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研究生:林豪駸
研究生(外文):Hao-Qin Lin
論文名稱:利用快速傅立葉轉換系統分析自感測壓阻式微懸臂梁於凝血反應之監測
論文名稱(外文):A Study on Monitoring Blood Coagulation Reaction by Use of Self-Sensing Piezoresistive Microcantilever and Fast Fourier Transform Analysis System
指導教授:黃榮山
口試委員:施文彬陳俊杉
口試日期:2015-07-02
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:應用力學研究所
學門:工程學門
學類:機械工程學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:86
中文關鍵詞:微懸臂梁壓阻凝血黏度
外文關鍵詞:piezoresistancemicrocantileverprothrombin timeviscosity
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本研究使用微奈米機電技術開發出具定點照護功能的振動式壓阻式微懸臂梁凝血感測器,搭配演算法分析訊號,應用於抗凝血劑用藥監測的評估方式─凝血酶原時間 (PT) 的監測。隨著現代人的飲食越來越精緻化,攝取過多膽固醇與油脂的結果是心血管疾病患者數逐年升高,為防止因血液與血管壁異常造成血管栓塞,病患需依賴抗凝血劑。然而抗凝血劑若用藥不當,將造成出血等副作用,故患者需定時監測血液的狀態是否在正常範圍內。目前因為血液的檢驗屬醫療等級,患者需到醫療單位接受生醫檢測,然而從檢體的處理、運送、儀器排程到最後取得報告的時間冗長,若能夠配合病患作息進行即時監測的定點照護技術會是一大貢獻,如何將醫療等級的血液檢測發展到能在病患家中監測將是未來重點。
量測方式參考分析血液凝固狀況的Sonoclot分析儀,使用定振幅的致動器來驅動壓阻式微懸臂梁,使其在待測樣品中振動,利用血凝樣品黏度變化時微懸臂梁的受力情形也會產生變化為基礎,擷取感測器之訊號來推知待測樣品性質的變化。搭配快速傅立葉轉換演算法得知特定頻率的振幅值,本研究以此值來反映出微懸臂梁的受力情形,進而分析並得到凝血酶原時間。
利用在不同濃度的甘油水溶液進行實驗來了解微懸臂梁在不同黏度環境中的受力情形,實驗結果得知微懸臂梁阻值改變量的10 Hz振幅與黏度有正相關的趨勢,且線性度相當良好,證實振動式微懸臂梁感測器能夠分辨不同黏度之液體且準確度相當高,也使用Reynolds number的分析方式來表現,得到∆R/R_0 (ppm)=2〖Re〗^(-0.659)方程式來表示本微懸臂梁在液體中振動的表現(R2 = 0.985)。接著將量測標的改為實際凝血情形,利用自行設計之演算法來處理訊號後可得知在凝血反應過程中特定頻率的振幅變化情形,以振幅明顯驟升所需時間做為微懸臂梁所量測到之凝血酶原時間,實驗結果得到第一級血凝品管液的PT為12.08秒(標準差1.53秒);的二級血凝品管液的PT為27.08秒(標準差1.61秒);第三級血凝品管液的PT為38.08秒(標準差2.75秒),與商用儀器的量測做比較,統計結果發現在95%信賴區間內兩者並無差異,且都在藥品的參考凝血酶原時間範圍內,證實本研究能夠監測到凝血反應時蛋白纖維聚集成血塊的情形。搭配微懸臂梁能夠感測不同黏度的實驗結果,本感測器能夠監測凝血反應過程的黏度變化情形,且使用快速傅立葉演算法能夠讓我們有效的去除雜訊得到適當的資訊。
本研究開發之振動壓阻式微懸臂梁感測器屬於半導體技術,故有可微型化與成本低的潛力,且後端訊號處理也可設計於晶片中,在定點照護領域中有很大的發展空間。量測凝血反應的技術中能夠量化描述凝血過程的並不多,如Sonoclot分析儀,但目前除了凝血時間的量測外,其他血液資訊的準確度屬研究階段。綜觀以上,本研究利用血液黏度的變化來描繪凝血反應過程,具有很大的發展潛力。


