Introduction

The clinical treatment of serious segmental bone defects caused by trauma or bone tumors is challenging. Moreover, seeking an alternative to autologous bone grafting is one of the major goals of bone tissue engineering. Bone engineering has been extensively studied by researchers over the past few decades. Consequently, many artificial bone materials have been developed. HA has garnered extensive attention from researchers because this main inorganic component of bone tissues (Jarcho et al., 1977; Zhan et al., 2005; Kutikov et al., 2015; Deville et al., 2006; Li et al., 2013; Poddar et al., 2023) is the most important bone repair/regeneration material owing to its excellent biocompatibility and osteoinductive properties. However, its poor mechanical properties and slow degradation limit its application to clinical practice (Rezwan et al., 2006). Researchers think that modifying HA may solve the mentioned problems.

Currently, the biological properties of HA-based materials can be improved by several methods, including doping other elements, heat treatment, and material coating (Shavandi et al., 2015; Shi et al., 2020; He et al., 2021; Boanini et al., 2010). Adding certain metal ions can improve the physicochemical properties of HA and enhance its antibacterial, angiogenic and bone regeneration capacity (Turhan et al., 2023). For example, strontium (Sr), magnesium (Mg), and zinc (Zn) ions can promote bone regeneration by regulating osteoblast and osteoclast activity.

Mg is the fourth most abundant element in the human body, with 60% of magnesium deposited in the bones (Laskus and Kolmas, 2017). Mg alloys began to be used in orthopedics and blood vessels in the mid-nineteenth century (Walker et al., 2014). Mg forms bone by promoting osteoblast differentiation. He et al., demonstrated that Mg metal enhanced the viability and osteogenic differentiation of human bone marrow-derived stromal cells (hBMSCs) (He et al., 2016), as did Yang et al., (Yang et al., 2010). It is reported that Mg2+ replacement of Ca2+ in HA occurs only to a limited extent, up to 10 at.% (Bigi et al., 1996; Yasukawa et al., 1996). Despite the limited substitution, the doping of Mg leads to an increase in the solubility of HA (Landi et al., 2008), which may be related to the decrease in crystallinity. Meanwhile, the morphology of HA is changed to a spherical shape (Berg et al., 2020).

Zn is an essential trace element in the human body, involved in DNA and RNA replication, protein synthesis, and bone metabolism (Prasad, 1995). Zn promotes bone metabolism by increasing osteoblast activity and collagen synthesis, as well as inhibiting osteoclast formation (Yamaguchi and Gao, 1998; Kishi and Yamaguchi, 1994). Zn2+ probably replace up to 20% of the Ca2+ in the HA lattice (Boanini et al., 2010). Since it causes defects in the structure, it makes the lattice more susceptible to disruption (Gutsalova et al., 2021), which makes Zn-doped HA less soluble than conventional HA (Osorio et al., 2014; Hu et al., 2012). Zn-doped HA crystals are irregular and form agglomerates, usually in the form of rods (Hu et al., 2012).

The trace element Sr is present in the human body at 0.008% - 0.01%, which is much lower than that of Ca. However, Sr has a strong affinity for bone, especially in metabolically active tissues (Dahl et al., 2001). Sr has a dual effect on bone: stimulation of bone formation and inhibition of bone resorption (Saidak and Marie, 2012; Hassan et al., 2023). On the one hand, Sr activates signaling pathways such as OPG/RANKL/RANK, NFκB to inhibit osteoclast activity; on the other hand, Sr enhances alkaline phosphatase (ALP) activity, collagen synthesis, and the formation of osteogenic markers to promote bone production (Huang et al., 2020; Zarins et al., 2019; Zarins et al., 2018; Rybchyn et al., 2011). Because Sr2+ (0.12 nm) has an ionic radius similar to Ca2+(0.099 nm), it can replace Ca in the HA structure throughout the compositional range (Boanini et al., 2010). A study showed that Sr2+ enters the HA lattice and enhances the mechanical strength (Geng et al., 2016). Landi et al., confirmed the increase in the solubility of Sr-HA (Landi et al., 2007). Dai et al., analyzed HX-BGC, a bioactive glass with 1.6 % Sr, was in the form of bands and plates (Dai et al., 2021b). Although Sr can replace up to 100% of Ca (Frangopol et al., 2016), in one study it was found that the HA structure was maintained at Sr molar ratios of 2% and 4% in the compound, while it disappeared at other different Sr molar ratios (Nagyné-Kovács et al., 2018). In addition, the Sr content has an effect on osteogenesis. When the Sr concentration exceeds a certain threshold, there will be toxic inhibition (Liu et al., 2016). Almeida et al., demonstrated that the optimal concentration range of Sr is 1-10 mM, and within this range, Sr can effectively enhance the proliferation and activity of preosteoblasts, and promote the maturation of osteoblasts into osteocytes (Almeida et al., 2016).

