A series of experiments is proposed to validate and initially test a new small animal model for revision total joint replacement. Following aseptic loosening of total joint replacements, the osteogenic environment of the implantation site is diminished because of the sequelae of the loosening process. Currently, the only pre-clinical in vivo screening tools rely on larger animal models such as the canine in which it is not possible to study multiple variables and time points or molecular endpoints because of the high costs involved. The first specific aim of the project is to develop a novel rat model for osteolysis-inhibited osteogenic potential that will provide researchers with a new high impact tool for developing strategies to attack this important clinical problem. The second specific aim is to test an approach known to enhance bone regeneration and implant fixation in less challenging models (transforming growth factor-beta treatment of the implant) in the newly developed model. Following validation of the new small animal model, subsequent research could be at the empirical level, e.g., determining if various bone graft substitutes, implant surface treatments, exogenous growth factors, or gene therapy approaches can be successful in this environment. In addition, follow-on studies could also explore molecular mechanisms of particle-induced diminution of osteogenesis, treatment of osteolysis without revision (e.g., bisphosphonate therapy) and successful revision implant fixation enhancement strategies. The proposed studies are high risk because no one to date has used a rat model to show that the osteogenic potential of the implantation site following particle-induced osteolysis is actually diminished. Consequently, there are no studies in the rat to test the ability of various agents to enhance bone regeneration and implant fixation in the challenging revision environment. Despite the risk, we believe that there is a strong likelihood that particle-induced osteolysis will reduce the osteogenic potential of the implantation site and that the environment can be rescued in the rat model. Of the 200,000 total hip replacements performed annually in the U.S., approximately 30,000 are revisions and of the 300,000 total knee replacements 25,000 are revisions. The present application focuses on resolving a major problem in revision joint replacement - enhancement of bone regeneration so that implant fixation can be achieved and lost bone stock can be restored. ? ? ?
