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系統識別號 U0026-0812200915285548
論文名稱(中文) 光介電泳晶片於生醫系統之應用
論文名稱(英文) Optically-induced dielectrophoresis chip for biomedical 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) 林彥亨
研究生(英文) Yen-Heng Lin
學號 n9895124
學位類別 博士
語文別 英文
論文頁數 76頁
口試委員 召集委員-楊瑞珍
口試委員-黎煥耀
口試委員-林哲信
口試委員-饒達仁
指導教授-李國賓
中文關鍵字 流式細胞儀  去氧核糖核酸操控  穿膜電壓  細胞胞解  光介電泳 
英文關鍵字 DNA manipulation  transmembrane potential  cell lysis  flow cytometry  optically-induced dielectrophoresis 
學科別分類
中文摘要 近二十年來,由於微流體系統在多種領域的應用,有其無可取代的特性,因此越來越多相關的研究被發表出來,其中對於生化樣品的處理,微粒子的操控扮演了相當關鍵的角色。近幾年來,光介電泳平台已被提出且應用於微粒子的操控,其最大的優勢在於僅需使用市售投影機投射出來的圖形,就可以操控微粒子。然而,利用此一平台所開發的生醫應用,目前為止數量尚不多。因此,本論文開發了數種以光介電泳平台實現的生醫系統及元件,如:微型細胞儀、細胞胞解元件及去氧核醣核酸單分子操控平台。
第一個系統為利用光介電泳的方式實現的細胞儀,它可以達到連續計數及分選微粒子的功能。系統首先利用市售的投影機產生所謂的”虛擬電極”,成功的將微粒子聚集在流道中央。之後利用晶片中的光纖偵測系統來計數及分辨粒子大小。利用9.7及20.9微米的粒子來測試,光纖偵測到的訊號大小分別為63.67及8.80個單位,其變異係數各為7.46及25.57%。因此,不同大小的微粒子,成功的被計數及分辨出來。在晶片的下游則有一個利用光介電泳形成的動態分選裝置,可以將不同大小的微粒子分選到不同的管道中。相較於傳統細胞儀,其具有降低邊削流污染樣品的風險,且不需複雜的微影製程製作產生介電泳力的電極。
第二個元件為一種利用光誘發之細胞胞解裝置,其主要特色為利用投影機打出之光點,可以選擇性的從一群細胞中只胞解其中一顆細胞並可依序胞解,這是以往細胞胞解工具所難以達到的功能。這種晶片大小的裝置是利用光導材料沈積在晶片上,再利用投影系統控制光點的位置,只要是光導材料被光點照射到的位置就會引發非均勻電場,這個電場會在細胞上引發穿膜電壓,當穿膜電壓大到一定程度後,就會引發細胞胞解,此過程為一不可逆反應。兩種細胞包含纖維母細胞及口腔癌細胞被用來證明元件的胞解能力。此元件除了可將整顆細胞(細胞膜、細胞核)打破外,還可選擇性的只打破細胞膜而不打破細胞核。此外,利用光來控制胞解時間的連續式細胞胞解裝置,亦被本研究開發出來。
最後,本論文成功地利用光介電泳平台達成單分子去氧核醣核酸的操控,單分子去氧核醣核酸一端固定在晶片上,另一端固定在微粒子上,因此,單分子去氧核醣核酸可間接的因為微粒子被投射在晶片上的電腦動畫操控而拉伸甚至旋轉。由於實驗進行在螢光及抗氧化系統之中,因此去氧核醣核酸的操控影像可被及時的呈現。利用10.1微米的粒子可產生最大的操控力為51.5微微牛頓,實驗數據顯示拉伸力量與拉伸長度的關係曲線與worm-like chain模型吻合。本平台對於未來單分子操控的應用,可成為一種極方便且大有可為的工具。
英文摘要 In the past two decades, microfabrication of miniature fluidic devices has attracted considerable interest since they have some unique merits when utilizing them in various fields. Among them, manipulation of micro-particles and cells in the microfluidic devices is a crucial technique for bio-samples treatment. Over the past few years, optically-induced dielectrophoresis (ODEP) has been proposed and adopted to investigate the manipulation of micro-particles and cells. The advantages of using this method are that the micro-particles and cells can be controlled just through optical images generated from a commercially available projector. Furthermore, there are still many biomedical applications that can be developed through this useful platform. In the dissertation, several kinds of biomedical devices by using this ODEP approach have been demonstrated, including a micro flow cytometer, a cell lysis device, and manipulation of single DNA molecules.
The first developed application is an optically-induced flow cytometry. This enables it to continuously count and to sort microparticles based on ODEP forces. The particles were first focused inside a sample channel by the ODEP forces and then passed through a detection region. A pair of optical fibers were embedded into fiber channels to count the number of particles and analyze the particle size in real time. Using 20.9 and 9.7-μm polystyrene microparticles, the average light intensity were about 63.67 and 8.80 units, with a coefficient-of-variation (CV) of 7.46 and 25.57%, respectively. This demonstrated that these two particle sizes could be successfully distinguished. After detecting the number and size of the micro-particles, an optically-induced dynamic switch was successfully used to sort the micro-particles to downstream fluidic outlets.
The second device is an optically-induced cell lysis device which can selectively lyse a single cell within a group of cells, a function which cannot be performed using traditional tools. This chip-scale device can induce a non-uniform electric field at a specific position under illumination of a beam spot generating a trans-membrane potential in the cell. With this approach, cell lysis can be performed using the optically-induced electric field. Fibroblast cells and oral cancer cells were used to demonstrate the capability of the developed chip. In addition to lysing the whole cell, the developed method also allowed one to selectively disrupt the cell membrane without damaging the nucleus. Besides, a continuous cell lysis device achieved by using time-controllable optical images was also presented.
Finally, a new platform for manipulating a single DNA molecule based on ODEP was presented. The ends of a single DNA molecule were bound with a micro-bead, which was then manipulated by interactions with optical patterns. Thus a single DNA molecule was indirectly manipulated by a projected animation pre-programmed using computer software. Real-time observation of the manipulation process was made possible by using a fluorescent dye and an oxygen scavenging buffer. Two types of DNA manipulation modes, specifically DNA elongation and rotation, were successfully demonstrated and were characterized. The maximum stretching force can be as high as 51.5 pN for a 10.1 μm bead. Experimental data showed that the force-extension curve measured using this platform fitted reasonably with the worm-like chain model. The developed platform can be a promising and flexible tool for further applications requiring single molecule manipulation.
In summary, we demonstrated several new biomedical applications of the ODEP platform. It may provide a powerful tool for cell and DNA studies.
論文目次 Chapter 1
Introduction
1.1. Introduction of tools for micro-particle manipulation…………………………………1
1.2. Dielectrophoresis (DEP)………………………………………………………………2
1.3. Optically-induced dielectrophoresis (ODEP)…………………………………4
1.4. Motivation and objectives……………………………………………………………5

