**3. Porous hydroxyapatite scaffolds for bone regeneration**

Bone scaffolds are intended as 3D porous bodies that can allow efficient cell colonization and neovascularization of newly formed tissues throughout the whole implant [21], also giving tight mechanical attachment to the porous scaffold. This is a key achievement for the stabilization of the defect and the recovery of bone-like mechanical performance [22, 23].

Different technologies have been investigated for the development of bone scaffolds with bone-like porosity associated to adequate biomechanical strength [24]. All techniques are based on sintering processes for the consolidation of porous structures formed by processing of ceramic suspensions. Many of them make use of sacrificial phases that are later removed by controlled processes. Methods using sacrificial templates use porogenic agents, such as polymer components, mainly, but also natural sources and inorganic-soluble salts, dispersed into ceramic suspensions and then decomposed by thermal treatments or extracted by chemical processes. The replica method uses organic sacrificial templates but, in the form of 3D bodies, is also derived by natural sources such as cellulose sponges [25], which are eliminated by burning after being soaked into ceramic suspensions.

**37**

**Figure 1.**

*Nature-Inspired Processes and Structures: New Paradigms to Develop Highly Bioactive Devices…*

Other very efficient techniques use the formation of bubbles driven by chemical components dispersed in the suspensions or the direct introduction of gases in the ceramic slurries to obtain foamed powder suspensions, which are sintered after casting and drying [26]. The key aspect in such direct foaming methods is to accurately control the suspension rheology by the use of stabilizing agents (**Figure 1**). Due to controlled macroporosity and pore interconnection obtained by this flexible method, scaffolds not only exhibit improved osteoconductive ability but also higher mechanical properties than those obtained using sacrificial templates [24]. A recent study reported a novel promising route based on a modified direct foaming method that gave HA bodies with 65% pore volume and a compressive strength

A relevant field of application for porous bone scaffolds is neurosurgery; here,

However, all these synthetic materials have the limitation of being bioinert: they have poor osteogenic and osteoconductive ability, so their implants may not inte-

An interesting alternative is in the use of synthetic porous HA ceramic that, due to its good bioactivity deriving from biomimetic composition, can stimulate new bone formation and tight integration of bone to the prosthesis, with recovery of the

cranial reconstruction often uses synthetic biomaterials implants (polymers, metals, and ceramics) instead of autologous bone [28], particularly for large bone defects. An important issue in this respect is the occurrence of bone resorption and infection, which can result in the removal of the implant and its replacement with other materials [29]. Nowadays, polymethyl methacrylate (PMMA) is the first option among synthetic materials for cranioplasty mainly because of its excellent tensile strength [30]; but its potential decomposition into the starting monomer may lead to fracture susceptibility, other than inflammation and infection [31]. To strengthen the prosthesis, titanium wire mesh is often used as a support for the acrylate thanks to its overall high strength and malleability [32]. Also, polyetheretherketone (PEEK), possessing mechanical strength and elasticity similar to

natural bone, is involved as implant for cranial reconstruction [33].

grate tightly with the surrounding newly formed bone [28].

*Scheme of the direct foaming process to obtain 3D bioceramic porous scaffold.*

original biomechanical performance [34, 35].

*DOI: http://dx.doi.org/10.5772/intechopen.82740*

σ = 16.3 ± 4.3 MPa [27].

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

Other very efficient techniques use the formation of bubbles driven by chemical components dispersed in the suspensions or the direct introduction of gases in the ceramic slurries to obtain foamed powder suspensions, which are sintered after casting and drying [26]. The key aspect in such direct foaming methods is to accurately control the suspension rheology by the use of stabilizing agents (**Figure 1**).

Due to controlled macroporosity and pore interconnection obtained by this flexible method, scaffolds not only exhibit improved osteoconductive ability but also higher mechanical properties than those obtained using sacrificial templates [24]. A recent study reported a novel promising route based on a modified direct foaming method that gave HA bodies with 65% pore volume and a compressive strength σ = 16.3 ± 4.3 MPa [27].

