**2. The need of mechanically competent bioactive implants for bone regeneration**

In most of load-bearing applications, the main target is the achievement of high mechanical strength. However, this approach can limit the success of the implant when it comes to obtain substantial bone regeneration. As a matter of fact, to date bioinert metallic prostheses are implanted upon occurrence of bone impairments or fractures. These devices are for sure mechanically competent in restoring the bone shape and eventually the biomechanical function of joints in relatively short timing [2]. However, their well-known great mechanical performance may be also detrimental, particularly in the long term. In fact, current implants utilized in orthopedic and maxillofacial surgeries suffer various clinical drawbacks, such as implant loosening, wear, and limited compatibility with the bone in permanent metal implants [3]. In this condition, the excessive stiffness exhibited by metallic implants, generally much greater if compared with the elastic behavior of the bone, results in improper prosthesis-to-bone load transfer and stress shielding that can impair the stability of the implant and its long-term performance (**Figure 1**) [4].

Composite Calcium Phosphate/Titania Scaffolds in Bone Tissue Engineering http://dx.doi.org/10.5772/intechopen.68867 45

**Figure 1.** Simple scheme of stress shielding [5].

biomechanical stimuli in vivo [1]. As the use of autografts or allografts suffers many restrictions and drawbacks, particularly in the case of large defects, synthetic biomaterials are today considered as elective in this respect; however, there is still a lack of suitable materials associating bioactivity and high strength. Natural bone is a hybrid nanocomposite capable of outstanding mechanical performance and ability to establish an active dialogue with cells. In particular, the bone is composed of an inorganic compound (60%), a nearly amorphous calcium phosphate with the crystal structure of hydroxyapatite (HA), heterogeneously nucleated on an organic component prevalently made of type I collagen. The collagen phase provides the bone with great flexural strength, while the mineral component increases the bone compression strength. The unique factors that contribute to the toughness of bone are the presence of nano-size apa-

For that reason, in the last decades, the research on biomaterials and scaffolds able to favor bone tissue regeneration upon implantation, while also mechanically supporting the anatomic site affected by lack of bone, has been increasing. In this respect elective materials are calcium phosphates, due to their high chemical similarity with the bone mineral. However, they suffer of low mechanical strength that makes them not suitable to be implanted in loadbearing site. Therefore, a new approach was focused on the development of ceramic compos-

The present chapter will provide an overview to illustrate novel potential approaches to develop reinforced bioactive scaffolds to assist the regeneration of load-bearing bony sites, considering that serious drawbacks can arise in case of mechanical mismatching at the bone/ biomaterial interface. In particular, the chapter will highlight the use of titanium dioxide, which is a well-established biomaterial for bone applications, as a promising nanomaterial

**2. The need of mechanically competent bioactive implants for bone** 

In most of load-bearing applications, the main target is the achievement of high mechanical strength. However, this approach can limit the success of the implant when it comes to obtain substantial bone regeneration. As a matter of fact, to date bioinert metallic prostheses are implanted upon occurrence of bone impairments or fractures. These devices are for sure mechanically competent in restoring the bone shape and eventually the biomechanical function of joints in relatively short timing [2]. However, their well-known great mechanical performance may be also detrimental, particularly in the long term. In fact, current implants utilized in orthopedic and maxillofacial surgeries suffer various clinical drawbacks, such as implant loosening, wear, and limited compatibility with the bone in permanent metal implants [3]. In this condition, the excessive stiffness exhibited by metallic implants, generally much greater if compared with the elastic behavior of the bone, results in improper prosthesis-to-bone load transfer and stress shielding that can impair the stability of the implant and its long-term

tite crystals and a dense network of collagen fibers.

ites associating high bioactivity and strength.

**regeneration**

44 Application of Titanium Dioxide

performance (**Figure 1**) [4].

with the ability to reinforce calcium phosphate matrixes.

Briefly, as a simple mechanical rule, considering every composite system composed of two materials where one component is stiffer, the stiffer component will sustain the greater part of the load. In the normal healthy skeleton, the stresses flow symmetrically from there downward through both hip joints, thighbones, knee joints, lower leg bones, and feet onto the floor (**Figure 1a**).

