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研究生:謝宗閔
研究生(外文):Tsung-Min Hsieh
論文名稱:提高熱均勻性之微小型熱循環晶片於核酸增幅之應用
論文名稱(外文):Micro Thermocyclers for Nucleic Acid Amplification with High Thermal Uniformity
指導教授:李國賓李國賓引用關係羅錦興羅錦興引用關係
指導教授(外文):Gwo-Bin LeeChing-Hsing Luo
學位類別:博士
校院名稱:國立成功大學
系所名稱:電機工程學系碩博士班
學門:工程學門
學類:電資工程學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:87
中文關鍵詞:陣列型加熱器反轉錄聚合酶連鎖反應微型反應器聚合酶連鎖反應微機電系統.自補償溫度均勻性
外文關鍵詞:self-compensationPCRmicro reactorstemperature uniformityarray-type heatersRT-PCRMEMS.
相關次數:
  • 被引用被引用:0
  • 點閱點閱:150
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  • 下載下載:48
  • 收藏至我的研究室書目清單書目收藏:0
生醫儀器微型化是現今一個重要的趨勢。也因此,本研究發展了一台微小型晶片核酸複製系統,不但具備有微小型溫度循環加熱系統的各項優勢,包含了小尺寸、低功率消耗、高升降溫速率以及可攜帶性,並經由微加熱晶片的改良,使得微小區域上的熱均勻性大幅提高,進而使該晶片型儀器之核酸複製的效能大幅地提升。
在本研究初步的測試中,先藉由方塊型微型加熱器以及電阻溫度感測器製作出一微型熱循環晶片,而後配合迴授控制和脈波寬度調變的技術,成功的實現聚合酶連鎖反應的熱循環機制並以沙門氏菌驗證了系統的可行性。其次,本研究中發展了兩種在晶片上提高溫度均勻性的新方法,用來增加DNA複製效率以及減少非專一性的產物。第一種方法是,首次發展出來之全新的陣列式薄膜加熱器並應用於此系統上。這種加熱器有近似於方塊型微型加熱器的低阻抗值並能同時提高特定區域上的熱均勻性。另外,搭配主動補償加熱器的設計也同時減少了來自外界的溫度場干擾。這樣的一個晶片型核酸複製系統已成功發展並以S. pneumoniae完成了系統複製效率的測試後,證實當晶片上熱均勻性提高時,DNA複製效率確有明顯之提升。
在第二種設計中,我們成功的發展了一種自補償的陣列型薄膜微型加熱器,此設計使特定區域上的溫度均勻型大幅提高,且不需要任何的額外控制電路、或是複雜的製程。這種加熱器的設計在薄膜加熱器上是一種真正二維的熱補償設計。藉由熱相儀拍攝而得的實驗結果,證實了在晶片的特定區域上,若以攝氏1度的熱變化量為基準實際量測變化量小於攝氏1度的加熱面積比例,分別在設定為94�aC, 55�aC 以及 72�aC時,擁有90.3%,99.9%以及96.8%的高比值。這台熱均勻性被大幅改善的晶片型核酸複製系統以登革熱第二型病毒來測試後,其複製效率明顯較未經過自補償的系統來的高。這種加熱器的設計概念,將可以促使在微小區域下需要精準溫度的反應系統,提供了一種有效大幅提高熱均勻性的設計方式。藉此,本研究實現了一提高了熱均勻性之微型晶片核酸複製系統,一方面符合了微小型生醫儀器之概念,也期望將能有助於今後在微全分析系統以及微型晶片實驗室上的研發,使得微機電系統所製作的元件,能夠在熱均勻性提高的情況下有著更高的效能。
The trend of miniaturization of biomedical instruments began in the last century, and is crucial for furthering progress in medical technology. In this study, an integrated chip–PCR/RT-PCR system is implemented successfully, meeting the requirements for use in miniature thermocyclers – small in size, low power consumption, high heating and cooling rates, and even portability, with resistance temperature detectors and thin-film micro-heaters. Furthermore, due to the modifications made to the micro thermocycler, the thermal uniformity of a specific region has been greatly enhanced, improving the performance of the micro device.
The initial approach of this study was to develop a block-type thin-film micro-heater and resistance temperature detectors on a glass substrate to form a micro thermocycler. Based on the techniques of feedback control and pulse width modulation, PCR thermal cycling was achieved, and the system was tested using Salmonella, with successful results. Two new approaches were then implemented and applied to increase DNA amplification efficiency and reduce non-specific PCR products. In order to achieve these aims, first, a novel kind of micro thin-film heater, an array-type micro-heater, was designed and developed. The main advantages of array-type micro-heaters are their lower resistance as compared with block-type heaters and their provision of greater thermal uniformity with a uniform heating density. Active compensating units were also added and applied in order to reduce the edge-effect, i.e., thermal loss from the edges. From these array-type micro-heaters and active compensating units, a miniature thermocycler with enhanced thermal uniformity was developed and the success of its performance verified with S. pneumoniae.
