# Nanostructured Strontium-Doped Calcium Phosphate Cements: A Multifactorial Design
## 4 Discussion  
The present study provides an overview about the role of a multitude of processing parameters on the rheological and mechanical performance of strontium-doped CPCs, according to multiple three-level Design of Experiment (DoE) schemes. In this way, the simultaneous variation of three factors was analyzed, in order to evaluate both the linear and the quadratic interactions between the factors [43] while also proposing modeling equations. \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline  & & & **Outputs** & & & \\ \hline
**Increasing Input** & \(\alpha\)**-TCP** & \(\alpha\)**-TCP** & **Average** & **Initial Setting** & **Final Setting** & **HA** & **Viscosity** \\
**Factor** & **Amount** & **Domain Size** & **Particle Size** & **Time** & **Time** & **Amount** & **Viscosity** \\ \hline Temperature & \(\uparrow\uparrow\) & \(\uparrow\uparrow\) & & \(\downarrow\) & & \(\uparrow\uparrow\) & \\ Dwell Time & \(\sim\) & \(\sim\) & \(\sim\) & \(\sim\) & & \(\sim\) & \\ Strontium Amount & \(\downarrow\) & \(\downarrow\downarrow\) & \(\sim\) & \(\uparrow\uparrow\) & \(\uparrow\uparrow\) & \(\downarrow\) & \\ Milling Time & & & \(\downarrow\downarrow\) & \(\sim\) & \(\sim\) & & \\ Milling Balls Diameter & & & \(\uparrow\) & \(\uparrow\) & \(\uparrow\) & & \\ Sodium Phosphate & & & & \(\downarrow\downarrow\) & & \(\uparrow\uparrow\) & \(\uparrow\) \\ Sodium Alginate & & & & \(\sim\) & & \(\sim\) & \(\downarrow\) \\ Liquid-to-powder ratio & & & & \(\uparrow\) & & \(\sim\) & \(\downarrow\) \\ \hline \hline \end{tabular}
\end{table} 
Table 2: The qualitative correlation of each increasing factor on the outputs is reported as positive (arrows up), negative (arrow down), statistical significance (double arrow), or negligible statistical significance (-). Figure 9: Effect of different mixing times and shear regime on extrusion force–plunger displacement profiles (ES: Empty syringe, S: Spatulated samples, M: Planetary-mixed samples, “45” or “90” refers to the correspondent mixing time, in seconds). Phase 1 profile includes several contributions, such as the plunger friction and the material compacting before paste extrusion. Phase 2 indicates the force profile during the extrusion of the material. Inset: Extrusion force calculated for each test, with the reported range for manual orthopedic surgeon injection in dotted line (*: \(p<0.05\), **: \(p<0.01\), ***: \(p<0.001\)). The previous literature reported contradicting results about the performance of CPCs [13; 19], probably ascribable to the difficulty of investigating the role of processing parameters by varying only one factor at a time. The main parameter relevant for the manipulation and characterization of CPCs is the setting time, which depends on a complex interaction between many factors. For example, several studies in the literature reported the preparation of self-hardening CPCs by hydrolysis of \(\alpha\)-TCP precursors, but only reporting a specific thermal treatment for the synthesis of \(\alpha\)-TCP [28; 33; 37; 57; 58; 59]. In this respect, it was observed that the firing step greatly affects the final reactivity of the \(\alpha\)-TCP upon mixing with liquid solutions [13]. The present work demonstrates that, rather than the dwell time, the temperature selected for the synthesis of \(\alpha\)-TCP is the main factor determining the rate of transformation of the cement into CDHA. However, the attainment of pure Sr-doped \(\alpha\)-TCP is hampered by the presence of strontium (Figure 2), as it promotes the formation of \(\beta\)-TCP polymorph [60]. In this respect, we found that the partial substitution of Ca\({}^{2+}\) with Sr\({}^{2+}\) ions is the predominant factor affecting the \(\alpha\)-TCP crystal size and inducing both a significant decrease of slackening of the setting times [13; 32; 42].