Strontium-Functionalized Biomaterials for Bone Regeneration: Mechanisms, Biological Functions, and Clinical Translational Progress

Introduction

Bone, as a key component of the human body, plays an indispensable role in life activities. The abundant cellular components in bones enable their self-repair and structural remodeling.¹ When the balance between bone formation and bone resorption is disrupted, it leads to bone loss and degradation of the bone microarchitecture, eventually resulting in the development of systemic osteoporosis—a common and challenging bone disease worldwide.² Data indicate that over 500 million people globally suffer from osteoarthritis (OA), and 43.5% of these patients typically experience limited joint movement due to the condition. According to the Global Burden of Disease Study (GBD) data from the U.S. Institute for Health Metrics and Evaluation (IHME), the prevalence of OA in the United States accounts for 10.5% of the total population, and this proportion increases significantly with age.³ Beyond inflammation, bone infections are often accompanied by bone loss. Common pathogens include Staphylococcus aureus (S. aureus), Streptococcus pneumoniae, and Escherichia coli (E. coli). Among these, S. aureus constitutes over 70% of the pathogenic flora due to its strong invasiveness, colonization ability, and proliferative capacity.⁴ For bone defects induced by chronic infections, conventional therapies often fail to achieve satisfactory outcomes. Another common issue affecting bone health is malignant tumors, such as bone cancer;⁵ additionally, oral and maxillofacial surgeries may cause severe bone defects.⁶ To repair bone defects larger than the critical size, autologous bone transplantation or bone graft substitutes are usually required.^1,2 Therefore, a key challenge in bone tissue engineering (BTE) is to develop biodegradable bone substitutes with appropriate mechanical and biological properties, as well as anti-inflammatory and antibacterial effects.⁷

Strontium ranelate (SrR), a unique anti-osteoporotic drug, has been effectively used for the prevention and treatment of osteoporosis in postmenopausal women.^8–10 Given the therapeutic efficacy of SrR in osteoporosis management, this has sparked growing interest in the application of Sr²⁺ in bone therapy.¹¹ Sr²⁺ exhibits a marked tropism for bone tissues and possesses bidirectional regulatory properties: it activates osteoblastic bone matrix synthesis while inhibiting osteoclastic resorption. Additionally, it exerts antibacterial activity and promotes neovascularization—collectively facilitating bone regeneration.^12–14 However, studies have shown that the oral absorption efficiency of Sr²⁺ is suboptimal, and concurrent calcium (Ca) intake or calcium-rich diets further impair its pharmacokinetic performance.^10,15

Consequently, bone engineering strategies advocate the implantation of resorbable Sr²⁺-loaded matrices to achieve controlled ion release for bone defect repair. Recent advances have enabled the integration of Sr²⁺ into various orthopedic biomaterials, including titanium-based prostheses, orthopedic cements, bioglass composites, collagen matrices, regenerative scaffolds, and therapeutic release systems.^16–20 The implantation of biomaterials triggers a cascade of immune responses through protein adsorption, involving macrophage phenotypic polarization and the dynamic regulation of cytokines (collectively referred to as the foreign body reaction, FBR).²¹ Bone integration is essentially a dynamic bone repair process regulated by the reprogramming of the immune microenvironment.^22,23 Various cells in the bone immune microenvironment interact with bone marrow mesenchymal stem cells (BMSCs), continuously remodeling bone to maintain its mechanical strength and structural integrity.^24,25 As the core cells of bone immunity, macrophages are crucial for organ development and inflammatory homeostasis, and their phenotypes and functions can be modulated by factors such as Sr²⁺.²⁴ Modulating macrophage phenotypic polarization to ameliorate inflammatory conditions represents a promising therapeutic strategy for disease management.^26,27

During bone remodeling, angiogenesis and bone formation are closely coupled.²⁶ Vascularization of bone repair materials is also a key issue to be addressed in the bone repair process.²⁷ In the early stage of angiogenesis, macrophages can exert vasculotrophic effects through physical contact and the secretion of potent angiogenic factors.²⁸ Mesenchymal stem cells (MSCs) and immune cells also participate in important intercellular communication,²⁹ guiding the host response and regulating the immune microenvironment.³⁰

Although research on strontium-containing biomaterials for bone repair has been increasing, existing reviews still lack systematic integration of the intrinsic relationships among material design, ion release behavior, biological mechanisms, and clinical translation. Sr²⁺ can improve the physicochemical properties of biomaterials in a concentration-dependent manner and simultaneously regulate key processes of bone regeneration, including osteogenic differentiation, osteoclast inhibition, immune microenvironment modulation, and angiogenesis.^31–33 Therefore, dose optimization, release regulation, and translational application of Sr-based materials have become important research directions. Previous reviews have mainly focused on strontium-containing bioactive glasses, Sr-related osteoimmunomodulation, or the general progress of recent Sr-functionalized materials, whereas the associations between material composition and fabrication methods, Sr²⁺ release, cellular behavior, and bone repair outcomes remain relatively underexplored. Based on this, this review systematically summarizes the dual regulatory mechanisms, concentration-dependent bioactivity, antibacterial properties, and clinical translational potential of Sr²⁺ in bone regeneration from an integrated perspective. In addition, by incorporating recent advances, this review further includes representative emerging materials such as Sr/Mg co-doped scaffolds, injectable Sr-based hydrogels, and Sr-based nanodelivery systems, aiming to further illustrate the developmental trends of Sr-functionalized bone repair materials in multi-ion synergy, local delivery, and precise regulation, and to provide references for the rational design and translational application of next-generation Sr-functionalized bone repair biomaterials.

