Jonathon Z. Zhao

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.

Drug-Eluting Stents

Coronary stenting is currently the dominant and most cost-effective interventional approach in managing symptomatic artery diseases. Stent restenosis is the phenomenon of arterial vessel re-narrowing following an angioplasty procedure and is the most common complication of the stenting procedure. Drug-eluting stents (DES) nearly eliminate stent restenosis in simple lesions and significantly reduce its incidence in complex lesions. This chapter provides an overview of the pathophysiology of restenosis and the various considerations that go into the design and development of a successful DES including stent platform and materials, drug carriers, selections of various classes of anti-restenotic agents, and the appropriate modulation of drug load and release duration. Detailed examinations of the leading marketed drug-eluting stents are provided, followed by a brief introduction to devices that are in the development stage which may become the next-generation DES.

Endothelial Cell Attachment and Proliferation Studies on Modified Metal Stent Surfaces

Flat coupons prepared from cobalt chromium alloy (CoCr) were modified using different methods (low energy excimer laser processing, electron beam irradiation, and immobilized covalently-bound heparin coating). Human coronary artery endothelial cell (HCAEC) attachment and growth kinetics were investigated on unmodified and modified metal surfaces. Results showed that HCAEC attach to unmodified CoCr coupons and surface-modified CoCr coupons. No change in cell number was observed when cells were grown on CoCr coupons and heparin coated coupons throughout the 72h study period. A decrease in cell number was observed for excimer treated coupons. HCAEC seeding on CoCr stents indicated that cells attached and proliferated on the stents over a ten day study period. This research showed that physical modifications did not improve cell proliferation. Very few non-viable cells were observed for unmodified and surface bound heparin coupons, and cells attached to the surface up to 72h. This shows that heparin can be coated on a stent surface to provide anti-thrombotic properties without any negative effect on cell attachment and proliferation. In vitro screening method of testing endothelial cell attachment and proliferation on modified metal stent surfaces can be used to gain insight for developing next generation drug eluting stents with improved endothelialization behavior.