Therefore, in this review, we systematically introduce the preparation method of Sr-HA and provide insights into the effects of implanted Sr-HA on osteogenesis and angiogenesis. Furthermore, the role of Sr in osteogenesis and vascularization in bone repair has also been discussed in detail.

Preparation of Sr-Doped hydroxyapatite

HA is an important component of the human skeleton. Because of its low solubility in physiological environments, as it is a bioactive material with a high osseointegration capacity that does not induce inflammatory reactions on direct contact with hard tissues. However, the properties of HA can be easily improved. The Ca2+ in the structure can be replaced by Sr2+, Zn2+, Cu2+, Fe2+, Ag+, Mg2+ and other ions (Dapporto et al., 2022; Ungureanu et al., 2023), so Sr can change the HA lattice to modify its biological properties in order to overcome any potential disadvantages; therefore, researchers have integrated Sr and HA. Sr-HA can be prepared by several methods, and four methods, namely chemical precipitation, wet processing, hydrothermal preparation, and wet microwave synthesis, have been discussed below. Furthermore, their advantages and disadvantages are presented in Table 1.

Chemical precipitation method

Chemical precipitation method is to use the reaction between the reactant solution, by controlling the pH value of the solution, the solution precipitates. The crystallization process of precipitation is carried out by controlling the reaction rate, temperature, and aging time. It is the most widely used and simplest method to prepare Sr-HA. Scaffolds prepared by this method exhibit good dispersion and ably meet the requirements of tissue engineering.

In this method, (CaNO₃)₂·4H₂O and (NH₄)2HPO₄ are used as the main reactants. First, 0.5 mol/L Ca(NO₃)₂ and Sr(NO₃)₂ solutions are mixed at 45°C together. After the reaction, the pH of the solution is adjusted to 10-11 with (NH₄)2HPO₄. After, precipitates are filtered, washed with anhydrous ethanol to remove impurities, vacuum-filtered and -dried, and ground to obtain Sr-HA powder (Fig. 1). The use of Sr/[Ca+Sr] and [Ca+Sr]/P at atomic ratios of 0.5 and 1.67, respectively, can yield 0.5-nm Sr-HA (Zhu et al., 2022; Catros et al., 2010). Ehret and Maqbool et al., (Ehret et al., 2017; Maqbool et al., 2021) prepared Sr-HA with good biocompatibility by this method without changing the phase composition and crystallinity of HA. The reaction mechanism of Sr-HA preparation by chemical precipitation is as follows:

(NH4) 2HPO4+NH4OH+ (10-α) Ca (NO3) 2+αSr (NO3) 2→H2O+SrαCa10-α (PO4) 6 (OH) 2+NH4NO3, α≤10

Fig. 1. Preparation of strontium-doped hydroxyapatite (Sr-HA) by the chemical precipitation method.

(Created with BioRender.com).

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Fig. 1. Preparation of strontium-doped hydroxyapatite (Sr-HA) by the chemical precipitation method.

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Wet process method

In this method, (NH₄)₂HPO₄, [Ca(NO₃)₂, and Sr(NO₃)₂] solutions are mixed at a molar ratio of 1:1, and the molar ratio of Sr/(Ca+Sr) is set to 1:100.The solution is then kept in a shaker incubator at 50°C for 24 h, centrifuged thrice at 3000 r/min, and dried at 80°C for 24 h. The obtained blocks are then ground and sieved. Part of the powdered samples are cold-pressed into blocks at 200 kg pressure and heat treatment at 300°C, 600°C, and 900°C for 1 h (Fig. 2) (Pan et al., 2009). Li et al., (Li et al., 2019) used this method to prepare Sr-HA, which exhibited good biocompatibility and stability, but its preparation time is long and the reaction speed is slow. It is not widely used in industrial production.

