**3. Alumina Zirconia Composites: Early Studies**

The abandon of zirconia in 2001 opened a technological gap, leaving unmet the urgent need of ceramic components for arthroplasty with effective design and increased reliability and longevity. Then, materials scientists turned their attention toward different zirconia-toughened ceramics (ZTCs), and promising results were obtained in the development of ceramic composites to be used as biomaterials in orthopedics. The work was focused on composites having alumina (in Zirconia-Toughened Alumina—ZTA) as the main component or zirconia (Alumina-Toughened Zirconia—ATZ).

Special attention was devoted to ZTAs. The basic concept of a ZTA material is to substantially increase the material fracture toughness and strength with respect to alumina, while maintaining relevant properties of alumina such as hardness, stiffness, and thermal conductivity, which are key factors for its successful clinical use in joint replacements. This is achieved by exploiting the tetragonal-to-monoclinic phase transformation of zirconia, which is introduced in ZTA as a reinforcing element. The key point for the excellent mechanical properties of ZTA ceramics is the transformability of the tetragonal zirconia. As a consequence, essential aspects are to retain a significant amount of the zirconia tetragonal phase at body temperature and its degree of stabilization in order to reach the desired toughening mechanism. The proper selection of the stabilizing oxide, the homogeneous and finely distribution of Y-TZP in the alumina matrix, and the control of the microstructure and grain size are key parameters to "tune" the stability of the tetragonal phase. In addition, the compressive residual stresses that develop on cooling, due to the mismatch in thermal expansion coefficients between the alumina matrix and the dispersed zirconia phase, increase the energy threshold for the T-M phase transformation, contributing to the strength of the composite [16].

This aspect is critical in the design of a ZTA composite: higher tetragonal zirconia stabilization as a consequence, for example, of a too high yttria concentration would lead to suppression of the zirconia phase transformation, then losing almost all the improvements of ZTA. On the other hand, poor zirconia stabilization—i.e., due to zirconia uncontrolled grain growth because of inappropriate sintering processes—would enhance the LTD of the material. Nevertheless, in the latter case, the mechanical properties might be outstanding, but the material could have unreliable performance, thus leading to catastrophic consequences due to the LTD of the zirconia phase.

Furthermore, it is perceived that the toughening mechanisms in monolithic Y-TZP and ZTA are significantly different. In monolithic zirconia, the stress induced by the single transformed ceramic grain makes the neighbor tetragonal zirconia transform as well, consequently spreading the transformation effect throughout the material. Such a transformation results in LTD and deterioration under long-term usage. In the case of alumina–zirconia composites, the zirconia phase is constrained in the stable alumina matrix, thereby preventing the transformation of the adjacent grains. Hence, the ZTA has a better retention of the tetragonal phase compared to the monolithic zirconia, when exposed to hydrothermal conditions in vitro [19].

The first studies on alumina–zirconia composites as biomaterials started during the mid-1980s by French researchers (INSA-Lyon, Ecole Centrale de Lyon) looking for a mate-

rial strong and tough as zirconia but characterized by better resistance to LTD [20]. Among the tested material, a hot-pressed ZTA (Alumina-20 vol % Y-TZP) showed bending strength (four-point bending) higher than 1100 MPa and fracture toughness of about 10 MPa√m. Aging tests carried out using small bars implanted under the skin of Wistar rats—then in unloaded conditions –showed a limited decrease of the strength due to LTD. Laboratory wear tests (pin-on-disk, cylinder-on-flat) carried out against UHMWPE demonstrated an improved friction and wear behavior of hot-pressed ZTA in comparison with Y-TZP [21].

A further research project was carried out in the framework of the EUREKA programme (project EU 294) under the scientific coordination of the Italian Ceramic Centre (Bologna, Italy). The main goals attained were the production by slip casting of ZTA ball heads with several Z/A ratios [22,23] and the assessment in a hip simulator of the wear behavior of ZTA-UHMWPE bearings. Wear tests were carried out in a hip simulator using Alumina-UHMWPE bearings as the reference. The results did not show significant differences between the experimental and reference material [24]. Cytotoxicity assays confirmed the absence of harmful effects elicited by the composite materials [25].