In case of total hip joint replacement, the shaft component generally takes over the majority of the stresses; in this case, the body weight primarily flows down from the joint center and then through the shaft of the device. As a consequence, the upper part of the thighbone is unloaded, thus resulting in weaker areas more susceptible to fracture. Moreover, the skeleton around the tip of the femoral component is overloaded, resulting in a thicker and stronger part. The shaft component of a total hip device is much stiffer than the skeleton and will take the greater part of the body weight load. Consequently, the shaft component is overloaded, whereas the skeleton around the shaft is unloaded (**Figure 1b**) [5].

Unfortunately, the thickening of the skeleton is, in most cases, painful. The patients with cementless shafts of total hip devices often claim about the pain in the thigh, especially during the first years after the surgery [6].

In turn, this can provoke localized osteoporosis and bone resorption, loosening, and detachment of the prosthetic device [7], thus impacting on the course of patient rehabilitation and on the need of repeated revision/correction surgery.

Commonly observed complications after prosthesis removal are infections, impaired wound healing, secondary fractures, tissue and nerve damage, and postoperative bleeding. There is some evidence indicating that the postoperative complication rate depends on the specific localization of the implanted material [8].

Indeed, the above reported drawbacks mostly occur as the used bone/implant systems are often integrated only at the surface [1].

In this respect, bone implants should exhibit substantial cell-instructive ability in order to trigger and sustain the cascade of cell-based phenomena at the basis of new bone formation and organization [9]. Key phenomena in this respect are protein adhesion including the formation of bonds between cell surface receptors (integrins) and the protein functional groups (ligands) (**Figure 2**) [10]. Then, cytoskeletal reorganization with progressive cell spreading on the substrate can take place. Upon implantation in vivo, there are several factors affecting how the proteins will adhere to the material, for example, surface chemistry, surface energy/ tension/wettability, roughness, crystallinity, surface charge, and mechanical properties. After this first-stage extensive implant, colonization should take place, driven by a diffuse porosity enabling cell penetration and new bone formation into the inner part of the implant. In this respect, the implant nanotopography can influence the attachment and function of bone cells by modulating key signaling effects essential for their survival [11].

**Figure 2.** Graphical overview of the effect of surface microstructure on the interaction between a metallic prosthesis and bone tissue: (a) osseointegration, the surface features are able to induce bone formation, leading to long-lasting interaction without side effects; (b) short-loss implant, the surface is now detrimental for bone tissue regeneration, leading to dead bone cells.

Nowadays, it is widely accepted that substantial mimesis of the physicochemical, morphological, and mechanical features of the bone are crucial requisites for regenerative bone scaffolds, particularly in case of repair of long and load-bearing bone segments [12–14]. Indeed, such features can properly drive physiological processes of bone regeneration, to obtain the full recovery of the diseased tissue with all its function. In this respect, recent progresses in materials science research developed a variety of bioactive scaffolds for the healing and repair of damaged or missing bone parts, which are progressively replacing bioinert implants in an increasing number of applications in orthopedic, maxillofacial, and neurosurgery fields [9].

Commonly observed complications after prosthesis removal are infections, impaired wound healing, secondary fractures, tissue and nerve damage, and postoperative bleeding. There is some evidence indicating that the postoperative complication rate depends on the specific

Indeed, the above reported drawbacks mostly occur as the used bone/implant systems are

In this respect, bone implants should exhibit substantial cell-instructive ability in order to trigger and sustain the cascade of cell-based phenomena at the basis of new bone formation and organization [9]. Key phenomena in this respect are protein adhesion including the formation of bonds between cell surface receptors (integrins) and the protein functional groups (ligands) (**Figure 2**) [10]. Then, cytoskeletal reorganization with progressive cell spreading on the substrate can take place. Upon implantation in vivo, there are several factors affecting how the proteins will adhere to the material, for example, surface chemistry, surface energy/ tension/wettability, roughness, crystallinity, surface charge, and mechanical properties. After this first-stage extensive implant, colonization should take place, driven by a diffuse porosity enabling cell penetration and new bone formation into the inner part of the implant. In this respect, the implant nanotopography can influence the attachment and function of bone cells

**Figure 2.** Graphical overview of the effect of surface microstructure on the interaction between a metallic prosthesis and bone tissue: (a) osseointegration, the surface features are able to induce bone formation, leading to long-lasting interaction without side effects; (b) short-loss implant, the surface is now detrimental for bone tissue regeneration,

by modulating key signaling effects essential for their survival [11].

localization of the implanted material [8].

