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研究生:賴宇亮
研究生(外文):Yu-Liang Lai
論文名稱:電化學沉積紫杉醇與肝素於金屬植入材之機制及其相關藥物釋放之探討
論文名稱(外文):Electrochemical Deposition Mechanisms of Paclitaxel and Heparin on Implant Alloys and Related Drug Releasings
指導教授:顏秀崗顏秀崗引用關係
口試委員:吳震裕方信元姚俊旭林建中
口試日期:2017-01-19
學位類別:博士
校院名稱:國立中興大學
系所名稱:材料科學與工程學系所
學門:工程學門
學類:材料工程學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:68
中文關鍵詞:紫杉醇氫氧基磷灰石鈦合金電化學沉積生醫應用藥物控制釋放鎳鈦合金肝素磷酸鈣明膠
外文關鍵詞:PaclitaxelHydroxyapatiteTitanium alloyElectrochemical depositionBiomedical applicationsDrug controlled releaseNi-Ti alloyRestenosisHeparinCalcium phosphateGelatin
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此研究利用電化學沉積法,將抗癌藥物-紫杉醇(paclitaxel)沉積於鈦金屬,抗凝血藥物-肝素(heparin)沉積於鎳鈦合金上,藉由其他生物相容性高之化合物,包括氫氧基磷灰石 (Hydroxyaptite)、明膠 (Gel)、磷酸鈣 (Calcium phosphate)之介入,調控藥物釋放速度。經由血管內支架塗佈藥物緩步釋放之機制與局部治療,使紫杉醇造成癌細胞自我凋亡以及防止轉移的治療效果。而肝素則是防止血管支架置入手術後之二次血管阻塞。藥物載入金屬植入片,一經電化學極化合成後,會經由一系列定性與定量分析,包括電子顯微鏡、聚焦式離子束與傅立葉轉換分析觀察試片表面型態及分析組成元素,X光繞射檢視試片主成分,紅外光譜、紫外–可見光光譜學檢查藥物承載與釋放量,最後再經由細胞毒性測試與凝血測試,檢視藥物載入金屬試片的完整功效。實驗結果顯示,紫杉醇經氫氧基磷灰石塗佈後,藥物承載量由395±95 μg/cm2 增加至 572±99 μg/cm2, 首日藥物暴衝釋放量下降,之後緩步釋放可延長至約一個月時間,而且達成更高比例之藥物釋放。至於藥物肝素在僅單層磷酸鈣塗佈的148μg/cm2,再經由氫氧基磷灰石塗佈與加入明膠 (Gel) 後之三層塗佈釋片上,因其多孔隙之特性,使藥物承載量增加至325μg/cm2,同時延長肝素緩步釋放時間從一天增加至至少35天。細胞毒性測試顯示紫杉醇功能完全不受實驗合成步驟影響,而肝素抗凝血功能在抗凝血測試上,亦呈現正常凝血功能。實驗結果顯示,利用電化學沉積法,將抗癌藥物-紫杉醇(paclitaxel)沉積於鈦金屬,抗凝血藥物-肝素(heparin)沉積於鎳鈦合金上,藉由其他生物相容性高之化合物,包括氫氧基磷灰石 (Hydroxyaptite)、明膠 (Gel)、磷酸鈣 (Calcium phosphate)之介入,調控藥物釋放速度利用電化學沉積法,將抗癌藥物-紫杉醇(paclitaxel)沉積於鈦金屬,抗凝血藥物-肝素(heparin)沉積於鎳鈦合金上,能有效增加藥物於載體上的塗佈量,進一步延長緩步釋放藥物的時間,在臨床醫學上的應用,是值得期待的。
In this study, paclitaxel, the drug for cancer treatment, is electrochemically deposited on Ti alloy as vascular stents for the tumor localized therapy by sustaining drug releasing to achieve the cancer cells apoptosis or the prevention of cancer metastasis. The other drug, heparin (Hep), combined with calcium phosphate (CaP) and gelatin (Gel), without any additive or solvent, is co-deposited on hydroxyapatite (HA) coated NiTi alloy in order to enhance the drug load and the sustaining release for promoting the hemo-compatibility of NiTi substrate. In the experiment, cathodic and anodic polarization tests coupled with electrochemical reactions were analyzed to speculate the deposition mechanism, and the field emission scanning electron microscope (FESEM), focused ion beam (FIB) system and Fourier transform infrared spectroscopy (FTIR) to observe the surface morphology and analyze constituent elements. A spectrophotometer (UV visible spectrometer) was used to measure drug loading and release. Finally, MTT Assay was carried out to analyze the cell viability for drug efficacy. It is concluded that paclitaxel can be successfully deposited on the titanium alloy by electrochemical method. Besides, the post hydroxyapatite coated specimen with high porosity can enhance the drug loading from 395±95 μg/cm2 to 572±99 μg/cm2, a lower burst release in the first day, a higher sustaining release rate in a month, and the more complete drug release. All results indicate that the paclitaxel/hydroxyapatite composite coating by the electrochemical deposition method is much more effective and promising. On the other hand, heparin accompanied respectively with CaP, and Gel through ionic bonds can be loaded on the NiTi alloy. The porous post HA coating can dramatically enhance the heparin content from 148 for the single layer coating (CaP-Hep) to 325μg/cm2 for the tri-layer coating (HA / CaP-Hep / Gel-Hep), also resulting in the heparin release duration from 1 to more than 35 days, supposed to meet the requirement to prevent the proliferation of VSMCs. Both the drug content and releasing time are remarkable. As the result of clotting tests in vitro, drug loaded composite coatings reveal good anticoagulant property which is proportional to the cumulative content of drug release in an hour, indicating no denaturalization of heparin found during the electrochemical process.
摘要..............................................................................................................................i
