本研究發展了一創新的液相分離微流體晶片，利用設計不同深度的管道結構創造足夠的毛細管作用力與液體表面張力之間差異，將兩不互溶且低表面張力液體達到近90%的分離效率，如:甲苯和水。此外，液滴式微流體系統擁有較多的雙液相界面，且藉由液滴內部持續循環的流場，有助於提供化學反應穩定且擴散均勻的液相混合，對於奈米粒子的合成有較佳的應用。因此，本研究開發之微流體晶片有效提升金奈米粒子(AuNPs)於雙液相合成，在T字型的管道中穩定控制還原劑(連續相)與金鹽甲苯溶液(分散相)的流速，便由連續片段的流體(Segmented flow)中合成出粒徑分布均勻的金奈米粒子，其粒徑尺寸相較於一般容器中所還原的粒徑小。利用液相分離微流體晶片，成功獲得簡易且高效率的方式收集金奈米粒子於甲苯溶液，減少粒子與過多還原劑反應而使粒徑持續成長。
本研究亦提出一種高靈敏度的多巴胺(DA)比色法檢測方式，由4-二甲氨基吡啶(DMAP)分子將甲苯中還原的金奈米粒子轉移到水相環境，再作為檢測樣品中多巴胺濃度的探針。實驗結果得知，經由相轉移的水相金奈米膠體加入多巴胺溶液後，金奈米粒子溶液會由原本珠紅色轉變為墨綠色，從吸收光譜亦可觀察到特徵吸收波峰發生藍位移(Blue shift)的情形。此外，由穿透式電子顯微鏡(TEM)更發現，原本溶液中存在粒徑13 nm的金奈米粒子被多巴鞍分子將核心蝕刻至粒徑約為2~5 nm，藉由粒徑的顯著變化來作為多巴胺生物樣品之檢測。本研究發展之DMAP-AuNPs探針對於多巴胺的檢測更擁有高靈敏度偵測極限(5 nM)，在常見的量測干擾物如:抗壞血酸(AA)、高香草酸(HVA)和鄰苯二酚(CA)等物質存在下，仍擁有良好的選擇性而不會對量測造成干擾。
然而，為了使金奈米粒子應用於生物檢測時，可獲得快速樣品反應且能夠即時的作量測，本研究最終整合其生醫檢測技術於微流體晶片之開發，以玻璃光纖作為樣品吸光度量測的訊號傳輸。本研究發展的光學量測感測器是將蝕刻後的多模光纖(Multimode optical fiber)導入晶片設計的管道中，待測樣品先由液滴式微流體系統達到均勻的混合，再注入晶片中的光學檢測微管道作即時吸收光譜量測。然而，利用光學量測感測器作為吸收光譜量測時，其消耗的樣品體積只需50 nL，相較於一般光譜檢測儀擁有相對微量的耗費。由實驗結果得知，液滴式微流體系統對於化學反應動力學擁有較快的反應速率，利用本研究發展的光學檢測微流體晶片，更可提供快速且連續動態的化學反應研究。由以上結果指出，本研究發展之液相分離微流體晶片，提供多樣性應用的潛力，有利於金奈米粒子的合成或作為液相樣品的萃取。此外，藉由整合簡易的光學量測系統，便可在微流體晶片中進行快速且連續的樣品檢測。因此，本研究發展之光學檢測微流體晶片與金奈米粒子生醫檢測技術，有助於未來開發高靈敏度且快速檢測的生醫感測器，以實際應用於生物、醫藥和病理等方面的分析與檢測，更有效的縮檢樣品之銷耗及檢測時間。

