整合型微流體晶片系統在分子生物標誌之篩選與應用

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研究生：	洪廉育 Hung, Lien-Yu
論文名稱：	整合型微流體晶片系統在分子生物標誌之篩選與應用 Application and Screening of Molecular Biomarkers on Integrated Microfluidic Systems
指導教授：	李國賓 Lee, Gwo-Bin
口試委員:	林哲信陳宗嶽吳旻憲王玉麟曾繁根張晃猷李國賓
學位類別：	博士 Doctor
系所名稱：	工學院 - 動力機械工程學系 Department of Power Mechanical Engineering
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	207
中文關鍵詞：	微流體、生物標誌、流感、奈米粒子、指數增幅型配子系統演化法、卵巢癌、癌症幹細胞
外文關鍵詞：	Microfluidics, Biomarkers, Influenza, Nanoparticles, SELEX, Ovarian cancer, Cancer stem cells
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微流體系統可以在僅使用少量的樣本及試劑下，完成高解析度的分離與高靈敏的偵測，並有低成本、分析時間短及實驗之硬體裝置不佔空間的優點。在微流體系統利用具生物相容性之材質製作後，越來越多分子生物學分析或是醫學的診斷可與微流體系統結合，可達到快速與高靈敏的偵測
此論文主要進行整合型微流體晶片系統在檢測診斷分子生物標誌之應用與篩選。首先是一整合型微流體系統用於流感病毒感染之快速檢測，其中包含負壓氣動式元件與控制模組，並利用磁珠螢光免疫檢測進行終端光學檢測。在此應用的分子生物標誌為蛋白質層級之生物標誌，主要為專一性小鼠 A 或 B 型流感病毒核蛋白之單株抗體。此系統能夠成功地在單一次晶片測試中於 15 分鐘內自動化檢測 A 與 B 型流感病毒。更甚者，在利用 86 組病人樣本診斷中，此系統可達到 84.8% 的靈敏度與 75.0% 的專一性。接著為了增進磁珠螢光免疫檢測的光學訊號，我們應用尺寸為 100 奈米的氧化錳鐵之磁性奈米粒子於流感病毒感染的快速檢測。於奈米粒子上接合 A 型流感病毒核蛋白之單株抗體後，並整合層疊式表面修飾流程明顯地減少奈米粒子非專一性吸附之背景訊號。與尺寸為 4.5 微米之磁珠比較，氧化錳鐵之磁性奈米粒子的光學訊號提升了兩倍，顯示此微流體平台將可能應用於感染性疾病的快速檢測。
由於抗體有著昂貴、不易保存與生產批次間的差異，因此體外篩選方法對於找尋高親和性或高疾病檢測準確性的生物標誌扮演了重要的角色。此研究利用指數增幅型配子系統演化法 (SELEX) 進行癌症專一性之適體篩選。不同組織學分類的卵巢癌細胞，包含: BG-1, TOV112D, IGROV1 與 TOV-21G 細胞株，被應用在此適體篩選流程，研究成功篩選獲得 13 條卵巢癌專一適體，其中包含四條亮細胞專一適體、七條內膜樣細胞專一適體與兩條漿液性細胞專一適體。本研究成功發展一能夠進行多種細胞株且高通量篩選之自動化整合型微流體系統。除此之外，近期研究發現癌細胞中存在著癌症幹細胞，其為一小群具有自我更新與無限生長能力之癌細胞，可能在癌症治療中扮演著關鍵的地位。此論文再針對大腸結腸癌幹細胞與大腸結腸癌細胞進行專一性適體篩選。篩選獲得八條大腸結腸癌幹細胞/大腸結腸癌專一適體。其中三條適體之解離常數分別為 27.4、28.5 與 12.3 nM，對其目標細胞具有高親合力。這些篩選獲得的大腸結腸癌幹細胞/大腸結腸癌專一適體生物標誌，將可在個人化醫學或藥物研發有更好的應用與發展。

