenchymal cells and reduce adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma2 (PPARgamma2)[43]. In addition to inhibiting lipogenesis, clinical studies have found that strontium ranelate may have a positive effect on cartilage metabolism and is a promising arthritis drug[6]. It has been reported that high-dose strontium ranelate treatment can significantly reduce the loss of cartilage matrix and chondrocytes, reduce chondrocyte apoptosis, increase the expression of SOX9, a key transcription factor for the expression of anabolic genes type II collagen and aggrecan, and reduce articular cartilage degeneration and subchondral bone remodeling in osteoarthritis rats[44]. In addition, strontium-containing drugs have a certain effect on improving the loss of joint function, alleviating the histological changes of articular cartilage and reducing the inflammatory process[45]. Deng et al. investigated the tissue regeneration effect of 3D printed Sr5(PO4)2SiO4(SPS) bioactive scaffolds in cartilage damage caused by osteoarthritis. The results showed that SPS scaffolds could significantly promote the proliferation of chondrocytes and the regeneration of osteochondral defects, and could reconstruct the composite interface structure of cartilage and subchondral bone[46]. The mechanism may be that strontium and silicon ions promote cartilage regeneration through synergistic activation of HIF signaling pathway, promote subchondral bone remodeling through activation of Wnt pathway, and inhibit hedgehog pathway to protect osteoarthritic cartilage. In addition, Ma et al. Prepared strontium alginate/chondroitin sulfate (Alg/CS-Sr) hydrogel with adjustable mechanical properties, which has good cell compatibility and can inhibit the apoptosis of osteoarthritic chondrocytes. In vivo studies further showed that Alg/CS-Sr composite hydrogel could accelerate the repair of cartilage defects in rabbits[47]. Therefore, further studies are needed to better clarify the mechanism of action of strontium-doped materials in bone metabolism (Table 1).

3.1 Strontium doped bone cement

Percutaneous vertebroplasty with bone cement is one of the commonly used fixation methods for osteoporotic thoracolumbar fractures.Poly(methyl methacrylate)(PMMA)bone cement has become one of the most commonly used curing materials in clinic because of its high mechanical properties,firm fixation,rapid solidification,convenient operation and low cost[48]。 However,the poor biocompatibility of PMMA seriously affects the long-term stability of the implant material.it has become a research focus to improve the bone cement by doping strontium,so as to apply It to the bone repair of osteoporosis.Ni et al studied the repair effects of strontium-doped hydroxyapatite(Sr-HA)bone cement and PMMA bone cement after revision hip joint and iliac bone surgery in goat and rabbit bone defect models,respectively[49,50]。 It was found that there was fibrous tissue between PMMA bone cement and bone,while Sr-HA bone cement had good biocompatibility and osteoconductivity,and had closer contact with bone and higher osseointegration strength.Thormann et al.Further compared the critical dimension bone repair of strontium-doped calcium phosphate cement(SrCPC)and non-strontium-doped control cement in the femoral metaphysis of osteoporotic rats[9]。 SrCPC can significantly promote the expression of bone morphogenetic protein-2(BMP-2),OCN,ALP and collagen.Moreover,studies have shown that strontium can be released from the material to the interface area to improve the effect of bone regeneration.Baier et al.Also compared the effects of strontium-containing calcium phosphate cement(SPC)and calcium phosphate cement on bone repair in osteoporotic rat models of metaphyseal bone defects.the results showed that SPC implants had faster osseointegration,more bone formation,and new bone could crawl in the internal crevices of implants[51]。 SPC implants only affect the surrounding host bone microenvironment,and do not cause excessive strontium concentration in the blood,resulting in systemic osteogenic side effects.in 2015,Zhang et al.Developed a new injectable bone cement(Sr-BBG)composed of strontium-doped borate bioactive glass particles and chitosan-based binding phase.Compared with the bone cement composed of strontium-free borate glass particles(BBG),Sr-BBG bone cement can promote the proliferation and osteogenic differentiation(Runx2,OCN,BMP-2 and BSP)of human bone marrow mesenchymal stem cells in vitro[8]。 After 4 and 8 weeks of implanting in the critical size of the rabbit femoral condyle defect model,the bone mass at different distances around the material was compared by micro-CT analysis,and it was found that Sr-BBG bone cement had better ability to promote bone regeneration than BBG bone cement at the implant-bone interface。

