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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李世光 | |
dc.contributor.author | Pei-I Tsai | en |
dc.contributor.author | 蔡珮漪 | zh_TW |
dc.date.accessioned | 2021-06-15T12:27:41Z | - |
dc.date.available | 2017-08-31 | |
dc.date.copyright | 2016-08-31 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-09 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50009 | - |
dc.description.abstract | 技術的創新應用不僅加速了科技知識的普及化,也增進了知識的再加值化。自2003年4月人類基因圖譜宣布完全解碼後,生醫領域的趨勢乃聚焦於蛋白質體的研究,而研究蛋白質體學所需的技術或設備,則以具有即時(real-time)、無標記(label-free)、可直接監測生物分子間相互作用情形的生物感測器最具競爭優勢。
本研究整合臺大奈米生醫微機電系統研究群累積多年之研發基礎-光生化形生醫晶片檢測儀(OBMorph),及電化學阻抗譜系統(EIS)技術於一新創檢測平台上,使用自製型感測晶片搭配本團隊自行合成之電誘導型雙噻吩生物連結分子作為鍵結蛋白質的橋接物,藉由表面電漿共振(SPR)技術反射光的相位變化及電化學氧化還原反應,同步量測丙型干擾素(interferon-gamma, IFN-γ)與其抗體間的結合作用,以相互驗證檢測平台的效能。此外,本研究亦驗證雙噻吩生物連結分子用於SPR商用儀器和晶片之適用性,平行開發檢測自體免疫型之抗丙型干擾素抗體(anti-IFN-γ Ab)的優化試驗程序。 實驗結果顯示,本研究團隊開發之檢測平台和生物連結分子皆具有優異的量測性能,同步以電化學量測系統整合於OBMorph平台,利用雙噻吩生物連接分子的導電特性可以同步量測丙型干擾素12.8 pM ~ 1000 nM的濃度,並具多功整合型生物感測平台獨特的靈敏度和靈活性。同時也成功證實雙噻吩生物分子可用於固定抗體或抗原,雙向檢測抗體-抗原或抗原-抗體,故為一有效的生物連結分子。雙噻吩基晶片固定IFN-γ的訊號響應為聚葡萄醣晶片的8.31倍,而分析物的訊號響應可再增為2倍,顯示出其高靈敏度的特性。所測得抗丙型干擾素抗體濃度為0.67 nM ~ 83.33 nM範圍,以3.33 nM的濃度進行六次再生循環測試之感測訊號耗損小於1%,再現性表現優良。本研究所開發之檢測程序模型簡化便捷,不僅具大量、 可快速篩檢潛伏性結核病或定量自體免疫病灶,襄助臨床診治與用藥判斷的潛能,且具有時間和成本的優勢。 聯合國防治結核病的重點工作之一,即為發展更適切且可用在第一線的診斷工具。此外,據市場分析,2015年至2020年全球免疫分析市場規模將增長70億美元,而生物感測器市場規模則將增長95.3億美元。因此,生物分子交互作用分析,尤其是抗體與抗原之間的親和作用力,在生命科學研究、新藥開發與醫學臨床檢驗等領域的應用益發重要。本研究結果證實了研究團隊所開發的即時、無標記的檢測方法與系統-雙噻吩基生物感測系統可應用於檢測潛伏型結核菌感染之生物標誌物IFN-γ和anti-IFN-γ Ab,即時監測與分析生物分子間的相互作用,所得結果更證明其為高靈敏度的生物感測器,同步的量測系統與數據則可加速臨床的診斷與處置,而anti-IFN-γ Ab檢測模組的開發,對於自體抗體的檢測程序及感測晶片的再生循環試驗,也提供了進一步臨床研究的應用及縮短檢測時間與降低成本的效益。希冀,本研究成果對於未來技術研發的運用、疾病的防治或多元的應用上,具有為本土性發展體外檢測器材帶來實質的助力,並得使其更臻完善的潛能。 | zh_TW |
dc.description.abstract | Innovations in technological applications not only accelerate the spread of knowledge in Science and Technology (S&T) but it can also increase the value of S&T knowledge. The integration of the fields of Life Science and Engineering has been a major research focus in achieving cross-disciplinary, cross-field knowledge. Since the completion of the Human Genome Project in April 2003, one of the major focus of biotechnology research has been on proteome-related research. New technology or equipment which are real-time, are label-free, and can handle direct detection of biomolecular interactions have been found to be the most advantageous. It is estimated that the global market for immunoassay technologies will grow by US$7 billion from 2015 to 2020 and the biosensor market will increase by US$9.53 billion. Biomolecular interaction detections, especially those between antigens and antibodies, have become more important in Life Science research, new medical development, and clinical studies.
