Abstract

Calcification (CALC) is the most frequent cause of the clinical failure of bioprosthetic valves (BHV's). Controlled-release (paravalvar) administration of the anticalcification agent ethanehydroxydiphosphonate (EHDP), as either Na 2EHDP or in combination (1:1) with the less soluble CaEHDP, from a silicone rubber matrix (20% w/w EHDP) was studied both in vitro and in vivo for the prevention of BHV CALC. Seventeen sheep (6–7 months old, male, Suffolk) underwent tricuspid valve replacement using Hancock I, 25 mm porcine aortic bioprostheses. BHV explant evaluation after 16–20 weeks revealed that two of the 7 control BHV were calcified (139 ± 20.8 μgCa 2+/mg of tissue), while none of the 9 BHV retrieved from animals receiving controlled release EHDP demonstrated CALC (4.41 ± 1.09 μg Ca 2+/mg of tissue). No adverse effects of EHDP on bone or calcium metabolism were noted. The cumulative percent of EHDP released per electron microprobe analysis was 40.4% ± 9.68 (Na, CaEHDP) to 79.0% ± 4.82 (Na 2EHDP) in vivo compared to 35.7% ± 7.72 and 78.6 ± 11.1 in vitro, respectively. Assessment of the Young's modulus (Y) using thermomechanical analysis (TMA) revealed a 1.5-fold (Silastic Q7-4840) to 9.5-fold (Silastic 382) increase in Y following drug loading. The Y for explanted, Silastic Q7-4840 polymer matrices ranged from 2.84 × 10 4 to 5.57 × 10 5 dyne/cm 2. In vitro osmotic related matrix swelling of the Na 2EHDP loaded, unsealed matrices (20% w/w) after 75 days was minimized to a 35.8% increase in weight due to coincorporation of CaEHDP with Na 2EHDP in a 1:1 ratio and was further reduced (22.2% increase in weight) by sealing 76% of the releasing surface, compared to Na 2EHDP matrices which demonstrated a 414% and 141% increase in weight, respectively.

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