Effect of Sr Incorporation on the Physicochemical Properties and Biological Performance of Bone Restorative Materials

Effect of Sr Incorporation on Crystal Structure, Physicochemical Properties, and Degradation Behavior

As a mineral, Sr²⁺ is absorbed in the body similarly to calcium ions (Ca²⁺). In Ca-based bioceramics, Sr²⁺ has been widely used as a substitute for Ca²⁺. Because the ionic radius of Sr²⁺ (118 pm) is larger than that of Ca²⁺ (99 pm), the substitution of Ca²⁺ by Sr²⁺ disrupts the structural arrangement and symmetry of the hydroxyapatite (HA) lattice, induces lattice strain, and expands the HA unit cell size.^34,35 X-ray diffraction (XRD) analyses demonstrated that increasing Sr²⁺ incorporation in HA reduced crystallinity and broadened the characteristic diffraction peaks with a shift toward lower angles, indicating the successful incorporation of Sr²⁺ into the HA crystal structure. Moreover, the Sr²⁺ doping amount may be a dominant factor affecting crystal size.³¹ In contrast, replacing larger-radius Ba²⁺ with smaller-radius Sr²⁺ results in unit cell shrinkage and reduced particle size.³⁶ Additionally, because Sr²⁺ possesses lower electronegativity (0.95) than Ca²⁺ (1.0), Sr²⁺ incorporation can alter the surface charge of HA and increase its positive surface potential.³⁴

The lattice distortion and reduced crystallinity induced by Sr²⁺ further influence the degradation behavior of biomaterials. Sr²⁺ substitution decreases the crystallinity of Ca-based bioceramics, thereby accelerating degradation and increasing ion release, which may contribute to enhanced material bioactivity.³⁷ In apatite structures, Sr²⁺ substitution for Ca²⁺ also promotes phosphate degradation, potentially generating an ion-rich microenvironment favorable for bone formation.³⁸ In hydrogel systems, increasing Sr²⁺ concentration improves structural stability and lowers the swelling rate during the early swelling stage, likely due to the increased cross-linking density caused by the chelation reaction between -COOH groups and Sr²⁺.³⁹

In addition, Sr²⁺ significantly affects the phase stability of calcium phosphate materials. Tovani et al developed a bioinspired physical confinement strategy for fabricating Sr-doped apatite [Sr(CaP)] nanotubes. In the absence of Sr²⁺, poorly crystalline apatite resembling bone mineral preferentially nucleated within the pores of polymeric membranes. However, introducing 10% Sr²⁺ induced lattice distortion in the apatite crystalline framework and caused broadened diffraction bands in XRD patterns.³⁸ Another study demonstrated that the biomimetic precipitation of Sr-doped amorphous calcium phosphate (Sr-ACP) in homogeneous media initiated only when 25% of Ca²⁺ in the apatite lattice was substituted by Sr²⁺. Furthermore, the amorphous phase remained stable only at higher Sr²⁺ substitution levels, such as 50% and 75%.³⁸ Xu et al further showed that incorporating 2.5 wt% Sr²⁺ into the ACP framework prolonged the persistence of the amorphous state under dehydrated conditions for at least 3.5 years. Compared with pure ACP, Sr-ACP may serve as a more favorable component for medical devices with enhanced bone repair potential.⁴⁰

Regulation of Osteogenesis and Biomineralization by Sr Concentration

The biological effects of Sr²⁺ on bone restorative materials exhibit a clear concentration-dependent manner. Appropriate Sr²⁺ release can generate an ion-rich microenvironment favorable for bone formation and promote osteogenic cellular responses. However, excessive Sr²⁺ concentrations may negatively affect both material stability and osteogenesis. For example, incorporating 50% Sr²⁺ may destabilize the apatite lattice structure, distort crystal symmetry, and impair osteogenesis.⁴¹

Studies on amorphous strontium calcium phosphate (Sr-Ca-ACP) particles with low Sr²⁺ content identified 10% as a relatively optimal proportion of Sr²⁺ for bone tissue application.³⁸ Increasing Sr²⁺ content from 10% to 50% destabilized collagen assembly, hindered the crystallization of bone apatite-like platelets, and generated Sr²⁺-enriched micrometer-sized ACP particles within collagen scaffolds. These changes disrupted the typical three-dimensional bone structure and impaired preosteoblast adhesion.⁴² At a concentration of 10 mol% Sr²⁺, the absorption peaks associated with the vibrational modes of OH⁻ groups in HA disappeared, which was likely caused by structural distortion induced by the larger Sr²⁺ ions.³¹

Notably, HA composites containing 10 mol% Sr substitution exhibited biomechanical properties similar to those of natural bone and supported bone formation, vascularization, and osseointegration in a sheep model of severe bone defects.⁴³ These findings further demonstrated that 10% Sr²⁺-enriched scaffolds possess considerable efficacy in stimulating the osteogenic differentiation of mesenchymal stem cells (MSCs) (Figure 1).⁴⁴ Therefore, higher Sr²⁺ incorporation is not necessarily associated with superior osteogenic performance, and maintaining a balance between structural stability and osteogenic bioactivity is essential (Table 1).

Figure 1 Effect of Sr2⁺ substitution for Ca2⁺ on the physicochemical and biological properties of biomaterials. Sr2⁺ substitution within hydroxyapatite alters crystallinity, crystalline phase stability, ion release behavior, surface positive charge, unit cell size, and degradability. Upward arrows indicate enhancement or increase, whereas downward arrows indicate reduction or decrease following Sr2⁺ incorporation.

