*2.2. Classification of Bioceramic Composites*

One major classification of bioceramics relies on the biochemical reactions occurring between the implanted scaffold and the surrounding tissue, particularly on the increasing capacity to be resorbed upon implantation in vivo. In this way, bioceramics can be considered as bioinert, bioactive, or bioresorbable materials [107]. Zirconia (ZrO2) and alumina (Al2O3) are examples of inert bioceramics with minimal adverse reactions on tissue and body organs after coming into contact with the human physiology [108]. They have inherently low levels of reactivity compared with other materials, such as polymers and metals, as well as surface reactive or resorbable ceramics. Strategies for the improvement of the biocompatibility of inert ceramics were proposed, such as surface modifications, coatings, or ion doping [109–112].

In contrast, bioactive ceramics, such as bioglasses, show an ability to superficially bond with the surrounding bone, thus improving their interfacial strength [103,113]. The ability to bond to bone tissue is a unique property of bioactive ceramics. Analyses of the bone implant interface revealed that the presence of hydroxyapatite is one of the key features in the bonding zone [103].

Bioresorbable bioceramics represent a further improvement in their long-term interaction with surrounding tissues, because in addition to their chemical similarity to the mineral component of bone, they are able to be gradually resorbed and replaced by new bone tissue over time. The in vivo behavior of ceramic bone substitutes includes three main steps: (i) solubility: if the compound is soluble in physiological conditions, dissolution and removal can occur; (ii) the dissolution kinetics, related to the speed at which the particular ceramic is removed from the body; and (iii) conversion into another compound via a dissolution–precipitation mechanism [114]. Bioresorbable bioceramics are represented by calcium sulphates (Plaster of Paris) and calcium phosphates, especially with ion doping with Sr, Mg, Si, and Zn, which can improve their biological activity [19,115–120]. However, there are some drawbacks of calcium phosphates, such as their poor mechanical strength, differences between the bone regeneration and degradation rate, inflammatory reaction of synthetic bioceramics, and limited ingrowth due to pore size [121–123].

In this context, the possibility to introduce additional inorganic phases in bioceramics opened a wider choice of materials for their use as implants. Some of these materials include ceramic/ceramic, ceramic/metal, and ceramic/polymer composites. However, ceramic/polymer composites have been observed to release toxic components in the surrounding tissues, while metals undergo corrosion-related issues as the ceramic coating on the metallic implant degrades over time [124–126]. Ceramic/ceramic composites are thought to have a better performance because they resemble bone minerals and exhibit high biocompatibility [127–129]. Nevertheless, the biological activity of bioceramic composites has to be defined, especially considering the specific implantation site [130]. Bioceramic composites have exceptional biocompatibility and are non-toxic [131–133]. Some additional features of bioceramics composites include their hydrophilicity and antibacterial properties [134–136].

#### *2.3. Surface Chemistry*

The effective chemical interaction between the surfaces of the implanted scaffolds and the surrounding tissues plays a crucial role in the regeneration of bone tissue [137,138]. The three different types of bioceramics (bioinert, bioresorbable, and bioactive) have significantly different superficial interactions [139]. It is worth mentioning here that these fundamental differences in surface chemistry result in different interacting conditions at the biomolecular interface with cells and proteins [23,140,141].

The implantation of a scaffold into a biological environment is followed by the hydration and hydrolysis of the surfaces, typically leading to the formation of chemical bonds, containing either hydrogen or hydroxyl groups, with a rate dependent on the pH environment [142].

The superficial properties essentially modulate the interaction with water molecules and the mechanisms of adsorption of biological macromolecules (e.g., proteins). This interaction ultimately determines the interplay between the implanted bioceramics and bone cells.

