## 4 Discussion
### Functionalization with Strontium
The release kinetics of strontium from these powdered materials also provide valuable insights into the material's behavior in biological environments, as nanostructured materials may release biologically active particles after their disintegration during the material absorption, as seen in studies where controlled release profiles were crucial for maintaining non-toxic yet therapeutic levels of strontium [12; 15]. Often, nanostructured materials and nanoparticles present biological effects of relevance to biocompatibility [68]. Coatings on substrates like titanium and magnesium alloys, examined by studies such as those by [PERSON] et al. [25] and [PERSON] et al. [34], are particularly relevant for orthopedic and dental implants. These coatings enhance the surface properties of the implants, promoting better osseointegration and reducing the risk of implant failure. The ability to control the strontium content and its release from these coatings ensures that the therapeutic benefits are maximized while minimizing potential adverse effects. In this review, it was possible to identify that very different amounts of strontium were incorporated into the biomaterials, varying from 0.5 to 100% substitution at the calcium site. However, the biological effect found is not directly related to the theoretical amount of strontium added since similar substitution amounts presented opposite effects. For example, in a comparison between [PERSON] [32] and Liang [34] that have the same Sr substitution amount (5, 10, and 20%), it can be seen that the former does not find statistical difference during an in vitro analysis between the different Sr concentrations at the biomaterial, whereas in the latter there is a significant decrease in the number of osteoblastic cells in contact with the conditioned medium with the material with 20% strontium substitution. These differences may be due to characteristics of the materials tested since they have different dissolution rates. The beneficial stimulus effect for osteogenesis of the supplementation of the culture medium with strontium is dose-dependent [69]. During in vitro experiments, a Sr supplementation of 2-5 ppm in the culture medium was able to stimulate osteoblastic cells to form mineralization and calcification nodules. However, a Sr concentration of 20-100 ppm inhibits the calcification [69]. Thus, a more soluble biomaterial releases a higher concentration of strontium in the environment, which combined with the strontium dose-dependent effect can determine the cellular behavior. In addition to that, bone tissue presents a particular type of cell, the osteoclasts, with the function of resorbing the mineral part of the bone. Therefore, it is expected that in their presence, the release of strontium ions is much higher than in their absence. However, a single article investigated in vitro the amount of Sr released in the presence of these cells and, in fact, the amount of strontium in the culture medium rose from 2 mg/dL in the absence of cells to 10 mg/dL when the biomaterial was in contact with mature osteoclasts [24]. [PERSON] et al. [58] identified the presence of osteoclasts in direct contact with material granules. It was hypothesized that ceramic materials that have a high percentage of substitution by strontium ions can generate a peak of Sr during the active reabsorption by osteoclasts, which may or may not be toxic in the microenvironment, even though the amount of strontium released into the environment was not evaluated. According to [PERSON] et al. [9], the incorporation and distribution of strontium in the skeleton depend on factors such as gender, skeletal size, the dose administered, and duration of treatment with strontium maleate. None of these factors was addressed in the studies about the effect of strontium associated with bioceramics.