Table 1 Effects of Sr Dose, Incorporation Level, and Release Behavior on Physicochemical Properties and Biological Responses

Design Strategies and Clinical Translation of Sr-Based Composite Biomaterials

Compared with other therapeutic ions, Sr is characterized by its dual regulatory effects on bone metabolism, including promotion of osteoblast-lineage activity and suppression of osteoclast-mediated bone resorption. In contrast, Mg mainly contributes to mineral metabolism, degradation regulation, and angiogenesis;⁵⁷ Zn is closely associated with antibacterial activity and osteogenic enzyme regulation;⁴⁶ Cu exhibits prominent angiogenic and antibacterial properties but requires careful cytotoxicity control;⁵⁸ while Se and Ga are commonly introduced to enhance antimicrobial or antitumor functions.^59,60 Therefore, Sr is particularly suitable as a core osteoimmunomodulatory ion, whereas Mg, Zn, Cu, Se, or Ga may be combined with Sr to compensate for the limitations of single-ion systems.

In strontium-based composite biomaterials, the focus of multi-ion design is not to simply increase the total ion loading, but to align the release profiles of Sr²⁺ and other functional ions with different stages of bone healing.⁶¹ Early-stage release may emphasize anti-inflammatory and antibacterial effects, intermediate-stage release may promote angiogenesis, and late-stage release may sustain osteogenesis and bone remodeling, thereby enabling complementary effects between Sr²⁺ and ions such as Mg, Zn, Cu, Se, or Ga. Meanwhile, fabrication techniques directly determine the distribution, release behavior, degradation profile, and mechanical performance of Sr²⁺.⁶² Ion substitution within calcium phosphate or HA lattices can achieve stable Sr²⁺ incorporation, although it may affect crystallinity and phase stability.³⁸ Sol–gel methods and mesoporous bioactive glasses are advantageous for regulating ion release, but require precise control of pore structure and dissolution kinetics.⁶³ Ti and PEEK surface coatings are suitable for enhancing local Sr²⁺ activity at the bone–implant interface, whereas 3D printing, injectable hydrogels, and bone cements are more appropriate for individualized bone defects, spatial multi-ion distribution, and minimally invasive delivery, respectively.^48–50 Therefore, the fabrication strategy of strontium-based biomaterials should be selected according to defect morphology, load-bearing requirements, degradation period, and infection risk (Table 2).

Table 2 Therapeutic Ions Combined with Sr in Bone-Regenerative Composites

Osteogenic Functions and Mechanisms of Sr²⁺

Sr²⁺ Can Be Directly Involved in Bone Regeneration and Its Regulatory Mechanisms

Ca is the fundamental element composing the mineral component of bone, and Sr²⁺ share similar chemical and physical properties as well as ionic size with Ca²⁺.⁶⁴ Sr²⁺ can substitute for Ca in hydroxyapatite, endowing bone graft substitutes with excellent osteogenic capabilities and upregulating the expression of osteogenic-related genes such as RUNX2 (runt-related transcription factor 2), Osterix, alkaline phosphatase (ALP), and collagen type 1 (COL-1).^65–67 Sr-coated biomaterials have been widely applied due to their superior tissue integration ability and osteogenic effects; various Sr-coated materials enhance the expression of osteogenic markers, including bone morphogenetic protein-2 (BMP2), osteocalcin (OCN), osteopontin (OPN), osteoprotegerin (OPG), osteoblast-specific transcription factor (OSX, also known as Osterix), ALP, RUNX2, and COL-1. This promotes the differentiation of osteogenic genes in bone defect regions and stimulates bone formation.^{48–50,63–67}

The differentiation of MSCs into other cell lineages is precisely regulated by signaling pathways,^68–70 and Sr²⁺ acts as one of the key factors governing this differentiation process.¹⁰ During bone remodeling, Sr²⁺ uniquely exerts both catabolic and anabolic effects by inducing prostaglandin (PG) synthesis and cyclooxygenase (COX) expression, thereby promoting the differentiation of MSCs into osteoblasts.¹³ Sr²⁺ helps maintain more cells in the cell cycle by increasing the proportions of S-phase and G2/M-phase cell populations. It also regulates the asymmetric stem cell division (ACD) of the Par complex via activating the atypical Wnt5a signaling pathway, and promotes bone formation by inducing the asymmetric distribution of Par3 and aPKC (atypical protein kinase C).⁷¹ The activation of the Wnt signaling pathway requires Wnt ligands to bind to Frizzled (FZD) receptors and cooperate with co-receptors LRP5/6 to initiate downstream signaling events.⁷² Sr²⁺ enhances the phosphorylation of glycogen synthase kinase-3β (GSK-3β), which in turn inhibits its enzymatic activity and stabilizes β-catenin.^49,73,74 This stabilization facilitates the translocation of β-catenin into the nucleus, where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating downstream genes such as c-myc and osteogenic markers.⁷²

Cui et al demonstrated that Sr²⁺ promotes the osteoblastic differentiation of human bone marrow mesenchymal stromal cells (hBMSCs) via the Wnt/β-catenin pathway, as evidenced by the increased expression of signaling components including Axin-2 and β-catenin.^49,73,74 Furthermore, Sr²⁺ stimulates the expression of c-myc, a β-catenin-dependent transcriptional target, which reinforces osteogenic signaling.^49,73,74 Mechanistically, Sr²⁺ interacts with the calcium-sensing receptor (CaR) on the cell membrane, thereby upregulating the expression of osteogenic transcription factors such as RUNX2, ALP, and OPN, and promoting the proliferation and differentiation of MSCs (Figure 2).⁷⁵ Additionally, Sr²⁺ promotes the proliferation and osteogenic differentiation of MSCs; it also enables treated human osteosarcoma cells (MG-63) to acquire mature cellular functions via the canonical Wnt signaling pathway, regulating cell proliferation, migration, and growth.⁷⁶

