**1. Introduction**

Bone tissue is classified as a calcified connective tissue with several important roles in the human body, including storing minerals, protecting vital organs, enabling movement, providing internal support, and providing the sites of attachment for muscles and tendons [1,2]. Bone can be considered as a natural composite made of inorganic components (naturally doped calcium phosphates, ~70 wt %), organics (Collagen Type I, non-collagenous proteins, proteoglycans, cells, ~22 wt %), and water (~8 wt %) [2–4].

The complex metabolism and 3D hierarchic structure of bone tissue give it an innate ability to heal from minor defects. However, the natural healing process of bone is limited when major injuries due to traumas or metabolic or neoplastic bone pathologies occur [1,2]. In such instances, the orthopedic surgeon is challenged to find out adequate regenerative approaches [3]. The use of natural bone grafting (i.e., autologous or heterologous bone) can be pursued to replace the bone defect. Autografts are considered as the gold standard for bone grafting, as they closely resemble the natural bone structure, without immunogenic response. Despite these benefits, some limitations are evident, including the morbidity of the donor site, increased operation time, increased blood loss, and risk of immunogenicity and pathogenicity [4–7]. In addition, the sterilization and irradiation processes of natural bone grafts have been reported as critical steps that limit their bioactivity [8–11].

In this context, a great deal of research effort has been devoted in the last decades towards the synthesis of synthetic scaffolds [12–15]. The naturally occurring mineral phase in bone tissue is represented by poorly crystalline calcium phosphates with the crystal structure of hydroxyapatite (HA). HA can be synthesized in laboratory, and it is currently under study for the development of bone grafts, due to its excellent biocompatibility, osteoconductivity, and osteoinductivity [16–22].

In the last decades, bioceramics have been considered as ideal candidates for bone grafting due to their ability to locally deliver biomolecules in vivo. Calcium phosphates are a major member of bioceramics, covering a wide range of biomedical applications in tissue engineering, including orthopedic and dental surgeries [23–26].

**Citation:** Abbas, Z.; Dapporto, M.; Tampieri, A.; Sprio, S. Toughening of Bioceramic Composites for Bone Regeneration. *J. Compos. Sci.* **2021**, *5*, 259. https://doi.org/10.3390/ jcs5100259

Academic Editor: Francesco Tornabene

Received: 29 July 2021 Accepted: 24 September 2021 Published: 29 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Bioceramics must meet strict criteria to be approved for biomedical applications, such as biocompatibility, bioactivity, and an absence of proinflammatory features [27]. The classification of bioceramics is generally based on their chemical composition, as well as on the basis of their interaction with natural tissues; thus, bioceramics can be considered as bioinert or bioactive, considering biodegradability as an added value that enables the replacement of damaged bone parts with new ones during the scaffold bioresorption [28–32]. In this respect, recent studies demonstrated that the modulation of composition and textural properties can be considered as a valuable strategy to control material resorption and bone formation [33,34].

Bioinert ceramics, including alumina, zirconia, and silicon nitride, are not able to undergo any modification upon implantation, and thus maintain their chemical structure and represent a foreign body within the biological environment [35,36]. In contrast, bioactive ceramics have the capability to form chemical bonds with the surrounding tissues, and actively interact with the surrounding environment [37,38]. Among them, calcium phosphates (CaPs), bioglasses, and calcium silicate (Ca-Si) bioceramics are intensively studied for skeletal bone regeneration applications [22,39–43].

