Controlled release of diphosphonate to inhibit bioprosthetic heart valve calcification: Dose-response and mechanistic studies

Calcification is the Principal cause of the clinical faliure of bioprosthetic heart valves (BHV) fabricated from glutaraldehy de-treated porcine valves or bovine pericardium. This study examined the dose-response of local controlled-release disodium 1-hydroxyethylidene diphosphonic acid (EHDP) therapy for BHV calcification and its mechanism of action. Controlled release of EHDP from ethylene-vinyl acetate matrices was regulated by co-incorporation of the insert filler inulin, and subdermal calcification of BHV cusps was studied with the co-implantation of these matrices in rats. Subdermal BHV tissue calcification was inhibited in vivo for 7, 60, and 84 days, without any adverse effects. At 84 days matrices (0.2, 2 and 20% w/w EHDP) co-implanted with BHV resulted in explant calcification levels of 210.4, 39.1, and 11.7 μg/mg in comparison to control values of 213.2 μg/mg (a level equivalent to that of clinically failed BHV). The partition coefficient of EHDP into unimplanted BHV (Ca²⁺ = 1.23 μg/mg) was K_p = 0.57, increasing with early calcification (72 h implant, Ca²⁺ = 19.6 μg/mg, K_p =1.6). The diffusion coefficient of EHDP through BHV was 0.8 × 10^-10 cm²/s reflecting low tissue permeability and high affinity. It is concluded that both in vitro and in vivo release of EHDP from the 20% w/w EHDP matrices was suitable to inhibit BHV calcification and that this effect is most likely due to interaction of EHDP with the BHV tissue surface.