Thai Minh Nguyen

A nonelutable low-molecular weight heparin stent coating for improved thromboresistance†

Low-molecular weight heparin (LMWH) has been widely used as a systemic anticoagulant during percutaneous coronary intervention. In this study, LMWH was covalently immobilized to the surface of a cobalt chromium reservoir-based sirolimus-eluting stent to create a nonelutable nanoscale coating for enhanced thromboresistance. Toludine-blue stained stents revealed uniform heparin coverage on all surfaces of the stent. Scanning electron microscopy of stent strut cross-sections showed identical coating thickness on all sides; while the thickness was determined to be 320 nm by a focus-ion beam system. Secondary ion mass spectrometry showed constant concentrations of O, N, and S atoms throughout the depth of the surface, confirming the uniformity of the heparin coating. The nonelutable nature of the coating was confirmed in a modified Factor Xa inhibition assay which showed the stent had an equivalent of 3-5 heparin units/cm(2), while no elutable heparin was detected in wash solutions. The antithrombin binding capacity of the immobilized heparin was determined to be 60-80 pmol/cm(2) in an antithrombin uptake assay. The enhanced thromboresistance of the heparin coating was demonstrated in an in-vitro bovine blood flow loop which showed minimal visual thrombus accumulation and 95% reduction in platelet deposition compared to uncoated control stents. Drug-eluting stents with such nonelutable LMWH coating would represent a significant advance in the treatment of patients with complex lesions who are at increased risk of developing stent thrombosis.

Control of cilostazol release kinetics and direction from a stent using a reservoir-based design†

Sustained release formulations of a potent antithrombotic drug, cilostazol, in poly-(lactic acid-co-glycolic acid) (PLGA) matrices were created for luminal release from a novel drug-eluting stent utilizing reservoirs (RES TECHNOLOGY™). The crystallinity of cilostazol and the morphology of the cilostazol/polymer matrix in the stent reservoirs were examined by cross-polarized optical microscopy and differential scanning calorimetry. An in vitro method was developed to study release kinetics of various cilostazol formulations and to examine correlation with in vivo release. Formulation parameters such as drug-to-polymer ratio and the use of a polymer barrier on the abluminal surface of the drug/polymer matrix were found to be effective in modulating drug release rate. Cilostazol/PLGA(75/25) in the weight ratio of 50/50 to 70/30 displayed first-order release kinetics for the majority of the drug load. Addition of an abluminal polymer barrier slowed cilostazol release rate when compared to the bidirectional reservoir design. Excellent correlation between cilostazol in vivo release profile from stents in a porcine coronary artery model and that measured in vitro in a modified USP-7 apparatus suggests that the in vitro release system is capable of predicting in vivo release of cilostazol from stent reservoirs.