**6. Biomaterials for bone tissue engineering: current applications and new perspectives**

One of the current problems in orthopedic clinic is represented by bone lesions caused by traumas, cancer resection degenerative diseases, or nonunion of fractures, which do not heal spontaneously but require surgical procedures. Today, the gold standard for osseous replacement is the autologous bone graft. This technique employs cells of the same patient generally taken from different sites such as fibula or iliac crest that are implanted in bone defect to promote a rapid healing. Although it minimizes the risk of autoimmune response, which was the critical side

#### *Innovative Biomaterials for Tissue Engineering DOI: http://dx.doi.org/10.5772/intechopen.83839*

of xenogenic grafts, it presents some disadvantages such as donor site morbidity, infections, and post-surgery chronic pain [55–57]. In sight of this, science aims to find innovative solutions like application of biomaterials to orthopedics in order to develop medical implant useful to accelerate the healing, restoring the physiological functions of bone.

The design of an implant for skeletal defects may consider the main characteristics of bone tissue which is divided into two different forms: cortical bone, almost solid with less than 10% porosity and trabecular bone organized in a sponge-like pattern with a porosity of 50–60% [58]. According to the classification of Hanch and Navarro, the evolution of bone implant devices has marked three different generations: (a) bio-inert materials (first generation), (b) bioactive and biodegradable materials (second generation), and (c) biomaterials capable of inducing specific cellular responses by incorporating into a 3D scaffold bone progenitor cells and growth factors [59, 60].

 The purpose of first generation of implants was the integration with host tissue without eliciting specific immune response. These implants include metals (Stainless steel, Ti-based, and Co–Cr-based alloys), ceramics (natural and synthetic HA), and polymers (silicone rubber, PE, acrylic resins, polyurethanes, polypropylene PP, and polymethylmethacrylate).

The second generation of implants was developed between 1980 and 2000 and intends to improve both the bioactivity and *in vivo* biodegradation. To this purpose, one of the possible strategies was to modify the first generation by strategic coating such as HA, *beta*-tricalcium phosphate (*b*-TCP), or bioactive glass. Another innovation was the use of natural or synthetic polymers like, poly(*p*-caprolactone), polylactide, polyglicolide, and chitosan with controlled *in vivo* biodegradation rate*.* 

Third generation of implants combines biomaterials useful to develop 3D porous bioactive, biodegradable scaffolds with the integration of progenitor cells, and specific growth factors. This innovation laid the foundations for modern bone tissue engineering strategies. Even if an ideal combination of biomaterials for scaffold production has not been identified yet, recent studies have demonstrated the great efficiency of ceramics in mimic chemical-physic characteristics of bone tissue ECM. Also, our group tested *in vitro* and *in vivo* potential of collagen type-1/Ha-Mg combination to promote bone injury healing. We demonstrated that although biomimetic scaffolds are "*per sè*" able to promote tissue regeneration thanks to their high osteoinductivity, their combination with progenitor cells and growth factors would be more efficient [19–21]. Generally, osteogenic cells such as adult stem cells (ASC) isolated from adult tissues like bone marrow, adipose tissue, or muscle are good candidate to be transplanted in skeletal lesion together with an appropriate scaffold. These kinds of cells are characterized by high capacity of self-renewal and potential of osteogenic differentiation. Moreover, it has been suggested that ASC possess immunosuppressive effects, which make them particularly privileged for transplantation in vivo.

Growth factors are cytokines normally secreted by different cell types. Acting on their own receptors, they induce intracellular pathways, which promote proliferation, cellular adhesion, and differentiation. Bone tissue produces different growth factors such as bone morphogenetic proteins (BMPs), transforming growth factor beta (TGFb), fibroblast growth factors (FGFs), insulin growth factor I and II (IGF I/II), and platelet-derived growth factor (PDGF), which have been proposed for tissue engineering strategies. In particular, BMP2 and 7 have been cloned and are commercially available as recombinant proteins. The interest in them for bone regenerative practices has increased since 1965 when Urist discovered that demineralized bone transplanted in subcutaneous tissue induces bone formation [61]. This potential was later attributed to the presence of

**Figure 1.**  *Schematic representation of bone tissue engineering.* 

BMP. Obviously, the choice to include a growth factor in the scaffold requires the use of biomaterials that can act as drug delivery systems protecting the cytokine from *in vivo* proteolysis and ensuring a progressive and controlled release over time. In this sense, a good alternative is the physical immobilization of the growth factor in a biodegradable hydrogel. In this case, the release will be controlled by the *in vivo* degradation of hydrogel cross-linked with generation of water-soluble hydrogel fragments [9] (**Figure 1**).

#### **7. Conclusions**

Recently, the interest in natural and synthetic biomaterials for medical devices production has increased, and more and more in-depth studies are carried out to better detect their possible applications linked to chemical-physical features and the extractive or synthetic methods, which do not alter their structural properties and biocompatibility. Moreover since tissue engineering strategies have become a valid alternative for body structure and function restoring, biomaterials are also used for the fabrication of 3D porous biomimetic bioactive scaffolds with controlled degradation rate *in vivo.* 

As previously mentioned, the main classes of biomaterials for scaffold production are ceramics, natural and synthetic polymers, metals, composites, and hydrogels. *In vitro* and *in vivo* studies have showed the advantages related to their use in regenerative medicine field but they have also highlighted the possible negative sides.

 Regarding the application of biomaterials to tissue engineering, the current aim of science is to find the natural or synthetic substance or the combination with the most satisfactory performance *in vivo,* able to promote cell proliferation and differentiation in a tissue lesion in order to restore the normal architecture of ECM.

In conclusion, tissue engineering strategies especially in orthopedic clinic field represent an effective and sophisticated alternative for the future, but their success strictly depends on an ever deeper knowledge about the characteristics of the biomaterials and the potentialities of their combinations.

#### **Conflicts of interest**

The authors declare no conflict of interest**.** 

*Innovative Biomaterials for Tissue Engineering DOI: http://dx.doi.org/10.5772/intechopen.83839* 