#### **4. Alumina–Zirconia Composites in Orthopedics**

#### *Zirconia-Toughened Alumina*

The first ceramic composite introduced into the orthopedic market in 2002 was the alumina matrix composite (AMC) BIOLOX®delta, made by CeramTec GmbH, Plochingen, Germany [26,27]. As reported by Burger [28], such a material was made of a fine-grained, high-purity alumina matrix (approximately 80 vol %) combined with three different oxides, so as to retain the relevant properties typical of alumina such as stiffness, hardness, thermal conductivity, but improving fracture toughness and strength. To this aim, such an alumina matrix contained a tailored amount of zirconia phase (i.e., ≈17 vol %), on the basis of indications provided by Pecharromán et al. [29], to obtain the best compromise between appropriate mechanical performance and chemical stability.

Previous works described the addition of strontium oxide (SrO) to the base formulation, with the purpose of activating solid-state reaction with alumina during sintering and triggering the in situ growth of elongated strontium hexa-aluminate (SrAl12O19—SHA) crystals with a magneto-plumbite structure. These platelet-shaped SHA grains, homogenously dispersed in the ceramic composite matrix, increased the toughness of the material through a mechanism of crack deflection/bridging. The effectiveness of this approach was demonstrated by Cutler et al. [30], who investigated a three-phase system formed by a 12 wt % Ce-TZP matrix containing Al2O3 and SHA platelets nucleated in situ during sintering. The maximum platelets length is about 5 μm with an aspect ratio of 5–10. Figure 1 shows the microstructure of BIOLOX®delta, where the gray-colored grains represent the alumina matrix, while the white-colored grains represent the zirconia phase.

Then, two mechanisms are concurring to toughen and to reinforce such a composite: on one hand, the phase transformation of Y-TZP triggered by the tensile stresses in proximity of a crack tip is an effective energy-dissipative mechanism. On the other hand, the volume expansion associated to the T-M transformation is contrasted by the high stiffness of the alumina matrix, thus resulting in a compressive stresses field, which is highly effective in blocking the cracks propagation. Furthermore, the elongated zirconium aluminate crystals—formed upon solid-state reaction between alumina and zirconia during the sintering process—gave an additional contribution to the enhancement of the mechanical performance, acting indeed as short fibers capable of increasing the fracture strength and exerting an additional toughening effect. In addition to the reinforcing components, there are minor stabilizing oxides added to the material, giving additional effects such as specific coloring, such as the example of doping alumina with little chromium oxide amount (Cr2O3), which gives the material its characteristic pink color.

**Figure 1.** SEM image of the microstructure of the AMC composite ceramic BIOLOX®delta (Courtesy CeramTec GmbH, Plochingen, Germany). The gray grains (1) are the alumina matrix, the white grains (2) are the zirconia phase, and the elongated grains (3) consist of reinforcing strontium hexaaluminate (SHA) platelets.

CeramTec BIOLOX®delta is considered as the golden standard for ceramics in joint replacements bearings. BIOLOX®delta—which is characterized by a pink color, patented in the European market—is presently used for the production of ball heads that are manufactured in nine different diameters from 22 to 44 mm with four different neck lengths. The production of inserts is more differentiated, because it considers not only the inner but also the external design of the insert, to comply with the metallic shells of the different cup design now on the market.

A number of new ceramic devices were developed thanks to the behavior of AMC, as illustrated in Figure 2. This is including THR ball heads expressly designed for use during revision surgeries, ceramic components for knee replacements, humeral heads for shoulder replacements, and ceramic hip resurfacing implants [31].

**Figure 2.** AMC BIOLOX® delta products (Courtesy CeramTec GmbH, Plochingen, Germany).

Kyocera Medical Corp (Kyoto, Japan—formerly Japan Medical Materials) followed an original approach. The company is a historical manufacturer of fine ceramics for biomedical applications, the first implants of its alumina Bioceram® may be traced back to 1976. In 2010, Kyocera developed a ZTA (BioCeram® AZ209) where zirconia is stabilized in the tetragonal state by residual stresses only [32]. This is obtained by fine tuning of the grain size during cooling.

