Calcification (CALC) is the most frequent cause for the failure of bioprosthetic heart valves fabricated from glutaraldehyde-pretreated porcine aortic valve, and contributes to the failure of glutaraldehyde pretreated bovine pericardial (BHV) bioprosthetic heart valves as well. Although systematic therapy in rats using ethanehydroxy disphosphonate (EHDP) has proven succesful in inhibiting CALC, adverse effects on serum calcium, bone development, and overall somatic growth have been noted. The present study was designed to evaluate the potential of site-specific delivery of EHDP to arrest CALC of glutaraldehyde-pretreated bovine pericardium when implanted subdermally in rats using a refillable reservior drug delivery device. The refillable reservior devices evaluated in these studies exhibited constant (zero-order) release of EHPD in vitro and replenishment of the drug supply when implanted subdermally in rats was achieved in a noninvasive fashion using an exteriorized entrance and exit cannula. The refillable reserviors evaluated were fabricated from a commercially available polyurethane (Biomer TM). Glutaraldehyde-pretreated bovine pericardium was implanted subdermally in 21-day-old rats either alone (control) or with refillable Biomer TM reserviors with (treatment) or without (sham) a 2 M solution of Na 2EHDP. Implanted reservoirs which initially contained a 2 M solution of Na 2EHDP were refilled with a fresh 2 M solution of Na 2EHDP on days 7 and 14 post-initial surgery using a syringe and the exteriorized entrance and exit cannulas. Pericardium retrieved following 21 days and assayed for calcium showed significant ( P <0.001) inhibition in CALC for tissue imp0lanted adjacent to refillable Biomer TM reserviors containing EHDP (6.9±2.1 μg/mg) compared to control (179.0±13.5 μg/ mg) and sham-implanted (152.0±10.2 μg/mg) rats. Unimplanted pericardium had a mean tissue calcium concentration of 3.0±0.5 μg/mg. Based on the in vitro release studies of EHDP from refillable Biomer TM reserviors, the estimated dose delivered when implanted subdermally in rats in the present study was 5.5±0.7 mg/kg per day. For rats implanted with EHDP- containing refillable reserviors, histological examination of retrieved pericardium and femurs from rats in each group confirmed both completed inhibition of CALC of the glutaraldehyde crosslinked pericardium and no untoward effects on bone development, respectively. In addition, blood samples obtained at sacrifice showed no change in serum Ca 2+ concentrations in EHDP-treated animals compared to controls. Thus, the site-specific delivery of EHDP using refilliable Biomer TM reservoirs was successful for inhibiting BHV CALC in a rat subdermal model with no untoward effects on bone development, serum Ca 2+ concentrations, or overall growth. The advantages if the refillable reservior system are its constant (zer-order) rate of EHDP release and its potential for replenishment of EHDP by noninvasive means when the EHDP solution inside the resevoir has been depleted.