According to the World Health Organization (WHO), tuberculosis (TB) is a top infectious disease killer worldwide. In 2014, it was estimated that 9.6 million people fell ill with TB and 1.5 million died from the disease. Data shows that latent tuberculosis infection (LTBI), affects about one-third of the world’s population and approximately 10% of people with LTBI develop into active TB later on. Methods which facilitate efficient detection and interpretation of biomarkers for screening LTBI have been an important research topic as it attempts to deal with an international public health problem. Interferon-gamma (IFN-γ) as a biomarker indicator for tuberculosis and with antiviral, immunomodulatory and anti-tumor properties can be used as a reference to assess inflammatory status associated with risk of the disease. In addition, since the body immune function abnormalities produce neutralizing anti-IFN-γ antibodies (anti-IFN-γ Ab), it has the potential to be used in the development of drugs for antagonistic auto-antibodies associated with autoimmune diseases. With the limitations of current detection methods and costs, latent tuberculosis infection has not yet undergone thorough, large-scale screening. To this end, the development of a more appropriate and more readily available first-line diagnostic tool is one of the major priorities of the United Nations in combating tuberculosis. The experimental approach in this investigation was based on creating a bio-sensing platform. This platform, called OBMorph, was developed by the National Taiwan University (NTU), Nano-BioMEMS group. It integrated a surface plasmon resonance (SPR) technology and a phase modulated ellipsometer to improve the performance of biomolecular measurements. Electrochemical impedance spectroscopy (EIS) was also integrated simultaneously onto this measurement platform. Furthermore, a bithiophene-based conductive biolinker was also developed with an attempt to improve the antibody-antigen interactions for biosensors and to verify the performance as well as potential for synchronous measurement of IFN-γ binding interaction by the OBMorph platform and EIS. In addition, the bithiophene biolinker was introduced into our newly developed biochip and adopted into a commercially available SPR instrument (Biacore T200). We wanted to test and verify the suitability of the bithiophene biolinker and to optimize the test procedures for detecting anti-IFN-γ Ab. Our experimental results show excellent measurement performance for the OBMorph as well as for the newly developed biolinker. The interactions of the IFN-γ with immobilized anti-IFN-γ Ab at various concentrations (12.8pM ~ 1000nM) were investigated both optically and electrochemically. It was also verified that the bithiophene biolinker used was an effective biolinker for immobilizing antibody-antigen/antigen-antibody bio-detection. More specifically, we compared the response and concentration of the anti-IFN-γ Ab on a bithiophene-coated and dextran-coated biochip as well as on different thickness-modified surfaces under SPR measurement conditions. Our results indicate that a response to the IFN-γ molecules immobilized on a sensor using a bithiophene biolinker improved more than 8-fold when compared to that of a sensor using a dextran biolinker. A higher sensitivity on the immobilization of the IFN-γ and specific binding of the anti-IFN-γ Abs were both found in the newly developed bithiophene biochips when compared to that of a commercially available dextran biochip SPR measurement tool. Furthermore, the detection range of the anti-IFN-γ Ab obtained was 0.67nM to 83.33nM using a biosensor method without resorting to the use of second molecules for signal amplification. The regeneration ability of the sensor surface showed good repeatability as less than a 1% decrease was found after repeating the experimental work over 6 cycles. In