Extensive efforts by both academic and industrial groups are yielding novel therapeutic agents to stimulate bone repair in specific local sites. For example, BMPs have been produced in large quantities by recombinant means and clinically tested for fracture healing in long bones. A better understanding of the protein delivery challenges, in particular controlling the local concentration of the proteins, has been paramount in developing these therapeutic agents for clinical use. To develop next-generation therapeutic agents, we are formulating the growth factors in nanoparticles so as to better control in situ release kinetics of the proteins. The proteins, however, have not been effectively used in systemic bone regeneration, again due to protein delivery challenges; i.e., proteins need to be delivered to bone sites after intravenous injection into the blood stream. We are exploring new ways to deliver the growth factors to bone after systemic administration (a review of bone targeting research can be found in Gittens et al., 2005 and Zhang et al., 2007). Once targeted to the site of activity, the growth factors are expected to stimulate bone formation at a low does and with minimal activity at extraskeletal sites. Ultimately, we are interested in developing clinically useful therapeutic agents for both local and systemic regeneration of the mineralized tissues.

Several approaches are underway in the lab

Identification of Appropriate Proteins for Therapy

We focused our initial efforts on two proteins, Bone Morphogenetic Protein-2 and basic Fibroblasts Growth Factor. Studies are being conducted to examine the potency of these growth factors to induce new bone formation, as well as other effects in cell culture and in animals. We are currently exploring other useful proteins, such as osteoprotegerin, to achieve normal bone tissue structure. Our goal is to identify the proteins with the most potent (effective at minimal dose) and lasting effects based on a variety of biological systems. Read more about this line of research in Varkey et al., 2006

Design of Bone-Seeking Ligands

Significant efforts are being directed to prepare novel compounds that (i) have strong bone affinity, and (ii) can carry proteins to bone after systemic injection. The compounds synthesized are based on bisphosphonates and involve their unique arrangement for an effective drug carrier. Organic chemistry and biochemistry expertise are applied to incorporate bone-targeting ligands with proteins. Read more about this line of research in Bansal et al., 2004