3.2.2. Extrinsic Material Modifications

The approaches proposed to increase the mechanical strength while limiting the brittleness of bioceramics include the combination with polymers, fibers or a dual setting system, especially for cements [104,107,108,119,120].

The dual setting system refers to the addition of reactive monomers to the liquid phase, together with an initiator into the inorganic component of the cement or eventually polymeric component that can be cross-linked [121,122]. In the first case, during the setting, there are simultaneous gelation/polymerization and dissolution–precipitation reactions, thus obtaining cement with a porous microstructure reinforced with a hydrogel-based matrix. As a consequence, an increase in compressive strength and hardness with stable rheological properties was achieved [102]. In turn, the cross-linking agent permits the binding of Ca2+ ions with carboxylic acid or organic phosphate fractions in the polymer chain, thus resulting in a reduction in brittleness and an increase in compressive strength [82,122].

The addition of fibers is one of the most effective approaches to increase the strength and toughness of bioceramics [123,124]. The mechanical behavior of fiber bioceramic composites is based on the interaction between the composite components and is time dependent due to the potential degradation of both fiber and CaP-based materials after implantation to allow bone regeneration. The reinforcements are related to several parameters, including (i) composition, mechanical properties and degradation of the matrix; (ii) fiber– matrix interface properties; and (iii) type, length, diameter, volume fraction, orientation and mechanical properties of fibers [124,125]. It was observed that the long-term strengthening effect of fibers was related to the type of fibers: the addition of non-resorbable fibers led to a stable increase in mechanical performance over time, while resorbable/biodegradable fibers provided only an initial reinforcement, followed by the creation of a macroporosity in the ceramic matrix after degradation of the fibers, favoring osteointegration [102].

The application of critical loads to brittle materials induces catastrophic fractures without any reversible deformation. The incorporation of fibers provides intergranular bridges increasing the tensile strength, flexural strength and fracture toughness.

There are three main fiber-reinforcing mechanisms [108,119,120]:


Fibers can be classified as natural and man-made fibers, further divided into resorbable and non-resorbable [71] (Table 9).


[109]

Cellulose [112]

**Table 9.** Fiber classification and some examples of fibers used in bioceramic reinforcement.

The introduction of carbon fibers (CF) in bioceramic scaffolds, including bone cements, has been explored in the past decades [123–125]. In particular, previous works showed that the addition of fibers led to an increase in compressive strength without interfering with HA formation during the setting of CPC [127]. The presence of CF induced a significant reinforcement also in calcinated HA-based scaffolds, while preserving biocompatibility and bioactivity; the mechanisms underlying the increase in mechanical properties were attributed to crack deflection, interlocking of the fibers, pullout and crack bridging [118]. Basically, the interaction between fibers and the surrounding ceramic matrix is based on

[103,113]

HA whiskers [122,127]

several properties of fibers, including chemical composition, wettability and surface modifications. HA bioceramics reinforced with silicon-coated CF with controllable alignment were prepared via hot pressing and pressureless sintering, leading to the formation of a SiO2 protective layer upon thermal decomposition of HA [118].

Various oxidation treatments were also implemented to improve the performance of CF as a strengthening agent of CPCs, including a preliminary treatment with aqua regia followed by immersion in CaCl2 [104]. This treatment favored the heterogeneous nucleation of apatite nanocrystals on the surface of fibers, thus reducing the setting times; the addition of 1 wt% of fibers led to a significant increase in both bending strength and the work of fracture, essentially due to the deflection of crack propagation, while the in vitro biocompatibility was preserved.

Moreover, silicate-based fibers, calcium silicate, glass and basalt fibers have been used to reinforce bioceramics [117,121,122,126]. In particular, wollastonite (CaSiO3) fibers were introduced into CPCs, showing that Si could favor the crystallization of needle-like apatite during cement setting, associated with a significant increase in compressive strength [126]. Furthermore, the presence of CaSiO3 fibers was a promoter of cell viability and ALP activity [121].

Glass fibers (GF), such as E-glass and bioactive glass fibers (BGF), have been proposed as CPC-reinforcing agents [128,129]. E-glass fibers are composed of alumino-borosilicate with about 1 wt% alkali oxides, while BGF is described by the ternary system SiO2-CaO-P2O5 [122]. Xu and co-workers had incorporated short and long E-glass fibers into CPC, obtaining an increase in elastic modulus, flexural strength and the work of fracture [115]. The addition of 15 wt% of BGF also determined an improvement of compressive strength, toughness and elastic modulus of CPCs [122].

In addition to fibers, apatite whiskers were proposed to improve the mechanical properties of CPCs; the enhancement of 120% of the work of fracture and 60% of flexural strength was obtained by adding 30 vol% of HA whiskers [127].

#### **4. Ion-Doped Bioceramics and Composite Scaffolds**

#### *4.1. Ion Doping*

Calcium phosphates, especially HA, are capable of hosting a variety of foreign (i.e., different from Ca and P) ions, involving the formation of atomic defects but with a limited modification of the overall crystal structure [39]. As biological apatites forming the inorganic part of bone are characterized by nanocrystallinity, poor crystal ordering and multiple ion doping, in the last few decades, various approaches were proposed to tune the biological properties of ceramics [129–136] in order to obtain novel biomaterials with multifunctional abilities, including antibacterial [137–140] and magnetic properties [128].

Some of the most studied substituting ions in bioceramics, with related biological roles, are listed in Table 10.


**Table 10.** Doping ions in calcium phosphate bioceramics, with related biofunctional ability.


**Table 10.** *Cont.*