this dissertation, we found that the OBMorph offered us a good platform for rapid screening, real-time monitoring and the potential for quantitative concentrations of the autoimmune antibody activities. Proper protocols were also developed to demonstrate the detection sensitivity, measurement resolution, dynamic detection range, and chip regeneration capability of this newly developed biochip. Effects associated with using the bithiophene as a biolinker for the anti-IFN-γ Ab interaction with IFN-γ are examined in this dissertation. Moreover, our newly developed integrated bio-sensing system has the potential to provide new insight into various conjugate phenomena and interfacial processes for observing molecular conformation changes. It provides an advantageous platform for proteomic research which is cost effective and cost efficient. In summary, the results obtained from the integrated bio-detection OBMorph platform in this dissertation, can be a good starting point for advancing future technology research. It can be used to further work on disease prevention or extending to other applications which has the potential to boost the local development of in vitro detection devices. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T12:27:41Z (GMT). No. of bitstreams: 1 ntu-105-D98525012-1.pdf: 12677492 bytes, checksum: d467e6c217932b2fdb368feb2ca5b184 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員會審定書
誌謝 I 摘要 III Abstract V 目錄 IX 圖目錄 XIII 表目錄 XVII 第一章 簡介與背景 1 前言 1 1.1 生物檢測技術的發展趨勢 7 1.2 生物感測器的需求與演進 8 1.3 生物分子交互作用的分析 11 1.3.1 蛋白質分子特性 12 1.3.2 親合力與動態平衡 14 1.3.3 生物分子在材料表面的作用 17 1.4 丙型干擾素蛋白質的結構及生化特性 20 1.4.1人體的免疫系統 20 1.4.2 丙型干擾素的角色 22 1.4.3 感染潛伏性結核病的診斷方式 23 1.4.4 生物資訊檢索 24 1.4.5 研究動機 27 1.5 各章節的介紹 28 第二章 整合性量測平台的發展 31 2.1 光學和電化學的測量原理 31 2.1.1 光學的原理與應用 31 2.1.2 電化學阻抗頻譜分析原理與應用 36 2.2 表面電漿共振和橢偏技術的系統整合 38 2.3 光學薄膜的特性 41 2.4 生物連結分子的設計和選擇 43 第三章 研究方法與材料 47 3.1 材料及試劑 47 3.1.1 化學品和材料的製備 47 3.1.2 生物感測晶片 50 3.2 主要儀器 52 3.2.1 橢球面生醫光學檢測儀(OBMorph) 52 3.2.2 生物分子交互作用分析系統 53 3.2.3 電化學阻抗譜分析儀 53 3.2.4 酵素免疫分析儀 54 3.2.5 原子力顯微鏡 54 3.2.6 光譜橢偏儀 55 3.3 實驗方法與步驟 56 3.3.1 生物感測器檢測策略-蛋白質生物標誌物 56 3.3.2 軟體模擬分析 57 3.3.3 薄膜厚度量測法 58 3.3.4 OBMorph感測平台光路調校 58 3.3.5 生物感測晶片表面生化反應關鍵程序 61 3.3.6 整合型生物感測平台系統分析 65 3.3.7 酵素免疫吸附法 67 第四章 實驗結果和討論 69 4.1 入射光角度與折射率、相位及薄膜厚度之模擬分析 69 4.1.1 入射角度、折射率與反射光相位之變化量 69 4.1.2 影響反射率之相關因素與參數模擬 71 4.2 雙噻吩生物連接分子修飾於金膜表面 73 4.2.1 金膜表面形貌的變化 73 4.2.2 雙噻吩基於金膜表面的厚度 75 4.2.3 雙噻吩基於金膜表面的阻抗變化 75 4.3 OBMORPH多功感測平台系統試驗結果 76 4.3.1 OBMorph及晶片感測系統效能驗證 76 4.3.2 OBMorph感測平台與EIS系統同步檢測分析 80 4.4 酵素連結免疫吸附法測試配體固定化的濃度 84 4.5 雙噻吩生物連接分子感測效能證明 86 4.5.1 雙噻吩基晶片表面非特異性結合測試 86 4.5.2 丙型干擾素蛋白質固定於晶片表面的能力試驗 87 4.6 抗丙型干擾素自體免疫抗體之偵測模型建構及可行性分析 89 4.6.1 雙噻吩基晶片檢測抗丙型干擾素抗體與其配體的親合力分析 90 4.6.2 抗丙型干擾素抗體與其配體的結合率(ka)與解離率(ka)分析 91 4.6.3 抗丙型干擾素抗體特異性的結合測試和濃度定量的線性關係 93 4.6.4 雙噻吩基晶片表面再生循環的檢測成效 94 4.7 綜合討論 95 第五章 結論 103 第六章 展望未來 107 參考文獻 109 附錄 121 附錄一、作者簡歷 123 附錄二、中英文專有名詞及縮寫對照 125 | |
dc.language.iso | zh-TW | |
dc.title | 雙噻吩分子修飾生物感測器表面的同步量測技術與驗證平台之研發
—丙型干擾素重組蛋白質及其抗體間交互作用模組的開發 | zh_TW |
dc.title | Synchronous Measuring Technique and Verification For the Development of the Biosensor Platform by Chip Surface Modification with Bithiophene Biolinker — A Module Developed For the Interaction of Interferon-gamma Recombinant Protein and Its Antibody | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林秋雄,李世元,李舒昇,楊鏡堂,陳奕帆 | |
dc.subject.keyword | 生物感測器,自體抗體,丙型干擾素,表面電漿共振,橢圓偏振技術,電化學阻抗頻譜,雙?吩生物連接分子,生物晶片,即時,無標記, | zh_TW |
dc.subject.keyword | biosensor,autoantibody,interferon-gamma,surface plasmon resonance,ellipsometry,electrochemical impedance spectroscopy,bithiophene biolinker,biochip,real-time,label-free, | en |
dc.relation.page | 132 | |
dc.identifier.doi | 10.6342/NTU201602079 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-09 | |
dc.contributor.author-college | 工學院 | zh_TW |
dc.contributor.author-dept | 工程科學及海洋工程學研究所 | zh_TW |
顯示於系所單位: | 工程科學及海洋工程學系 |
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