非接觸暨無螢光標定即時生物醫學感測器之研究

Study of Real-Time Non-Contact and Label-Free Biomedical Sensors

路建華(Jiann-Hwa Lue)

指導教授 ： 張榮森

國立中央大學/理學院/光電科學與工程學系/博士(2014年)

摘要

本論文旨在探討TE偏振入射光入射至次波長（週期< λ）的Lamellar光柵波導感測器時，光柵及波導之厚度對其靈敏度的影響。此外，吾人也成功的研製出非接觸式即時音波脈搏量測器，作為傳統中醫師把脈的有效且客觀的參考依據。
Lamellar光柵厚度對感測器靈敏度的模擬結果顯示，感測器的共振模態將會隨Lamellar 光柵的厚度增加而增加。證實了Lamellar 光柵在物理上，確實具有ㄧ等效折射率之波導層的特性。儘管如此，在靈敏度模擬時，結果顯示其基態模(fundamental mode)之峰值位移在同樣波導厚度時，卻難以區別。其次，波導厚度對Lamellar光柵耦合波導感測器的模擬結果顯示，感測器的共振模態也將會隨著波導的厚度增加而變多。引導模式和基本模式的靈敏度的變化也進行了研究。計算結果表明，較厚的波導層將誘發更多的導模。比較不同波導厚度的基模的光譜靈敏度，較薄的波導層的峰值位移遠大於波導層較厚者。換句話說，較薄的波導層是一種使用傳感器的一個更好的選擇。
本研究之內容規劃如後 ：第一章討論無螢光標定生物傳感器發展的近況，包括目前技術的概述：表面等離子體共振(Surface Plasmon Resonant) ，干涉式感測器(Interference Sensor)，光學波導(Waveguide)，光纖(Optical fiber)，光子晶體(Photonic crystal)等類型的生物感測器。
第二章為光柵耦合式波導之基本理論與模擬方法介紹。旨在將近期各種光柵耦合式波導之相關理論，作系統化之整理與說明，並簡述此類波長光譜峰值的取值方式。
第三章探討一維Lamellar 光柵耦合式光子晶體感測器與效率的關係。個人利用精確耦合波分析法(rigorous coupled-wave analysis method)及有限時域插分法(finite difference time domain, FDTD)計算一維週期性低折射率Lamellar光柵之厚度與波長關係。模擬結果顯示，隨著光柵結構厚度的增加，將會誘發更多的高階導模。然而，基模(fundamental mode)的峰值(peak wavelength)位置，主要由波導層之厚度來決定。在感測器對生物鍵結敏感度的模擬，我們設定一等效折射率(effective refractive index)接近水(nf =1.334)薄膜層取代生物反應層。模擬的結果顯示，即便光柵厚度較薄者(dg=100nm)，當等效生物層厚度增加至1000nm時，感測器之峰值波長位移(peak wavelength shift, PWS) 為5.1 nm ，不足作為敏感度量測標準。若參考導模峰值之Q值(Quality Value, Q-Value)，當薄膜層厚度少於100nm時，Q值的差異則十分明顯。因此，當波導厚度相同而光柵深度不同時，Q值可作為感測器敏感度之有效參考。
第四章旨於探討波導層厚度對Lamellar 光柵耦合光感測器之敏感度，參考第二章之結果，將光柵之厚度設為100nm(薄光柵)，探討其反射率能帶(energy band)，並就薄、厚光柵層(100nm, 1000nm)，在不同厚度之波導，其導模特性進行模擬。模擬結果顯示，波導厚度增加將誘發更多高階模態，且結合100nm之薄光柵層之波導感測器，波導厚度越薄者，其基態模的變化率遠大於較厚者，由此可見，用作為感測器之光柵波導，不論光柵或波導之厚度，厚度越薄，其靈敏度越高。
第五章與第六章旨在研究並製造高敏感度單音頻與雙音頻之音波量測器，以作為傳統中國醫學脈診之客觀參考依據。吾人以簡單的電容式麥克風作為音頻接收器，搭配商用LabVIEW 軟體，設計出高度音頻敏感的脈搏診測器，藉由量測出之脈搏訊號波形，進行傅立葉轉換(Fourier Transform)，除了可得到受測者之生物健康訊號，更可提供中醫師脈診之即時且可靠的參考，更重要的是，此為非接觸無害式可重複使用之量測器，可以節省患者就診時冗長的等待時間，也可有效的為不適移動之患者提供即時診斷。本研究之設計理念，主要是希望以一般的筆記型電腦，搭配一些隨手可得的電子元件，製作出簡易且低成本的音頻脈搏感測器。實驗結果證明，我們不但可以用單音頻音效卡正確的擷取出單音頻脈搏信號，也可以用雙音頻感測器正確無誤的獲取並解調出相關的脈搏訊號。我們深信此即時非接觸式之脈搏音頻量測技術，可有效的提供中醫師在脈診時的客觀診斷參考，以降低脈診人為失誤的機率。未來，若將此技術應用在中醫脈診的測量上，也可大幅的節省診斷時多餘的物力及時間耗費。