3.2 Strontium doped calcium phosphate bioceramic

Calcium phosphate ceramics have been widely used in bone tissue engineering because of its good biocompatibility,osteoconductivity and osteoinduction[52]。 the conventional calcium phosphate materials include dicalcium phosphate(DCPD),anhydrous dicalcium phosphate(DCPA),hydroxyapatite(HA),biphasic calcium phosphate(BCP,HA/α-TCP and HA/β-TCP),tricalcium phosphates(α-andβ-TCP)and octacalcium phosphates(OCP).Vestermark et al.Found that 5%Sr-doped HA(SrHA)implants could significantly accelerate the healing of the bone-material gap,but did not improve the mechanical fixation of the implants[53]。 In our group,whisker calcium phosphate bioceramics(WCP)and strontium doped whisker calcium phosphate bioceramics(SrWCP)with enhanced mechanical properties were prepared by hydrothermal treatment[38]。 These two bioceramic scaffolds were implanted in a defect model of the distal femur of an osteoporotic rat and compared with another group of individuals implanted with a WCP and treated with strontium ranelate(Sr-Ran+WCP)(fig.3).After 12 weeks of implantation,the Sr-WCP group had more new bone formation at the bone defect and in the implant-bone gap area than the WCP group,achieving the effect of the Sr-Ran+WCP feeding group.Osteoporosis-induced bone loss and trabecular microstructural destruction were improved around the implants in both SrWCP and Sr-Ran+WCP groups.However,blood Sr concentrations were abnormally high in the Sr-Ran+WCP group,whereas no adverse effects were observed in the Sr-WCP group.in addition,some researchers have prepared injectable strontium composite systems by embedding strontium-doped HA microspheres in strontium-crosslinked RGD sodium alginate hydrogel[54]。
Compared with the undoped group,the degradation rate of the strontium composite group was increased,the cell infiltration in the defect center was higher,and More new bone was formed.more importantly,there was no statistical difference in the concentration of strontium in the whole body organs and serum among the different groups,indicating that the safety of the material was good.Gao et al.Synthesized HA doped with strontium,silicon and fluorine by one-pot hydrothermal method[55]。 Cell experiments show that the multi-doped HA has good biocompatibility and can promote the adhesion and proliferation of osteoblast MG63。

3.3 Strontium-doped bioactive glass

Bioactive glass(BG)has good characteristics of bone conduction and bone induction.in body fluid,silicon,calcium and phosphorus ions In BG are released rapidly,and a hydroxycarbonate apatite layer is formed on the surface of the material,which can induce osteoblast differentiation and stimulate bone regeneration[56]。 Studies have shown that strontium-doped mesoporous bioglass(Sr-MBG)significantly promotes the proliferation of osteoporotic bone marrow stromal cells in a concentration-dependent manner,and stimulates the expression of osteoblast differentiation markers such as Runx2,ALP and Bglap(bone gamma-carboxyglutamate protein)[57]。 In vivo experiments showed that Sr-MBG scaffolds could significantly promote the formation of new bone in osteoporotic bone defects compared with MBG scaffolds,and the release of strontium in blood of Sr-MBG group was maintained at a lower level,while the excretion of strontium,silicon,calcium and phosphorus in urine was maintained at a similar level as the blank control group,so there was no systemic side effect.in addition,Sr-SBG can appropriately regulate the inflammatory state and promote the osteogenic differentiation of mMSCs,and Sr-SBG can inhibit the osteoclastic differentiation of RAW264.7 cells compared with pure materials[34]。 In vivo studies Further confirmed that Sr-SBG could improve bone regeneration,with less inflammatory fiber formation around the defect and thicker new bone at the boundary In the Sr-SBG group.further studies showed that strontium-doped bioactive glass microspheres(SrBGM)/gelatin scaffolds prepared by freeze-drying method could significantly promote early angiogenesis by regulating the phenotype of macrophages to M2 phenotype and expressing high levels of PDGF-BB.In vivo study showed that new bone formation was significantly promoted after the scaffold was implanted into the skull for 6 weeks.Immunohistochemical staining also confirmed that the positive staining areas of osteoblast-related proteins BMP-2 and OCN were more[39]。 Kargozar et al.Found that strontium and cobalt-substituted bioactive glass(Sr-CoBGM)can promote the adhesion of endothelial cells in vitro and increase the expression level of genes related to osteogenesis and angiogenesis[7]。 After 4 and 12 weeks of implantation in vivo,Sr-CoBGM showed higher collagen synthesis and better osteogenic and vascular capacity compared with other groups,and the strength of new bone in Sr-CoBGM group(37.10±1.50 HV)was significantly higher than that in control group(9.42±2.61 HV)。

