Several major progresses and improvements have been introduced in the field of bone regenerative medicine during the last few years, as innovative alternatives to current therapies which still present many limitations. Natural processes of bone repair are sufficient to restore the skeletal integrity for most fractures. However, the auto-regenerative potential of bone cannot handle large size "critical" lesion. Therefore, manipulation of natural healing mechanisms to regenerate larger bone segments is often required in reconstructive surgery. Tissue Engineering (TE) has represented surely the most innovative and attractive approach for potentially solving many of the problems in orthopedic surgery. Tissue Engineering, a relatively new field in medicine, has to be considered as a sequence of phases going from the research project to the design and production of bioactive matrices and ideally of a living tissue substitute. This main objective can be approached in different ways. In this chapter, we will limit our discussion to the use of stem/progenitor cells and biomaterials in the TE scenario, with a particular focus on regeneration of bone tissue through cell therapy. Cell therapy is the branch of TE which is mainly dealing with cells considered as a key element to achieve the regeneration of the target tissue (Fig. 15.1). In this context and in a reductive view, biomaterials are intended as mere cell delivery vehicles. However, biomaterials are not only simple bio-inert "cell carriers", but they should have the difficult task of driving tissue regeneration in vivo and, most importantly, of being "informative" for cells, which means to direct cell differentiative fate providing a correct microenvironment and physicalchemical inputs (Fig. 15.2). Furthermore, modern biomaterials should start a regenerative process and properly drive it. At the same time, they should also be resorbed in vivo proportionally to tissue regeneration gradually loosing their original mechanical performance. They should finally disappear as soon the neo tissue formed is able to fully substitute the graft. In general, the TE philosophy relies on providing the region to be reconstructed with initial biomechanical properties, encouraging progenitor cells to form new bone, and then degrading the synthetic carrier to allow the new bone to remodel and to gradually restore the required biomechanical support function. Basic requirements of these biomaterials include the development of biomimetic scaffolds with an internal architecture able to favor cell migration and in vivo vascularization, and a chemical composition conducive for cell attachment and maintenance of cellular functions. Fig. 15.1 Concept of cell therapy: this approach requires a source of stem cells which, being usually scarce in the tissue of origin, needs to be selected, and expanded in vitro. After choosing the required biomaterial, stem cells will be allowed to adhere to it to be finally delivered at the lesion site 450 S. Scaglione and R. Quarto Stem cell therapy of skeletal tissues has proven to be a potentially successful strategy by providing a novel therapeutic approach that responds to pathological conditions of patients suffering large bone losses because of injuries or diseases. Among different sources of osteoprogenitor cells which have been proposed, mesenchymal stem cells (MSC) represent in most cases the first choice, due to their ability to proliferate in culture and to give rise to specialized cells. Their use hold promises of wide spread applications particularly in areas of spinal cord injury, non-unions, critical bone defects, spinal fusions, augmentation of ligament reconstructions, cartilage repair, and degenerative disc disorders (Garbossa et al. 2006, Ge et al. 2005, Jorgensen et al. 2001, Klein and Svendsen 2005, Krampera et al. 2006, Leung et al. 2006, Marcacci et al. 2003, Noth et al. 2005, Sakai et al. 2005, Sykova et al. 2006). Although they may be routinely isolated and expanded in culture, their use for therapeutic strategies requires technologies not yet perfected. In this context, different strategies have been reported for using MSC in the regeneration of bone tissue in vivo. MSC can be "driven" by specific bioactive molecules, ex vivo gene transfer, and other physical factors to form mineralized matrix in vitro for future re-implantation in vivo (Caterson et al. 2001, Luskey et al. 1990, Partridge et al. 2002). Fig. 15.2 Biomaterials can influence stem cell fate. Biomaterials should not be thought as bioinert cell delivery vehicles, but they have to be considered as informative scaffolds able to provide the cell with a correct microenvironment and physical-chemical inputs. As an example, in the figure a stem cell population is directed towards two different differentiation pathways by two chemically distinct biomaterials 15 Clinical Applications of Bone Tissue Engineering 451 Alternatively, these cells are combined with special matrices, which can carry bioactive molecules such as growth factors, and implanted in the attempt to enhance bone regeneration (Caterson et al. 2001, Luskey et al. 1990, Partridge et al. 2002). Although the interest of this approach is very high and many studies have been performed in vivo in both small and large animal systems, still only two pilot clinical studies have been reported (Quarto et al. 2001, Vacanti et al. 2001). How should we interpret this apparent failure? Potentially several elements may have limited the experimental applications and a wider diffusion of this fascinating approach: (a) the field of stem cells still needs time and knowledge before being considered a standard approach in regenerative medicine, (b) some "caveat" should induce scientists to explore side effects of stem cells as therapeutic agent; (c) biomaterials, although improving fast, are still far from being optimal for a TE use; (d) guidelines for use of cells in therapy are becoming more and more rigorous and stringent.
ASJC Scopus subject areas
- Materials Science(all)