黃榮山臺灣大學：應用力學研究所洪嘉明Hung, Chia-MingChia-MingHung2007-11-292018-06-292007-11-292018-06-292006http://ntur.lib.ntu.edu.tw//handle/246246/62423近年來在生物科技領域中，由於生物科技與工程技術的跨領域整合，生物分子感測技術(bio-molecule assay technology)正以相當快的速度發展。過去的醫學檢驗設備由於其昂貴、笨重、不易使用和速度緩慢的缺點，而逐漸被新型的生物親合型生物感測器(bioaffinity-based biosensor)所取代。 由生物體內的免疫系統所產生的抗體(antibody)，針對其特定的抗原(antigen)有極高的辨識性及專一性，用於生物分子檢測時可以提高辨識的靈敏度並減少誤判的情況。利用此技術發展出的生物感測器(biosensor)，擁有快速、便宜、容易使用和可用於即時監測之優點，可以應用於環境監控、慢性疾病之監控和治療、突發性急性疾病之診斷。 本論文研究，對於壓阻材料之電子特性與微懸臂梁結構進行了詳細的分析並利用微機電(Micro-Electro-Mechanical System, MEMS)技術與半導體離子植佈(ion implantation)技術開發出可偵測奈米級變形量的壓阻式微懸臂梁生物感測器。特定生物分子進行專一性鍵結(specific binding)時所引入的表面應力將藉由架構在惠斯通電橋(Wheatstone bridge)電路上的壓阻式微懸臂梁轉換成電壓訊號。此外，本研究中亦針對微流體系統(micro-fluid system)及信號調理系統(signal conditioning system)進行了分析與製作，並提出嶄新的封裝方式將微流體及信號處理系統進一步整合，使此系統具有可微小化、可攜帶、可量產、可拋棄、價格便宜及容易使用之優點。 在結果中，本研究除了利用了原子力顯微鏡(atomic force microscope)對壓阻式微懸臂梁生物感測系統之機械、電子特性進行詳細的分析，也利用了免疫球蛋白及其抗體(IgG and anti-IgG)驗證了其對於量測生物分子鍵結反應之能力。 總結，本研究中所製作出的壓阻式微懸臂梁生物感測系統已展現其廣泛之應用性，且進一步可相容於半導體製程以及向下整合無線感測裝置(wireless sensor networks)而達到晶片系統(system on chip, SOC)的目標。Portable, miniaturized biomedical devices for on-site diagnosis and prognosis of diseases are recently becoming a great interest in bio-, nano- or micro-engineering research. The integrated biomolecular detection system was developed, which consists of micro-fabricated piezoresistive microcantilever-based sensor, micro-fluidic package, and electrical readout platform. This work has shown the device performance of converting the biomolecular recognition into a direct nanomechanical response of microfabricated cantilever beams. With the bottom-up assembly technology of biomolecule functionality and the top-down device microfabrication technology, the nanomechanics-based transduction establishes a biosensor platform in real-time, label-free, and quantitative analysis on biomolecular recognition and interaction. The piezoresistance is one of the key of the electrical sensing of microcantilever beams, which was characterized by using the atomic force microscope (AFM). The gauge factor is obtained with approximate 22.25. The result of the microcantilever sensitivity was measured to be 8.862×10-7 nm-1, which presents a superior feature capable of probing a minute concentration of biomolecules. The result of biofilm-induced surface stress and thus converted electrical signal corresponding to biomolecular adsorption and protein-bound conformation change on the cantilever surface has been successfully measured.Abstract I 摘 要 II 謝 誌 III CONTENTS IV LIST OF FIGURE VIII LIST OF TABLE XIV NOMENCLATURES XVI CHAPTER 1 INTRODUCTION 1 1-1 Motivation and Innovation 1 1-1-1 Biosensors applications 1 1-1-2 Overview of bio-analytical tools 3 1-2 Literature survey for mechanical-based micro-cantilever biosensor 5 1-2-1 Literature survey for micro-cantilever biosensor 5 1-2-2 Literature survey for piezoresistive micro-cantilever biosensor 8 1-3 Thesis Organization 10 1-4 Chapter overview 11 CHAPTER 