46 Application of Titanium Dioxide

often integrated only at the surface [1].

leading to dead bone cells.

Biomaterials based on hydroxyapatite (HA, Ca10(PO4 )6 )(OH)2 ) or β-tricalcium phosphate (TCP: β-Ca<sup>3</sup> (PO4 )2 ) have attracted considerable interest for orthopedic and dental applications, thanks to their noticeable chemical resemblance to the mineral component of the bone which provides intrinsic biocompatibility and osteointegration ability [15, 16].

Particularly, tricalcium phosphate has been used in clinics to repair bone defects for many years [17, 18]. As well, a wide range of bioactive materials has been investigated so far, in alternative to calcium phosphates, including bioglasses and apatite-wollastonite glass-ceramics [19–21]. The main attractive feature of such bioceramics is their ability to form a direct bond with the host bone resulting in a strong interface compared to bioinert or biotolerant materials that form a fibrous interface [22]. For biomedical applications the incorporation of biomimetic foreign ions in the HA structure (CO3 2−, Mg2+, SiO4 4−) is needed to increase its functionality in terms of stimulation of the natural bone regeneration processes [23].

However, applications of these materials for long bone replacement are hindered by their insufficient strength and toughness [24].

Also, some calcium phosphates can suffer a relatively high dissolution rate in simulated body fluid that affects their long-term stability [25]. In this context, a great deal of research effort has been devoted so far to develop methods of processing hydroxyapatite with good mechanical properties and high resistance to corrosion [26]. As a general rule, ceramic oxides or metallic dispersions have been introduced as reinforcing agents [27, 28]. In respect to the use of reinforcing ceramics, several attempts have been performed by the addition of aluminum or zirconium oxide to calcium phosphate matrices [29, 30]. The main problems arising when developing such materials mainly concern phase decomposition as a consequence of the chemical interactions between HA and the reinforcing phases at high temperatures. In fact, ceramic materials have to be subjected to sintering process for physical consolidation; in the case of ceramic composites, the phenomena of grain coalescence induced by the thermal treatment can thus coexist with solid-state reactions between the ceramic components which often gives rise to formation of undesired phases and phase decomposition. In this context, HA largely decomposes into tricalcium phosphate, and although in many cases the presence of zirconia improves the mechanical resistance of the final composite, secondary phases depressed the bioactivity and bioresorbability of the scaffolds. In various cases, the formation of secondary phases also resulted into volume modifications in the ceramic body, thus possibly inducing microcracks in the final scaffold after the sintering treatments [31, 32].

Among the most interesting ceramics for composite scaffolds, bioactive calcium silicates were also explored as biomaterials for hard tissue repair and replacement since the early 1970s, when Hench and coworkers invented Bioglass®, a silico-phosphate-based glass with composition close to that of bone mineral [20]. However, due to their nature, bioactive glasses were not indicated for scaffold reinforcement; however, the presence of silicon in bone scaffolds has always been addressed as promoter of new bone formation in vivo, due to its ability to be a center for nucleation of apatite phase in physiological environment [33]. On this basis, calcium silicate phases such as dicalcium and tricalcium silicate, as well as wollastonite or pseudo-wollastonite (CaSiO3 ), were widely investigated as scaffolds or cements [34, 35]. In particular, the development of composites made of HA reinforced with dicalcium silicate was investigated [36], on the basis of its high flexure strength (≈200 MPa) and reduced elastic modulus (≈40 GPa) [37], compared with HA, thus resulting as promising compositions for bone scaffolding. As a main drawback, calcium silicates exist in a variety of polymorphs stable in different conditions of temperature [38], thus making difficult to obtain pure phases and avoid decomposition detrimental for the mechanical properties.

A different system that recently attracted the interest of scientists is given by titanium (Ti) and its alloys, particularly titanium dioxide (TiO2 ), which have been already validated and extensively used as implantation materials due to their favorable properties such as lower modulus, good tensile strength, excellent biocompatibility, and enhanced corrosion resistance [39].