In the conventional sample extraction approach, to achieve efficient liquid-liquid phase separation for the sample analysis is an important issue. However, it is challenging to separate the immiscible liquid of low surface tension from water by using microfluidic device. Therefore, this study developed a microfluidic chip that composed of T-junction, reaction channel and a novel liquid-liquid phase separator for continuously synthesizing fine gold nanoparticles (AuNPs) in the organic solvent (toluene). The design of glass chip is capable for separating water (surface tension = 72.75 mN/m) and toluene (surface tension = 30.9 mN/m) with 92% separation efficiency, owing to design different depths of microchannel that creates large difference between liquid surface tension and capillary force. Furthermore, AuNPs that synthesized in the microdevice exhibits narrower size distribution and better dispersion in comparing to the typical vessel synthesis process.
Besides, this study successfully developed a novel and high performance colorimetric probe for dopamine (DA) detection. Aqueous-phase AuNPs extracted via 4-(dimethylamino) pyridine (DMAP) from toluene were used as the reaction probes. Interestingly finding that the original diameter of AuNPs around 13 nm which separated into 2-5 nm size after adding DA. This exhibits change in the color of AuNPs colloid from red to blackish green. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) showed the AuNPs break into the smaller sizes right after addition of DA. The DA concentration is quantitatively monitored by using UV-Vis spectrometer with a limit of detection (LOD) as low as 5 nM. In addition, the developed DA detection approach appears no significant problems in detecting DA with present common interferents such as ascorbic acid (AA), homovanillic acid (HVA) and catechol (CA).
However, many study reported that using microfluidic chip is capable to provide fast chemical reaction and rapid detection approach for biochemical analysis. This study developed a novel optical detection sensor by using the etched multi-mode optical fibers assembling in a droplet-based microfluidic system to achieve on-site absorbance measurement. Hence, the reaction of AuNPs detecting DA biosample was also capable to achieve rapid and continuously detection by using the microdevice. The proposed optical detection sensor composed by initially forming AuNPs droplet in segmented flow and measuring for sample absorbance in a 10 mm long of optical detection channel. Note that using the microdevice for absorbance measurement only required sample volume for 50 nL, which exhibits lower sample consumption in comparing to detect in the conventional cuvette system. Results indicated the developed microdevice capable for steady measuring sample absorbance with operating flow rate in the range from 5-25 μL/min. In addition, the detection approach shows faster reaction response for kinetic measurement of DA core etching AuNPs.
Therefore, this study successfully developed microfluidic chip to provide efficient liquid-liquid phase separation, which benefit to use for the sample extraction and synthesizing AuNPs of uniform size distribution in toluene. In addition, assembling optical fibers on the microfluidic chip that have offers simple and high performance optical detection to the bioanalysis. In this regard, the proposed microdevice with using AuNPs probes shows great potential to achieve high sensitivity detection for the future applying to such as biology, medical and clinic diagnostic applications.

論文審定書 i
Acknowledgements ii
中文摘要 iii
Abstract v
List of Figures x
List of Tables xv
Nomenclature xvi
Abbreviations xviii
Chapter 1 Introduction 1
1.1 Motivation and objectives 3
1.2 Thesis organization 5
Chapter 2 Background and literature reviews 9
2.1 Multiphase microfluidic systems 9
2.1.1 Microfluidic systems 9
2.1.2 Droplet-based microfluidic systems 10
2.1.3 Multiphase droplet formation in microfluidic systems 10
2.1.4 Segmented flow in microfluidic systems 12
2.1.5 Taylor circulation of the segmented flow 14
2.1.6 Different patterns of the segmented flow 16
2.2 Liquid-liquid phase separation 17
2.2.1 Liquid phase separation in microfluidic systems 17
2.2.2 Capillary force for liquid-liquid separation 18
2.3 Gold nanoparticles 20
2.3.1 Applications of gold nanoparticles 20
2.3.2 Gold nanoparticle synthesis in aqueous-phase 22
2.3.3 Gold nanoparticle synthesis in organic-phase 25
2.3.4 Gold nanoparticles phase transfer 26
2.3.5 Gold nanoparticle synthesis in microfluidic systems 29
2.3.6 Gold nanoparticles for colorimetric detection 32
2.3.7 Core etching technique for gold cluster formation 34
2.3.8 Gold nanoparticles for dopamine detection 36
2.4 Detection in microfluidic systems 38
2.4.1 Optical detection in microfluidic systems 38
2.4.2 Optical fiber-based detection in microfluidic systems 38
Chapter 3 Working principle and theory 40
3.1 Chip design for liquid-solvent separation 40
3.2 The working principle of using DMAP-AuNPs for DA detection 41
3.3 The design of optical detection sensor by using microfluidic chip 42
3.4 Absorbance detection theory 43
Chapter 4 Materials and methods 46
4.1 Experiment of AuNPs synthesis by using microfluidic chip 46
4.1.1 Reagents and apparatus 46
4.1.2 Microfluidic chip fabrication 47
4.1.3 AuNPs synthesis using typical vessel system 48
4.1.4 AuNPs synthesis using the microfluidic chip 49
4.2 The preparation of DMAP-AuNPs for DA detection 49
4.2.1 Reagents and apparatus 49
4.2.2 Preparation of the DMAP-AuNPs probes 51
4.2.3 Colorimetric detection of DA biosample 52
4.3 Optical detection sensor using microfluidic chip 53
4.3.1 Reagent and apparatus 53
4.3.2 Optical fibers assembling on the microdevice 54
4.3.3 Microfluidic chip fabrication 55
Chapter 5 Results and discussion 57
5.1 Liquid-solvent separation for synthesizing AuNPs in toluene 57
5.2 Core etching of DMAP-AuNPs for colorimetric DA detection 62
5.3 DA detection in microfluidic chip 69
Chapter 6 Conclusions and Future works 82
6.1 Conclusions 82
6.2 Future works 84
Reference 85

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