Figure 2 Schematics of nHA/CS@PDA-Sr.75 (A) Schematic overview of the synthesis of nHA/CS@PDA-Sr and bone defect repair. (B) Sustained release of Sr2+ from nHA/CS@PDA-Sr promotes mesenchymal stem cell osteogenesis and endothelial cell angiogenesis. Arrows in the figure indicate activation, promotion, release, differentiation, migration, or process direction.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) acts as the master regulator of adipogenesis.^10,71 This process is also regulated by a series of transcription factors, including CCAAT/enhancer-binding proteins (C/EBPs), signal transducers and activators of transcription (STATs), and adipocyte determinant and differentiation-dependent factor 1/sterol regulatory element-binding protein 1c (ADD1/SREBP1c).⁷⁷ Some researchers have proposed that knockdown of the adhesion molecule CDH2 in MSCs leads to increased mRNA expression of DLX5, SP7, and ALP, along with decreased PPAR-γ expression—this in turn reduces cell viability and concurrently impairs osteogenic differentiation.⁴⁹

Sr²⁺ acts as a pivotal modulator of MSC differentiation, mediating the downregulation of PPARγ2 to attenuate adipogenesis while directing cellular commitment toward osteoblastic phenotypes.¹⁰ Aimaiti et al demonstrated that Sr²⁺ can reactivate the extracellular signal-regulated kinase (ERK) signaling pathway to antagonize the inhibitory effect of dexamethasone (DEX) on osteogenesis, enhance ERK phosphorylation, and thereby inhibit adipogenesis by downregulating the expression levels of PPAR-γ and adipocyte fatty acid-binding protein (aP2), ultimately promoting osteogenic differentiation and matrix mineralization.⁷⁸ The molecular target of Sr²⁺ may be located between signal transducer and activator of transcription 3 (STAT3) and PPAR-γ; it significantly reduces the protein expression levels of PPAR-γ and STAT1 in BMSCs.⁷⁷

Most scholars believe that Sr²⁺ promotes osteogenesis by regulating the differentiation direction of MSCs or precursor cells, rather than acting on already differentiated adipocytes. Ataie et al also confirmed this, showing that Sr²⁺ significantly upregulates the expression of osteogenic genes (RUNX2 and OCN) in human adipose-derived stem cells (hADSCs).⁷⁹

Shimizu et al demonstrated that the surface micro/nanostructure of implants promotes cell adhesion and enables the sustained release of Sr²⁺ from the coating.⁸⁰ This stimulated cellular adhesion results in enhanced expression of integrin β, coordination of intrinsic signaling pathways, and activation of the FAK/MAPK and PI3K/Akt signaling cascades.⁸⁰ Activation of the FAK/MAPK cascade increases the phosphorylation levels of FAK, ERK1/2, and p38 in BMSCs.^76,81 FAK, an intracellular non-receptor tyrosine kinase, plays a pivotal role in adhesion-mediated signaling mechanisms.⁸²

Sr²⁺ can activate integrins, which in turn block the activity of glycogen synthase kinase 3 (GSK3) via the CaSR/PI3K/Akt signaling pathway, thereby enhancing nuclear transcription.⁸³ Researchers exposed MC3T3-E1 cells to ion release extracts from SrHPO₄-coated JDBM (Mg-Nd-Zn-Zr alloy), which significantly increased the expression of PI3K and phosphorylated Akt (at Ser 473 and Thr 308) in the cells.⁸⁴ Treatment with a TLR4 inhibitor (CLI-095) resulted in a significant decrease in these protein levels, highlighting the TLR4/PI3K/Akt signaling pathway as a potential mechanism regulating the osteogenic response (Figure 3).⁸⁴

Figure 3 Osteogenic effects of SrHPO4-coated JDBM extracts on MC3T3-E1 cells via the TLR4/PI3K/Akt signaling pathway.84 (A) ALP, OCN and TLR4 expression after treatment with Ti6Al4V, JDBM, SrHPO4-coated JDBM, and SrHPO4-coated JDBM + CLI-095 extracts. (B) pan-Akt, p-Akt (Ser473), p-Akt (Thr308), p-PI3K (p85), and PI3K expression after the same treatments. (C) Alizarin Red S staining after 21 days of incubation. Data are presented as mean ± SD. Statistical significance is indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

Effects of Sr²⁺ Concentration on Bone Tissue Engineering Repair

Sr²⁺ exhibits a marked concentration-dependent influence on various cell types.⁴⁵ It was shown that low amounts of Sr²⁺ induced osteogenic responses in human MSCs, increasing the expression of transcription factors (including RUNX2 and OSR) and osteogenic markers including ALP, OPN, OSP, OSC, and bone salivary proteins (BSP).⁸⁵ Whereas excessive concentrations of Sr²⁺ were unfavorable for cellular activity.³⁹ Nevertheless, with rising strontium ion levels, the quantity of TRAP+ cells exhibited a progressive reduction, and even trace Sr²⁺ concentrations (under 0.2 mg/L) effectively suppressed osteoclastic function and maturation,³⁸ falling within the range of Sr²⁺ positive concentrations (0.01–1mM) that stimulate osteogenesis and inhibit osteoclastogenesis.⁸⁶ The highest osteogenic potential was noted in BMSCs grown in 2% Sr²⁺-enriched medium, characterized by markedly upregulated levels of BMP-2, OCN, Col-I and VEGF, along with significantly increased ALP activity and Ca deposition. Additionally, assessments for cartilaginous tissue development, vascular neotissue formation, and tendon integration with surrounding tissues demonstrated superior outcomes compared to other concentration groups.³¹

