臨床研究指出，目前藥物釋放型血管支架所使用的高分子塗層，易刺激血管壁引發程度不一之過敏或是發炎反應，導致晚期的血栓或血管再狹窄。為了降低高分子所造成之不良反應，本研究乃以特殊的疏水性肝素(DurafloTM heparin)取代傳統的高分子塗層，包覆抑制血管內膜過度增生藥(sirolimus)，僅於DurafloTM heparin塗層外添加一層超薄的聚乳酸(polylactide)作為阻絕層，以隔絕血液中的離子親和分子對heparin的影響，製備出一具有超薄高分子塗層之雙效型藥物釋放血管支架。實驗結果證實，本研究可利用少量多層式的噴塗方式，分別將DurafloTM heparin與sirolimus塗佈於支架表面，且塗層與支架表面具有足夠的附著力，可承受氣球導管擴張之撐開測試，並無剝落或分離的情形。隨著噴塗層數或噴塗藥物濃度的提高，藥物的塗佈量會呈明顯的線性上升，可成功製備出三種不同劑量的藥物釋放型血管支架，其sirolimus與DurafloTM heparin的包藥量分別為51±10/1551±21(low dose)、100±9/2562±182(medium dose)與147±17/3415±157(high dose) μg/cm2。在體外藥物釋放方面，由於高黏性的DurafloTM heparin會將sirolimus緊緊包裹並黏覆於支架表面，阻礙sirolimus之釋放，因此必須添加少量的酒精於磷酸鹽緩衝液中，藉由酒精將DurafloTM heparin溶解才能順利釋放sirolimus。最後，由高分子塗層之阻隔效果測試證實超薄的聚乳酸確實具有阻絕的功效，能防止血清中的蛋白質競爭heparin，降低DurafloTM heparin在血清中的流失量，應可有效延長藥物在體內之釋放時間。本研究所開發出的藥物釋放血管支架，可同時包覆抗凝血與抑制內膜增生雙重藥物，不須藉由高分子做為包藥載體，能降低對血管壁的刺激，很有潛力成為新一代的藥物釋放型血管支架。

Some clinical reports have shown that the polymeric coating of the drug eluting stent (DES) may induce an adverse reaction (e.g. hypersensitivity or inflammatory) in the coronary artery. This can lead to subsequent thrombosis or neointimal thickening. To reduce the deleterious effects induced by the polymeric coating, a dual DES which utilizes a unique DurafloTM heparin coating as a drug reservoir was developed in this study. Using a spray-coating method, DurafloTM heparin and sirolimus solution were coated layer-by-layer alternatively onto the surface of a metallic stent. An ultra-thin polymeric topcoat(～2.5 μm) was then used as a barrier to prevent the leaching of heparin when in contact with the blood. The results obtained in the scanning electron microscopy (SEM) examination showed that the spray-coated DurafloTM heparin was tightly adhered to the surface of the stent and allowed balloon expansion of the stent without cracking or peeling from the wire. It was found that the amount of the drugs loaded on the stent was linearly related to the amount of sprayed drugs or the number of layers of coated drugs. Three types of stents loaded with different amounts of DurafloTM heparin/sirolimus were successfully prepared: the low-dose stent (1551±21/51±10 μg/cm2); the medium-dose stent (2562±182/100±9 μg/cm2); and the high-dose stent (3415±157/147±17 μg/cm2). The ultra-thin PLA topcoat can serve as a barrier to prevent serum leaching of DurafloTM heparin from stent. The in vitro drug release study showed that drug release rate increased as the ratio of ethanol in PBS is increased. The aforementioned results indicated that the developed DES can simultaneously provide the anti-thrombotic and anti-proliferative effects without recourse to polymeric carrier, suggesting that such dual DESs can be a potential alternative for the treatment of coronary artery disease.

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