Chapter 2
Operating principle of the optically-induced dielectrophoresis
2.1. Amorphous silicon as a photoconductive material……………………………………9
2.2. Working principle of the ODEP chip………………………………………………9
2.3. Structures of the ODEP chip…………………………………………………………11
2.4. ODEP chip fabrication………………………………………………………………11

Chapter 3
Optically-induced microflow cytometer
3.1. Introduction…………………………………………………………………………13
3.2. Materials and methods………………………………………………………………16
3.2.1. Chip design and theory……………………………………………………………17
3.2.2. Chip fabrication……………………………………………………………………19
3.2.3. Optical fiber insertion………………………………………………………………20
3.2.4. Experimental setup…………………………………………………………………22
3.2.5. Sample preparation…………………………………………………………………23
3.3. Results and discussion………………………………………………………………23
3.3.1. ODEP for particle focusing………………………………………………………24
3.3.2. Counting and analysis of particles…………………………………………………25
3.3.3. ODEP for particle sorting…………………………………………………………28

Chapter 4
Optically-induced cell lysis device
4.1. Introduction…………………………………………………………………………31
4.2. Materials and methods………………………………………………………………32
4.2.1. Principle of electrical cell lysis……………………………………………………32
4.2.2. Experimental setup…………………………………………………………………33
4.2.3. Sample preparation…………………………………………………………………34
4.3. Results and discussion………………………………………………………………35
4.3.1. Individual and sequential cell lysis using an optical image………………………35
4.3.2. Disruption of a cell membrane without damaging the nucleus…………………38
4.3.3. Effects of illumination power density and size of light spot……………………40
4.4. Continuous cell lysis device using time-controllable optical images………………41

Chapter 5
A new platform for stretching a single DNA molecule using an optical image
5.1. Introduction…………………………………………………………………………45
5.2. Materials and methods………………………………………………………………47
5.2.1. Chip design………………………………………………………………………..47
5.2.2. Sample preparation………………………………………………………………49
5.2.3. Experimental setup………………………………………………………………51
5.3. Results and discussion………………………………………………………………52
5.3.1. Stretching DNA by fine-tuning the magnitude of the ODEP force…………………53
5.3.2. Stretching and manipulating DNA using an optical image……………………55
5.3.3. Characterization of the ODEP forces for DNA extension…………………58

Chapter 6
Conclusions and future works
6.1. Conclusions……………………………………………………………………62
6.2. Future works……………………………………………………………………64

References………………………………………………………………………………66
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