# Nanostructured Strontium-Doped Calcium Phosphate Cements: A Multifactorial Design
## 4 Discussion
This study also showed that higher hydraulic reactivity of the precursor powders (i.e., higher \(\alpha\)-TCP amount, in respect of \(\beta\)-TCP) favors the achievement of nanostructured morphology, represented by sharp needle-like apatite crystals developed upon setting at 37 \({}^{\circ}\)C (Figures 3 and 4). In particular, higher sintering temperatures led to an increase in crystal growth (\(\alpha\)Ds), resulting in a powder with reduced specific surface area and slower rate of dissolution and precipitation to CDHA, while the introduction of strontium induced a retarded hydration of \(\alpha\)-TCP as observed by calorimetry studies [54]. The kinetics of the hydration reaction of the precursor powder basically affects the morphology of the final apatite crystals: The faster the dissolution of the \(\alpha\)-TCP powder, the faster the supersaturation of the solution with respect to calcium and phosphate ions, causing the formation of small and highly entangled needle- to flaky-like apatite crystals, whereas in the case of strontium-doped formulation, the delayed setting produced larger, poorly entangled crystals. In this respect, the kinetics of the hydration process affects the nanostructure of the CPCs, thus tailoring both setting times and mechanical performance. On this basis, the thermal treatment at 1400 \({}^{\circ}\)C for 1 h was chosen to maximize the amount of \(\alpha\)-TCP (i.e., the hydraulic reactivity of the powders), while preventing the microstructural coarsening reported in the case of longer firing steps [59]. The hydrolysis of the \(\alpha\)-TCP powders is also influenced by the particle size distribution [61]. In this work, the average particle size and the crystallinity of the powders was mainly reduced by increasing the milling time and decreasing the milling media diameter (Figure 5 and Figure S5), possibly due to the higher surface area exposed by the milling spheres [62; 63]. Conversely, both the initial and setting times were basically slackened by the strontium doping, if compared with milling parameters. Interestingly, powders milled with smaller media exhibited significantly reduced hardening times and have given rise to cements with improved compressive strength (Figure 6). In this work, the Sr2 formulations obtained by milling with 2 mm diameter balls exhibited a prevalence of sharper needle-like crystals (Figure 7) and the highest compressive strength, even comparable to that of previously reported apatite-cement formulations reinforced with fibers [17]. It was hypothesized that the increase in the strontium content induced an increase in the crystal defects, leading to the slackening of hydrolysis and setting processes and to reduced strength [64]. A critical aspect in the setting behavior of cements is also given by rheological properties. The major role of the setting solution composition and liquid-to-powder ratio on the rheology of CPCs was quantified in Equation (10), while only being qualitatively reported in previous studies [13; 17; 19]. In particular, the addition of sodium alginate improved the flowability and injectability of the cement without interfering with the hydrolysis of the powder and the setting times, as previously observed [42]. In this respect, the addition of a small amount of alginate enhanced the setting times and the production of a much denser microstructure, as well as higher mechanical performance, possibly ascribable to the cross-linking of sodium alginate by Ca\({}^{2+}\) released from \(\alpha\)-TCP [65], while higher amounts of alginate were even reported as setting delays [66]. The formation of precipitated HA was mainly favored by increasing the sodium phosphate concentration (Figure 8). Deep rheological investigation of the early stages of the reaction yielding the CTCs hardening has been limited so far probably due to the difficulties in measuring a very large viscosity range and to the problems of measuring the real material viscosity rather than the interactions between the material and the rheometer during the test [36].