It was reported that an electrostatic attraction primarily affects the protein adsorption on bioceramic surfaces, and effective surface charge modulation can be achieved by the immobilization of biomolecules such as bisphosphonates (BPs), amino acids, or carboxylic acid on the bioceramic surface [140]. Additional factors affecting the protein adsorption and cell adhesion include surface wettability and surface energy. The tuning of the chemical and morphological features of bioceramics can be performed by chemical or physical surface modifications, including atomic layer deposition, chemical vapor deposition, plasma vapor deposition, and electrochemical deposition [141,143,144].

Chemical treatments generally result in the formation of coating layers or the induction of specific chemical functional groups (e.g., carbidization, nitration, oxidation), while physical modifications result in micro- to nanoscale morphological or topographical alterations via a multitude of processes (e.g., machining, grit-blasting, and etching) [145–147].

#### *2.4. Mechanical Properties*

The mechanical properties of bioceramics, including compressive strength, stiffness, fracture toughness, and fatigue resistance, represent the key factors for effective bone regeneration [148]. These criteria include "static" mechanical properties (e.g., stiffness, hardness, strength), as well as "dynamic" mechanical properties (e.g., fatigue cycle resistance, crack propagation stability, and fracture toughness) [149].

A major concept in defining mechanical properties of ceramics is the difference between strength and toughness. They are frequently considered to be overlapped, despite the fact that they are mutually exclusive—strength is a stress representing the intrinsic capability of a material to resist to irreversible deformations, while toughness refers to the energy required to induce a fracture [150].

Toughness can also be determined using fracture mechanics methods, which determine the critical value of a crack-driving force, such as the stress intensity *K*, strain-energy release rate *G*, or nonlinear elastic J-integral, required to initiate and/or propagate a previously formed crack.

However, the intrinsic brittleness of ceramics basically limit the capability to improve the toughness, primarily because they cannot be toughened by promoting plasticity [151].

The compressive strength of the human cortical bone is reportedly in the range 90–209 MPa, while the reported flexural strength is 135–193 MPa [152,153]. The mechanical strength of bioceramics is reported to be in the range of cortical and cancellous bones [154]. The ideal scaffolds for bone regeneration should be designed considering this feature, but also considering that extensive bone penetration in a porous scaffold will increase the mechanical properties of the bone-scaffold construct until reaching physiological levels [44]. In particular, fracture toughness is important because it refers to the ability of the scaffold to contrast the propagation of a crack defect [155]. Hence, compressive strength and fracture toughness are relevant properties to be considered for effective bone regeneration [156,157]. The particle size, composition, porosity, and crystallinity of bioceramics significantly affect their mechanical performance—an increase of porosity and particle size leads to the decrease of mechanical properties [158–160].

The fracture toughness of cortical bone (*K*Ic = 2–12 MPa·m0.5) is higher than that of ceramics or inorganic glass [160–162]. Numerous methods have been developed over time to measure the fracture toughness and hardness [163–165]. The low fracture toughness and poor mechanical strength of bioceramics limits their usage in load-bearing applications [166,167]. It was reported that the fracture toughness and flexural strength of bioceramics increase in wet environments [168].

The toughness and flexibility of bone tissue can be ascribed to the complex biomineralization of collagen fibers with apatitic crystals, associated to the multi-scale hierarchical

architecture [168]. The toughness of bioceramics can be improved by including additional biocompatible phases [169,170], crack bridging, or phase transformation, in order to control the crack growth [171–173]. The dispersion of second phase such as fibers, whiskers, and particles for creating toughness in bioceramics was also reported [174–177].

The mechanisms for increasing the toughness of ceramics can be classified as either intrinsic or extrinsic. Intrinsic toughening is primarily related to plasticity, that is, enlarging the plastic zone, mainly against the initiation of a crack. Conversely, extrinsic toughening acts to limit an initiated crack, reduce the stress and strain fields at the crack tip, preventing further opening, including crack bridging by fibers or ductile phases in composites.

