Targeting ATAP-mediated Apoptosis in Treatment of Prostate Cancer

DESCRIPTION (provided by applicant): The lifetime of total joint replacement prostheses has been limited by three factors: oxidative degradation, wear and mechanical failure of its polyethylene components. In recent years, the problem of wear and oxidationresistance has been addressed. Radiation crosslinking substantially increases the resistance of polyethylene to particulate wear. Studies have shown that incorporation of antioxidants can combat oxidative degradation of polyethylene. However, the issue ofmechanical damage and cracking of polyethylene components has not been adequately addressed. Also, crosslinking is known to decrease the mechanical properties of polyethylene, which is already limited, evident from its clinical history in which catastrophic failure of patellar components, delamination in tibial components and rim-cracking in mal-aligned acetabular components have been observed. The incidence of such mechanical failure can be limited by using a design approach, which can decrease applied stress on components. However, they often lead to a decrease in range of motion for the patient. Cushion bearings based on elastomers can prevent brittle fracture since elastomers are highly compliant. Also, they are associated with very low friction since they can deform microscopically to induce fluid film lubrication associated with synovial fluid. This makes it unnecessary for the material to be wear resistant since the two articulating surfaces of the joint replacements do not make contact with each other. However, this strategy fails when asperities associated with third body particles such as bone chips and cement get embedded on their surfaces and create conditions of abrasive wear. The primary objective of this research is to investigate a new bearingmaterial based on a blend of polyethylene and an ultra-low density polyethylene, which is essentially an elastomer. The latter is expected to be biocompatible since it is compositionally similar to polyethylene. Crosslinking of this blend can render it wear resistant while incorporation of an antioxidant would render it oxidation resistant. This hybrid multiphase material has the potential to activate fluid film lubrication or elastohydrodynamic lubrication at certain volume fractions of elastomer comparedto pure polyethylene, which has higher friction associated with mixed boundary lubrication. Regardless of the mechanism of lubrication that it can activate, this class of bearing materials has the potential to be highly compliant and resistant to brittlefracture. The specific aims of the proposal are: (1) To induce oxidation resistance in polyethylene-ultra low density polyethylene bearing materials. (2) To determine the effect of ultra- low density polyethylene content in altering the friction, wear andmechanical properties of polyethylene-ultra- low density polyethylene bearing material. This proposal has the potential to guide in the fabrication of long lasting components for a variety of joints, including meniscus, disc, glenoid, hip and knee components, all of which have the potential to be resistant to wear, oxidation and fracture. Longer lasting joint replacements would greatly benefit the elderly afflicted with osteoarthritis who require these implants for mobility. PUBLIC HEALTH RELEVANCEPUBLIC HEALTH RELEVANCE: The in vivo lifetime of total joint replacement prostheses has been limited by three factors: oxidative degradation, wear and mechanical failure of its polyethylene component. While radiation crosslinking is known to decrease therate of wear and incorporating antioxidants can decrease oxidative degradation, mechanical damage in polyethylene has not been adequately addressed. The primary objective of this research is to investigate a new multiphase bearing material based on a hybrid ultra-high molecular weight polyethylene-ultra low density polyethylene, thermoplastic-elastomer material, as a candidate for cushion bearings that, for the first time, has the potential to be resistant to oxidative degradation, wear, as well as fracture, which would greatly benefit the elderly who have joint disease and rely on the longevity of joint replacements to maintain an active lifestyle in their ol age.