A more complex composite was released to the market in 2015 under the trademark of Bioceram®AZUL, which was likely chosen for its characteristic blue color [33,34]. AZUL contains approximately 19 wt % zirconia and 2 wt % oxide additives mixed with highpurity fine alumina. The addition of a mixture of oxides characterized by platelet-like grains, such as TiO2, MgO, Co3O4, SiO2, and SrO, aimed to reduce the grain size and induce the precipitation of platelet-like SHA grains. Additives used in the ZTA synthesis, except for silicon, were located in that platelet-like grain, substituting for strontium and/or aluminum [35]. Stress relaxation due to the zirconia particles and the crack-diverting effect of S6H crystals are relevant factors promoting the high strength and toughness of Bioceram®AZUL.

A further ZTA (25 vol % Y-TZP, alumina balance) was introduced on the orthopedic market under the trade name Symarec® on 2015 by Mathys Orthopedie (Bettlach, Switzerland), who incorporated the company Keramed (formerly Keramik Werk Hermsdorf— KWK Moesdorf, Germany). Keramed is among the pioneers in bioceramics, manufacturing alumina Bionit® since the early 1970s. Symarec® contains 25 vol % Y-TZP finely dispersed in the alumina matrix (75 vol %) [36].

#### **5. Alumina-Toughened Zirconia**

Similarly to the ZTA, the ATZ aimed to combine the advantages of the two monolithic materials. Although ATZ may appear of relatively simple design, the properties of these special materials depend significantly on the production steps and conditions, as already previously pointed out.

So far, Mathys Orthopedie (Bettlach, Switzerland) introduced the only ATZ for orthopedic applications in the market in 2007 under the trade name Ceramys® [37]. The mechanical behavior of the material is remarkable and, in some cases, it produced better results than the ZTA alternatives (see Table 3).


**Table 3.** Selected properties of alumina–zirconia composites for orthopedic applications. Adapted from [31]. (n.s.: not specified; \*: measured by ring-on-ring bending).

> Ceramys® is presently the oxide ceramic composite with the higher toughness now on the market. The production of ball heads covers the most significant diameters now in clinical use (29, 32, 36 mm). Mathys is manufacturing also sleeved ball heads using the ATZ Ceramys®, for use in revision surgery or in primary implants thanks to extra-long sleeves.

> The Ceramys® is sometimes described as a composite made of 80 wt % zirconia and 20 wt % alumina. More in detail, Schneider, et al. [38] describe the Ceramys® as formed by 61% tetragonal zirconia, 17% cubic zirconia, approximately 1% monoclinic zirconia, and alpha-alumina. The tetragonal zirconia phase is stabilized with 3 mol % yttria as for the standard monolithic zirconia (3Y-TZP). The alumina grains are finely dispersed in the zirconia matrix, and the average grain size approaches 0.4 μm, both for ZrO2 and Al2O3.

According to Oberbach et al. [39] the biaxial flexural strength (acc. to standard ISO 6474) surpassed 1200 MPa. The pin-on-disk wear test with ATZ/ATZ couplings using serum as a fluid test medium was shown to be comparable to Al2O3/Al2O3 couplings (i.e., 0.152 mm<sup>3</sup> and 0.157 mm<sup>3</sup> of weight loss, for ATZ and Al2O3, respectively) [40].

Some properties of currently manufactured alumina–zirconia ceramic composites for orthopedic applications are summarized in Table 3.

The interest for zirconia-toughened ceramics (ZTCs) in dentistry is mainly due to the present evolution in the device design. Namely, metal-free dental implants are becoming more and more demanded by patients, and in the last 20 years, Y-TZP is used to produce crowns and bridges as a structural ceramic as well as in dental implants [41].

Several alumina–zirconia ceramic composites are already in use in dentistry. The one with the longer clinical record is known under the trade name NANOZR® (Matsushita/Panasonic, Osaka, Japan). Developed by Nawa et al. in the late 1990s, it is an ATZ composite ceramic constituted of 10 mol % Ce-TZP matrix with 30 vol % Al2O3 [42,43]. This material shows an intergranular type nanostructure, in which several 10–100 nm Al2O3 particles are trapped within the ZrO2 grains and several 10 nm ZrO2 particles are trapped within the Al2O3 grains. NANOZR® is now in use in CAD/CAM milling blanks for dental restorations (crown, bridges, etc.), and tests are now in progress in the view of its use in dental implants [44].