Fig. 2. Preparation of strontium-doped hydroxyapatite (Sr-HA) by the wet process method.

(Created with BioRender.com).

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Fig. 2. Preparation of strontium-doped hydroxyapatite (Sr-HA) by the wet process method.

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Hydrothermal method

In this method, a 0.5 mol/L [Sr(NO₃)₂, Ca(NO₃)₂] solution and a 0.3 mol/L (NH₄)2HPO4 solution are prepared. The pH values of these Ca and Sr solutions are adjusted to >11 using concentrated ammonia and to >10 using a phosphorus solution. Next, a certain amount from both solutions is mixed thoroughly, followed by the addition of 0.4 g of polyethylene glycol and magnetic stirring to dissolve polyethylene glycol. Under the stirring condition, the (NH₄)2HPO₄ solution is added slowly in a dropwise manner to maintain the n (Ca+Sr)/n (P) atom ratio at about 1.67, and again the mixture is stirred well. Then, it is transferred to a teflon-lined stainless steel hydrothermal kettle and heat-treated at 900°C. The product is then washed with water, followed by an ethanol wash, and filtered. Then the powdered product is dried at 80°C overnight (Fig. 3) (Li et al., 2022; Donazzon et al., 1998). The reaction mechanism of Sr-HA preparation by hydrothermal method is as follows:

(10-x)Ca2++xSr2++6PO43++2OH-→Ca10-xSrx(PO4)6(OH)2

Fig. 3. Preparation of strontium-doped hydroxyapatite (Sr-HA) by the hydrothermal method.

(Created with BioRender.com).

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Fig. 3. Preparation of strontium-doped hydroxyapatite (Sr-HA) by the hydrothermal method.

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Wet microwave synthesis method

This method is characterized by the simultaneous generation of heat at different depths of the material being heated. Compare the other three methods, this method allows for faster and more uniform heating (Fig. 4).

Fig. 4. Film formation of strontium-doped hydroxyapatite (Sr-HA) coating deposited on the surface by microwave.

(Created with BioRender.com).

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Fig. 4. Film formation of strontium-doped hydroxyapatite (Sr-HA) coating deposited on the surface by microwave.

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The crystals of SrCl2, Ca(NO₃)₂·4H₂O, (NH₄)₂HPO₄ are used in this method. First, [Ca(NO₃)₂·SrCl₂] and (NH4)₂HPO₄ solutions of the 0.5 mol/L are prepared and pH is adjusted to 11 using concentrated ammonia. Next, the (NH₄)₂HPO₄ solution is rapidly poured int°o the [Ca(NO₃)₂·SrCl₂] solution and kept in a heating water bath at 80°C. The reaction is performed in a microwave oven with the power set to 800 W. The slurry is allowed to stand for a while, followed by filtration. The sediment is washed with distilled water and then with anhydrous ethanol, dried at 800oC, and finally ground (Yu et al., 2017; Agrawal et al., 2018). However, the resulting product is unstable; hence, this method is not used widely.

Osteogenic effects of Sr and Sr-HA

Owing to the similarity between Sr and Ca, Sr exhibits osteogenic properties similar to that exhibited by Ca, which can increase the levels of runt-related transcriptional factor 2 (RUNX2) and further stimulate Ca sensing receptor (CaSR), thereby inducing mitogen-activated protein kinase phosphorylation and activating cell signaling pathways, and ultimately increasing primary osteoblast formation (Gu et al., 2013). Sr promotes collagen secretion in osteoblasts via CaSR, thus increasing the levels of osteopontin (OPN), ALP, bone sialoprotein, salivary protein, and osteocalcin during osteoblast differentiation (Li et al., 2015). Thus, when Sr-HA is implanted, HA forms a strong bond with bone tissues. After coming in contact with body fluids, HA is degraded over time, thereby increasing the local Sr2+ concentration at the action site. The released Sr2+ exerts its osteogenic properties, inducing osteoblast differentiation (Fig. 5) (Wan et al., 2020). Brennan observed a dose-dependent increase in RUNX2/CBFA1 levels in human primary osteoblasts after Sr-Ran administration for 10 days. Moreover, OPN mRNA levels were increased by 50% after Sr-Ran (1 mM) administration (Brennan et al., 2009). Additionally, Sr promotes bone matrix synthesis (Barbara et al., 2004). Frasnelli observed that the cultures of rat skull osteoblasts exposed to Sr-Ran showed an increased synthesis of collagen Ⅰ, a marker of osteoblast differentiation (Frasnelli et al., 2017).

