*Nature-Inspired Processes and Structures: New Paradigms to Develop Highly Bioactive Devices… DOI: http://dx.doi.org/10.5772/intechopen.82740*

One of the most critical issues of injectable CPCs is the control of the chemistry of setting reactions and rheological properties, to achieve adequate injectability, setting time, and mechanical properties [53]. A recent interesting approach involves the addition of natural polymers or their derivatives, such as sodium alginate [54], hydroxypropyl methylcellulose [55], hyaluronic acid [56], chitosan [57], and modified starch [58], into the starting powder or in solution into the cement paste [59]. Biopolymers can be developed as low-viscosity solutions for easy injection and have the ability to cross-link in situ after injection under physiological conditions (temperature or pH) or by the action of an initiator (light or cationic cross-linkers) [53]. In general, due to the higher viscosity of the CPC paste, the presence of polymers tends to increase setting time and to enhance CPC injectability and cohesion. Furthermore, the use of biopolymeric additives can be an effective method to improve the mechanical performance of CPCs [53]. Depending on the final CPC properties desired, different polymers may be incorporated into CPCs, and the polymeric solution may be altered by changing concentration, molecular weight, and polymer chain length [59].

Among the several approaches proposed for the synthesis of CPCs, the use of α-tricalcium phosphate (α-TCP) powder [60] as a metastable precursor is particularly of interest for introduction of foreign ions, such as Mg2+, CO3 <sup>2</sup><sup>−</sup>, SiO4 <sup>4</sup><sup>−</sup>, and Sr2+, enhancing bioactivity and providing efficient therapies against degenerative bone diseases [19, 20, 61].

In particular, CPC formulations based on Sr-doped apatitic cements are very interesting because of strontium ability to enhance cell proliferation and differentiation into bone-forming osteoblasts and decrease the resorbing activity of mature osteoclasts; this is a key achievement for the restoration of the bone turnover balance, especially when the cement is used to treat osteoporotic bone fractures [62]. Sr-substituted TCP was shown to slow down the cement setting as well as the transformation into Sr-doped HA. Moreover, due to apatite lattice expansion, the introduction of strontium in the apatite structure is associated with an increased solubility of the cements, leading to an increase of ions released, which in turn was found to have a positive effect on cell proliferation and osteogenic differentiation [62]. In particular, Sr-substituted CPCs previously tested in vivo exhibited increased new bone formation compared to Sr-free CPCs. Due to the different preparation routes and properties of the set samples, such as phase composition and porosity, contradicting results of Sr effect on the mechanical characteristics of substituted CPCs can be found. In most compositions setting into Sr-HA, strontium substitution either increased compressive strength or had no significant effect on the mechanical characteristics [63].

Recently, novel injectable, self-setting Sr-HA bone cements were prepared by mixing Sr-substituted α-TCP phases as unique inorganic precursors with disodium phosphate solutions enriched with alginate. In vitro tests showed that different concentrations of Sr2+ were able to promote an inductive effect on mesenchymal stem cell differentiation, especially at 2 mol% concentration, and on pre-osteoblast proliferation and an inhibitory effect on osteoclasts activity [64]. Moreover, the addition of alginate significantly improved both injectability and cohesion, leading also to significantly higher compression strength when compared with alginatefree cements, without affecting the hardening process and with the absence of cytotoxic effects. On the basis of these results, a selected Sr-HA cement formulation was further tested in vivo in a rabbit model by compositional, morphological, and histological/histomorphometric analysis. The cement exhibited complete transformation into HA, thus showing a biomimetic composition, and enhanced the ability to induce new bone formation and penetration, provided also by its porous microstructure [65].

*Bio-Inspired Technology*

performances [39, 40].

