臺灣博碩士論文加值系統

以目前生醫檢測系統來說，其高成本、檢測時間長、佔空間與無法符合即時監測為主要的缺點。而隨著生物奈米技術的快速發展，生物感測工具的設計與發展必須趨向於微小化、高靈敏度、可攜帶式以及可無線傳輸功能等。
而市面上使用的微生化感測器大多利用化學方法或螢光標定進行檢測，且須架設光場，來進行檢測，本研究將以力學為基礎發展壓阻式微懸臂梁感測器(Piezoresistive micro-cantilever biosensor)進行生物檢測，以取代化學與螢光標定之檢測方法。但因光源不易聚焦於微懸臂梁上，檢測出來的訊號易產生極大誤差；本文擬以壓阻式微懸臂梁檢測方式取代傳統光學檢測。藉由壓阻式微懸臂梁建構在惠斯登電橋電路(Wheatstone bridge circuit)上作為轉換機制，先將生物與化學的反應過程轉換為奈米力學的變形運動，此變形經過壓阻效應可轉換成電壓訊號。當生物分子在壓阻式微懸臂梁生物晶片的表面結合時，會引入表面應力使其彎曲，約在數十個奈米左右，藉由電阻的改變而傳出訊號，經放大電路放大訊號。再經無線傳輸系統單晶片將訊號傳出到電腦分析，以達到遠端即時診斷的目的。
在本研究中已成功的利用微機電製程製作出壓阻式微臂梁生物感測器，經由無線傳輸的方式量測出自組裝分子(bio-linker)與抗體(Anti-CRP)的訊號。而以壓阻式微懸臂梁生物感測器之架構具有微小化、低成本、高功能性、高效率與可攜式的優點。未來將可繼續朝向系統晶片(System-on-chip)設計與無線感測的目標繼續往前邁進。

Bio-sensing tools have been moving towards miniaturization, high sensitivity, portability and wireless networking. While fluorescent labeling of nucleic acids is becoming a standard procedure, protein labeling techniques are not yet as well established. The purpose of this paper is to demonstrate a novel reusable biosensor which achieves the continuous label-free recognition of biological substances in real-time, which based on the nanomechanics of a piezoresistive microcantilever.
Over the past few years, an increasingly evident number of studies have been conducted on using the microcantilevers as transducers in biochemical-sensing systems. In principle, adsorption of biochemical species on a functionalized surface of a micro-cantilever will cause bio-induced surface stress and accordingly the cantilever bends. We used this technique in the immunoassay.
A microcantilever based biosensor with piezoresistive has been developed using surface micromachining technique in this paper, which is cost effective, miniaturized and high applicability. This provides a novel method to detect bio-molecules which is due to molecule binding induced cantilever deflection. We have demonstration of wireless real-time label-free detection of bio-linker and anti-CRP antibody, the signal was successfully detected by using piezoresistive cantilever biosensor. The tendency of cantilever deflection is agreement with optical-based cantilever detection. In the future, the piezoresistive cantilever biosensor will offer a powerful plateform for high-throughput bioassays in proteomics and immunology.

謝誌 i
中文摘要 iii
Abstract iv
目錄 v
圖表目錄 viii
表格目錄 xi
符號目錄 xii
第一章 緒論 1
1-1前言 1
1-2研究動機及目的 3
1-3文獻回顧 6
1-3-1微懸臂梁感測器於生物分子辨識分析之發展背景 6
1-3-2壓阻式微懸臂梁之發展背景 9
1-4研究方法 12
1-5論文架構 13
第二章 生物感測器 15
2-1生物感測器之基本工作原理 15
2-1-1生物感測器之分類 16
2-1-2生物分子之辨識 19
2-1-3抗原與抗體之特異性鍵結 22
2-1-4生物分子間之親和力作用 23
2-2微懸臂梁生物感測器之轉能機制 24
2-2-1共振式微型懸臂梁感測器 25
2-2-2溫度效應式微型懸臂梁感測器 27
2-2-3表面應力變化式微型懸臂梁感測器 29
2-3懸臂梁生物感測器之彎曲機制 30
第三章 壓阻式微懸臂梁生物感測器 33
3-1壓阻式微懸臂梁生物感測器之工作原理 33
3-2壓阻特性 34
3-3壓阻式懸臂梁之表面應力靈敏度 37
3-4惠斯登電橋電路之設計原理 39
第四章 壓阻式微懸臂梁生物感測器之設計與製作 42
4-1微懸臂梁生物感測器之壓阻設計 43
4-2微懸臂梁生物感測器之系統規格設計 47
4-3微懸臂梁生物感測器之製作 50
4-3-1材料之選用 51
4-3-2離子佈植法 53
4-3-3壓阻式微懸臂梁生物感測器之製作程序 54
4-3-4微流道之製作程序 60
4-3-5生物感測器與微流道之組合 62
4-4實驗系統設備架設 64
4-5無線傳輸生醫單晶片系統 65
4-6 C反應蛋白簡介 67
第五章 實驗結果與討論 70
5-1利用絕緣膠當作絕緣層之方法 70
5-2利用聚亞醯膜當作絕緣層之方法 73
5-3利用PECVD沉積Si3N4當作絕緣層 76
5-4免疫反應實驗量測結果 78
5-4-1免疫反應實驗流程 78
5-4-2免疫反應實驗量測結果 80
第六章 結論與未來展望 83
6-1結論 83
6-2未來展望 85
參考文獻 86

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