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系統識別號 U0026-0812200915284230
論文名稱(中文) 整合微混合器之微流體系統及其相關應用
論文名稱(英文) Microfluidic Systems Integrated with micromixers and Their Applications
校院名稱 成功大學
系所名稱(中) 工程科學系碩博士班
系所名稱(英) Department of Engineering Science
學年度 97
學期 2
出版年 98
研究生(中文) 楊松益
研究生(英文) Sung-Yi Yang
學號 n9895131
學位類別 博士
語文別 英文
論文頁數 92頁
口試委員 口試委員-楊瑞珍
口試委員-黎煥耀
口試委員-饒達仁
指導教授-李國賓
口試委員-林哲信
中文關鍵字 磁珠  微流體  生物微機電系統  流式細胞儀  微混合器  微幫浦  微閥門  奈米粒子  免疫分析 
英文關鍵字 flow cytometer  microvalve  microfluidic  nanoparticle  magnetic bead  immunoassay  Bio-MEMS  PDMS  micromixer  micropump 
學科別分類
中文摘要 近年來,由於微機電系統(Micro-electro-mechanical-system, MEMS)科技的迅速發展,並應用其各種創新之製程技術,可精密的製作出各式各樣的微型元件。將大型生化分析儀器縮小並整合至一微小的生物晶片中,可有效將進樣、反應、分離、偵測及分析等操作步驟整合於一微型晶片中,並具有晶片體積小、分析樣本需求少、反應時間快及頻率響應高、檢測精確度高等優點,再結合可大量批次製造之優點,因此可達到提升量測之靈敏度、減少生物試劑耗量及儀器成本的效果,進而達到晶片實驗 (Lab-on-a-chip, LOC)之目標,可使多種關鍵之微流體樣本之操控及偵測功能於單一實驗流程中完成。
在微流體處理技術中微混合器(Micromixer)是最重要的課題。微混合器通常可整合在微型全分析系統(Micro-total-analytical-system, -TAS)用於生物或化學的前處理上,如何能快速提高混合效能是非常重要在生物或化學領域。本研究提出兩種利用氣壓操控薄膜在反應槽中產生混合流場的主動式微混合器,分別是薄膜式微混合器及渦旋式微混合器。實驗中探討不同薄膜樣式設計及操控頻率對混合效率的影響,並利用數值模擬方式去驗証實驗的結果,其實驗結果秀出兩主動式微混合器可在短時間內達到高的混合效率,這兩種微混合器可成功的分別應用在生物樣品的前處理及奈米粒子合成。
依據上述所提到的薄膜式微混合器,本研究提出一種整合型微流體生醫晶片可達到快速自動化疾病檢測功能。利用微機電技術整合多個微元件於微流體晶片中,其用包含微幫浦、薄膜式微混合器、微閥門及微管道,可完成樣品傳輸混合、純化分離、聚焦偵測及分選功能。首先在磁珠表面接上特定的鍵結抗體,專一性的鍵結抗體只會與特定病毒鍵結,最後再與專一性的螢光抗體鍵結,形成一三明治免疫分析法,經螢光分析儀可在晶片上測得螢光抗體的螢光值。實驗結果可得到最小病毒偵測極限為103 PFU/mL,全程操作時間不超過40分鐘。本研究晶片之體積甚小,具有可攜式的優點,且晶片製作成本低廉,相當適合臨床上快速檢測。
依照上述所提到的渦旋式微混合器,本研究提出一種微流體反應晶片,其中包含一微幫浦、一被動式微閥門及一渦旋式微混合器,能自動化完成液體的傳輸及混合,可應用在合成不同尺寸的奈米粒子。其中,渦旋式微混合器可以在1秒內達到95%以上的高混合效率,使用微流體反應晶片於奈米金粒子合成的時間約13分鐘。實驗結果秀出,調整不同反應試劑體積可合成出不同尺寸的奈米粒子,其平均粒徑的分佈為19、28、37 和 58 nm,不同奈米金尺寸吸收波長分別是521、525、530 和 537 nm。未來利用此高效率的微流體反應晶片能合成出不同材質的奈米粒子,可分別應用在生物及化學領域上。
英文摘要 In recent years, a new technology called bio-micro-electro-mechanical-systems (Bio-MEMS), which combines knowledge from biology and micro-electro-mechanical-systems (MEMS), has attracted considerable interest and has been used to fabricate biochips with dimensions of several centimeters. Since MEMS techniques can mass-produce micro devices using low-cost materials such as glass and polymers, the unit cost of these biochips can be drastically reduced such that disposable chips to prevent cross-contamination become feasible. Bio-MEMS technology can be used to fabricate micro biochips with excellent analytical capability at a lower unit cost. When the size of a bio-analytical instrument is scaled down, it provides several advantages such as compactness of size, low sample/reagent consumption, fast reaction time, high precision, high sensitivity, portability, low power consumption, low unit cost, and the potential for automation and integration. The idea of a lab-on-a-chip (LOC) can be achieved when several microfluidic components are integrated onto one single biochip.
