Controlled release of anticalcification agents (ethanehydroxydiphosphonate and/or Fe3+) will be investigated for the prevention of calcification of porcine aortic valve bioprostheses (BHV). Calcification is the principal failure mode of BHV and virtually all of the previous attempts to prevent this disease process have been either ineffective or have resulted in bone toxicity. Our hypothesis is that local controlled release of minimal but optimal amounts of a drug will be effective while minimizing adverse effects. Mechanistic studies will focus on: Local dose response, synergism, drug localization with respect to calcium-phosphate, effects on bulk calcium-phosphate and mineral phase, and alkaline phosphatase; matrix transport phenomena will be studied to characterize formulations through mathematical modeling of drug release.
Our aims are to: 1) Formulate silicone rubber matrices containing ethanehydroxy- diphosphonate (EHDP) and/or Fe3+ with sustained (>30 years), constant, controlled release characteristics: Controlled release matrices will be formulated with silicone rubber dispersions of either EHDP (as mixtures of Na2EHDP and CaEHDP) or Fe3+ (as FeCl3 or Fe-EHDP) with formula variations to optimize efficacy and sustain release. Rate limiting membranes will be used to fabricate matrices with zero-order release properties. 2) Assess in vitro the controlled release of EHDP/Fe3+ and its distribution in BHV tissue under both perfect sink conditions and hydrodynamics physiologic blood flow: Porcine aortic valve bioprostheses will be investigated in vitro via exposure to the controlled release agents of interest. This will permit assessment of drug tissue binding properties and turnover. The effects of Fe3+/EHDP on the bioprosthetic surfaces will be assessed in vitro with scanning electron microscopy, Indium labeled platelet binding, ESCA and SIMS both and pre- and post-drug exposure. 3) Investigate in vivo the mechanism of action of sustained controlled release formulations on the pathogenesis of calcification: In vivo drug efficacy and dose response will be determined first with subdermal implant studies (in rates) followed by mitral valve replacement in calves for assessment in the circulation. Localization of the site of pharmacologic action will be studied and related to the initial sites of calcium-phosphate crystal formation.
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