From the previous section, it is known that Sr²⁺ can trigger a variety of signaling pathways and promote osteogenesis.⁸⁷ At very low doses of Sr²⁺, Sr-incorporated carbon nitride nanosheets (CNS) can activate the FAK/RhoA/ROCK1 signaling pathway, promote stress fiber formation, and enhance intracellular mechanical tension, thereby facilitating osteogenic differentiation.⁸⁷ Submicromolar Sr²⁺ doses (0.1 μg/mL, ie., ~1.14 μM) reprogrammed SMAD phosphorylation equilibria, enhancing cell proliferation while suppressing chondrogenic differentiation in articular chondrocytes by biasing the TGFβ1 pathway toward SMAD3 activation, concomitantly at the expense of SMAD1/5/9 signaling axes.⁸⁸ Additionally, the MAPK/ERK pathway is an important osteogenic mechanism.⁵¹ With increasing concentrations of Zn²⁺ and Sr²⁺ in co-supplemented cultures, the osteogenesis-related gene expression of BMSCs increases initially and then declines gradually. When the concentration of Sr²⁺ exceeds 10 mM and that of Zn²⁺ exceeds 80 μM, BMSC viability is significantly impaired. At the optimal concentrations of 6 mM Sr²⁺ and 40 μM Zn²⁺, Sr²⁺ significantly enhances the phosphorylation of Erk1/2 and p38, while Zn²⁺ specifically promotes p38 phosphorylation; additionally, Zn²⁺ markedly enhances Erk1/2 phosphorylation.⁵¹ Furthermore, researchers can regulate the surface charge by modulating Sr²⁺ concentrations.⁸⁹ The data shows that changes in the membrane potential of cells treated with Sr²⁺ barium titanate (nBa²⁺: nSr²⁺ = 7.9:0.1) enhance the elevated expression of the L-type voltage-gated Ca²⁺ channel Cav1.2.⁸⁹ This channel governs cytosolic Ca²⁺ levels by altering its gating state or modulating its abundance on the plasma membrane.³⁹ Consequently, increased intracellular Ca²⁺ acts as a secondary signaling molecule, initiating downstream signaling through the calcium-dependent calmodulin/calcineurin-NFAT cascade to stimulate bone formation processes.^36,89

The results of some studies showed that Sr²⁺ concentration promoted MSCs proliferation at ion release accumulation levels of 0.5 and 1 mM, while the opposite effect was observed for ion release accumulation levels ranging from 1 to 10 mM.⁹⁰ In addition, the CCK-8 assay demonstrated that elevated SrR levels (0.5, 1.0, and 2.0 mM) markedly suppressed cellular viability (P<0.05), whereas lower doses (0.125, 0.25, and 0.5 mM) exerted no notable influence on BMSC growth, suggesting that Sr²⁺ concentrations of 0.5 and 1 mM significantly restricted MSC proliferative capacity.⁴⁵ However, low concentrations of SrR (0.125, 0.25, and 0.5 mmol/L) did not affect the proliferation of BMSCs, which suggests that different concentrations of Sr²⁺ will have different effects on cells. Literature has shown that concentrations of Sr²⁺ between 1.9 mg/L and 7.3 mg/L have beneficial effects on osteoblast activity and proliferation, with 16.4 wt%-Sr²⁺ substituted magnesium phosphate (MgP) scaffolds having the best physical and osteogenic properties.⁹¹ Ding et al reported that the optimal Sr²⁺ concentration (25–500 µm) for promoting osteogenic differentiation of stem cells was 500 µm, and that this Sr100nHA/hydroxypropyl chitosan/aldehyde dextran hydrogel (CDH) group also promoted osteogenesis in vivo and accelerated the reconstruction of bone defects.⁴¹

In addition, quantitative analysis of Von Kossadye solution staining and alizarin red S staining demonstrated that mineralization of the extracellular matrix inside and outside the hydrogel increased dramatically with increasing Sr²⁺ concentration (P<0.05).³⁹ 3D-printed alginate-collagen composite hydrogels seeded with MC3T3-E1 osteoblasts were crosslinked using varying concentrations of 1% strontium-enriched calcium polyphosphate (SCPP). The optimal Sr²⁺ concentration for cell proliferation and mineralization, as well as the concentration of 1% SCPP that minimized cytotoxic effects (0.3–0.5 mg/mL), were determined. Additionally, 0.5 mg/mL SCPP was found to produce sufficient amounts of Ca nodules.⁹²

Sr²⁺ May Indirectly Promote Osteogenesis by Inhibiting Osteoclasts

In the research process of osteogenesis, Wang et al have proposed a novel central mechanism: Sr²⁺ induces autophagy, thereby leading to rapid osseointegration by activating the time-dependent regulation of the Akt/mTOR signaling pathway. Additionally, increased secretion of OPG by osteoblasts alters the RANK/RANKL/OPG axis (receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin axis), indirectly inhibiting osteoclastogenesis.⁹³ An elevated LC3II/LC3-I ratio and high expression levels of Beclin1 (autophagy-related protein Beclin1) demonstrated that Sr²⁺ activates both the early and late stages of autophagy. As a critical regulator in autophagosome nucleation, Beclin1 triggers this process by mobilizing other autophagy-related proteins to the phagophore assembly site.^93–95