3.4 Composite strontium bioactive coating

Although metal and polymer materials have excellent mechanical properties,they are all biologically inert materials.In order to endow them with good bioactivity,surface modification is the best choice.It has been found that bioactive coatings can be synthesized on titanium,titanium alloy and polymer substrates by pulsed laser deposition,plasma spraying or biomimetic methods,which can significantly improve the stability of the interface of implant materials[48]。 in 2010,Li et al prepared HA and 10%SrHA coatings on the surface of titanium implants by sol-gel impregnation method.After 12 weeks of implantation,compared with HA,10%SrHA coating implants could significantly improve the osseointegration of implants In osteoporotic rats,increase the bone area ratio by 70.9%,increase the bone-implant contact by 49.9%,and increase the maximum push-out force and ultimate shear strength by 107.2%and 132.9%,respectively[58]。 Fielding et al.added silver(Ag-HA)to the plasma sprayed HA coating to improve the antimicrobial properties of the implanted titanium material.In order to counteract the potential cytotoxic effects of silver,strontium was also Added as a binary dopant[59]。 the results showed that Ag-HA coating had cytotoxicity,which was manifested by poor cell morphology,cell death and almost complete loss of functional ALP activity.Compared with pure HA coating,the addition of strontium can effectively offset these negative effects and improve the biological properties of the coating.Later,it was also found that the release of silver in the strontium-silver nanotube(NT-Ag.Sr)structure inhibited the colonization of bacteria,thus minimizing the formation of bacterial biofilm,while strontium incorporation enhanced the adhesion,migration and proliferation of MC3T3-E1 cells,up-regulated the expression of osteogenic genes(ALP,Runx2 and OCN)and induced mineralization[25]。 in vivo experiments showed that NT-Ag.Sr accelerated the repair of bone defects by promoting the repair of damaged cortical bone and increasing the microstructure of bone trabeculae.Bianchi et al prepared strontium-doped calcium phosphate coating on polyetheretherketone(PEEK)substrate by pulsed electron deposition technology.Compared with pure PEEK,the roughness and wettability of the surface modified material were significantly improved,but the bone fixation effect of PEEK implant In vivo needs further study[60]。 In 2011,Wang et al combined porous PEEK with strontium by hydrothermal method,and deposited adiponectin(APN)protein film on the material by polydopamine-assisted deposition method[61]。 the APN coating is used to regulate the release rate of strontium and mediate the interaction between cells and materials.In vitro experiments showed that the proliferation and differentiation of MC3T3-E1 cells were significantly promoted under the synergistic regulation of strontium and APN。

