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研究生： 宮輔辰
Fu-Chen Kung
論文名稱： 透析膜接枝共軛亞麻油酸或肝素對其血液相容性改進之探討
Effect of conjugated linoleic acid or heparin grafting on the hemocompatibility of hemodialyzer membranes.
指導教授： 楊銘乾
Ming-Chien Yang
口試委員: 楊禎明
Jen-Ming Yang
楊台鴻
Tai-Horng Young
王大銘
Da-Ming Wang
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： 2006
畢業學年度： 94
語文別： 英文
論文頁數： 103
中文關鍵詞： 自由基 、抗氧化力 、中空纖維透析器 、血液相容性 、內毒素 、表面改質
外文關鍵詞： oxidative stress, endotoxin, platelet adhesion., lipopolysaccharide, Conjugated linoleic acid
相關次數： 點閱：313  下載：7 
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    • 本研究以高分子透析膜為基材(Cellulose acetate、Polysulfone、Polyacrylonitrile)，表面改質後接枝抗凝血藥劑(肝素及共軛亞麻油酸)，以改善中空纖維在臨床使用上的功能性。實驗進行以傅立葉轉換紅外光儀(FTIR)、X光電子能譜儀(XPS)分析經改質接枝後之薄膜表面特性的差異。此外接枝亞麻油酸的效能評估則以血液作為測試的主體，分析血液與薄膜接觸後其血小板吸附情形、凝血時間之變化、免疫反應之狀態以及血液中自由基變化之監測；實驗進行並使用ELISA對內毒素掃除的效率做一評估。最後並以HUVECs作為細胞培養的測試， 作為其生物相容性之評估。實驗結果顯示，接枝亞麻油酸能進一步改善其血液相容性、抗氧化力、避免補體活化的啟動、能有效清除內毒素等優點，在內毒素去除的效率上接枝共軛亞麻油酸後之PAN、CA及PSF膜其去除效率分別為未經改質透析膜之1.6、1.2及1.5倍，結果也顯示接枝共軛亞麻油酸在全血液檢查(CBC)中測定值與正常血液之測定值無太大變化，此外在自由基離子產生分析中，經改質接枝之透析膜並不會造成大量自由基離子的產生，反之未經改質之透析膜卻有明顯的自由機離子累積產生。本實驗結果顯示接枝共軛亞麻油酸能提高透析器之附加價值及其應用性。
    實驗第二階段接著將商業用中空纖維表面改質接枝肝素(heparin)，以新鮮血漿做體外模擬測試，進一步評估此一接枝反應應用於中空纖維上的可行性。實驗進行對中空纖維之廓清率、凝血時間(APTT、PT、FT)、補體活化反應及全血液檢測(red blood cell (RBC)、hemoglobin (Hgb)、hematocrit (Hct) white blood cell、(WBC) 及 platelet)進行測試，結果顯示接之heparin不會改變其廓清率，且可以有效改善其抗凝血性、並有效去除內毒素以及提升其抗氧化力；本實驗結果可作為日後商品化之初步參考評估。

    In this study, hollow fiber membrane (PAN,CA and PSF) membrane was hydrolyzed and grafted with conjugated linoleic acid (CLA) via esterification with 1,3-propanediol. The resulting CLA grafting membranes were characterized with Fourier transform infrared spectrometer (FTIR) and X-ray photoelectronic spectroscopy (XPS). The effects of CLA grafting on the blood coagulation, platelet aggregation, and oxidative stress were evaluated using human blood. The complete blood count (CBC) and coagulation time (CT) was evaluated in vitro for the hemocompatibility. Furthermore, the removal of bacterial endotoxin (lipopolysaccharide, LPS) by CLA-bonding membrane was measured with ELISA. After CLA-grafting, the proliferation of human umbilical vein endothelial cells (HUVECs) on the membranes were improved. In addition, the production of reactive oxygen species (ROS) was measured by chemiluminescence (CL) method to evaluate the oxidative stress. The concentration of LPS can be reduced by CLA-bonding membrane of PAN, CA and PSF were 1.6, 1.2, 1.5 times more than unmodified one. The results showed that the CLA-grafting membrane could keep the CBC values more stable than unmodified membrane. The CLA-grafting membranes also showed longer CT. CLA-grafting membrane could keep the CL counts of hydrogen peroxide and superoxide values more stable than unmodified membrane. These results suggest that a CLA-grafting membrane could offer protection for patients against oxidative stress and would be helpful for reducing the dosage of anticoagulant during hemodialysis.
    Secondly, CLA or heparin was immobilized onto cellulose acetate hollow fiber to improve the anticoagulation performance during hemodialysis. In vitro evaluation was carried out using mini-hemodialyzer circulating with fresh porcine whole blood to simulating kidney therapy. The dialysis performance and hemocompatibility were estimated. The results showed that CLA-grafting or heparinized hemodialyzer could be used through out the whole dialysis time (4 hrs) without injecting additional heparin to prevent coagulation in the dialysis system. In addition, the hemocompatibility was evaluated by measuring activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen time (FT). The complete blood counts (CBC) including red blood cell (RBC), hemoglobin (Hgb), hematocrit (Hct), white blood cell (WBC), and platelet were determined. The results showed that CLA-grafting or heparinization could keep the CBC stable during dialysis, whereas unmodified cellulose acetate hemodialyzer would cause decrease in RBC unless heparin was injected during dialysis. CLA-grafting or heparinized hemodialyzer showed longer APTT, PT, and FT than unmodified hemodialyzer. CLA-grafting or heparinized hemodialyzer also showed slightly higher clearance than unmodified hemodialyzer. These results indicated that the dialysis performance and hemocompatibility of cellulose acetate hemodialyzer could be improved by the immobilization of heparin or CLA-grafting.

