Heparin-immobilized polymers as non-inflammatory and non-thrombogenic coating materials for arsenic trioxide eluting stents

Abstract

We have synthesized heparin-immobilized copolymers of l-lactide (LA) and 5-methyl-5-benzyloxycarbonate-1,3-dioxan-2-one (MBC) as non-inflammatory and non-thrombogenic biodegradable coating materials. These copolymers were used in fabricating arsenic trioxide (As 2O 3)-eluting stents to reduce the late-stage adverse events, such as thrombosis, localized hypersensitivity and inflammation, that occur when applying stents to treat coronary artery diseases. Heparinized copolymers effectively reduced platelet adhesion and protein adsorption while increasing the plasma recalcification time and thromboplastin time in vitro. Histological analysis of the polymer-coated stents in a porcine coronary artery injury model indicated that one heparinized copolymer (Hep-Co90, LA:MBC = 90:10), with the highest LA content of 90% and the lowest degradation rate, induced the least foreign body reactions and inflammation, which were as small as those induced by bare metal stents. Consequently, Hep-Co90 was used as the stent coating material for local As 2O 3 delivery. Histomorphometric evaluations suggested no significant difference between bare metal stents and As 2O 3-eluting stents at 1 and 3 months post-implantation. At 6 months, the lumen area in the porcine coronary arteries treated with As 2O 3-eluting stents is 32.4% higher than those treated with bare metal stents while the neointimal area, neointimal thickness and stenosis rate decreased by 25.8%, 32.5% and 31.2%, respectively. The As 2O 3-eluting stent using Hep-Co90 as the drug carrier and stent coating material presented in this study represents a novel promising device in preventing in-stent restenosis.