原台大無線奈米生醫微機電系統研究群所研發之具有表面電漿共振技術的光生化形檢 測儀，此系統命名為Opto-BioMorph，簡稱 OBMorph（圖 5.1），本計畫已大幅修改原OBMorph 設計，特別將兩大光生化型的重要技術：(1)可以精準控制與改變量測光入射試件的角度和 方向之橢偏儀及(2)具有極高靈敏度，可達 10-10m 解析度的光相位表面電漿共振(SPR)技術 進行整合，此一系統稱為ESPR (Ellipsometer Surface Plasma Resonance )，其光路架構較 OBMorph 精簡許多，成為一套超小型精準光電檢測儀器。本計畫把 OBMorph 系統改良為 專供結核病的篩檢至結核病藥物篩選的檢測系統原型，故此一創新研發之系統及其相關平 台技術統稱為TBMorph(Tuberculosis Morph)。目前 TBMorph 系統已具有動態生醫訊號之檢 測功能。
Gly Gly
Anti-IgG100
EA-HCL IgG50 IgG100 IgG200 IgG500
PBS PBS PBS PBS PBS PBS
反射鏡
圖 5.1 Opto-BioMorphin: Ellipsometer 之架構圖
在光路架構上，延續本研究團隊之經驗，利用拋物面反射鏡與球面反射鏡之數學特性，
準試片之布魯斯特角（Brewster angle）做為參考依據，提升角度之精確度。本架構中另一 個特點是採用波板來進行調制相位動作，因為波板之相位延遲量較為穩定，較不受外界環 境之影響，可有效效降低量測時間與提高系統精確度。而系統中所加入的參考光路，可根 據此參考光路量測所得之光強進行校正並消除光源強度的不穩定性，亦可增加量測精度。
由於以波板進行相位調制的功能，故可以達到高速化檢測之目的。
在進行薄膜厚度量測與生化反應量測時，必須先利用系統之轉換函數來校正與分析橢 偏參數，提升其整體的精確度。嘗試以平面反射鏡、鍍厚膜鉻之矽晶圓、以及純矽晶圓作 為系統較準的標準試片，實驗所得之結果發現以矽晶圓所得之系統參數為基準，量測並計 算所得之膜厚與商用量測儀器之結果最相近，誤差僅為3%。在生化反應量測中，以酵素連 結免疫分析反應(enzyme-link immunosorbent assay, ELISA)作為量測之基本生化反應流程，
從量測結果之數據圖可知，在生物反應薄膜檢測應用上，OBMorph 顯現出極高之分辨力。
本論文研究的實驗結果與理論值之相契合度，成功證實了OBMorph 在橢偏儀功能上擁有良 好的解析度，且亦達到高速化之功能。在生物檢測方面，OBMorph 的流道子系統之設置，
可使系統擁有量測生物動態鍵結反應的能力，證實OBMorph 在生醫檢測上之潛力。
新式電化學檢測技術為本研究的另一研究主軸，承接研究團隊所提出之新式電化學檢 測方法，本研究以輸入弦波電壓為主要供電模式，將血糖酵素檢測試片以及不同濃度之葡 萄糖標準試液作為主要待測樣本，驗證此新式電化學檢測方式在血糖檢測中具有高度之重 複性，且與傳統電化學血糖檢測方式相比，此供電模式具有更高度之電流反應表現，藉由 調整弦波電壓之頻率與振幅即可得到比傳統供電模式更高之線性度以及解析度更高之濃度 與電流關係；在研究中也以數學積分之方式得到另一可測量血糖濃度之參考方式，亦驗證 其優於傳統供電方式之表現。此外，以本研究之光機系統量測不同濃度之血糖標準試液，
觀察其表面電漿共振角之改變與相位變化，使本光機系統於醫療檢測上有更寬廣之應用。
此外，為了解決表面電漿共振術和橢偏術應用於生醫檢測領域所面臨的困難，表面電 漿共振術由於檢測原理的限制只能使用 TM 偏極態量測，所得資訊較無法直接進行複雜的 生物反應研究分析；而橢偏術因入射光正向打入樣本時須在水溶液內全反射，會有折射現 象造成判讀角度上的困難。雙偏極光之波導干涉術一方面因同時使用 TE 和 TM 偏極態可 得到較多訊號進行生物參數反解，另一方面由於入射光在波導內傳遞，不會有入射介質折 射率改變的問題，同時解決上述兩種檢測技術遭遇的困難。此外由於波導干涉術入射光在 波導內多次全反射其訊號為疊加，和上述兩種技術僅為單點量測方式相比具有較高的解析 度。
本研究計畫目前所架設雙偏極光之波導干涉儀已完成相關的生物反應檢測驗證。在 ELISA 生化反應和重現性實驗，成功的量測出 Anti-IgG 與不同濃度的 IgG 反應結果，所得 訊號將可提供生物醫學領域人員進行複雜生化反應的分析研究。為增進系統的精確度和應 用面，已就光機架構、訊號偵測、波導晶片、流道系統等方面做更進一步的研究，使本論 文研發之創新生醫檢測技術－雙偏極光波導干涉儀功能更為完備。
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