Furthermore, Sr²⁺ inhibits bone resorption by decreasing the osteoclastogenic factor ratio of RANKL to OPG.^68,96 Sr²⁺ also suppresses RANKL-induced osteoclastogenesis by promoting the expression of nuclear factor kappa-B inhibitory protein (IκB-α), significantly inhibiting the phosphorylation of the NF-κB subunit P65, and downregulating the NF-κB signaling pathway.⁷² Simultaneously, it increases the expression level of OPN, thereby limiting the interaction between the receptor activator of NF-κB (RANK) and its ligand RANKL, and consequently inhibiting osteoclast activity.⁹⁷ Moreover, enhanced OPG expression and inactivated nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) block RANKL binding and further suppress osteoclast formation.⁹⁸

Zeng et al found that supplementation with Sr²⁺ significantly inhibits NFATc1, a key transcription factor regulating the expression of multiple genes associated with osteoclast differentiation and function.⁹⁹ As a core transcription factor, NFATc1 regulates the expression of various genes related to osteoclast differentiation and function, thereby downregulating target genes such as c-FOS, OSCAR (osteoclast-associated receptor), TRAP (tartrate-resistant acid phosphatase), MMP-9 (matrix metalloproteinase-9), and TRAF6 (tumor necrosis factor receptor-associated factor 6) to inhibit osteoclast differentiation and activity.^72,100 The results are summarized as follows (Figure 4).

Figure 4 Sr2⁺ inhibits bone resorption by regulating the RANKL/OPG ratio, inhibiting the NF-κB signaling pathway, and downregulating the NFATc1 transcription factor.

Sr²⁺ May Influence Bone Repair by Participating in Immune Modulation

Modulation of the immune milieu has emerged as a promising therapeutic focus for osseous repair,¹⁰¹ with immune cells interacting with osteoblasts through direct contact or paracrine mechanisms.¹⁰² The effect of macrophages on osteoblasts depends on their polarization profiles and the paracrine factors they secrete.¹⁰³ As a highly plastic cell population,¹⁰⁴ macrophages exhibit diverse roles throughout inflammatory responses and tissue repair, serving as a key regulatory cell population that modulates subsequent phases of bone-implant integration.¹⁰⁵

Sr²⁺-doped implants inhibit the expression of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) by attenuating the activation of nuclear factor-κB (NF-κB).¹⁰⁶ In RAW264.7 macrophages, the expression levels of IL-1β and matrix metalloproteinase 9 (MMP9) are downregulated by approximately 0.6-fold, while the mRNA levels of cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), and interleukin-6 (IL-6) are also reduced.¹⁰⁷ BMP2, a potent osteoinductive cytokine involved in skeletal regeneration, is significantly upregulated by Sr²⁺, and it plays a pivotal role in initiating fracture repair and enhancing the expression of osteogenic markers—including ALP, RUNX2, OCN and collagen-related proteins.¹⁰⁶ This process fosters an immunomodulatory microenvironment that suppresses RANKL-mediated osteoclastogenesis.¹⁰⁶

Additionally, Sr²⁺ can induce neutrophils to play an important role in bone immunity. By suppressing the NF-κB signaling pathway and increasing the phosphorylation level of STAT3, Sr²⁺ induces the polarization of neutrophils toward the N2 phenotype and promotes neovascularization.¹⁰⁸

Macrophage cytoarchitecture and catalase (CAT)/superoxide dismutase (SOD) activity are influenced by oxidative stress (OS) and inflammation.^102,103 In early inflammatory environments, Sr²⁺ upregulates the expression of OMSR/IL6st/STAT3—key genes in the oncostatin M (OSM) pathway—to promote osteogenesis.⁴⁶ Through the ERK signaling pathway, Sr²⁺ polarizes macrophages from the M1 to the M2 phenotype. Subsequently, M2 macrophages overexpress osteogenesis-related cytokines such as transforming growth factor-β (TGF-β), platelet-derived growth factor-BB (PDGF-BB), and BMP2; they also stimulate the expression of the anti-inflammatory genes arginase and interleukin 10 (IL-10), reducing the inhibitory effect of the pro-inflammatory factor TNF-α on BMP, OSX, ALP, and RUNX2. Sr²⁺ downregulates the expression of inflammation-related genes (IL-1β, TNF-α, and IL-6) in macrophages.^102,103,105 The upregulated IL-10 can suppress the production of pro-inflammatory cytokines (including IL-1β, TNF-α, and IL-6), thereby exerting anti-inflammatory effects and enhancing tissue repair (Figure 5).¹⁰⁹

Figure 5 Sr2⁺ induces M2 polarization of macrophages through the ERK pathway, upregulates osteogenic factor TGF-β1/PDGF-BB/BMP2 and inhibits inflammatory factors (IL-1β, TNF-α, IL-6), and activates IL-10 to enhance anti-inflammatory effect, thereby promoting bone regeneration.

Macrophage paracrine signaling activated by Sr-containing implants promotes the proliferation of osteoblasts and the osteogenic differentiation of MSCs.¹¹⁰ Additionally, biomaterials containing mixed metal ions—such as the slow-release Cu²⁺/Sr²⁺ bone cement designed by Li et al and the sustained-release Zn²⁺/Sr²⁺ composite scaffolds prepared by Qian et al via selective laser sintering—upregulate the expression of anti-inflammatory genes (IL-10, Arg-1 (arginase-1), IL-1Ra (interleukin-1 receptor antagonist), and TGF-β1) while downregulating the pro-inflammatory genes (TNF-α, IL-1β, and IL-6) when co-cultured with macrophages.^111,112

This immunomodulatory effect further regulates bone healing and suggests superior bone-enhancing effects compared to using Sr²⁺ alone.^111,112 This favorable osteogenic microenvironment prompts macrophages to significantly upregulate the expression of osteogenesis-related genes involved in cellular development, including ALP, OSM, RUNX2, BMP-2, Wnt10b, and OSX. This, in turn, increases ALP activity and promotes the formation of mineralized nodules.¹¹² Notably, during the late stages of NFATc1/Maf and Wnt signaling pathway activation, Sr²⁺ can significantly elevate the expression of osteogenic factors in BMSCs by stimulating macrophages to establish an appropriate bone immune microenvironment.⁴⁶

