2.2.7. Zirconia

Zirconia was first recognized by M.H. Klaproth in 1789 and used as a pigment for ceramics for a long time [364]. Since the 1970s, zirconia received massive consideration as a biomedical material in association to its chemical and biological inertness [365]. Consequently, zirconia was also used to overcome the brittleness of alumina and the consequent failure of implants [366], and as a material for the repair and replacement of bones due to its unique biomechanical properties [367].

Investigations on zirconia biomaterials began in the 1960s. Classical orthopedics studied for many years have used zirconia in the area of hip replacement [368,369]. Zirconium oxide (zirconia) possesses improved mechanical properties and has become one of the most popular ceramic materials in the field of healthcare due to its high biocompatibility and low toxicity [364,370].

Zirconia is one of the most useful structured ceramics because it provides high resistance to bending and fracture. However, zirconium oxide with a low fracture toughness due to the presence of alumina abrasive grains [371] also was introduced as an alternative to having excellent wear resistance due to the unwanted release of orthopedic alumina. Porous zirconia stents can be manufactured by cutting CAD/CAM blocks in the desired shape, and zirconia stents assembled with HA significantly increase the volume of new bone formation in vivo [372].

While it might be concluded that zirconia has one of the best combinations of mechanical strength, fracture resistance, biocompatibility, and biological activity, its performance can be further enhanced via a proper modification of material's surface or by combining the material with some other bioactive ceramics and glass [367]. In addition, as a result of the introduction of Zr into the Ca-Si system, no toxicity was observed. Previous studies confirmed that the optimum content of zirconium and strontium increases the surface energy of the magnesium alloy and enhances the ability to stimulate bone formation around the implant [373,374]. Hydroxyapatite and fluorapatite slurry coated zirconia scaffolds induce osteoconductivity and enhance bonding strength up to 33 MPa [375]. The dispersion of zirconia with alumina lead to produce ZrO2-toughened alumina (Al2O3), known as zirconia-toughened alumina (ZTA) [376].

Zirconia (ZrO2)/β-tricalcium phosphate (β-TCP) composite has shown excellent mechanical properties and supports osteoblast regeneration [377]. Silk fibroin-chitosan-zirconia (SF/CS/nano ZrO2) and chitin–chitosan/nano ZrO2 composites provide a suitable environment for cell infiltration and colonization [378,379]. Different temperature based hydroxyapatite-zirconium composites such as 873 K (HZ600), 923 K (HZ650), and 973 K (HZ700) demonstrated that osteoblast growth and mineralization were not influenced by any composite [380]. A new biphasic calcium phosphate (BCP) scaffold reinforced with zirconia (ZrO2) was fabricated through the fused deposition modeling (FDM) technique. The 90% BCP and 10% ZrO2 scaffold thus created had significantly better mechanical properties than 100% BCP and 0% ZrO2 scaffold [381].

ZrO2 nanoparticle (NP)-doped CTS–PVA–HAP composites (ZrCPH I–III) showed improvement in the tensile strength of ZrCPH I–III with respect to the CTS–PVA–HAP scaffold [382]. Sol–gel cum solvothermal derived mesoporous titanium zirconium (TiZr) oxide nanospheres were used for ibuprofen, dexamethasone, and erythromycin drugs loading and in vitro release studies [383]. The excellent biocompatibility of Zr makes it a good material for metal–organic frameworks (MOFs). Surface functionalization of Zr-fumarate MOF (Figure 19) was used for dichloroacetate (DCA) drug loading, which is more efficient at transporting the drug mimic calcein into HeLa cells [384].

**Figure 19.** Schematic showing the Zr-fumarate structure with preferred properties of a metal–organic framework (MOF)-based drug delivery device (adapted with permission from © 2018 American Chemical Society [384]).