Dental implants made of Y-TZP are rather common today, and the large majority of the devices on the market are single-piece devices. As an alternative, a growing number of manufacturers are proposing two-piece dental implants made of Y-TZP. The design of the connection in two-piece implants is a challenging issue because of the small overall diameter of the device (3.5–4 mm) and the reduction in thickness of the walls in the zone of connection. The reliability of these devices can be improved by the use of composites. In addition, alumina–zirconia ceramic composites are expected to increase the reliability of small diameter implants (e.g., 3.5–3.25 mm in diameter) that are the most critical from the mechanical viewpoint.

The ATZ now in clinical use for dental implants is BioHip® (Metoxit, Tahingen, Switzerland) [45]. This material is a fine and homogeneous dispersion of Al2O3 grains (D ≈0.4 μm) in a submicron-size Y-TZP matrix, and it shows a marked improvement in the mechanical behavior with respect to Y-TZP (see Table 3). Zeralock and Zeramex Plus dental implants too (Dentalpoint, Zurich, Switzerland) are made out of ATZ BioHip®. The retrospective analysis of the company database demonstrates the excellent success rate of these two systems, 98.5% at >2 years follow up (Zeralock) and 99.4% at >1 year follow up (Zeramex Plus) [46].

#### **6. Developments in Progress**

The developments in progress in alumina–zirconia ceramic composite as biomaterials are presently based on the development of new medical devices using materials already established. This is true especially for applications in dental implants fostered by manufacturers developing two-piece and small diameter (<4 mm) dental implants. In addition, the present regulatory framework is making it difficult to introduce new materials in dental implants due to their class of risk (IIb).

As an illustrative example of this situation, it is noted that the small diameter implants now under development (2021) are based on a Ce-TZP-based triphasic composite already described six years ago [47,48]. Ceramic composites replacing Y-TZP by Ce-TZP are being studied for application in dentistry, i.e., by Apel et al. [49], who reported the processing of a ceria-doped tetragonal zirconia polycrystal-based composite (10Ce-TZP/16 vol % MgAl2O4), obtained by slip casting and die pressing of commercially available powders. Their work shows that the material is enhanced by the inter- or intra-granular dispersion of nano-scaled (max 200 nm) magnesia spinel, mostly at the grain boundaries of the Ce-TZP matrix but also within the zirconia grains. Moreover, this material contains very fine

zirconia crystals within the spinel grains. Negligible LTD was observed after aging at 134 ◦C in saturated steam for 450 h [49].

Ce-TZP/Al2O3 composites were extensively studied in the framework of two EUfunded research projects, named LONGLIFE and SISCERA. The Ce-TZP/8 vol % Al2O3/8 vol % SHA composites (referred to as ZA8Sr8) were recently developed using as a precursor a powder obtained by the surface-coating route [50]. Reveron et al. reported that using coated powders allows homogeneous distribution of the second phases in the zirconia matrix, the tailoring of grain size and morphology, and a close control of the stoichiometry [51]. The mechanical properties of the triphasic composite ZA8Sr8 are summarized in Table 4. In addition, ZA8Sr8 shows optimum LTD resistance; the monoclinic fraction after 50 h of hydrothermal treatment (134 ◦C, sat. steam) is about 10 vol % in comparison with 70 vol % in Y-TZP treated in the same conditions [52].

**Table 4.** Selected characteristics of some ZTC of interest as materials for dental implants. Flexural strength measured on 4-p bending bars. \* Biaxial measure on discs following ISO 6872.


A further approach to increase the strength and toughness of ceramics is based on the introduction of elongated phases that increase the toughness of the material by crack deflection/bridging as discussed previously in the case of SHA platelets in an alumina matrix. Similar platelet-like grains made out of lanthanum hexaluminate (LaAl11O18— LHA) nucleated in Ce-TZP during sintering were reported by Miura et al. [53].

Similar structures reinforced by LHA can be obtained in a Y-TZP matrix, leading to materials with variable behavior depending on the volume fractions of the different phases, i.e., the ZCA10P composite (Oximatec GmbH, Hochsdorf, Germany) containing 10 vol % platelets described by Burger [54], illustrated in Figure 3.