Effects of Sr²⁺ on Angiogenesis

Bone is highly vascularized, with blood vessels playing an integral role in maintaining bone and bone marrow homeostasis.¹¹³ The vascular network acts as a multifunctional circulatory structure, exerting pivotal functions in organ morphogenesis, tissue renewal, and stem cell dynamics. Within osseous microenvironments, specific vascular niches sustain perivascular stem cells or osteoprogenitors, thereby orchestrating osteogenic processes.¹¹⁴

Slowly released Sr²⁺ can upregulate the expression of miR-146a (microRNA-146a),¹¹⁵ and angiogenic genes (vascular endothelial growth factor, VEGF; basic fibroblast growth factor, bFGF).¹¹¹ It also inhibits the expression of Smad4 and NF2 proteins,¹¹⁵ as well as the pro-inflammatory factor IL-6, in HUVECs.²² This combined regulatory effect, in turn, promotes developmental vascularization and vascularized bone regeneration.¹¹⁵

Xing et al demonstrated that Sr²⁺ can inhibit apoptosis in rat cardiomyocytes (CMs) by decreasing caspase-3 activity and promote angiogenesis by enhancing cell proliferation, strengthening paracrine capacity, and regulating interactions among cardiac cells.¹¹⁶ Sr²⁺ stimulates the release of myogenic regulatory factors (myogenin, MyoG; myoblast determination protein, MyoD) and angiogenic factors (VEGF; hypoxia-inducible factor-1α, HIF-1α), which directly protect injured muscle tissues and facilitate microvascular repair.^105,109 Additionally, Sr²⁺ facilitates the M2 polarization of macrophages and suppresses their M1 polarization, indirectly protecting muscle tissues and promoting angiogenesis.¹¹⁷

In bone defect regions, Sr²⁺ activates the platelet-derived growth factor-BB (PDGF-BB)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway to enhance angiogenesis, leading to increased AKT phosphorylation and PDGF-BB expression in HUVECs.¹¹⁸ Furthermore, due to their immunomodulatory effects, HUVECs can polarize macrophages from the M1 to the M2 phenotype and secrete high levels of VEGF and PDGF-BB. These factors promote vascular development in defect regions, accelerate new bone formation, and ultimately improve bone repair outcomes.²⁷

Sr²⁺ Elements Function in Other Ways

Antimicrobial Effects of Sr²⁺

It has been reported that 6 mM Sr²⁺ can significantly inhibit the growth of Streptococcus mutans (S. mutans), halting its proliferation within 10 hours. However, its inhibitory effect is weaker than that of 40 μM Zn²⁺, which can arrest S. mutans growth within 8 hours.⁵¹ A high-Sr content nanomaterial (15 wt% Sr-CaP, strontium-doped calcium phosphate) exerts significant antibacterial activity against Pseudomonas aeruginosa (P. aeruginosa; the original term “Mycobacterium glauciobacterium” was incorrect), and can completely inhibit P. aeruginosa growth. This effect is associated with Sr²⁺-mediated alterations in the zeta potential of the material surface.¹¹⁹ Strontium-containing hydroxyapatite (Sr-HA) coatings indirectly inhibit bacterial adhesion by alleviating zinc-based degradation and Zn²⁺ cytotoxicity. Their surface properties, such as smoothness, are superior to those of single-layer Zn(OH)₂ or HA coatings, further reducing the risk of bacterial colonization.¹²⁰

The combined release of multiple ions (eg., Zn²⁺/Sr²⁺/Mg²⁺) disrupts bacterial metabolism by creating an alkaline microenvironment. It also induces bacterial membrane potential differences and triggers reactive oxygen species (ROS) production, achieving synergistic antimicrobial effects.^52–54 The combination of gallium ions (Ga³⁺) and Sr²⁺ significantly inhibits S. aureus on implant surfaces; this synergistic effect enhances both osteogenic and antimicrobial properties.⁵⁵ Selenium ions (Se²⁺)/Sr²⁺ co-doped HA exhibits broad-spectrum antibacterial activity against E. coli (a Gram-negative bacterium) and Gram-positive bacteria (eg., S. aureus). The addition of Se neutralizes the cytotoxicity of Sr-HA.³⁴ The Sr²⁺/Zn²⁺/Se²⁺ ternary composite scaffold integrates antimicrobial, antitumor, and osteogenic functions.⁵¹ Calcium-aluminate cement (CA) composites containing 20 wt% strontium borosilicate glass (SrBG) exhibit the optimal biofilm inhibitory effect against E. coli and S. aureus. However, antimicrobial activity is negatively correlated with surface porosity: high Sr²⁺ content enhances surface smoothness, inhibiting biofilm formation via physical barrier effects rather than direct bactericidal action.⁵⁶ Other studies have shown that Sr-doped materials can inhibit biofilm formation but exert no direct killing effect on specific strains (eg., S. aureus and E. coli), suggesting that their antimicrobial mechanism may be primarily mediated by indirect regulation (eg., microenvironmental changes or material surface modification).⁵⁶

Antioxidant Effects of Sr²⁺

Sr²⁺-doped modified amino-functional mesoporous bioactive glass (MBG) has been developed as a bioactive scaffold. This scaffold not only facilitates superior bone regeneration and vascularization but also reduces ROS levels in BMSCs by activating the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway, thereby counteracting OS.⁹

