## 4 Discussion
### Functionalization with Strontium
Therefore, the study of the amount of strontium that must be added to the biomaterial is essential for medical application so that it releases in the biological medium, and the presence of osteoclasts, a safe and also effective amount of strontium. The biological responses to the investigated biomaterials may be dependent on the level of Sr incorporation. [PERSON] et al. [39] observed that titanium biomedical devices coated with strontium-doped calcium phosphate ceramics supported desirable bone regeneration by enhancing cell adhesion and proliferation. The study indicated that sufficient strontium doping concentrations in the coatings could significantly improve cellular attachment and proliferation, making these coatings promising for bone regeneration applications. [PERSON] et al. [25] demonstrated that strontium-substituted hydroxyapatite coatings on magnesium alloys significantly controlled the degradation rate and enhanced the osteoblast response in vitro. The study indicated that the Sr content in the coatings could be adjusted to optimize the degradation behavior and cytocompatibility of Mg alloys for biomedical applications. [PERSON] et al. [33] found that strontium-doped hydroxyapatite coatings on titanium implants significantly enhanced the osteogenic differentiation of human bone marrow mesenchymal stem cells and improved osseointegration in rabbit models. That study emphasized the importance of optimizing strontium concentrations in hydroxyapatite coatings to maximize their osteogenic potential. [PERSON] et al. [36] reported that strontium-substituted hydroxyapatite coatings on titanium implants significantly enhanced osseointegration and bone-implant contact in rabbit models. The study concluded that the optimal concentration of strontium in hydroxyapatite coatings was crucial for maximizing bone regeneration while minimizing potential adverse effects. The incorporation of Sr may impact the structural properties of calcium phosphate biomaterials. [PERSON] et al. [42] revealed that the synthesis of strontium-doped hydroxyapatite from Mercenaria clam shells enhanced mechanical properties such as microhardness and fracture toughness while maintaining excellent biocompatibility. The Ca/Sr ratio may also be relevant both to the structure and biological performance of the biomaterial. [PERSON] et al. [49] reported that strontium inhibits bone regeneration under low calcium concentrations but promotes it under high calcium concentrations, suggesting that the calcium-strontium balance is relevant to optimize bone healing outcomes. The reviewed studies indicate that the incorporation of strontium into calcium phosphate-based biomaterials at different strontium concentrations influence cytotoxicity, osteoblast differentiation, proliferation, osteoclast inhibition, and new bone formation. The biological effects may be dose-dependent, as demonstrated by [PERSON] et al. [54], who showed that strontium-doped scaffolds not only enhanced new bone formation in osteoporotic rat models but also increased vascular-like structures, indicating a dose-dependent osteogenic and angiogenic response to strontium release from the biomaterial. [PERSON] et al. [41] found that strontium-doped bioceramics enhanced osteogenic differentiation and mineralization in mesenchymal stem cells, supporting their potential for use in bone tissue engineering, suggesting dose-dependent effects of strontium on cellular responses and emphasizing the importance of optimizing strontium concentrations in biomaterials for therapeutic applications [41]. Figure 2 highlights the concentration ranges of strontium ion incorporation and their respective biological impacts, facilitating a better understanding of the dose-dependent nature of strontium in these biomaterials. At lower concentrations (0.5% to 2.5%), the biomaterials exhibit non-cytotoxic properties, making them safe for cellular applications.