Micromixers are commonly employed for chemical or biological analysis in micro-total-analysis-system (μ-TAS) applications. Micromixers make rapid and efficient chemical or biological reactions possible, and mixing performance is an important parameter for evaluating their performance. In this study, two new active micromixers, membrane-type and vortex-type micromixers, which utilize pneumatically-driven membranes to generate mixing flow in a mixing chamber, are reported. The micromixer chip is fabricated using MEMS technology as well as a computer numerical controlled (CNC) machining process for rapid prototyping. Two different membrane layouts and driving frequencies are evaluated to determine if there is a significant improvement in the mixing performance. Furthermore, numerical simulations are also employed to characterize the mixing flow field, the concentration distribution, and the mixing mechanism. The membrane-type and vortex-type micromixers are then used for viral sample purification and synthesis of the nanoparticles, respectively.
Two important applications of these micromixers are then reported. First, a new miniature microfluidic flow cytometer integrated with several functional microdevices that are capable of viral sample purification and detection by utilizing a magnetic bead-based immunoassay was first demonstrated. The magnetic beads are conjugated with specific antibodies, which can recognize and capture target viruses. Another dye-labeled anti-virus antibody is then used to mark the bead-bound virus for subsequent optical detection. Several essential components are integrated onto a single chip, such as a sample incubation module, a microflow cytometry module, and an optical detection module. The sample incubation module consisting of pneumatic micropumps and a membrane-type active micromixer are used for purifying and enriching the target virus-bound magnetic beads with the aid of a permanent magnet. The microflow cytometry module and optical detection module are used to perform the functions of virus counting and collection. Experimental results show that virus samples with a concentration of 103 PFU/ml can be automatically detected successfully by using the developed system. In addition, the entire diagnosis procedure including sample incubation and virus detection takes only approximately 40 minutes. Consequently, the proposed microflow cytometry system may potentially provide a powerful platform for rapid diagnosis and future biological applications.
Then, a new microfluidic reaction chip that is capable of mixing, transporting, and controlling reactions is demonstrated. This micromixer is developed for the size-tunable synthesis of gold nanoparticles. This chip allows for an accelerated and efficient approach for the synthesis of gold nanoparticles. The microfluidic reaction chip is manufactured by CNC machining and polydimethylsiloxane (PDMS) casting processes that integrate a micromixer, a normally-closed valve, and a micropump onto a single chip. The micromixer is capable of generating a vortex-type flow field that achieves a mixing efficiency as high as 95% within 1 second. Successful synthesis of dispersed gold nanoparticles has been demonstrated within an 83% shorter period of time (13 minutes) as compared to traditional methods (around 2 hours). Dispersed gold nanoparticles of average diameters of 19, 28, 37, and 58 nm are obtained by using different volumes of reagents. The optical absorption spectra indicate that these synthesized nanoparticles have different surface plasmon resonance (SPR) peaks—521, 525, 530, and 537 nm, respectively. The development of such a microfluidic reaction system is promising for the synthesis of functional nanoparticles for more biomedical applications.
論文目次 Abstract I
中 文 摘 要 IV
誌 謝 VI
Table of Contents VIII
List of Figures X
Nomenclature XV
Chapter 1
Introduction 1
1.1 MEMS technology for biological applications 1
1.2 Active micromixers 3
1.3 Microflow cytometry 5
1.4 Nanoparticle synthesis for biological applications 8
1.5 Motivation and objectives 9
Chapter 2
Design and theory of active micromixers 12
2.1 Membrane-type micromixer 12
2.1.1 Materials and methods 12
2.1.2 Experimental setup 14
2.1.3 Mixing performance 15
2.2 Vortex-type micromixer 18
2.2.1 Materials and methods 18
2.2.2 Numerical simulation 20
2.2.3 Flow field inside the mixing chamber 21
2.2.4 Mixing performance of two and four operating modes 26
Chapter 3
Microflow cytometry system with membrane-type micromixer for rapid virus detection 33
3.1 Introduction 33
3.2 Design and fabrication 36
3.2.1 Design 36
3.2.2 Fabrication 45
3.3 Experimental procedure 46
3.4 Results and discussion 49
3.4.1 Characterization of micropumps and microvalves 49
3.4.2 Variable hydrodynamic focusing effect 51
3.4.3 Characterization of membrane-type micromixer 53
3.4.4 Virus detection 54
Chapter 4
Size-controlled synthesis of gold nanoparticles using a vortex-type micromixer system 58
4.1 Introduction 58
4.2 Design and fabrication 60
4.2.1 Design 60
4.2.2 Fabrication 63
4.3 Experimental section 65
4.4 Results and discussion 68
4.4.1 Characterization of the micropumps and microvalves 68
4.4.2 Synthesis of gold nanoparticles 69
Chapter 5
Conclusions and future perspective 73
5.1 Overview of the dissertation 73
5.2 Future work 74
References 76
個 人 簡 歷 89
發 表 著 作 90
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