**1. Introduction**

Oxides are among the most stable inorganic materials since no further oxidative processes (e.g., corrosion, ion release) can take place. This is a major reason for the use of oxides as ideal bioceramic materials since the 1960s because their chemical inertness was considered as the basis for biocompatibility. The first ceramic oxide used in orthopedics was alumina (Al2O3), while ceramic composite oxides, prevalently made of alumina-zirconia (Al2O3-ZrO2) were subsequently developed, seeking improved mechanical performance [1].

The first use of alumina as a biomaterial is due to Dr. Sami Sandhaus, a Swiss dentist, who in 1962 developed a screw-shaped dental implant named Crystalline Bone Screw— CBS® and used it in a significant number of cases [2]. In 1963, L.W. Smith and J.F. Estes (Haeger Potteries, Dundee, IL, USA) developed CerosiumTM as a bone substitute in case of large bone defects, i.e., a silica aluminate matrix where pores (about 50% in volume) were filled with epoxy resin [3].

At that time, hip arthroplasty was taking its first steps. Although keenly interested by the potential of such a procedure, orthopedic surgeons were very concerned about the failures of implants due to the wear of bearings. The cooperation between Dr. Boutin—an orthopedic surgeon working in Pau, a town in Southern France—and one of his patients, the manager of a factory sited nearby manufacturing high alumina electric insulator, led to the first total hip replacement (THR) with an alumina-on-bearing in 1970 [4]. Such an implant had a stainless-steel stem and a Ultra-High Molecular Weight Polyethylene (UHMWPE) socket—soon replaced by a socket made of alumina—both cemented into bone.

In the same years, several scientists in Germany (i.e., G. Langer in Keramed, G. Heimke in Friedrichfeld, H. Dörre in Feldmüle, M. Saltzer in Rosenthal) gave a decisive contribution to the development of alumina for orthopedic components and overall for alumina as a

**Citation:** Piconi, C.; Sprio, S. Oxide Bioceramic Composites in Orthopedics and Dentistry. *J. Compos. Sci.* **2021**, *5*, 206. https://doi.org/ 10.3390/jcs5080206

Academic Editor: Francesco Tornabene

Received: 6 July 2021 Accepted: 30 July 2021 Published: 3 August 2021

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biomaterial. This resulted in the development of a number of ceramic orthopedic devices, among which it is worthwhile to mention the BIOLOX® alumina developed by H. Dörre in Feldmüle (now CeramTec GmbH), which became "*the ceramic*" in orthopedics until this attribute was overtaken by the higher-performing BIOLOX® delta alumina–zirconia ceramic composite [5].

Indeed, alumina showed critical issues particularly related to failure of THR implants [6], leading some manufacturers to withdraw from the market of implantable ceramics. Alumina exhibits low fracture strength and toughness and is very sensitive to microstructural flaws that lead to a poor resistance to stress concentration or mechanical impact. As the presence of intergranular pores and large grain size are the main microstructural features that affect the mechanical strength of alumina, the efforts of ceramists were focused on decreasing the porosity and the grain size in alumina ceramics. This was obtained by the selection of proper precursors (e.g., alkoxide-derived powders) and by the optimization of the overall manufacturing process, from batch preparation to final densification by hot isostatic pressing (HIP). Such improvements resulted in the so-called "third generation alumina" based on high-purity precursors and characterized by finer grain size and density near the theoretical one, as illustrated in Table 1.


**Table 1.** Selected properties of alumina, evidencing the development of the material [5].

Nevertheless, the feasibility to obtain alumina components with specific design was limited by its typical brittle fracture behavior [7]. In response to these issues, the company Desmarquest (now Saint Gobain Céramiques Avancées Desmarquest—SGCAD, Evreux, France) followed a different approach: they focused their attention on a different, intrinsically tough ceramic, Yttria-stabilized Zirconia Polycrystal (Y-TZP). Zirconia (zirconium dioxide, ZrO2) is characterized by the polymorphism of its crystal lattice; therefore, it exists in three thermodynamically stable crystalline phases: monoclinic (up to 1170 ◦C), tetragonal (1170–2370 ◦C), and cubic (2370–2680 ◦C). Effective applications of zirconia ceramics in medicine were made possible since the discovery of the stabilization of the tetragonal phase at room temperature based on the introduction of small amounts of oxide phases as stabilizers. Such a discovery led to the development of Partially Stabilized Zirconia (PSZ) [8] because the low concentration of the stabilizing oxide did not allow the full stabilization of the cubic phase. PSZ was firstly obtained by using calcium oxide as stabilizer, but successively either magnesium oxide (magnesia, MgO) or yttrium oxide (yttria, Y2O3) were used for this purpose. The real breakthrough in the development of zirconia ceramics occurred in 1975 with the publication of the research paper "Ceramic Steel?" by Garvie, Hannink, and Pascoe [9]. They reported the increase in toughness in MgO-stabilized PSZ (Mg-PSZ) due to the transformation of the tetragonal phase into monoclinic. Such a transformation, taking place in a "martensitic" way as in some steels, results in an effective dissipative mechanism for fracture energy and, finally, in a self-toughening effect.