This study has developed a real-time coagulation monitoring sensor by using an externally vibrated, self-sensing piezoresistive microcantilever for disposable point-of-car coagulation device. With the increasing use of oral anti-coagulant drugs and increasing adverse drug events, the need for point-of-care coagulation devices has become necessary. Prothrombin time (PT) is a measure of the extrinsic pathway of blood coagulation, and it is an index for anticoagulant therapy to determine the blood condition in coagulation reaction.
In this study, the measurement was performed by vibrating the piezoresistive microcatilever immersed in the sample liquid at a fixed frequency of 10 Hz and fixed amplitude of 40 μm. The acquired signal of resistance change in microcantilever was processed by Fast Fourier Transform algorithm, and the resistance amplitude in 10 Hz indicated the amount of force exerting to the cantilever. In coagulation reaction, the viscosity of samples was sharply changed due to the clot formation, and the increased force can be sensed when the resistance amplitude in 10 Hz rises. Prothrombin time can be obtained by the time needed for fibrin clot formation. The method was initiated by Sonoclot analysis.
The amplitude of resistance in the specific frequency was found in a well linear correlation with kinematic viscosity changes of glycerol/water solutions (R2 > 0.99). It was also found that the amplitude-kinematic viscosity curve behave differently in very low kinematic viscosity, probably due to the decrease in viscous drag of low kinematic viscosity fluids. Also, the Reynolds number correlation can be achieved to present the relation of vibrated microcantilevers in sample liquid. Thus, ∆R/R_0 (ppm)=2〖Re〗^(-0.659)(R2 = 0.985) was derived to successfully describe the relation between acquired signals and vibrated Reynolds number. In addition, three types of commercially standard human plasma samples for measurement of coagulation prothrombin time were used for characterizing microcantilever sensors. The measured results of resistance amplitude in specific frequency with specific patterns of signature indicated the viscoelastic changes in blood coagulation reaction process. In coagulation reaction of human plasma control level 1, the PT measured by the microcantilevers was 12.08 sec with std. of 1.53 sec; PT = 27.08 sec with std. of 1.61 sec in human plasma control level 2; and PT = 38.08 sec with std. of 2.75 sec in human plasma control level 3. Compare with commercial coagulation device, the PT showed an excellent agreement between the microcantilever sensor and commercial device in 95% confident range. All results lay in the PT ranges of references. The experiment results demonstrated that the PT can be measured by vibrated microcantilevers accurately and precisely. Thus, this microcantilever sensor has demonstrated the real-time measurement for point-of-care coagulation monitoring, and shown its potential in miniaturization for personal diagnosis.


中文摘要 iii
ABSTRACT v
圖目錄 x
表目錄 xiv
Chapter 1 緒論 1
1.1 前言 1
1.1 研究動機 2
1.2 文獻回顧 4
1.2.1 凝血監測技術 4
1.2.2 微懸臂梁應用於黏度測量 8
1.3 論文大綱 10
Chapter 2 止血與凝血反應概論 12
2.1 人體止血機制 12
2.1.1 人體內之止血機制 12
2.2 凝血路徑(coagulation pathway) 13
2.3 凝血時間 16
2.3.1 凝血酶原時間 17
2.3.2 活化部分凝血活酶時間 18
Chapter 3 壓阻式微懸臂梁之理論分析 20
3.1 壓阻材料特性分析 20
3.1.1 多晶矽之電阻率 21
3.1.2 壓阻效應 22
3.2 微懸臂梁機械性質分析 25
3.2.1 彈簧常數與共振頻率 25
3.2.2 微懸臂梁上的應力分析 27
Chapter 4 壓阻式微懸臂梁凝血感測系統之設計與製程 34
4.1 微懸臂梁之壓阻層設計理念 34
4.1.1 壓阻層與中性軸位置探討 34
4.1.2 形狀設計與製程分析 34
4.2 壓阻式微懸臂梁晶片之尺寸 38
4.3 壓阻式微懸臂梁晶片之製程 39
4.3.1 基底與薄膜沉積 40
4.3.2 壓阻層位置定義 42
4.3.3 金屬導線及絕緣保護層之沉積 43
4.3.4 電極區製程 44
4.3.5 絕緣保護層蝕刻 45
4.3.6 微懸臂梁形狀定義 46
4.3.7 背蝕刻製程 46
4.3.8 背蝕刻懸浮微懸臂梁 47
4.3.9 晶圓切割處理 50
4.4 印刷電路板之設計與製作 51
4.5 壓阻式微懸臂梁凝血感測器之封裝 52
4.6 壓阻因子 52
4.6.1 壓阻因子量測理論計算 53
4.6.2 壓阻因子量測結果 54
Chapter 5 實驗方法與結果討論 56
5.1 實驗材料與藥品 56
5.2 軟硬體實驗設備 56
5.3 實驗設計與架構 57
5.4 使用快速傅立葉轉換處理壓阻式微懸臂梁感測器訊號 59
5.4.1 快速傅立葉轉換理論 59
5.4.2 應用快速傅立葉轉換於微懸臂梁感測訊號 61
5.5 壓阻式微懸臂梁凝血感測系統於不同黏度液體之量測 62
5.5.1 實驗方法 62
5.5.2 實驗結果與討論 62
5.6 壓阻式微懸臂梁凝血感測系統於凝血反應監測之應用 70
5.6.1 實驗方法 70
5.6.2 實驗結果與討論 70
Chapter 6 結論與未來展望 81
6.1 結論 81
6.2 未來展望 82
參考文獻 83


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