Fig. 5. The degradation and precipitation reaction of bioactive strontium-doped hydroxyapatite (Sr-HA) regulates local ion concentrations and influences surrounding physiological processes, including osteoblast differentiation.

Abbreviations: bMSC, bone marrow-derived stromal cell; Sr, strontium. Source: Wan et al., 2020. Licensed under CC BY.

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Fig. 5. The degradation and precipitation reaction of bioactive strontium-doped hydroxyapatite (Sr-HA) regulates local ion concentrations and influences surrounding physiological processes, including osteoblast differentiation.

Abbreviations: bMSC, bone marrow-derived stromal cell; Sr, strontium. Source: Wan et al., 2020. Licensed under CC BY.

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Effects of Sr on osteoclasts

Osteoclasts are specialized cells within the bone tissue responsible for bone resorption or the breakdown of bone matrix. They play a crucial role in the dynamic process of bone remodeling, which involves the continuous removal of old bone tissue and the formation of new bone. Osteoclasts achieve bone resorption by secreting enzymes and acids that dissolve the mineralized matrix, making room for the subsequent action of bone-forming cells like osteoblasts.

Studies have shown that Sr promotes osteoclast apoptosis, inhibiting their proliferation and differentiation, thereby reducing bone resorption (Bonnelye et al., 2008). Owing to their similar atomic and ionic properties, both Ca and Sr are agonists of CaSR (Luo et al., 2018). Sr probably acts on CaSR to affect the apoptosis of mature osteoclasts (Fig. 6) (Neves et al., 2017; Borciani et al., 2022). Furthermore, Sr regulates inflammatory states to promote the osteogenesis of BMSCs and accelerate the inhibition of macrophage RAW264.7 differentiation (Li et al., 2016). In another study, consistent with in vitro results, Capuccini proved that the activity and differentiation of MG-63 were increased and the differentiation of osteoclasts was inhibited by Sr (Capuccini et al., 2008), confirming that Sr incorporation reduced the immune response to the material, thereby promoting bone regeneration in vitro (Lee et al., 2021). Additionally, Sr reduces the levels of carbonic anhydrase II and glass agglutinin receptors in osteoclasts, thereby inhibiting cell differentiation and reducing osteoclast resorption by up to 66% (Baron and Tsouderos, 2002). The above studies suggest that Sr promotes osteogenesis.

Fig. 6. Schematic diagram of influence of strontium (Sr) administration on osteoblasts and osteoclasts and their crosstalk.

Source: Borciani et al., 2022. Licensed under CC BY 4.0.

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Fig. 6. Schematic diagram of influence of strontium (Sr) administration on osteoblasts and osteoclasts and their crosstalk.

Source: Borciani et al., 2022. Licensed under CC BY 4.0.

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Effects of Sr and Sr-HA on blood vessels

Pro-vascularization function of bone repairing biomaterials

Fracture healing is a gradual process of restoring normal bone form and function. It is important to realize that in addition to the development of new bones, the regeneration of bones involves blood vessel remodeling, implying that cells in new bone tissues require nutrients and excrete waste materials via blood vessels; in other words, the ideal bone tissue material should exhibit the function of pro-vascularization (Mao et al., 2009). The endothelial cells are pivotal in angiogenesis; therefore, the prerequisite for biomaterial graft vascularization is good affinity and compatibility with endothelial cells (Chen et al., 2006). Angiogenesis is mainly affected by vascularizing growth factors, and among all known members of vascular endothelial and angiogenic growth factors, vascular endothelial growth factor (VEGF) is the most specific pro-angiogenic factor, which plays a central regulatory role in physiological and pathological angiogenesis (Hirschi and D’Amore, 1997).

