具有形狀記憶與可自我膨脹之生物可分解式藥物釋放型血管支架

Self-Expandable Biodegradable Drug-Eluting Stents with a Shape Memory Property

陳美瑾(Mei-Chin Chen)

指導教授 ： 宋信文

國立清華大學/工學院/化學工程學系/博士(2008年)

摘要

臨床結果顯示，藥物釋放型血管支架(drug-eluting stent)可有效地抑制，經皮冠狀動脈血管擴張術(percutaneous transluminal coronary angioplasty, PTCA)後血管再狹窄的發生機率。目前市售的藥物釋放型血管支架，如CYPHER(Cordis Corp.)與TAXUS(Boston Scientific Corp.)支架等，皆是利用不可分解之合成高分子，將藥物包覆並塗佈於金屬支架上。文獻指出，這些不可分解之合成高分子，可能會引起血管內的過敏性反應，造成晚期的血栓產生，甚至危害病患的生命。由於血管再狹窄一般只發生在PTCA手術後的3~6個月內，過了這段期間，血管支架的存在便不是如此必要。基於以上的考量，本研究利用幾丁聚醣作為血管支架的主要材料，以化學共價交聯的方式，製備出可完全生物分解的藥物釋放型血管支架。本研究分為三大部份，第一部份先利用改良後的幾丁聚醣混成膜，以環氧樹脂(epoxy)進行交聯塑形，製做具有形狀記憶(shape memory)的螺旋形血管支架。此螺旋型支架可經水合作用，快速地膨脹撐開(~150秒)，不僅可縮短手術置放時間，且能防止支架位移的情形發生。初步的動物實驗結果來看，將製備的高分子血管支架，以French sheath植入兔子腹主動脈中，24小時後取出，並沒有支架位移與急性的血栓生成，初步證實此血管支架之可行性。第二部份進行包覆抗血管內膜增生藥(sirolimus)，以製備出藥物釋放型的血管支架。為了提高親水性材料與殊水性藥物之間的作用力，本研究以乳化方式，將疏水的sirolimus包覆在pluronic L121奈米微胞的疏水核心區，防止疏水藥物的流失，並利用微胞之親水外殼區，將藥物均勻地分散於高分子支架中。由體外藥物釋放之結果來看，利用此奈米包藥技術，確實能有效地防止藥物burst release的現象發生，製備出能sustained release的藥物釋放血管支架。最後，我們同樣地將研發的藥物釋放型血管支架，植入兔子體內，1個月後進行病理切片評估。實驗證實，與未包藥之支架相比，本研究所製備之藥物釋放型血管支架，確實能有效地抑制血管內膜的增生，很有潛力實際應用於治療動脈粥狀硬化上。

關鍵字

血管支架 ； 生物可分解 ； 奈米微胞 ； pluronic L121 ； 形狀記憶

並列摘要

The clinical importance of drug-eluting stents has been demonstrated by their unparalleled success in preventing restenosis after stenting procedures. However, hypersensitivity reactions caused by their nonerodable polymer coatings and bare-metal stents may result in serious clinical sequelae. In this report, a new biodegradable sirolimus-eluting stent, made from chitosan-based strips fixed by an epoxy compound, was developed. Due to the covalent crosslinks formed in the stent matrix, the fabricated stent had a shape-memory property to memorize its permanent shape. The developed polymeric stent could rapidly expand (~150 s) from its crimped (temporary) state to fully expanded (permanent) state stimulated by hydration, which is advantageous considering avoiding its migration during in vivo deployment. The preliminary animal study showed that this stent had a sufficient mechanical strength and a superior hemocompatibility in the stent-implanted vessel. To enhance the interactions between the poorly soluble anti-proliferative drug (sirolimus) and the hydrophilic stent matrix, a nanoscale drug-entrapment strategy was utilized to construct the sirolimus-eluting stent. Differing from other particle-embedded hydrogel systems, such an entrapment strategy substantially increases the loading efficiency of lipophilic drugs, prevents the drug from aggregation, and beneficially enhances the interaction between the drug and the stent matrix via amphiphilic Pluronic L121 micelles. Our experiments demonstrated that the developed stent can provide a sustained release profile without initial burst effect, thus evading undesirable side effects such as delayed endothelial healing caused by the overdose of sirolimus. When compared to the unloaded stent, neointima formation was significantly suppressed after implantation of the developed sirolimus-eluting stent in rabbit abdominal aortas. These findings suggested that the developed sirolimus-eluting polymeric stent can be a potential alternative for treatment of coronary artery disease.

並列關鍵字

HASH(0x1ac70990) ； HASH(0x1ac70a30) ； HASH(0x1ac70ad0) ； HASH(0x1ac70b70) ； HASH(0x1ac70c10)

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