A relevant field of application for porous bone scaffolds is neurosurgery; here, cranial reconstruction often uses synthetic biomaterials implants (polymers, metals, and ceramics) instead of autologous bone [28], particularly for large bone defects. An important issue in this respect is the occurrence of bone resorption and infection, which can result in the removal of the implant and its replacement with other materials [29]. Nowadays, polymethyl methacrylate (PMMA) is the first option among synthetic materials for cranioplasty mainly because of its excellent tensile strength [30]; but its potential decomposition into the starting monomer may lead to fracture susceptibility, other than inflammation and infection [31]. To strengthen the prosthesis, titanium wire mesh is often used as a support for the acrylate thanks to its overall high strength and malleability [32]. Also, polyetheretherketone (PEEK), possessing mechanical strength and elasticity similar to natural bone, is involved as implant for cranial reconstruction [33].

However, all these synthetic materials have the limitation of being bioinert: they have poor osteogenic and osteoconductive ability, so their implants may not integrate tightly with the surrounding newly formed bone [28].

An interesting alternative is in the use of synthetic porous HA ceramic that, due to its good bioactivity deriving from biomimetic composition, can stimulate new bone formation and tight integration of bone to the prosthesis, with recovery of the original biomechanical performance [34, 35].

**Figure 1.** *Scheme of the direct foaming process to obtain 3D bioceramic porous scaffold.*

*Bio-Inspired Technology*

increasing it, and retards its crystallization, affecting the shape and size of mineral nuclei. The substitution of Ca2+ with Mg2+ into the HA structure leads to a continuous ion exchange from the outer hydrated layer to the well-crystallized apatite lattice, inducing a disordered state on the HA surface. Moreover, the incorporation of magnesium in surface crystal sites increases the number of molecular layers of coordinated water; all of these phenomena favor the adhesion of cells to the scaffold because the protein adsorption is increased. A greater osteoconductivity over time and higher material resorption, compared to stoichiometric HA, were detected in granulated Mg-HA powders that were implanted in a rabbit's femur, proving the increase of osteogenic activity in the presence of magnesium-substituted HA. A higher expression of specific markers of osteoblast differentiation and bone formation, which are associated with a lower osteoclastogenic potential, was revealed by

studies of osteoblast gene expression profiles from Mg-HA grafts [17, 18].

**3. Porous hydroxyapatite scaffolds for bone regeneration**

nated by burning after being soaked into ceramic suspensions.

Bone scaffolds are intended as 3D porous bodies that can allow efficient cell colonization and neovascularization of newly formed tissues throughout the whole implant [21], also giving tight mechanical attachment to the porous scaffold. This is a key achievement for the stabilization of the defect and the recovery of bone-like

Different technologies have been investigated for the development of bone scaffolds with bone-like porosity associated to adequate biomechanical strength [24]. All techniques are based on sintering processes for the consolidation of porous structures formed by processing of ceramic suspensions. Many of them make use of sacrificial phases that are later removed by controlled processes. Methods using sacrificial templates use porogenic agents, such as polymer components, mainly, but also natural sources and inorganic-soluble salts, dispersed into ceramic suspensions and then decomposed by thermal treatments or extracted by chemical processes. The replica method uses organic sacrificial templates but, in the form of 3D bodies, is also derived by natural sources such as cellulose sponges [25], which are elimi-

The incorporation of strontium into the HA structure reduces bone resorption while enhancing osteogenesis; this effect improves physical stabilization of the new bone matrix, enhancing collagen synthesis, as shown in in vitro and in vivo studies. The incorporation of strontium ions into the HA lattice has been practiced in recent years, due to its potential as an anti-osteoporotic agent, and increasing effort is being dedicated to the development of strontium-containing bone cements [19]. Biomimetic HA powders can be synthesized and used as granules to fill bone defects of limited size, but if the regeneration of an extended bone part is necessary, the implantation of a 3D porous scaffold is required because the lack of mechanical stability and specific morphology of granulated bio-devices does not enable regeneration of extended bone segments; therefore, the porous scaffold must have, in addition to bioactivity and osteoconductivity characteristics, also biomechanical performance suitable for the specific implant site. The scaffolds must provide both the space for the new bone formation and the necessary support for the cells to proliferate and maintain their differential function. Furthermore, they should present suitable architectures for inducing the formation and maturation of well-organized tissue. The use of bioactive scaffolds aids the process of osteoconductivity that establish physical and mechanical integration with the surrounding bone, which in turn avoids micro-movements and the possibility of early mechanical loading

**36**

in vivo [20].

mechanical performance [22, 23].

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 performances [39, 40].

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