Stenosis caused by neointimal hyperplasia (NH) often occurs focally at the anastomoses of arteriovenous (AV) grafts used for hemodialysis, leading to thrombosis and occlusion. This is a competitive renewal resubmission for a project to develop novel sustained drug delivery systems that could be injected percutaneously and allow local delivery of anti-proliferative drugs to prevent graft stenosis. The Bioengineering area is """"""""Clinical Medicine, Therapeutics and Drug Delivery"""""""". Using a unique polymeric drug depot (ReGel) to deliver paclitaxel perivascularly, we have demonstrated the feasibility of this approach in a canine model. We have now perfected a porcine model and demonstrated the sustained, quantifiable delivery of dipyridamole and rapamycin from the perivascular depot into the vessel walls over weeks. The 4 specific aims in this renewal are to: (1) optimize sustained-release polymer gel systems for local delivery of specific anti-proliferative drugs based on each drug's physicochemical, pharmacokinetic and pharmacodynamic properties;(2) develop and validate finite element models to predict the long-term pharmacokinetics of drugs administered perivascularly using sustained-delivery systems at the anastomoses of AV grafts;(3) identify drugs that are safe and efficacious in preventing stenosis at the graft anastomoses when administered using sustained-delivery systems;(4) adapt and refine 3D imaging modalities, including magnetic resonance angiography (MRA), for more accurate quantification of stenosis progression and drug efficacy at the graft anastomoses in the porcine model. There are 6 Leading Investigators in 5 departments: (1) R. Rathi, MacroMed, Inc. (development of polymers for drug delivery);(2) S. Kern, Depts. of Pharmaceutics and Bioengineering and M. Kirby, Scientific Computing &Imaging Institute (pharmacokinetic modeling and validation in tissues);(3) D. Blumenthal, Dept. of Pharmacology &Toxicology (characterization of in vitro drug efficacy and mechanism of action);(4) A. Cheung, Dept. of Medicine, U. of Utah (animal experiments and clinical correlation) who also serves as the PI and Project Manager;(5) D. Parker, Dept. of Radiology (MRA imaging development and 3D reconstruction of NH morphology). This multidisciplinary team, using an integrative systems approach, is essential for the development of innovative methods to solve an important clinical problem. It will also offer excellent opportunities for trainees of various disciplines to interact with each other in a collaborative manner. It is highly likely that, within this 5-year proposal, the results of this project can be applied to pilot clinical studies.
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