**6. Conclusion**

Biomaterials such as polymers, ceramics, and metals are widely used in bone for regenerative therapies, including in bone grafts and in Tissue Engineering as well as for temporary or permanent implants to stabilize fractures (Navarro et al., 2008). In recent years, biomaterials in general and bone-related implant materials in particular have been considerably refined, with the objective of developing functionalized materials, so-called smart materials, containing bioactive molecules to directly influence cell behaviour (Mieszawska and Kaplan, 2010). Rapid developments in nanotechnology have yielded many clinical benefits, in particular in the field of bone tissue engineering. The main advantage in that several novel biomaterials can be fabricated into nanostructures that closely mimic the bone in structure and composition. The optimization in the surface features of biomaterials has strongly improved cell behaviour in terms of adhesion, proliferation, differentiation and tissue formation in three dimensions. In this context, nanoparticles that are in the same size range as integral parts of natural bone, such as HA crystals or cellular compartments, are promising candidates for local applications. In bone, locally applied nanoparticles may be suitable for numerous potential uses with respect to the improvement of tissue regeneration, the enhanced osseointegration of implants, and the

Increasingly refined nanoparticles are being developed for a wide range of applications (Fig. 9). These include cell labelling to broaden research possibilities as well as to improve and noninvasively monitor cell therapy approaches (Bhirde et al., 2011; Andrades et al., in press (b). Moreover, drug delivery systems with improved pharmacologic characteristics are being developed. They promote enhanced therapeutic outcome by providing controlled release of bioactive molecules, such as growth factors or anticancer drugs (Allen and Cullis, 2004). In addition, gene therapy concepts with good prospects are required for future treatment options

The heterogeneous picture of research on the interactions of nanoparticles with MSCs makes it difficult to draw general conclusions. However, it becomes clear that parameters such as chemistry, size, and shape in some cases greatly affect the particle uptake behaviour of MSCs as well as their natural differentiation potential. Different strategies for nanoparticle applica‐

prevention of infections.

based on intracellular manipulation (Evans, 2011).

**Figure 9.** Overview of nanoparticle applications in bone regeneration

632 Regenerative Medicine and Tissue Engineering

Over the last decades we have advanced in many aspects of bone defects treatment. We have good understanding of the components involved in the healing of bone. Osteoprogenitor cells are necessary to replace the inserted scaffold and to create new bone tissue. These cells, MSCS, can come from the periosteum, the BM, or from chemotaxis and blood vessels entering the haematoma at the fracture site. Specific mechanical and biological stimulants cause the cells to differentiate into osteoblasts, which are the bone forming cells (Fig. 10). However, in critical size bone defects the natural migration of osteoprogenitor cells does not suffice for fracture healing. In normal conditions MSCs are rare (one in 10 million cells) (Pittenger et al., 1999). However, when a bone is broken, these cells, using special probing signals, roam in the blood and settle in the fracture site, differentiate into bone cells and start to construct the callus. The number of stem cells differs from person to person and is affected by age, sex and environ‐ mental factors.

Also, we have strived forward in defining different components of bone regeneration and have achieved a good combination of biology and technology leading to solid and reproducible answers to the *in vitro* and animal *in vivo* problem of bone defects. However, there is still one more step to take (the human *in vivo* step). There are scant data with respect to this part of the question, and in the next few years this field must undergo a transition, giving clinicians tools to deal with these critical everyday problems. The solution will come from a collaborative work of biologist, surgeons, engineers and chemists who possess the social understanding that there has to be a limit to the cost that the patient (and the society) can bear for healing a fracture.

Consequently, the search for the new bone regeneration strategies is therefore a key interna‐ tional priority fuelled by the debilitating pain associated with bone damage, and the increasing medical and socioeconomic challenge of our aging population.