Notably, Sr²⁺ itself can also downregulate ROS levels via activating the cAMP/PKA signaling pathway. Furthermore, Sr²⁺ modulates the behaviors of osteoblasts and osteoclasts by enhancing the activities of antioxidant enzymes (catalase, CAT; superoxide dismutase, SOD), increasing local oxygen tension, and scavenging excessive endogenous ROS in osteoblasts. These effects endow Sr-containing samples with excellent osteoinductive and antioxidant properties.^121,122 Kaur et al also confirmed that Sr-doped bioceramic materials exert favorable protective effects against oxidative stress, among which the 5 mol% Sr-doped bioceramic exhibits the strongest protective effect against hydrogen peroxide (H₂O₂)-induced oxidative stress.¹²³

Clinical Applications of Sr-Containing Biomaterials

The clinical translation of strontium-containing biomaterials requires a comprehensive evaluation of material forms, defect indications, ion release characteristics, mechanical requirements, surgical applicability, and risk-benefit balance.¹²⁴ Accumulated evidence has verified that strontium acts as a promising functional ion for the fabrication of bone cements, hydrogels, porous scaffolds, and surface-modified coated implants.¹²⁵ Nevertheless, most current studies remain confined to in vitro experiments and small-animal models.¹²⁴ Local strontium delivery strategy is particularly critical throughout the clinical translation process. This approach can construct a favorable therapeutic microenvironment at the bone defect and implant interface, reduce systemic strontium exposure, and circumvent the pharmacokinetic limitations of oral administration.⁶² For load-bearing skeletal sites, the fatigue resistance of strontium-modified ceramics and 3D-printed scaffolds should be assessed to ensure matched material degradation and bone ingrowth behavior. In terms of irregular craniofacial and jaw defects, injectable strontium-doped hydrogels and cements exhibit superior defect adaptability and enable minimally invasive implantation.¹²⁶

A variety of strontium-containing biomaterials have been fabricated in recent years, including strontium-doped hydroxyapatite/silk fibroin (SrHA/SF) nanospheres,¹²⁷ strontium-incorporated biocomposite scaffolds,¹²⁸ phase-change lysozyme-modified strontium-containing titanium implants (Ti-Ly-Sr),¹²⁹ strontium carbonate-based composite bioceramics (SrC-SrP), strontium-containing phosphate glass (SrP),¹³⁰ and strontium-releasing nanoscale bone cement.⁹⁸ Over the past several years, numerous studies have systematically summarized the classification and clinical application potential of strontium-based bioactive materials, covering bone repair scaffolds, bone cements, hydrogels, and surface-modified implants (Table 3).

Table 3 Representative Sr-Containing Biomaterials in Bone Tissue Engineering

Meanwhile, multi-ion composite systems have further expanded the functional scope of Sr-based biomaterials.¹⁴² Within multi-ion composite systems, strontium serves as a functional component to construct coordinated therapeutic ion systems. Sr/Mg co-doping synergistically enhances osteogenesis and angiogenesis and improves the deposition of mineralized matrices.⁶² Sr/Zn composite systems can strengthen antibacterial capacity and regulate the activity of osteogenesis-related enzymes.⁴⁶ Sr/Cu composites are applicable for bone defects requiring simultaneous vascularization and anti-infection performance, while the dose-dependent cytotoxicity induced by copper ions needs strict control.⁴⁷ Additionally, Sr/Se and Sr/Ga composites are suitable for specialized repair scenarios requiring antibacterial and even antitumor properties.^59,60 Collectively, the clinical applicability of strontium-containing composites depends on whether the ion combination matches specific clinical demands, including osteoporotic osseointegration, infected bone defects, vascularized bone regeneration, and craniofacial bone reconstruction.^62,143–145

Conclusion

Sr-functionalized biomaterials have shown substantial potential for bone regeneration by integrating osteogenesis, osteoclast inhibition, osteoimmunomodulation, angiogenesis, antioxidant activity and antimicrobial protection. Mechanistically, Sr²⁺ regulates multiple pathways, including CaSR/Wnt/beta-catenin, MAPK/ERK, PI3K/Akt, RANKL/OPG/NF-kappaB/NFATc1 and macrophage-related inflammatory signaling. From a materials perspective, Sr incorporation modifies crystallinity, surface charge, degradation and local ion-release behavior; therefore, the biological outcome is closely linked to material chemistry and fabrication strategy. Multi-ion composites further broaden the functional spectrum of Sr-containing biomaterials, especially when Sr is combined with Mg, Zn, Cu, Se or Ga to address angiogenesis, infection control and immune regulation.

Future research should place greater emphasis on optimizing Sr-based biomaterials for different clinical applications. Since material systems such as ceramics, coatings, hydrogels, bone cements, and 3D-printed scaffolds differ in their structural characteristics and degradation behaviors, their optimal Sr concentrations and release profiles may also vary. Therefore, more stable and controllable therapeutic parameters still need to be established. Meanwhile, before broad clinical application, long-term biosafety, degradation behavior, and the potential risk of systemic Sr accumulation should be systematically evaluated through animal studies. In addition, current fabrication strategies should gradually shift from simple ion doping toward more precise local release systems in order to improve therapeutic efficiency while reducing side effects. The antimicrobial mechanisms of Sr also remain insufficiently understood, particularly regarding reactive oxygen species generation, membrane interference, and biofilm regulation. Future translational studies may focus on challenging clinical conditions such as osseointegration in osteoporotic implants, infected bone defects, craniofacial reconstruction, and vascularized bone regeneration. Overall, Sr-functionalized biomaterials show promising potential in bone repair; however, their successful clinical translation will still depend on further advances in material design, ion-controlled release strategies, and high-quality preclinical and clinical investigations.