**and nanostructure**

Despite the advantages, HA is reported to have the tendency to fragmentation due to its brittle character, typical of ceramic materials [28], which do not allow its use for load-bearing bone (e.g., femur, tibia, and metatarsus) reconstruction. In this respect, the current research in scaffold materials is directed toward the design and development of bioactive ceramic composites, especially as biodegradable implants, with bone-like three-dimensional structure and improved mechanical performances. Several attempts were made to join a bioactive/bioresorbable component (particularly HA and other calcium phosphates, such as tricalcium phosphate (TCP)) and a bioinert/bioactive reinforcing phase (ZrO2, calcium silicates, Al2O3, TiO2, and others) [36–38]. Among them TCP/TiO2 composites are considered very interesting for bone regeneration because β-TCP presents accelerated degradation and optimal reactivity with the bone tissue, thanks to its calcium to phosphorus ratio lower than that of HA [38], while TiO2 can form a tightly bound superficial HA layer, thanks to its bioactivity, and presents high mechanical

It has been recently demonstrated that dense and porous TCP/TiO2 bodies, obtained by optimized sintering process, display high values of flexural strength and fracture toughness, thanks to the presence of a reinforcing network made of TiO2-coalesced nanoparticles [41]. Moreover, increased proliferation, colonization, and viability were found demonstrating good osteogenic properties, thus showing

**4. Injectable self-hardening bone cements with biomimetic composition** 

Bone diseases, such as hemangioma, multiple myeloma, osteolytic metastases, and osteoporosis, can yield bone weakening, thus commonly resulting in fractures in the vertebrae, femur, and radius, especially in the elderly [43]. Minimally invasive surgery procedures, such as vertebroplasty and kyphoplasty, are currently used to regenerate osteoporotic fractures with bone cements as bone defect fillers [44]. Ideally, bone cements should exhibit adequate mechanical support to withstand the early biomechanical loads and should establish effective integration with newly formed bone. The most common injectable cements are based on polymethyl methacrylate (PMMA), thanks to their favorable mechanical properties and robustness [45]. However, PMMA bone cements lack the necessary bioactivity and resorbability, for which it is a foreign body presenting excessive rigidity, in comparison with the bone, so to potentially provoke secondary fractures at adjacent vertebrae. Moreover, PMMA hardening occurs through an exothermic polymerization process, leading to the risk of thermal necrosis of the surrounding bone tissue [46]. In contrast with these drawbacks, calcium phosphate-based bone cements (CPCs) have attracted great attention due to their excellent bioactivity, deriving from the chemical similarity with the bone tissue, and bioresorbability, which lead to the

Numerous CPC formulations with different initial reactants (which include α-tricalcium phosphate, β-tricalcium phosphate, anhydrous dicalcium phosphate, and monocalcium phosphate monohydrate), producing either an apatitebased or brushite-based cement [49], have been reported [50, 51]. In addition to their excellent biological behavior, CPCs are intrinsically microporous: pores in the size range of submicro-/micrometers are left by extra aqueous solution after hardening of CPCs [52]; such micropores are effective for the impregnation of biological fluids into the bone cements and help resorption and replacement of

good potential as scaffolds for load-bearing bone reconstruction [42].

formation of new bone that can replace the implant [47, 48].

**38**

implants by bone.

## **Figure 2.**

*(a) Scheme of the development of self-hardening formulations as printable pastes, (b) typical nanostructure of hardened apatite cements, and (c) very tight interface between Sr-substituted apatite cement and bone in rabbit test.*

Ion-doped apatites obtained as bone cements offer interesting perspectives as a new class of injectable biomaterials that can found application as bioactive pastes for the regeneration of bone defects with complex geometry and not easily accessible by implantation of 3D solid scaffolds (e.g., femur head, tibial plateau, vertebral body, and maxilla). A very interesting perspective, further extending the possible application of bioactive pastes and cements, is the development of printable self-hardening biomaterials (**Figure 2**). Such pastes, to be prepared with rheologic properties enabling flowability, cohesion, and hardening in short times, to allow layer-by-layer deposition, can be processed by micro-extrusion to obtain solid scaffolds with enhanced bioactivity, thanks to the possibility to maintain biomimetic chemical composition, without the need of conclusive sintering process for consolidation.