2 BIOSENSOR TECHNOLOGY 13 2-1 Basic working principle of biosensors 13 2-2 Classification of biosensors 15 2-3 Biomolecular recognition 20 2-3-1 Mechanics of biomolecular recognition 20 2-3-2 Introduction of antibodies 23 2-3-3 Interaction of antibodies with specific antigens 27 2-4 Nanomechanical-based microcantilever biosensor 28 2-4-1 Microcantilever-based transduction principle 29 2-4-2 Cantilever deflection detection techniques 31 CHAPTER 3 ANALYSIS, DESIGN, AND FABRICATION OF PIEZORESISTIVE CANTILEVER BIOSENSOR 34 3-1 Introduction of piezoresistive effect 34 3-2 Properties of semiconducting material 36 3-2-1 Resistivity in polycrystalline silicon 36 3-2-2 Relation between Boron ion implantation Silicon and carrier properties 37 3-3 Piezoresistive effect 40 3-4 Bending of piezoresistive micro-cantilever induced by surface stress 43 3-4-1 Resistance change of the single layer piezoresistive cantilever 43 3-4-2 Resistance change of the composite piezoresistive cantilever beam 47 3-5 Noise in piezoresistive micro-cantilever 50 3-5-1 Mechanical noise in piezoresistive cantilever 50 3-5-2 Electric noise in piezoresistive cantilever 51 3-6 Wheatstone bridge for piezoresistive micro-cantilever 53 3-7 Design and fabrication of piezoresistive cantilever biosensor 56 3-7-1 Design criterions of piezoresistive bio-cantilever 56 3-7-1-1 Considerations of the piezoresistive effect and the electrical noise 57 3-7-1-2 Considerations of the mechanical properties of piezoresistive cantilever and the MEMS process 61 3-7-2 Fabrication of piezoresistive bio-cantilever 62 CHAPTER 4 DESIGN, FABRICATION, AND INTEGRATION OF BIOSENSOR SYSTEM 68 4-1 Design and fabrication of the micro-fluid system 68 4-1-1 Design of microfluid system 68 4-1-2 Fabrication of micro-fluid system 70 4-2 Design and layout of the electronic system 74 4-2-1 Design criteria for electronic system 74 4-2-2 Selection of instrumentation amplifier 75 4-2-3 Signal conditioning techniques 77 4-2-4 Layouts of disposable sensor and electronic system 86 4-3 Procedures for assembly 91 4-4 Set-up of the biosensor system 93 CHAPTER 5 RESULT AND DISCUSSION 96 5-1 MEMS process result 96 5-1-1 150-nm PECVD nitride as top insulating layer 96 5-1-2 200-nm Cr as the releasing hard mask 98 5-1-3 300-nm PECVD nitride as top insulating layer 100 5-2 Device Characterization 103 5-2-1 Gauge factor measurement 103 5-2-2 Noise and circuit analysis 112 5-2-3 Specification of the sensor system 114 5-3 Bio-recognition experiment 116 5-3-1 Immobilization and bio-recognizing experiment 116 5-3-2 Baseline drift and calibration 119 5-3-3 Result of Bio-recognizing between IgG1 and anti-IgG1 121 CHAPTER 6 CONCLUSION AND FUTURE WORK 126 6-1 Conclusion 126 6-2 Future works 128 REFERENCES 1296607496 bytesapplication/pdfen-US壓阻效應壓阻式微懸臂粱生物感測器系統微機電製程Piezoresistive EffectPiezoresistive MicrocantileverBiosensor SystemMEMS Fabricationthesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/62423/1/ntu-95-R93543079-1.pdf