Microfluidics is a technology to manipulate a small amount of fluids by using well-designed microchannels, microchambers and microdevices. It offers a number of advantages, including low sample/reagent consumption, high-resolution separation, fast detection, high sensitivity, low cost and automation. While the micro-fabrication process uses bio-compliable materials, increasing numbers of molecular biological and medical diagnosis could be performed on microfluidic systems for rapid and accurate diagnosis. In this work, we presented the application and screening of molecular biomarkers for disease diagnosis on the microfluidic systems. First, a new integrated microfluidic system for rapid detection of influenza infections was developed, which integrated a suction-type, a pneumatic-driven microfluidic control module, a magnetic bead-based fluorescent immunoassay and an end-point optical detection module. The molecular biomarker used was a protein-based biomarker- the specific mouse anti-influenza nucleoprotein (NP)-A mAb or anti-NP-B mAb. This system could successfully distinguish between influenza A and B using a single chip within 15 minutes automatically. Furthermore, the results of diagnostic assays from 86 patient specimens have demonstrated that this system has 84.8% sensitivity and 75.0% specificity. Then, in order to improve the optical signal of a magnetic bead-based FIA, we produced MnFe2O4 magnetic nanoparticles around 100 nanometer for diagnostic applications. After the nanoparticles were coated with anti-influenza-NP-A mAbs, we further adopted a layer-by-layer surface modification process to significantly reduce the background noise due to non-specific adhesion of nanoparticles. When compared with the 4.5-µm magnetic beads, the optical signals of the MnFe2O4 nanoparticles were twice as sensitive, providing a promising platform for rapidly diagnosing infectious diseases.
Because antibodies are relatively expensive, hard to preserve and may vary from batch to batch fabrication, in-vitro screening methods for high-affinity biomarker searching attract intensive attention recently. Among them, systematic evolution of ligands by exponential enrichment (SELEX) has been explored extensively. In this work, we used SELEX for cancer-specific aptamer screening. The different histologically classified ovarian cancer cells, BG-1, TOV112D, IGROV1 and TOV-21G, were applied for aptamer screening. Thirteen OvCa-specific aptamers were successfully selected, including four specific aptamers for the clear-cell-type cell line, seven specific aptamers for the endometrioid-type cell lines, and two specific aptamers for the serous-type cell line. An automatic screening system which enabled one to use multiple cell lines for high-throughput screening work in one integrated microfluidic system was developed. Furthermore, cancer stem cells (CSCs), which are a tiny group of cancer cells having the ability to self-renew and proliferate indefinitely, may play an important role for cancer therapy. In this dissertation, colorectal-CSCs (CR-CSCs) and colorectal cancer (CRC) cells were applied for specific aptamer screening. Eight CR-CSC/CRC-specific aptamers were successfully selected. Three of them showed high affinities towards their target cells with dissociation constants (Kd) of 27.4, 28.5 and 12.3 nM. These selected aptamer biomarkers specifically for CR-CSCs and CRC cells may be further applied for personal medical screening or drug discovery.