    摘要 I Abstract II Acknowledgement IV Contents V Figures VIII Tables X Chapter 1: Introduction 1 Chapter 2: Background and previous works 4 2.1. Hemodialyzer 4 2.2. Conjugated linoleic acid 5 2.3. Endotoxin 7 2.4. Blood coagulation 8 2.5. Blood counts 9 2.6. Complement system 10 2.7. Oxidative stress 11 2.8. Human Umbilical Vein Endothelial Cells 12 Chapter 3: The reduction of oxidative stress, anticoagulation of platelet, and inhibition of lipopolysaccharide by conjugated linoleic acid bonded on hemodialyzer membrane. 13 3.1. Motivation and objectives 13 3.2. Experimental procedures 14 3.2.1. Materials 14 3.2.2. Preparation of polyacrylonitrile membranes 14 3.2.3. Preparation of Flat-Sheet PSF Membrane 15 3.2.4. Preparation of cellulose acetate membranes 17 3.2.5. Characterization analysis 18 3.2.6. Measurement of water contact angle 18 3.2.7. Blood coagulation time 19 3.2.8. Grafting density of CLA 19 3.2.9. Complement test method 19 3.2.10. Determination of LPS level 20 3.2.11. Measurement of the level of reactive oxidants in plasma. 20 3.2.12. Cell proliferation assay 22 3.3. Result and discussion 22 3.3.1. The hydrophilicity of PAN membranes 22 3.3.2. PSF Ozone treatment 23 3.3.3. Surface characterization 24 3.3.4. Blood coagulation 30 3.3.5. Surface density of CLA 35 3.3.6. The complete blood count assay 38 3.3.7. Removal of LPS 40 3.3.8. Measurement of the level of reactive oxidants in plasma. 42 3.3.9. Complement activation 49 3.3.10. Cell proliferation 49 3.4. Conclusions 50 Chapter 4: In vitro evaluation of CA hemodialyzer immobilized with heparin. 51 4.1. Motivation and objectives 51 4.2. Experimental procedures 52 4.2.1. Oxidation of cellulose acetate dialyzer 52 4.2.2. Grafting of heparin 52 4.2.3. Stability Test 53 4.2.4. Surface density determination 54 4.2.5. Surface density of heparin 54 4.2.6. Dialyzing performance of hemodialyzers 54 4.2.7. Protein adsorption 55 4.2.8. Blood samples 56 4.2.9. Hemodialysis 56 4.2.10. Hematological Parameters 56 4.2.11. Blood coagulation time 57 4.2.12. Complement test method 57 4.3. Results and discussion 57 4.3.1. Oxidization of CA dialyzer 57 4.3.2. Stability of Immobilized Heparin 59 4.3.3. Surface density of heparin 60 4.3.4. Dialysis performance of hemodialyzers 62 4.3.5. Protein adsorption 62 4.3.6. The CBC assay of the dialysis system 64 4.3.7. Blood coagulation 72 4.3.8. Complement activation 77 4.4. Conclusions 77 Chapter 5: Overall conclusions and suggestions 78 5.1. Conclusions 78 5.2. Suggestions 79 References 81

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