Controlled release of 1-hydroxyethylidene diphosphonate: in vitro assessment and effects on bioprosthetic calcification in sheep tricuspid valve replacements

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 2 EHDP 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/~g CaE+/mg of tissue), while none of the 9 BHV retrieved from animals receiving controlled release EHDP demonstrated CALC (4.41 + 1.09 pg Ca2+/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 (Na2EHDP) 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 X 10 5 dyne/cm 2. In vitro osmotic related matrix swelling of the NaEEHDP loaded, unsealed matrices (20% w/w) after 75 days was minimized to a 35.8% increase in weight due to coincorporation of CaEHDP with Na2EHDP in a 1 : 1 ratio and was further reduced (22.2% increase in weight) by sealing 76% of the releasing surface, compared to NaEEHDP matrices which demonstrated a 414% and 141% increase in weight, respectively.