A significant increase of flexural strength, flexural modulus, and fracture toughness of ceramic dental composites was also reported through the addition of zirconia-silica (ZS) or zirconia-yttria-silica (ZYS) nanofibers (2.5 wt % or 5.0 wt %) [178,179].

Bioceramic composites made from HA and TZP (tetragonal zirconia polycrystal) powders coated with Al2O3 also exhibited significantly higher strength and fracture toughness, due to the integration of ZrO2 (15 vol %) and Al2O3 (30 vol %) [180].

The microstructural and mechanical changes of Al2O3 matrixes, after the incorporation of Cr2O3, was also studied, resulting in improved hardness and elastic modulus, while fracture toughness deteriorated with the addition of 2 mol % Cr2O3 particles [181].

It was also reported that Zr–Ti–Nb–Cu–Be glasses containing 42–67 vol % dendrites exhibited 100–160 MPa√m toughness at tensile yield strengths of 1.1–1.5 GPa [182]. A monolithic and amorphous Pd–Ag–P–Si–Ge glass alloy with 1.5 GPa tensile strength and 200 MPa·m0.5 toughness properties was also recently reported; its properties were a result of the generation of shear band after loading, which resembles large-scale plasticity [183]. Nevertheless, it has drawbacks related to critical processing and production costs [150].

Moreover, researchers produced novel dental restorative composites by using hydroxyapatite whiskers. They reported that the efficiency of reinforcement depends on the filler morphology. Hydroxyapatite has good wettability with polymer which leads to increased toughness in comparison to nano-size HA powder [184,185]. Two composite materials have been produced by using ZrO2-Al2O3 system: zirconia toughened alumina (ZTA) and alumina toughened zirconia (ATZ) [186–191]. The ZTA ceramic composites with 0.5 wt % MgO content exhibited the best attributes, such as a fracture toughness value of 9.14 MPa·m0.5 and a hardness value of 1591 HV. Similarly, the effect of TiO2 phase composition and mechanical properties of Ca-TZP (calcium stabilized tetragonal zirconia) ceramic have been observed, with fracture toughness values up to 9.1 MPa√m after reinforcement with TiO2 in the range of 0.5–0.65 mol % [192].

A great research effort for the reinforcement of bioceramics with carbon fibers (CF) has been established, due to their excellent biocompatibility and mechanical properties [193–195]. The addition of CF to HA matrix effectively improves the bending strength and fracture toughness of HA [177,196]. ZrO2-HAp composites (40 and 60 vol % of ZrO2) were fabricated and evaluated, demonstrating the reinforcing effect of ZrO2 [174].

#### **3. Toughening Strategies for Bioceramic Composites**

The brittleness of bioceramics significantly limits their applications because in addition to strength, adequate toughness is required to sustain the biomechanical loads [86].

Any crystallographic defect or irregularity within the crystal structure represents the main cause for dislocations, the mechanisms of which are related to the Peierls–Nabarro (PN) barrier energy that defines the fracture toughness of a material [197].

Metals contain mobile dislocations, leading to local plasticity and desirable toughness [197,198], while ceramics are characterize by the immobility of dislocations and low fracture toughness, especially at room temperature [199]. In this respect, the high-strength ionic bond typical for ceramic structures plays a crucial role, limiting atomic slip systems.

The mechanical performance of bioceramics is closely related to several factors, including microstructure, chemical composition, ionic impurities, and structural defects. The strategies to improve the toughness or fracture strength of ceramics refer to the capacity to control or limit the propagation of cracks along the powder particles and grains.

Several methods have been reported to improve the toughness of ceramics, including crack-bridging, crack-deflection, microcrack-induced toughening, generation of phase transformations, and reduction of the defect size (Figure 2).

**Figure 2.** Different strategies to improve the toughness of bioceramics.

Moreover, the basic scaffold structure can be combined with polymer coatings, or interpenetrating polymer-bioactive ceramic microstructures can be formed to improve the toughness of the ceramic as a simple and effective approach [200].