The osteogenic capability of bioceramic scaffolds is significantly correlated to their intrinsic pore size distribution and interconnection, enabling cell infiltration, migration, and neo-vascularization. The pore distribution and geometry of the scaffold strongly influence the ability of cells to penetrate, proliferate, and differentiate as well as the rate of scaffold degradation [44–48]. In spite of their great potential, a main drawback associated with bioceramics is their intrinsic brittleness, i.e., incapacity to withstand deformation without rupture, which is a major problem that can potentially cause a sudden failure of the scaffold structure under physiological mechanical loading. This is particularly relevant for porous calcium phosphates that associate brittleness to limited fracture strength, in comparison with inert ceramics such as zirconia or alumina [38,49,50]. In the last century, an intense research effort has been devoted to the reinforcement of bioceramics for different applications. In this respect, various approaches have been proposed, including modified sintering treatments [51–53], combination with polymeric phases to produce composites [49,54,55], the addition of fibers or the development of additive manufacturing as a 3D technique to prepare complex-shaped bioceramic structures [34,56–60]. A major approach to this purpose is the addition of ceramic particles, whiskers, and fibers to the ceramic matrix to improve the fracture toughness [61–65]. Ceramic fibers selected for their lightweight, adequate strength and modulus, and biocompatibility have been tested in the last decade for improving the mechanical properties of bioceramics [66–69]. The key factor influencing the performance of the final material is represented by the interfacial adhesion between fibers and the surrounding matrix [70]. The main factors affecting the fabrication of fiber-reinforced scaffolds include the chemical composition of fibers and matrix, the physical interaction between them, and the amount and alignment of fibers [59,71,72]. These factors affect the mechanical strength and degradation properties of the scaffold, leading to changes in the cell response. In this respect, many studies have reported the biocompatibility of fiber-reinforced ceramics both in vitro and in vivo [73–77].

It was observed that smooth fibers with a chemically inert surface are provided with less reactive functional groups, resulting in poor adhesion with the matrix [78]. Some studies reported chemical approaches to activate the fibers' surfaces, in order to strengthen this interaction [59,79–85].

The present review summarizes the relevant progress made on the mechanical reinforcement of bioceramic composites. The fabrication techniques for these scaffolds, along with the current strategies for toughening mechanisms, are described. Furthermore, the concerns related to porosity along with the mechanical and biological properties of fibrous ceramics are reported. As the advances in bone tissue engineering move toward application in the clinical setting, achieving adequate bioceramic toughness for clinical applications is particularly critical. In this context, recent computational approaches have been proposed

in order to predict the crack propagation pathways, while increasing the toughness of ceramic-based bioinspired materials [86].

#### **2. Bioceramic Composites in Bone Regeneration**

*2.1. Bone Tissue Formation and Remodeling*

The adult human skeleton is made up of 206 bones. Each bone is a very complex hierarchical structure consisting of osteon, lamellar, fibrils, and mineral and collagen fibers (Figure 1). The bone is a dynamic tissue that continuously remodels during the life span of an individual: the term "bone remodeling" refers to a complex biochemical process involving the degradation of the mineralized bone via osteoclasts followed by the deposition of newly formed bone matrix by osteoblasts [87]. Due to this remodeling, the timing for complete bone tissue renewal is about 5 to 10 years [88–90]. This helps it in adapting to ever changing biomechanical forces by replacing the old or micro-damaged bone with a new and mechanically stronger bone, thereby preserving bone strength [91]. The bone has a unique ability to shift the intricate balance between osteoclastic and osteoblastic activities depending upon the external stimuli [92–94]. Such mechano-transduction signals can amplify the osteoblastic activity, resulting in an enhanced deposition of bone matrix [44]. In other circumstances, this equilibrium can be triggered by a chemical rather than a mechanical signal [44,95,96]. After receiving the mechanical signal, osteoclasts are deployed to the bone to initiate resorption. This process results in the release of calcium or phosphate to the body fluid as it is crucial for specific metabolic reactions. It is also assumed that chemokines are responsible for the differentiation-fusion of monocytes into osteoclasts and for carrying out the subsequent osteoclastic activity [97–99].

In this context, the regulation of osteoblasts-osteoclasts mediated processes plays a key role in achieving effective bone tissue regeneration [100]. Bioceramic composites can be engineered for better resorption and bone remodeling by mixing different ceramic materials [101]. The incorporation of strontium (Sr) into bioceramic composites can improve the bone tissue density via increasing osteoblast function and inhibiting osteoclast activity [102–105]. In addition, the surface topography also affects the resorption capacity of osteoclasts [104,105]. It was observed that human peripheral blood monocyte derived osteoclasts were more actively resorbed onto sub-micro structured β-TCP compared to microscale topography [106].

**Figure 1.** Hierarchical structure and mechanism of the formation and remodeling of long bone.
