Many contemporary medical and dental therapies include the replacement or repair of tissues using materials such as metal. Currently there are at least 150,000 hip replacements, 300,000 knee replacements, and 500,000 dental implant procedures performed in the US each year (Kurtz, Mowat et al. 2005). These numbers are expected to increase as the baby boom generation ages. While a large number of individuals experience uncomplicated healing, there are a significant number of complications associated with metal implants. For example, the revision rate for arthroplasty varies between 10-20% (Fitzpatrick, Shortall et al. 1998) and it has been estimated that 16% of the annual total joint surgeries in the US are revisions (Mahomed, Barrett et al. 2003). The majority of these revisions are due to failure at the implant-bone interface, suggesting a need for improved technologies to increase bone growth onto the implants. Improving the integration of metal implants will be advantageous to society benefiting from next generation devices. In phase I, we used phage display to identify peptides that bound to titanium with high affinity. These titanium-binding peptides were synthetically linked to a cell attachment RGD sequence to generate peptides that promoted rapid attachment and differentiation of osteogenic cells on titanium. We have also identified unique general cell attachment sequences and peptides with high affinity for Bone Morphogenetic Protein 2. The goal of this Phase II proposal will be to develop a prototype IFBM coating for metal implants that promotes cell attachment and improves osseointegration. In Phase II, we will bring these advances together to develop a coating that utilizes: 1) improved metal, 2) improved cell, and 3) BMP binding peptides to promote osseointegration of metal implants.
In aim 1 we will: 1) optimize metal-binding peptides in the presence of biologic fluids and 2) identify peptides that bind specifically to osteoblasts.
In aim 2, we will generate different classes of IFBMs: 1) a general cell-binding peptide that promotes the attachment of osteoblast-progenitors; 2) an osteoblast specific binding peptide that promotes mature osteoblast attachment; 3) a BMP-2 binding peptide that recruits, binds, and retains BMP-2 and other members of the BMP family. Each class of IFBM will be tested individually in a series of in vitro assays. IFBMs will then be combined to generate a mixed coating that will bind and guide the biologic response of osteogenic cells and BMP-2 on the surface of titanium.
In aim 3, we will complete: 1) biophysical, 2) molecular, 3) mechanical, and 4) toxicological characterization of prototype IFBMs. Finally in aim 4, we will examine the efficacy of these IFBM coatings in a rat femoral model of osseointegration in collaboration with Dr. D. Rick Sumner (Kuroda, Virdi et al. 2004). Upon successful completion of Phase II, Phase III would involve testing the prototype coating in a large animal model such as gap healing in a canine humeral model (Sumner, Turner et al. 2004) or a canine hip replacement model (Sumner, Turner et al. 2001). ? ? ?