Abstract    I
中文摘要    II
誌謝    III
Table of Contents    IV
List of Tables    VIII
List of Figures    X
Nomenclature    XVI
Abbreviations    XVIII
Chapter 1: Introduction    1
1 Microfluidic technologies and related fields    1
2 Biomarkers and category    4
2.1 Biomarkers application and screening on bench-top methods    5
2.2 Biomarkers discovery and application on Microfluidic system    7
2.3 In vitro Biomarkers Screening on Microfluidic system    12
3 Viral infectious diseases, ovarian cancer and colorectal cancer    16
3.1 Viral infectious disease    16
3.2 Ovarian cancer    18
3.3 Colorectal cancer and cancer stem cells    20
4 Motivation and Objectives    22
4.1 A microfluidic immunomagnetic bead-based system for the rapid detection of influenza infections：From purified virus particles to clinical specimens    22
4.2 Magnetic Nanoparticle-based Immunoassay for Rapid Detection of Influenza Infections by Using an Integrated Microfluidic System    24
4.3 An on-chip Cell-SELEX process for automatic selection of high-affinity aptamers specific to different histologically-classified ovarian cancer cells    26
4.4 An integrated microfluidic system for screening of aptamers specific to colorectal cancer cells and colorectal cancer stem cells by utilizing On-chip Cell-SELEX    28
5 Scope and structure of the dissertation    29
Chapter 2: A microfluidic immunomagnetic bead-based system for the rapid detection of influenza infections：From purified virus particles to clinical specimens    38
1 Introduction    38
2 Materials and methods    39
2.1 Working principle and experimental procedure    39
2.2 Chip design and fabrication    41
2.3 Materials and the magnetic bead-coating process    43
2.4 Virus particles and clinical specimens    44
2.5 Experimental setup and optical detection    46
3 Results and discussion    48
3.1 Characterization of the microfluidic system    48
3.2 Selectivity of anti-NP-A/or B mAb-PE    50
3.3 Limit of detection of the integrated microfluidic system    51
3.4 Diagnosis of influenza infections using clinical specimens    54
4 Summary    55
Chapter 3: Magnetic Nanoparticle-based Immunoassay for Rapid Detection of Influenza Infections by Using an Integrated Microfluidic System    74
1 Introduction    74
2 Materials and methods    75
2.1 Working Principle of the Diagnosis Assay    75
2.2 Fabrication of Microfluidic Chip and Surface Modification    76
2.3 Synthesis and Characterization of Nanoparticles    77
2.4 Preparation of reagents, virus and cell lines    78
2.5 Experimental setup    80
3 Results    81
3.1. Nanoparticles characterization    81
3.2. α-A-NP mAbs binding performance    82
3.3 Characterization of the Integrated Microfluidic System and Surface Modification    83
3.4 Limit of detection    84
4 Discussion    86
5 Summary    88
Chapter 4: Development of specific aptamers with different histological classified ovarian cancer cells by utilizing On-chip OvCa Cell-SELEX    102
1 Introduction    102
2 Materials and methods    103
2.1 Experimental procedure    103
2.2 Chip design and fabrication process    104
2.3 Mixing and pumping devices    106
2.4 ssDNA library, primers, reagents and operating conditions    107
2.5 Cell culture and preparation of immunomagnetic beads    109
2.6 The binding assay for the different rounds of enriched ssDNA pools with flow cytometric analysis    111
2.7 The determination of the dissociation constants from flow cytometric analysis    112
2.8 Fluorescent imaging of OvCa aptamers binding to different histologically-classified ovarian cancer cells    112
2.9 Testing binding selectivity of OvCa aptamers with different types of cancer cells    113
3 Results and discussion    114
3.1 Characterization of the integrated microfluidic chip for OvCa Cell-SELEX    114
3.2 Binding assays of the enriched ssDNA pools with different histologically-classified ovarian cancer cells    116
3.3 Identification of selected aptamers specific to different histologically-classified ovarian cancer cells    117
3.4 Identification of selected aptamers specific to different histologically-classified ovarian cancer cells    118
4 Summary    121
Chapter 5: An integrated microfluidic system for screening of aptamers specific to colon cancer cells and stem cells by utilizing On-chip Cell-SELEX    141
1 Introduction    141
2 Materials and methods    142
2.1 Experimental procedure    142
2.2 Chip design and fabrication process    142
2.3 Mixing and pumping devices    143
2.4 ssDNA library, primers, reagents and operating conditions    144
2.5 Tumorspheres culture, adherent cell culture and preparation of immunomagnetic beads    146
2.6 The binding assay for the different rounds of enriched ssDNA pools with flow cytometric analysis    148
2.7 The determination of the dissociation constants from flow cytometric analysis    149
2.8 Fluorescent imaging of CR-CSC/CRC aptamers binding to CR-CSCs and HCT-8 cells    149
2.9 Testing binding selectivity of CR-CSC/CRC aptamers with different types of cancer cells    150
3 Results and discussion    151
3.1 Characterization of the tumorspheres cultured CR-CSCs with specific biomarkers    151
3.2 Binding assays of the enriched ssDNA pools with CR-CSCs and HCT-8 cells    151
3.3 Identification of selected aptamers specific to CR-CSCs and HCT-8 cells    152
3.4 Identification of selected aptamers specific to different histologically-classified ovarian cancer cells    153
4 Summary    155
Chapter 6: Conclusions and Future Perspectives    165
1 Conclusion    165
2 Future Perspective    166
References    169
Publication lists    203

                                

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