Notably, biomaterials are widely used in the treatment of bone defects and bone regeneration, where immune modulation, especially the abatement of inflammation, and the pro-vascularizing effect of biomaterials are crucial, where macrophages and neutrophils have a key role in the process of tissue-engineered angiogenesis. It is widely accepted that M2 macrophages are associated with promoting angiogenesis, while M1 macrophages have a comparatively weaker effect on angiogenesis (Wang et al., 2017). Li et al., (Li et al., 2021) prepared Sr-HA nanofibrous gelatin scaffolds to study Sr-mediated regulation of neutrophil polarization and subsequent effects on angiogenesis and macrophage polarization. Sr-HA-doped gelatin scaffolds released by Sr were found to polarize neutrophils to an N2 phenotype and act on subsequent macrophages and effector cells, thereby promoting angiogenesis and tissue regeneration. Liu et al., (Liu et al., 2023) summarized the mechanisms associated with Sr in bone regeneration (Fig. 7): Sr induces macrophage differentiation and promotes vascular regeneration.

Fig. 7. Strontium (Sr) induces macrophages to differentiate toward M2 instead of M1, which benefits the promotion of osteoblast proliferation; Sr also raises early vascular regeneration.

(A) Sr induces macrophage differentiation towards M2 not M1, which is conducive to promoting osteoblast proliferation, and Sr also promotes early vascular regeneration. (B) Sr promotes the differentiation of mesenchymal stem cell and the proliferation of osteoblasts, which is conducive to bone formation. (C) Sr can inhibit the differentiation of mesenchymal stem cell and the proliferation of osteoclasts, thus reducing bone resorption. Source: Liu et al., 2023. Licensed under CC BY 4.0.

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Fig. 7. Strontium (Sr) induces macrophages to differentiate toward M2 instead of M1, which benefits the promotion of osteoblast proliferation; Sr also raises early vascular regeneration.

(A) Sr induces macrophage differentiation towards M2 not M1, which is conducive to promoting osteoblast proliferation, and Sr also promotes early vascular regeneration. (B) Sr promotes the differentiation of mesenchymal stem cell and the proliferation of osteoblasts, which is conducive to bone formation. (C) Sr can inhibit the differentiation of mesenchymal stem cell and the proliferation of osteoclasts, thus reducing bone resorption. Source: Liu et al., 2023. Licensed under CC BY 4.0.

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Mature osteoblasts and endothelial cells can express VEGF and basic fibroblast growth factor (bFGF). Sr-HA signaling increases VEGF and bFGF levels, which play a crucial role in the vascularization of the material. VEGF promotes blood vessel development by inducing endothelial cell proliferation and participates in bone development via pro-angiogenesis. Furthermore, it is involved in bone formation and metabolism as a paracrine factor. BFGF promotes the proliferation and differentiation of as well as protein synthesis in its own and surrounding cells in autocrine and paracrine ways (Hu and Olsen, 2016). Therefore, Sr-HA with pro-vascularization function can be used as a potential material, providing a new idea to solve the problem associated with vascularization in bone tissue engineering.

Conclusions

Herein, we systematically review Sr-HA preparation and provide insights into the effects of implanted Sr-HA and Sr on osteogenesis and angiogenesis. Among the four preparation methods mentioned, the chemical precipitation method yields more efficient and stable materials; thus, it is the most widely used method. Additionally, Sr promotes osteogenesis by inhibiting osteoclast differentiation and promoting osteoblast differentiation. Hence, a better osteogenic effect can be achieved by adding Sr to HA. The formation and reconstruction of blood vessels play a vital role in bone healing. Sr-HA increases VEGF and BFGF levels noticeably; thus, Sr-HA can be used as a potent pro-angiogenic material. However, the involvement of inflammation and angiogenesis in bone healing leads to the complex mechanism of Sr-HA-mediated osteogenesis. Therefore, the specific osteogenic mechanism of Sr-HA needs further elucidation to maximize the effect of HA and Sr on osteogenesis.

Acknowledgements

This work was supported by Natural Science Foundation of Sichuan Province, China (2022NSFSC1510), Medical Scientific Research Project of Chengdu City, China (2021043), the Industry-university Cooperative education program of Ministry of Education, China (220506007260254), the Innovation team project of Clinical Medical college and Affiliated hospital of Chengdu University (CDFYCX202208), Sichuan Provincial Science and Technology Foundation (22NZZH0031), Higher education talent training quality and teaching reform project of education department of Sichuan province, China (JG2021-1102). The authors would like to thank all the reviewers who participated in the review, as well as MJEditor (www.mjeditor.com) for providing English editing services during the preparation of this manuscript.

Abbreviations

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