Further materials that are expected to originate innovative devices in dental implantology are the ones described by Gottwik et al. [55]. They disclosed a new material with remarkable mechanical behavior. Identified as HTZ500, it consists of a matrix of 2 mol % Y-TZP (grain size: 0.27 μm) containing a dispersion of 5 vol % SHA platelets [55]. The bending strength is ≈1.6 times the Y-TZP one. This material is especially of interest for its strength after scratching or after indentation, which is defined by the author as "damage tolerance" [56]. Namely, the abutment of one-piece dental implants is finished by grinding, which may originate a network of subsurface cracks that may grow until fracture, which is driven by the stresses applied during clinical use [57].

Other approaches to increase the mechanical behavior of ZTA were followed by Duntu et al. [58]. They observed a relevant increase in hardness and toughness after the addition of graphene to the material. In hot pressed ceramics, fracture toughness was increased up to 115%, while the fracture toughness (KIC) of alumina—10 wt % ZrO2–was increased up to 164% thanks to the refinement in grain size of the alumina matrix and to the toughening effects of intergranular graphene and ZrO2 grains.

**Figure 3.** Microstructure of Ce-TZP/LaAl11O18 composite (ZCA10P) (courtesy Dr. W. Burger, Oxymatec Gmbh, Hochdorf, Germany).

> A further approach to improve the mechanical behavior of ZTA consists in adding TiO2 to the composite, thus increasing the composite density [59,60].

> Khaskhoussi et al. [61] reported the results of the biological characterization in vitro of experimental ternary alumina/12 mol % ceria-stabilized zirconia/titania ceramic composites. Adding TiO2 in ZTA is known as an effective way to increase alumina and zirconia density [60]. The tests demonstrated that these composites may be able to promote cell adhesion and bonding in the tissue and implant interface, but these promising results must be confirmed in vivo. In addition, genotoxic effects were observed in the composites with higher concentration of TiO2 tested (10 wt %), indicating the need to establish a threshold for this component in the ceramic.

#### **7. Conclusions**

Alumina—zirconia ceramic composites have wide acceptance in orthopedics, and their relevance is growing in dentistry. This due to the biological safety of the materials now in production, their stability, and their outstanding mechanical properties.

In orthopedics, the large majority of orthopedic companies rely on BIOLOX®delta for ceramic components for THR bearings. This ceramic covers more than 90% of the worldwide market, while the ones made by competitors rely on niche markets only. More than 5 million patients so far are taking advantage of ceramic components made out of this material.

BIOLOX®delta is today "the ceramic" in hip replacement bearings worldwide, and it is becoming the material of choice for ceramic bearings in the growing field of shoulder arthroplasty. Attempts to use ZTA components in knee arthroplasty are limited to niche markets mainly due to the high pricing of bioceramic knee replacements because of their design, which is much more complex that the spherical joint of the hip or of the glenoid component for shoulder replacements.

In dentistry, especially in implantology, ceramic devices had to cope with the clinical success of titanium implants. Although ceramic dental implants have had a clinical outcome analogous to the titanium ones, the share of ceramic implants—although steadily growing—is today no more than 10% of the market.

The diffusion of ceramic implant in dentistry is depending on the formation of practitioners, who could hence add these devices to the array of solutions that they propose to their patients.

The standard material for ceramic dental implants is Y-TZP, but some implant manufacturers already use ATZ. The growing interest for two-piece implants and for small diameter may widen the application of oxide ceramic composites, especially the ternary ones making use of ceria-stabilized zirconia and SHA platelets, because of their mechanical properties.

Although several experimental materials are under study, their future appears uncertain due to the strict rules of the regulatory systems for medical devices that are making the approval of new materials more and more difficult.

We note the growing attention on ceramic implants by the global players of the dental market, which will lead to significant changes in the dental implantology field during the next few years. The major companies recently made agreements with, or acquisition of, companies involved in material development and/or in the manufacture of ceramic dental implants. A new momentum to metal-free implantology and to oxide ceramic composites biomaterials in this field can be expected from these operations.

**Author Contributions:** writing—original draft preparation, P.C.; writing—review and editing, S.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

