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系統識別號 U0026-1209201703594100
論文名稱(中文) 介電泳式微流體生物晶片應用於登革熱感染之快速診斷
論文名稱(英文) Dielectrophoresis-based Microfluidic Biochip for Rapid Diagnosis of Dengue Infection
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 105
學期 2
出版年 106
研究生(中文) 安迪
研究生(英文) Edwar Iswardy
學號 P88017018
學位類別 博士
語文別 英文
論文頁數 84頁
口試委員 指導教授-張憲彰
口試委員-彭貴春
召集委員-吳靖宙
口試委員-鄭宜肪
口試委員-陳榮治
口試委員-葉才明
中文關鍵字 登革病毒  非結構性蛋白1  介電泳  微流體晶片  免疫螢光 
英文關鍵字 Dengue virus  Non-structural protein 1 (NS1)  Dielectrophoresis  Immunofluorescence-assay  Microfluidics 
學科別分類
中文摘要 傳染性疾病對於人類造成極大的威脅與負擔,對於疾病預防,檢測工具的研發極具需求性。登革熱在全世界屬於一種危急的病毒傳染性疾病,快速、靈敏、準確的登革感染檢測技術,對於疾病的及早治療與管理將扮演重要的角色。本研究利用微流體介電泳晶片整合螢光免疫分析技術,應用於登革熱病毒與其非結構性蛋白1的快速檢驗,其檢測原理係藉由介電泳力捕捉具有抗黃熱病毒或抗非結構性蛋白1單株抗體的微珠於微流體流道中的V型電極,再由微珠表面的抗體辨識登革熱病毒、非結構性蛋白1與具螢光標誌的相對應二抗,以完成整體的免疫反應,使用螢光顯微鏡獲取螢光強度,最後透過軟體進行影像分析定量目標分子濃度。此新穎平台技術不僅可縮短檢測時間至5~10分鐘(免疫反應1小時),也證實針對病毒與非結構性蛋白1的檢測極限,分別可下降至104 pfu/mL與10 ng/mL;此外,此研發平台的優勢亦可大幅減少待測檢體體積約15 μL,以及可重複使用50次以上。整體而言,相較於傳統技術,此平台以免疫螢光為基礎整合微流體介電泳晶片將提供一快速、靈敏、便宜的檢測技術,未來具有潛力符合臨床診斷的需求。
英文摘要 The infectious diseases have caused a threat and burden for the humankind and the effort for the discovery and development of a diagnostic tool is continuously required along with the prevalence of diseases. Dengue is an emerging viral infection increasing annually worldwide. A rapid, sensitive and accurate result of the dengue infection diagnosis are still a crucial issue to provide a proper treatment and management. In this report, the proof of concept of utilizing a method based on microfluidic dielectrophoresis (DEP) chip for diagnosis of dengue virus (DENV) infection is introduced. The sensing principle is that hydrodynamic and DEP forces allow the immuno-reaction on the designed chip. The subject of this thesis is divided into two topics related to the target of detection that is the dengue virus particle and recombinant dengue virus non-structural protein 1 (rNS1). I. Detection of dengue virus particle in vitro. The DEP force was employed to capture the modified beads (mouse anti-flavivirus monoclonal antibody-coated beads) flowing in the microfluidic chip and the DENV modified with fluorescence label, as the detection target, can be then captured on the modified beads by immunoreaction. The fluorescent signal obtained was then quantified by image processing software. The platform can accelerate an immuno-reaction time, in which the on-chip detection time was 5 min, and demonstrating an ability for DENV detection as low as 104 PFU/mL. II. Detection of recombinant dengue virus non-structural protein 1 (rNS1). In this part, the beads was immobilized by anti-NS1 specific antibodies (DN5C6 monoclonal antibody-immobilized beads) and the rNS1 was labeled by fluorescent probe via biotin-streptavidin binding, as the target detection. By immunoreaction mechanism allowed on the chip, the platform enables to quantify rNS1 based on fluorescence signal with a detection limit of 10 ng/mL within 10 min of on-chip detection time. Furthermore, the required volume of DENV and rNS1 samples used were reduced become ~15 µL, and the chip was reusable (>50x). Overall, this platform provides a rapid detection (5-10 min) with a low sample volume, compared to conventional methods. In summary, this proof of concept with regard to a microfluidic dielectrophoresis chip thus shows the potential of immunofluorescence based-assay applications to meet diagnostic needs.