The second approach was the design of a novel self-compensating array-type micro-heater. This kind of micro thin-film heater not only increases the thermal uniformity in the specific heating area, but also eliminates additional control themes on thermal compensating. Based on self-compensating array-type micro-heaters, this device is of a fully two-dimensional thermal compensating design used in thin-film heaters. Experimental results from infrared images showed that the percentage of the uniformity area with a thermal variation of less than 1�aC was 90.3%, 99.9% and 96.8% at PCR thermocycling temperatures of 94�aC, 55�aC and 72�aC, respectively, which represents a significant improvement over conventional block-type or serpentine-shaped micro-heaters. The performance of the chip–PCR system based on self-compensating array-type micro-heaters was assessed by amplifying a detection gene (171bp) associated with the dengue virus serotype 2, the results of which were successful, the amplification efficiency having been found to be statistically greater than that of other micro-heaters without a self-compensation function. The micro-heater proposed in this study was based on the aim of finding an efficient approach to greatly improve the thermal uniformity of a specific micro area requiring precise thermal conditions, and a micro thermocycler for nucleic acid amplification with high thermal uniformity was developed. This system not only satisfies the requirements of micro biomedical devices, but could be also useful in the design of a micro-total-analysis-system and a lab-on-a-chip, which require high thermal uniformity in order to improve the performance of the miniature devices.
摘要 i
Abstract iii
致謝 vi
Table of Contents viii
List of Tables xi
List of Figures xii
Nomenclatures xix
CHAPTER 1 INTRODUCTION 1
1.1 Approach to the development of a chip-based PCR/RT-PCR device 1
1.2 Background and literature survey 3
1.3 Motivation and objectives 8
CHAPTER 2 THEORY, DESIGN AND FABRICATION 10
2.1 Nucleic acid amplification 10
2.1.1 Polymerase chain reaction 10
2.1.2 Reverse-transcript polymerase chain reaction 11
2.2 Micro sensing/heating elements 13
2.2.1 Resistance temperature detectors 13
2.2.2 Thin-film heaters 14
2.3 Design of micro-heaters 15
2.3.1 Block-type micro-heaters 15
2.3.2 Serpentine-shaped micro-heaters 16
2.3.3 Active-compensation array-type micro-heaters 16
2.3.4 Design of self-compensating array-type micro-heaters 18
2.4 Fabrication process 23
2.4.1 Fabrication process overview for micro thermocyclers 23
2.4.2 Cleaning of the glass substrate 24
2.4.3 Deposition and patterning of the heating elements and micro temperature sensors 24
2.4.4 Bonding of isolation layers 26
2.4.5 PDMS casting technique 26
CHAPTER 3 EXPERIMENTAL SETUP AND MEASUREMENT 27
3.1 Temperature control system 27
3.2 Implementation process of the proposed temperature control system 27
3.2.1 Chip–PCR thermocycling control system 27
3.2.2 Active-compensation PCR control system 30
3.2.3 Self-compensation PCR control system 31
3.3 Sintering process of the temperature sensor 32
3.4 Calibration process 33
3.5 Sample preparation 34
3.5.1 PCR reagents of S. pneumoniae 34
3.5.2 RT-PCR sample preparation and protocols 35
3.6 Measurement techniques and instruments 36
3.6.1 Infrared imaging 37
3.6.2 Electrophoresis and slab gel electropherograms 37
CHAPTER 4 RESULTS AND DISCUSSION 39
4.1 The portable miniature chip–PCR system 39
4.1.1 Characteristics of the proposed system 39
4.1.2 Power consumption measurements and thermocycling 43
4.1.3 PCR verification 46
4.2 Active-compensated micro PCR device 47
4.2.1 Thermal conditions without heat sink 47
4.2.2 Thermal conditions with heat sink 51
4.2.3 PCR verification 54
4.3 Self-compensated micro PCR/RT-PCR device 57
4.3.1 Optimization of array-type heaters 57
4.3.2 Exploration of the self-compensation factor 61
4.3.3 Comparison of different kinds of micro-heater 64
4.3.4 RT-PCR verification 68
4.4 Comparison of micro-heater designs 70
CHAPTER 5 CONCLUSIONS 72
5.1 Overview of this dissertation 72
5.2 Future work 74
REFERENCES 76
PUBLICATIONS LIST 84
Journal papers: 84
Conference papers: 85
BIOGRAPHY 87
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