3.5 Other strontium-doped multiphase composites

M Müller et al.Found that amorphous strontium polyphosphate microparticles(Sr-a-polyP-MP)significantly promoted the expression of ALP,BMP-2,and mineralization genes compared to amorphous calcium polyphosphate.Sr-a-polyP-MP embedded in PLGA microspheres can accelerate the healing of bone defects after implantation into the critical size bone defect model of rat skull[62]。 Lin et al.prepared porous Strontium-substituted calcium silicate(SrCS)ceramic scaffolds.strontium and silicon ions in SrCS materials synergistically stimulated MSCs to differentiate into osteoblasts,and also promoted human umbilical vein endothelial cells to form blood vessels.in vivo experiments also showed that SrCS significantly promoted bone regeneration and angiogenesis in osteoporotic skull critical bone defects[36]。 Li et al.developed an absorbable strontium-calcium sulfate hemihydrate(Sr-CaS)bone substitute with good biocompatibility[63]。 In the rat bone defect model in vivo,the bone mineral density and bone volume fraction in the Sr-CaS group were significantly higher than those in the pure CaS group,and there was no significant difference between the Sr-CaS groups with 5%and 10%strontium substitution,indicating that strontium ion doping enhanced the bone repair ability of CaS.Boda et al.synthesized strontium hexaferrite(SrFe12O19,SrFe)nanoparticles and found that SrFe with a particle size of 30-100 nm and a dose of up to 1000μg/mL was relatively non-cytotoxic to human bone marrow mesenchymal stem cells.Then they compounded SrFe with HA and found that the osteogenic marker genes(Runx2,ALP and OPN)of SrHA-Fe composite were significantly up-regulated compared with HA[64]。 Wong et al.doped strontium-Doped hydroxyapatite(Sr-HA)into PEEK polymer matrix,and successfully prepared Sr-HA/PEEK composites by compression molding technology[65]。 The flexural modulus and strength of The composite were comparable to those of human cortical bone.The bioactivity of Sr-HA/PEEK composite was proved to be higher than that of HA/PEEK by qualitative comparison of apatite formation in simulated body fluid and quantitative determination of MG-63-mediated mineralization in vitro。

4 Conclusion and prospect

From 2010 to 2020, a total of 8200 articles on strontium-doped biomaterials for osteogenesis were published (data source: google scholar, search: strontium, doped, material, bone, search time: 2020.05), and the number of articles increased year by year (Figure 4). These studies provide valuable practical value for the industrial development and clinical application of strontium-doped materials. Combined with the in vivo experimental results in some literatures, we found that compared with the pure material, more new bone tissue was found in the strontium-doped material, mostly distributed at the bone-material interface and around the material[8,34,38,51,54,76]. On the one hand, the introduction of strontium accelerates the degradation of bioactive materials, thus providing more space for the growth of new bone tissue near the interface. On the other hand, strontium doping significantly improves the osseointegration effect of the material, and the strontium released from the material is absorbed by bone tissues and cells around the implanted material, thereby improving the bone mass around the implanted material, and particularly has a certain inhibitory effect on bone resorption of osteoporotic bone. However, the effect of strontium doping on the bioactivity of the material is not good enough from the point of view of the improvement of bone mass in the material. Webster et al. Suggested that the adhesion of osteoblasts may be more dependent on the physical morphology of the surface of biomaterials than on the chemical composition of the surface[77]. Therefore, in order to further improve the bioactivity of Sr-doped materials, it is necessary to further study the surface morphology of the materials.
At present, the research on strontium-doped biomaterials mainly focuses on the regulation of strontium content and the preparation of multifunctional scaffolds doped with multiple elements, and further biological experiments are needed to detect their safety and osteogenic effect[78⇓~80]. One of the problems that is easy to be ignored is the influence of strontium release amount and release cycle on osteogenic effect. Strontium content in newly formed bone after strontium ranelate treatment was found to be strongly dose-dependent, and after 3 years of treatment, strontium content in bone reached a plateau, at which time strontium supplementation would not be effective[12]. After the end of treatment, ion substitution between strontium and calcium occurs again in the newly formed bone, and a subsequent decrease in the mechanical properties of the bone can be expected. Therefore, the study of strontium-doped coatings also needs to consider the action time of strontium. In addition, many scholars at home and abroad have done relevant research on the mechanism of strontium at the cellular and molecular levels, and put forward different opinions, but the specific mechanism of action and the safe and effective dosage are still inconclusive, which restrict the application of strontium doped materials. Therefore, it is very important to seek the balance point of different element loadings for strontium and multi-element doped composite multifunctional materials with therapeutic functions.

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Funding

the National Natural Science Foundation of China(8197155)

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