Controlled release of ethanehydroxy diphosphonate from polyurethane reservoirs to inhibit calcification of bovine pericardium used in bioprosthetic heart valves

摘要

Calcification (CALC) of bioprosthetic heart valves (BHVs) fabricated from either glutaraldehyde-pretreated bovine pericardial tissue or porcine aortic valves is the most frequent cause of clinical failure of these devices. Previous studies have demonstrated that calcification is inhibited by diphosphonate compounds released into the vicinity of bioprosthetic tissue implanted subcutaneously in rats. Controlled release of the anticalcification agent ethanehydroxy diphosphonate (EHDP), as a 1:1 mixture of Na2 EHDP and CaEHDP from cylindrical polyurethane (PU) reservoirs (o.d. = 0.36 cm i.d. = 0.33 cm, length = 4 cm) fabricated by solvent casting was assessed in vitro and in vivo. The diffusivity (D), determined independently using standard diffusion cells, for ionic EHDP diffusion across the PU membrane was 1.2 x 10 cm2/s. Volume influx of buffer into the reservoirs in vitro was observed experimentally to reach a maximum at 7.8 days (288 +/- 44 [mu]l) with a biexponential decline to 147 +/- 6 [mu]l at 70 days. The cumulative EHDP released in vitro after 70 days was 4.2 +/- 0.6% (4.8 +/- 0.7 mg) compared to 15.7 +/- 3.2% (18.1 +/- 3.7 mg) in vivo (subcutaneously in 3 week-old, male, CD rats) over 21 days. The release rate of EHDP from the reservoirs was not a zero-order process. Reservoir administration of EHDP effectively inhibited pericardial BHV-CALC in 21-day subdermal explants (Ca2+ = 4.5 +/- 1.4 [mu]g Ca2+/mg tissue; control, Ca2+ = 120 +/- 13 [mu]g Ca2+/mg tissue) without diphosphonate-related untoward effects at a dose of approx. 3 mg/kg per day.