More recently, Gupta et al. [10] reported that a tetragonal zirconia ceramic showing grain size ≈0.3 to 0.5 μm could be obtained by using 2–3 mol% of Yttrium Oxide (Yttria— Y2O3) as a stabilizer, thus resulting in minimal residual cubic and monoclinic zirconia. Since then, although many studies had been dedicated to materials stabilized by CaO, MgO,

and CeO, the main zirconia ceramic that was developed industrially for the production of medical devices was the one stabilized by Y2O3. The tetragonal grains in Y-TZP being metastable—can shift to the monoclinic natural form at the expense of an external source of energy, i.e., the elastic stress field that yields an advancing crack. Thus, phase transformation results as an efficient dissipative mechanism for the energy that otherwise would lead to fracture. Indeed, it was evaluated that the tetragonal–monoclinic phase transformation implies (for a free grain) a volume expansion 4–5 vol %. As each grain is constrained by its neighbors (the matrix), the constrained phase transformation generates a compressive stress field that increases the energy threshold that a crack has to overcome to develop further. These concurrent, energy-dissipative, microscopic-scale phenomena above outlined result, at a macroscopic level, in the remarkable bending strength and toughness of Y-TZP (see Table 2).


**Table 2.** Selected properties of Y-TZP. Alumina data reported for comparison.

Several manufacturers worldwide started the production of Y-TZP ball heads. Among them, SGCAD—the main manufacturer of zirconia (Y-TZP) ball heads worldwide—and Kyocera (Kyoto, Japan) developed also zirconia knee condylar components for total knee replacements (TKR).

The metastability of Y-TZP is the key for its outstanding mechanical performances. However, the metastability of Y-TZP was a cause of concern since the beginning of the clinical use of Y-TZP components. In the biologic environment, Y-TZP may spontaneously transform from tetragonal to monoclinic, drastically decreasing its mechanical properties [11]. Such an undesired phenomenon is named aging or low-temperature degradation (LTD). In THR bearings, the onset of LTD at the surface of the component is related to an increase of the surface roughness, in turn leading to the wear increase of UHMWPE acetabular cups that are usually coupled to Y-TZP heads [3]. The studies on the physicochemical mechanisms giving rise to LTD are still running: several models have been proposed to explain such a behavior, but none have been fully satisfactory to date [12], although it is acknowledged that LTD kinetics is promoted by temperature (especially for T > 100–150 ◦C), by the presence of water in the environment, and by applied stresses. In addition, different LTD kinetics were observed in Y-TZP ball heads obtained from different manufacturers or from different batches produced by the same manufacturer, thus leaving open the main questions about the possible influence of the production process on LTD [13]. Finally, the unexpected high rates of failure in some batches of Y-TZP since 2000 [14] led to the abandon of its use in orthopedics.

#### **2. Biocompatibility of Alumina and Zirconia Composites**

The biological safety of alumina and zirconia and of alumina–zirconia composites has been established for a long time and was recently confirmed [15–18]. Tests on alumina, zirconia, and alumina–zirconia composites were performed using materials in the form of powders or dense ceramics, particularly addressing physicochemical features such as surface reactivity, chemical composition, impurity content, and type of stabilizer. The in vitro assays were performed using extracts in various media, in either direct or indirect contact, by using various cell lines such as macrophages, lymphocytes, fibroblasts, and osteoblasts. Similar considerations can be made on the in vivo tests, which had been performed in several implantation sites in different animal models, to analyze either adverse reactions in soft tissue and/or bone, as well as systemic toxicity. An absence of adverse reactions in cell culture either in tissues or organs after in vivo implants was observed whatever the culture conditions or the implants site.
