# Nanostructured Strontium-Doped Calcium Phosphate Cements: A Multifactorial Design
## 1 Introduction  
In the last decades, the use of self-hardening injectable pastes for bone tissue engineering, such as calcium phosphate cements (CPCs), has been widely considered as a promising approach, due to their ability to mold to the shape of the bone cavity and set in situ upon injection [1]. CPCs are bioactive, especially due to their chemical resemblance with the inorganic component of bone, as well as their nanostructured morphology. In this respect, their intrinsic ability to interact with the surrounding tissue, avoiding both pH and temperature fluctuations during hardening, allows the drawbacks typically reported for bio-inert acrylic cements to be overcome [2, 3, 4]. Among the various formulations proposed for CPCs [5], the hydrolysis of \(\alpha\)-tricalcium phosphate (\(\alpha\)-TCP) phases (i.e., \(\alpha\)-\(\alpha_{\mathrm{Ca}}\)(\(\mathrm{PO}_{4}\))\({}_{2}\)) as a unique cement inorganic precursor is particularly interesting: When \(\alpha\)-TCP is mixed with water, it dissolves and the precipitation of nano-sized elongated calcium-deficient hydroxyapatite (CDHA) particles occurs, leading to the hardening of the cement and the increase in mechanical strength [6, 7]. Furthermore, ion substitutions in calcium phosphates have become the subject of intense investigations in the last decades [7, 8, 9, 10, 11], with the aim of enhancing bioactivity and also gaining the ability to deliver therapeutic ions such as Sr\({}^{2+}\) directly in situ, which is a promising approach to sustain bone regeneration also in osteopororotic patients, as an alternative to oral administration of drugs. In particular, strontium-doped CPCs [12, 13] have shown excellent osteogenic and osteointegrative properties, and a dose-dependent ability to modulate the bone cell fate [14, 15]. Nevertheless, CPCs are generally associated with low compressive strength, limited porosity, and poor injectability [5], so new strategies to optimize their processing arehighly desired to make them desirable for clinical applications [16; 17; 18; 19]. The performance of CPCs strongly depends on the fine adjustment of multiple parameters, including powder particle size distribution and shape, ion doping, liquid-to-powder ratio (LP), and polymeric additives [17; 19; 20]. Despite some attempts of modeling the performance of CPCs being reported [19; 21; 22], even by means of artificial intelligence methods [23], a comprehensive overview on the multifactorial interaction among the CPCs processing parameters is still lacking [19]. The precise investigation about the rheology of CPCs also represents a critical point, due to the inherent heterogeneity of the material. In this respect, some works are focused on the study of the injectability of calcium phosphate pastes based on \(\beta\)-TCP-water systems, mainly because of longer setting times if compared with \(\alpha\)-TCP formulations [20; 24]. These studies aimed to improve the understanding of phenomena impairing the cohesion of CPCs during extrusion, thanks to their slow hardening kinetics. Nevertheless, those results cannot easily translate to the comprehension of the rheological properties and extrusion ability of any self-hardening formulation [19]. New approaches to improve the injectability and cohesion of CPCs have been mainly investigated by increasing the viscosity of the setting solutions [25; 26]; however, the increase in the cement cohesion was often related to significant deviations from the desired setting times and mechanical performance [27]. In this respect, it was observed that smaller CaP precursor particles promote faster transformation into apatite, a more packed structure, and higher mechanical strength [19; 28; 29; 30]; on the other hand, the introduction of foreign ions into the calcium phosphate structure generally leads to the slackening of the setting times [31; 32]. Several approaches were explored to improve the hydraulic reactivity of the powders, including both thermal calcination [33] and different milling treatments [28; 34; 35; 36; 37; 38; 39; 40].