2.2.3. Nano Hydroxyapatite

Hydroxyapatite (Ca10(PO4)6(OH)2) is a significant natural mineral constituent of bones (70% wt.) and teeth (96% wt.) [278,279]. Synthetic HA is a biocompatible ceramic material, used for biomedical applications (Figure 13) because it may replicate the behavior of mineral part of the bone [280,281]. It shows outstanding biocompatibility with bones, teeth, skin, and muscles, both in vitro and in vivo [282,283]. The stoichiometric molar ratio Ca/P in synthetic HA of 1.67 is not the actual ratio in the hydroxyapatite of normal bones, because of the presence of other elements such as C, N, Fe, Mg, and Na [284]. Hydroxyapatite (HA) can be easily synthesized by using different methods such as hydrothermal, sol–gel, and co-precipitation methods [285]. The comparison of mineral compositions of hydroxyapatite, bone and teeth is shown in Table 3 [286,287].


**Table 3.** Mineral composition of hydroxyapatite, bone, and teeth.

HA shows such excellent biocompatibility, bio-inertia and bioactivity without toxicity, immunogenicity [288,289]. It has a good ability to make bonds with bone directly and it is primarily used in therapeutic applications such as implants and fillers for bones and teeth in different forms [290]. To overcome the low mechanical strength of hydroxyapatite scaffolds, a large number of natural and synthetic polymers were combined with HA such as collagen, polyethylene, polylactic acid, alginates, poly(methyl methacrylate), and polycaprolactone [136].

Woodard et al. [291] compared the activity of nano- and microsized ceramic materials in the body. Their studies demonstrated a substantial increase in osteoblast adhesion and protein adsorption in nanomaterials. The major components of the inorganic nanostructure can have a higher biological activity than micro-components [245]. Polydopamine (pDA)-templated hydroxyapatite (tHA) was introduced into polycaprolactone (PCL) matrix to make bioactive tHA/PCL composite based fibrous scaffold; in vitro and in vivo investigations (Figure 15) showed a favorable cytocompatibility at a given concentration of tHA (0–10% wt.) [292].

**Figure 15.** Schematic illustration of preparation and evaluation of tHA/PCL composite nanofibers. (Adapted with permission from © 2016 American Chemical Society [292].)

A new type of scaffold with bamboo fiber (5%) incorporated nano-hydroxyapatite/poly(lactic -co-glycolic) (30%) was fabricated via freeze-drying; bamboo fibers improved biomechanical properties of n-HA/PLGA composite scaffolds thus developing a superior potential for bone tissue engineering [293]. Sol–gel synthesized hydroxyapatite–TiO2-based nanocomposites synthesized in supercritical CO2 have better Young's and flexural moduli than PCL/HAp composites [294]. A set of techniques including molding/particle leaching and plasma-treated surface deposition were used to fabricate bilayered PLGA/PLGA-HAp composite scaffold [295]; the in vivo rat model experiment proved that the new composite is suitable for osteochondral tissue engineering applications. Electrospinning mediated poly(ε-caprolactone)−poly(ethylene glycol)−poly(ε-caprolactone) (PCL–PEG–PCL, PCEC) and nano-hydroxyapatite (n-HA) composite scaffolds showed good biocompatibility and nontoxicity [296]. Hydroxyapatite/Na(Y/Gd)F4:Yb<sup>3</sup><sup>+</sup>, Er3<sup>+</sup> composite fibers [297], and gadolinium-doped mesoporous strontium hydroxyapatite nanorods [298] were successfully used in drug storage/release applications.
