Prevention of calcification of glutaraldehyde pretreated bovine pericardium through controlled release polymeric implants: studies of Fe3+, Al3+, protamine sulphate and levamisole.

Abstract Calcification is the principal cause of the clinical failure of bioprosthetic heart valves fabricated from glutaraldehyde pretreated porcine aortic valves or bovine pericardium. The present study investigated controlled-release implants for prevention of the calcification of glutaraldehyde pretreated bovine pericardium in a rat subdermal model. Either Al 3+ and Fe 3+ (inhibitors of the growth and dissolution rate of hydroxyapatite crystals), levamisole (alkaline phosphatase inhibitor) or protamine sulphate (charge modifier) were individually incorporated into various polymeric carriers (either silicone rubber. Polyurethane or silicone rubber-polyurethane copolymer). Polymeric implants were evaluated for in vitro release kinetics, which revealed that sustained drug release was obtained from 21 d to more than 90 d from various drug matrices. In vivo efficacy was studied by co-implanting the polymeric delivery systems with glutaraldehyde pretreated bovine pericardium for 21 d using a subdermal rat model; glutaraldehyde pretreated bovine pericardium calcium levels were quantitated by atomic absorption spectroscopy in the explanted tissues. Fe 3+ and Al 3+ polymeric implants were the most effective for inhibiting deposition of calcium mineral. Al 3+ demonstrated 82% inhibition of calcification compared to controls and Fe 3+ resulted in 80% inhibition of calcification. Specific histologie staining methods showed that Fe 3+ and Al 3+ were localized within the devitalized cells of the explanted glutaraldehyde pretreated bovine pericardium. No adverse effects on somatic growth or recipient bone morphology were noted following controlled-release drug administration. Controlled release of protamine sulphate or levamisole did not significantly inhibit glutaraldehyde pretreated bovine pericardium calcification. It is concluded that regional controlled release of Fe 3+ or AI 3+ inhibits glutaraldehyde pretreated bovine pericardium calcification in the rat subdermal model without adverse effects.