論文目次 Abstract …………………………………………………… ii
中文摘要 …………………………………………………… iv
Acknowledgment …………………………………………… v
Table of Content ………………………………………… vii
List of Figures …………………………………………… x
List of Tables.. …………………………………………… xiii
Chapter 1 Introduction ………………………………… 1
1.1 Research Background …………………………… 1
1.1.1 The review of Diagnostic Technology ……… 1
1.1.2 Biosensor for Medical Diagnosis ……………. 5
1.1.3 Ideal Criteria for In Vitro Diagnostic (IVD)
Devices …………………………………………… 9
1.1.4 In Vitro Diagnostics (IVDs) Devices for
Dengue Infection …………………………………… 11
1.2 Motivation and Objective ………………………… 14
Chapter 2 Theories and Principles ……………………… 19
2.1 Dielectrophoresis ……………………………………… 19
2.1.1 Polarized particle ………………………………… 19
2.1.2 Dielectrophoresis on a polarized particle …… 21
2.1.3 Dielectrophoresis on a biological particle ……… 24
2.2 Microfluidic Technique ……………………………… 26
2.3 Microfluidic-integrated Dielectrophoresis Platform 27
Chapter 3 Application of The Microfluidic Dielectrophoresis
Platform for Detection of Dengue Virus Particle ……. 29
3.1 Introduction ……………………………………………… 29
3.2 Materials and Methods …………………………………… 32
3.2.1 Chip Design and Fabrication ………………………… 32
3.2.2 Anti-flavivirus Monoclonal Antibody (4G2)
Immobilization on Silica Beads ………………………… 36
3.2.3 Dengue Virus Labeling with Fluorescence Probe … 36
3.2.4 Chip Pretreatment and Sample Preparation ……… 38
3.2.5 Experimental Configuration …………………………. 39
3.2.6 Quantification of Fluorescence Intensity …… 41
3.3 Results and Discussion ………………………………… 44
3.3.1 Binding Affinity Evaluation of Mouse Anti-Flavivirus (4G2) Antibody Immobilized on Silica Beads …………. 44
3.3.2 Binding Affinity Evaluation of DENV Labelling with AF 488 Fluorescence Probe ………………………………………… 46
3.3.3 Chip Performance for Guiding and Capturing Samples47
3.3.4 DENV Detection Based on Fluorescence Intensity on A 3D Dielectrophoresis Microfluidic Chip ……………………. 51



Chapter 4 Application of The Microfluidic Dielectrophoresis
Platform for Detection of Recombinant Dengue Virus
Non-Structural Protein 1 (rNS1) …………………………… 57
4.1 Introduction ……………………………………………… 57
4.2 Materials and Methods …………………………………… 60
4.2.1 Preparation of DN5C6-immobilized Microbeads …… 60
4.2.2 Architecture and Working Principle of The Designed Chip ……. 60
4.2.3 Fluorescence Detection for Quantifying rNS1 Antigen ………… 61
4.3 Results and Discussion ………………………………………………. 63
4.3.1 Chip Performance on Guiding and Capturing
DN5C6-immobilized Microbeads ………………………………. 63
4.3.2 Evaluation of Binding Affinity Between rNS1 Labeling
with AF488 Fluorescence Probe ………………………… 64
4.3.3 rNS1 detection by using a 3D DEP microfluidic chip65
Chapter 5 Conclusions, Prospect and Future Work ........69
5.1 Conclusions …………………………………………… 69
5.2 Prospect ……………………………………………………. 70
5.3 Future Works ………………………………………………. 70
References ……………………………………………………… 73
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