**2. Nanostructured hydroxyapatite**

CaP exhibit different characteristics as Ca/P atomic ratios, crystal systems, and solubility (in physiological conditions, T = 37°C, pH = 7.3) [14, 15]; some most common CaP used for biomedical applications are summarized in **Table 1**. CaP materials which have Ca/P atomic ratio external to 1–2 range are not suitable for implantation into the body because of their high acidity (low Ca/P), basicity (high Ca/P), and solubility. As a result, among the known CaP compounds, OCP, α/β-TCP and CDHA/HA are significantly most useful for biomedical applications, like orthopedic surgery and dentistry.

 The different crystal morphologies of CaP exhibited in the various biological hard tissue have addressed the research to develop these materials with high control of nanostructural properties, as particle size, nano-surface, dimensional anisotropy, etc. For example, in the bone tissue, the HA crystallites have rod shape owning dimension of about 50 × 25 × 4 nm; in contrast, in the tooth enamel, larger hexagonal prism crystallites have the dimension of about 100 × 70 × 25 nm, with c-planes that are preferentially parallel to the collagen fibrils or enamel surface, respectively [16]. For this reason, crystals exhibit enhanced adsorption properties because of their higher charging surface and with plate-like and hexagonal morphologies, may find promising application in dental implants.

Lee et al. reported enhanced bioactivity of nanostructured HA compared to sintered and coarser ceramics: nanophase HA promotes the osteogenic differentiation of periodontal ligament cells and more efficiency of osteoclast-like cell adhesion [7]. Besides, HA nanoparticles are used for cell targeting, gene transfecting, and drug delivery thanks to their strong molecular adsorption property and increased surface area [17]. The size of HA particles also play critical roles in biological response, including cell proliferation modification, oriented cell differentiation, and cell apoptosis [18]. HA nanowires and nanosheets are capable for moderated reinforcement of the biomaterials and can be used as mechanical components to stiffen isotropic composite materials. In the case of sinterability of bioceramics, nanoparticles exhibit improved feature if compared to coarser particles [19].

Stoichiometric HA has typically hexagonal crystal system with the P63/m space group and two principal crystal planes: a-plane and c-plane (see **Figure 1**); its crystal unit cell is characterized by a = b = 0.942 nm and c = 0.688 nm, α = β = 90° and γ = 120°. Positively charged calcium ions (Ca2+) are mainly present in the a-planes,


#### **Table 1.**

*Main CaP compounds used for biomedical applications.* 

**Figure 1.** 

*Hexagonal crystal structure of stoichiometric HA, where a-plane is Ca site (positive charge) and c-plane is PO4 site (negative charge).* 

and hence negatively charged phosphate (PO4 <sup>3</sup><sup>−</sup>) and hydroxide (OH<sup>−</sup>) ions are present in the c-planes. That is, HA surfaces present anisotropic characteristics such as adsorption profiles for electrolytes or biomolecules [16].
