Aiming to enhance bone formation with less adverse systemic side effects, Sr has been recently included in many bone substitutes[14]. This ion is a trace element which induces bone development and hinders bone resorption, simultaneously[22–24]. The safety and efficacy of Sr-doped biomaterials for inducing bone formation and remodeling have significantly been reviewed[14]. In our earlier study, we also proved hat Sr substitution for Ca in Gel/BG scaffolds improves the mechanical, biological, and angiogenic properties of the scaffold[17]. In this experiment, we additionally investigated the osteogenic potential of Gel-BG and Gel-BG/Sr scaffolds in critically sized rabbit calvarial defects. Histological assessments were performed on the harvested scaffolds four, eight, and 12 weeks’ post-surgery. No chronic inflammation was observed following implantation of the scaffolds, which confirms tissue compatibility of BG containing scaffolds[25, 26]. Analysis of decalcified samples with Alizarin red staining presented much more new bone in defects filled with Gel/BG-Sr compared to those contained Gel/BG and the control groups. This indicates that Sr substitution in BG could remarkably increase bone regeneration capacity.
One reason that Sr promotes bone formation and remodeling could be its impact on the expression of genes, including cytokine IL-6. This cytokine, a pro-inflammatory stimulator that recruits osteoclast and induces bone reabsorption, is decreased by Sr effect[27]. Also, Sr induces genes and proteins involved in the bone formation, such as bone morphogenetic proteins and osteocalcin [28]. It has been shown that Sr ions can increase MSCs response as well as to hinder the differentiation of osteoclasts via inhibiting the expression of receptor activator of nuclear factor Kappa-B (RANK) ligand in MSCs [23, 29]. Besides, this ion can stimulate osteoprotegerin expression, which in turn stops the RANK and its ligand interaction, inhibiting osteoclast activity[30, 31]. It has been demonstrated that the acceleration of osteoprogenitor cells differentiation into osteoblasts could be due to the activation of membrane-bound calcium sensing receptor (CaSR) and the Wnt/β-Catenin signaling pathway[32, 33]. Interestingly, Sr has emerged to induce angiogenic factors expression, including vascular endothelial growth factor[30]. Enhanced neovascularization caused by Sr substitution could also provide more nutrients for bone-forming cells in bone defects[19]. Therefore, activation of osteogenesis and angiogenesis could be considered as improving features for Sr containing scaffolds, as has been previously confirmed[19]. Apart from contributing factors mentioned above, the synergistic effect of the released bioactive Sr and Si ions from BG is possibly another factor enhancing bone regeneration ability of the Gel/BG-Sr scaffold[19]. In a study, it was confirmed that Sr and Si in the structure of BG could synergistically activate the NFATC and Wnt/βCatenin signaling pathways, respectively, which in turn mediate osteogenesis[34]. Zhao et al. assessed the osteogenic capability of Sr-MBG fabricated by three dimensional (3D) printing method in critical-sized defects made in rat calvarial. Sr-MBG scaffolds exhibited superior osteocunductivity and more new vessel formation compared to MBG scaffolds for eight weeks[19].
The process of bone healing can be delayed due to the bacterial infection ,which can subsequently lead to surgical failure by replacement or removal of the implanted biomaterials[35, 36].Therefore, biomaterials with anti-infective properties are required in line with the specific clinical application[37]. Many studies have indicated that BGs, even without ionic additions, have growth-inhibitory influence against several important pathogens[38, 39]. Although the exact antibacterial mechanisms for the BGs remain unclear, one possible reason could be the fact that the glass sodium is being released, which is unfavorable for bacteria and increases the pH level. In fact, increased osmotic pressure caused by dissolution of ions, including silicon, calcium, sodium, and phosphate provides an undesirable environment for the bacteria growth. Besides, several activities in the bacterial cell, including glycolysis, trans membrane proton translocation and acid tolerance can be inhibited by dissolution ions such as zinc form BGs depending on the concentration[40, 41]. Antibacterial studies of this experiment suggest that strontium substitution could increase the bactericidal effectiveness against S. aureus and E. coli. The outcome was more pronounced against S. aureus. It has been reported that Sr-BGs antibacterial activity could be a result of the higher concentration of Ca, P and Sr ions being released in the simulated body fluid (SBF) solutions and the higher pH values compared to the BG samples[42]. In a study by Liu et al., strontium-substituted BGs significantly inhibited the growth of sub-gingival bacteria depending on the ratio of strontium in the glasses[43]. Interestingly, the authors stated that even the base glass with no Sr displays an apparent antibacterial activity, which may be due to the increased amount of phosphate to 4 mol% compared to the Bioglass®45S5 with 2.5 mol% P2O5[43].Significant antimicrobial properties of strontium and silver-containing BG powder has also been formerly confirmed against S.aureus and E.coli bacteria. Previously, antibacterial test results have shown that the strontium substituted 58S BG could exhibit the antibacterial effect against methicillin-resistant staphylococcus aureus (MRSA) bacteria which are resistant to methicillin and other associated antibiotics of the penicillin class. Bacterial activities ,including growth and reproduction, cell wall synthesis, cell metabolism as well as chromosomal replication can be inhibited by the release of Sr2+ ions, as well[42, 44–46].
While Sr doped materials are safe and effective for stimulating bone formation and remodeling, this effect may be more noticeable over time under the concentration applied[14]. Possible factors that could affect the potential evaluation of results for Sr-enriched biomaterials activity are the rate in which Sr is being released, Sr content, experimental animal models, size, location, type of the defects, as well as the applied methods to evaluate the final response[14]. However, despite the good results, more information is required about the safety and effectiveness of local Sr usage [14]. Precautions still need to be considered as the safety of oral Strontium Renelate for the cardiovascular system could be a matter of concern [47, 48].