Abstract.........................................................................................................................iii
Contents......................................................................................................................... v
Figure captions.............................................................................................................vii
Table captions..............................................................................................................ix
Part A: Paclitaxel / Hydroxyapatite Composite Coatings on Titanium Alloy for Biomedical Applications
1. Introduction............................................................................................................1
2. Materials and methods...........................................................................................4
2.1. Sample preparation..........................................................................................4
2.2. Cathodic polarization tests and deposition......................................................4
2.3. Coating characterization..................................................................................5
2.4. Drug loading and release.................................................................................5
2.5. Cell tests..........................................................................................................6
3. Results and discussion...........................................................................................7
3.1. Polarization......................................................................................................7
3.2. Coating characterization................................................................................11
3.2.1FTIR.........................................................................................................11
3.2.2. Surface morphology................................................................................13
3.2.3. Cross-section observations by focused ion beam (FIB) system.............16
3.3. Drug loading..................................................................................................16
3.4. In vitro paclitaxel release..............................................................................19
3.5. MTT test.....................................................................................................20
4. Summary and conclusions...................................................................................21
5. References...........................................................................................................23


Part B: Electrolytic deposition of hydroxyapatite / calcium phosphate-heparin / gelatin-heparin tri-layer composites on NiTi alloy to enhance drug loading and prolong releasing for biomedical applications
1. Introduction……………………………………………………………………..27
2. Materials and methods………………………………………………………….31
2.1. Materials …………………………………………………………………..31
2.2. Cathodic polarization tests and deposition ……………………………..32
2.3. Coatings characterization ……………………………………………..33
2.4. In vitro drug loading and release ………………………………………..34
2.5. Toluidine blue colorimetric assay ………………………………………..35
2.6. Kinetic clotting tests …………………………………………………..35
3. Results and discussion ………………………………………………………..36
3.1. Polarization ……………………………………………………………..36
3.2. Coatings characterization ……………………………………………..40
3.2.1. X-ray diffraction………………………………………………...40
3.2.2. FESEM ………………………………………………………..43
3.2.3. FTIR ………………………………………………………..49
3.3. Deposition Mechanism …………………………………………………..50
3.3.1. Cathodic deposition ……………………………………………..50
3.3.2. Anodic deposition ……………………………………………..51
3.4. Weight Gain & Drug Loading …………………………………………….52
3.5. In vitro heparin release……………………………………...……………..54
3.6. Kinetic clotting test 58
4. Conclusions……………………………………………………………………..60
5. Reference……………………………..…………………………………………62
Papers list...……………………………..…………………………………………...68
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