4.1.1. Magnesium

Magnesium is considered as the main ion capable of replacing Ca in biological apatite, in an amount close to 1 wt% [132]. Mg2+ ions play a key role in bone metabolism, taking part of the biochemical reaction beyond bone formation, while also controlling bone growth and metabolism [47,142,148].

Magnesium phosphates are also associated with a higher dissolution rate than calcium phosphates [149]. Mg has been shown to inhibit the formation of crystalline minerals, such as hydroxyapatite, whereas more soluble phases, such as brushite, are minimally affected by the presence of Mg [150–152]. Specifically, it was observed in basic solutions that HAP precipitation is inhibited by Mg substitution for Ca higher than 10%, and amorphous calcium phosphate (ACP) or whitlockite, the Mg polymorph of β-tricalcium phosphate, forms [153,154].

The incorporation of magnesium was also associated with increased protein adsorption and cell adhesion on the surface of bioceramics [17,18]. Furthermore, an intrinsic antibacterial activity was described for Mg-HA [136,139].

#### 4.1.2. Strontium

Strontium (Sr2+) is a natural component of bones and teeth and have affinity with Ca2+ ions, thus representing a calcium-like entity within cells, acting along similar biochemical and cellular pathways [136,141]. At a low concentration, strontium inhibits osteoclast activity, reduces bone resorption, enhances osteoblast proliferation and promotes bone formation. In this context, the addition of strontium in bioceramics is promising for the local treatment of bone affected by metabolic diseases, such as osteoporosis [45,155–159]. Several approaches can be implemented to obtain Sr-doped bioceramics, including the addition of strontium salts in wet synthesis processes [160] or of Sr-doped inorganic reactants involved in solid-state reactions at high temperatures [73,159]. The incorporation of strontium ions replacing Ca2+ in the crystal lattice of calcium phosphates generally induces deformations in the crystal lattice due to its higher ionic radius in respect to calcium. This affects the physicochemical properties of CaPs; for instance, it was observed that Sr2+ ions stabilize the β-TCP polymorph during

thermal synthesis reactions. Furthermore, various previous studies reported a mechanical reinforcement ascribed to strontium doping, possibly due to enhancement of the interatomic bond strength in the CaP crystal in respect to calcium [161–163].

#### 4.1.3. Silicon

Silicon plays a key role in the physiological formation of bone and cartilage tissues, especially due to its intrinsic capacity to act both as a cross-linker in ECM and to favor the precipitation of HA and bone mineralization [29,135]. When used in the synthesis of bioceramics, such as tricalcium phosphate (TCP), normally obtained with high-temperature treatments, silicon has the capacity to favor the formation of α-TCP polymorph against β-TCP [164,165]. Silicon-containing bioceramics exhibit high bioactivity, including bioglasses (Na-Ca-P-Si), wollastonite (CaSiO3) and Si-doped bioceramics (e.g., Si-HA and Si-TCP) [24,27,29,32,48].

The pivotal role of Si-containing bioceramics, such as silicon-doped HA, in bone tissue regeneration was confirmed by in vivo studies revealing the enhanced formation of collagen fibrils after 6 weeks at the bone/Si-HA interface and after 12 weeks with the bone/HA interface [134,135]. In addition, the enhanced formation of mature osteoclasts from mononuclear precursor cells was observed, thus showing the potential of silicon to favor the complex bone regeneration cascade by stimulating the various cell lines involved in new bone formation and remodeling. Long-term in vivo studies also reported the significantly higher bioresorbability of Si-doped HA scaffolds compared to pure HA scaffolds, as only few residues of the doped scaffold were observed at one year upon implantation, while non-doped HA scaffolds remained unchanged even after five years from implantation [129].

### 4.1.4. Silver

The incorporation of silver ions into bioceramics, as a replacing element for calcium, is possible due to their similar ionic radius [133].

Silver doping has been proposed as a valuable antibacterial strategy due to its ability to interfere with the electron transfer process on bacterial membranes and to promote the production of reactive oxygen species (ROS), finally causing cell death [148].

#### 4.1.5. Iron

The incorporation of iron ions into bioceramics has been widely studied in recent decades, together with its neighboring transition elements from the fourth period of the periodic table (Mn, Co, Ni, Zn) [39], with the purpose of generating new bioceramics with magnetic properties. Indeed, super-paramagnetic iron oxide nanoparticles (SPIONs) are widely approved magnetic biomaterials (usually composed of magnetite Fe3O4 or maghemite γ-Fe2O3) as a contrast agent in magnetic resonance imaging applications for cancer diagnosis or hyperthermia-based cancer treatments. Nevertheless, their iron oxide core also causes long-term cytotoxicity; therefore, intensive effort is today dedicated to develop iron-doped magnetic ceramics preserving good biocompatibility and bioactivity [166].

In this respect, iron-doped CPCs for magnetic hyperthermia were obtained, exhibiting improved osteoconductive and antibacterial properties [167–169]. A new concept of magnetic CaP was obtained by synthesizing apatite nanocrystals doped with Fe2+/3+ ions, so as to generate intrinsic superparamagnetic ability, generated by the specific positioning of Fe2+ and Fe3+ ions in the crystal lattice and in the outer hydrated layer of the apatite [128,145]. Such a new phase exhibited a magnetization ability similar to that of iron oxides but with excellent biocompatibility and enhanced osteogenic ability [170].

#### 4.1.6. Fluorine

Fluorine ions take part in several biochemical processes, becoming particularly important for oral care applications, neuromodulation and bone structure [136]. Fluorine promotes osteoblast proliferation and inhibits osteoclast activation and differentiation; moreover, when present in a low concentration, it can enhance in vivo bone formation [147,171].

The substitution of OH− groups of apatite with F− ions accelerated the crystallization process, increasing the stability of the crystals while decreasing their solubility [147,171]; the incorporation of fluorine also affected the crystal morphology toward flattened hexagonal rod-like shapes [147,171].

Fluorine-doped HA also exhibited antibacterial behavior, inhibiting the adhesion and proliferation of bacteria typically detected in an oral environment [147,171].
