研究生: |
黃皪瑩 Li-Ying Huang |
---|---|
論文名稱: |
不鏽鋼表面固定生物高分子應用於釋藥型心血管支架之製備與探討 Study of Biopolymer Immobilization on Stainless steel for Durg-Eluting Stent |
指導教授: |
楊銘乾
Ming-Chien Yang |
口試委員: |
張豐志
none 楊台鴻 none 王大銘 none 李振綱 Cheng-Kang Lee |
學位類別: |
博士 Doctor |
系所名稱: |
工程學院 - 材料科學與工程系 Department of Materials Science and Engineering |
論文出版年: | 2008 |
畢業學年度: | 96 |
語文別: | 英文 |
論文頁數: | 99 |
中文關鍵詞: | 藥物釋放型支架 、藥物釋放 、血液相容性 、內皮細胞 、平滑肌細胞 、生物高分子 、SUS316L不鏽鋼 |
外文關鍵詞: | SUS316L stainless steel, biopolymer, drug-eluting stent, drug controlled release, hemocompatibility, smooth-muscle cells, endothelial cells |
相關次數: | 點閱:396 下載:1 |
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新一代包覆藥物型心導管支架(stent),目前已經慢慢取代傳統不鏽鋼的stent,主要的概念在於包覆一層高分子材料,以降低不鏽鋼直接摩擦血管及提升生物相容性,並且可在高分子裡面包覆藥物,降低血栓形成、抗發炎反應及抑制平滑肌細胞(smooth muscle cells)成長於stent上去形成再狹窄(restenosis)的情況發生,雖然目前大都未通過FDA的認證,但是還有很大的空間等待我們去發掘研究,是目前生醫界最熱門的研究題目之一。
此論文的第一部份主要著重在於透明質酸(HA)/肝素(HEP)的表面接枝於SSU316L 不鏽鋼表面之血液相容性及包覆藥物其藥物釋放之情形。我們使用ATMS為不鏽鋼-高分子的表面接著劑,接著HA及HEP被共價鍵結於不鏽鋼板上(1-5層)。AFM、ESCA、接觸角及橢圓儀將被使用來評估接枝層的表面特性。結果顯示藉由橢圓儀的量測,HA/HEP接枝厚度約為280-630 nm,而在ESCA上也可以證實HA與HEP的確能共價鍵
結於基版上。在血液相容性測試上,結果發現HA/HEP接枝層可以明顯延長凝血時間(APTT),及減少血小板的吸附,證明血液相容性已經被改善。另外,在藥物釋放方面,sirolimus藥物包覆量約為1.02~3.12 g/cm2,且在5層的接枝層上其釋放天數可以超過30天,達到延長釋放的效果。
此論文的第二部份主要著重在於硫酸軟骨素(Chs)/肝素(HEP)的表面接枝於Au塗佈之SSU316L不鏽鋼表面,並探討改質後的表面之血液相容性及藥物對於平滑肌及內皮細胞的影響。我們使用DMSA(硫醇類)作為不鏽鋼及高分子的連結劑,藉由硫醇化(thiolizing)與Au之反應來作共價鍵結。結果顯示sirolimus藥物能有效抑制平滑肌細胞生長避免再狹窄的機率發生,但並不影響內皮細胞的成長。另一方面,改質的表面一樣也可以改善不鏽鋼板的血液相容性。
第三部分,將之前接枝之條件,實際使用接枝在stent上,利用螢光顯微鏡觀察可以發現類似之前的情況,sirolimus的包覆可以抑制平滑肌細胞的成長去避免再狹窄的情況發生,但內皮細胞依然可以正常代謝。因此,此生物高分子改質及包覆藥物之心導管支架能被預期去改善血管再狹窄及血栓(thrombus)形成,對於心血管病患將是一大福音。
This thesis is aiming to develop a drug-eluting stainless steel stent to curtail in-stent restenosis induced by conventional stents. The purpose to coat biomolecules is to avoid the friction of blood vessel to improve biocompatibility, to load drug to decrease the formation of thrombus, inflammation, and the growth of smooth muscle cells to prevent the formation of restenosis.
The first part is focused on stainless steel (SUS316L) sheets coated with hyaluronic acid (HA) and heparin (HEP), and their in vitro characteristics and drug release pattern were investigated. The surface of stainless steel (SS) was treated with nitric acid and followed by anchoring aminotrimethoxysilane (ATMS), then a nanolayer of HA was covalently immobilized onto the surface. A model drug (sirolimus) was embedded in assembled HA/HEP layers at a density ranging from 1.02 to 3.12 g/cm2. Heparin was then covalently bonded to the HA-immobilized SS substrate. After repeating 1 to 5 cycles, 1 to 5 layers of polyelectrolyte complex (PEC) nanobrush of HA/HEP were resulted with the thickness ranging from 280 to 630 nm (measured with ellipsometry). The SS-ATMS-HA-HEP substrates were evidenced by X-ray photoelectron spectroscope (XPS), contact angle, and AFM measurement. The effect of this surface modification on the coagulation time of the resulting SS substrates was investigated. The results show that the multi-layer HA/HEP stainless steel would exhibit longer coagulation time than pure SS substrates. In addition, the results of the in vitro drug delivery study showed that release of sirolimus from the 5-layer-HA-HEP stainless steel was able to maintain more than 30 days. Thus layer-by-layer HA/HEP PEC can improve the hemocompatibility of SS surface and control the drug released rate by multiple layers of HA/HEP PEC.
The second part is focused on a thin layer of gold sputtered onto SUS316L stainless steel (SS) sheet. After thiolizing the Au layer with dimercaptosuccinic acid (DMSA), layers of chondroitin 6-sulfate (ChS) and heparin (HEP) were alternatively immobilized on the Au-treated SS. The resulting stent would be both anti-atherogenic and anti-thrombogenic. After repeating 1 to 5 cycles, 1 to 5 layers of polyelectrolyte complex (PEC) of ChS/HEP were successfully fabricated. Sirolimus was loaded in the ChS/HEP layers. The SS-ChS-HEP surface was examined by X-ray photoelectron spectroscopy (XPS), contact angle, and atomic force microscopy (AFM) measurement. Biological tests including hemocompatibility, drug release pattern, and the inhibition of smooth muscle cell proliferation were also performed. The results show that the multilayer of ChS/HEP exhibits longer blood clotting time than pure SS substrates. Therefore this biopolymer multilayer can avoid thrombosis on the stainless. The releasing rate of sirolimus can be controlled through the number of ChS/HEP PEC layers. With a five-layer coating, sirolimus can be released continuously for more than 20 days. Furthermore, the multi-layer ChS/HEP loaded with sirolimus can suppress specifically to the growth of smooth-muscle cells to avoid restenosis.
The third part is focused on the metallic stent coating according to previous optimum procedure. Similar to past investigation, the resulting samples of loading sirolimus stents could prevent the proliferation of smooth muscle cells, but did not affect the growth of endothelia cells examined by fluorescence microscopy.
It can be anticipated that these multi-layer biomolecules coated on the stainless steel stent might be applied in biomedical devices, such as drug eluting stents.
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