關鍵字

感測器 ； 生醫 ； 免標定 ； 即時的 ； 非接觸式 ； Lamellar光柵 ； 基態模 ； 次波長 ； TE 偏振

並列摘要

The purpose of this thesis is to investigate the thickness effects on sub-wavelength (period <λ) Lamellar grating waveguide sensors with TE polarization incidence and the effects of waveguide thickness on the sensitivity of the sub-wavelength Lamellar grating waveguide sensor with TE polarization incidence. In addition, two simple and low cost prototypes of real-time non-contact pulse measurement devices have been successfully developed; they could be useful, efficient and objective reference for Traditional Chinese Medicine (TCM) pulse diagnosis.
According to the simulation result of Lamellar grating thickness versus sensor sensitivity, it reveals that as the thickness of Lamellar grating is increased, the more resonance modes will be induced as well. This proves that the Lamellar grating possesses the characteristics of the effective refractive index waveguide layer in physics. However, it is difficult to recognize the peak shift of the fundamental mode while the thickness of grating is different and the thickness of waveguide is the same. On the other hand, referring to the simulation of the effects of waveguide thickness on the sensitivity of the sub-wavelength Lamellar grating, the calculation shows that the thicker waveguide layer will induce more guided modes. Also, the variation of guided modes and the sensitivity of fundamental mode are investigated. Comparing the spectrum sensitivity of fundamental mode of different waveguide thickness, the peak shift of the thinner waveguide layer is larger than the thicker one’s. In other words, thinner waveguide layer is a better selection for the use of sensor.
The first chapter discusses the overview of present techniques of label-free biosensor, optical label-free biosensor structures including: surface plasmon resonance, interference sensor, optical waveguide, optical fiber, photonic crystal and the detection limits of optical biosensors.
The second chapter mentions the basic theory of the grating-coupled waveguide and makes a brief introduction of simulation method. The purpose is to systematize various theories of relevant grating-coupled waveguide and to do a brief introduction of how to estimate the wavelength spectrum peak.
The third chapter talks about thickness effects on the Lamellar grating waveguide sensors with TE-polarization incidence. The relationship between the Lamellar grating coupled sensor and efficiency is discussed. Rigorous coupled wave analysis (RCWA) method and finite difference time domain (FDTD) are used to calculate the relationship between the thickness of one-dimension low refractive Lamellar grating and the wavelength. Simulation results reveal that as the thickness of Lamellar grating is increased, the more high order modes will be induced. Nevertheless, the position of peak wavelength of the fundamental mode is mainly determined by the thickness of the waveguide layer. Concerning about the simulation of sensor sensitivity, we set a thin film of the effective refractive index close to water (defined as nf = 1.334) to replace the bio donor and acceptor layer. Simulation result reveals that for the thinner grating (dg = 100nm), the thickness of the bio donor and acceptor layer is increased to 1000nm, the maxima peak wavelength shift (PWS), δλmax=λP. Longest -λP. shortest = 742.48-737.38, is 5.1 nm, still unable to be treated as sensitivity measurement standard. However, if we refer to the Q-value (quality value) of peak wavelength of the guided modes, as the thin film thickness is less than 100nm, Q-value difference is easy to be recognized. Therefore, while waveguide thickness is the same and the grating thickness is different, Q-value could be a valid index for the sensitivity.
The fourth chapter focuses on waveguide thickness effects on the sensitivity of the sub-wavelength Lamellar grating waveguide sensor. Referring to Chapter 3, the thinner grating defined as dg=100nm and the energy band of thinner structure are studied. Also, we study the characteristics of guided modes while the grating thickness dg=100nm and dg=1000nm are under different waveguide thickness (dWG). The calculation results show that the thicker waveguide layer will induce more guided modes. Comparing the spectrum sensitivity of fundamental mode of different waveguide thickness, the peak shift of the thinner waveguide layer is larger than the thicker one’s. Therefore, no matter we take the grating thickness or the waveguide thickness as grating waveguide sensors, less thickness has higher sensitivity.
Chapter five and Chapter six respectively present that simple and low cost prototypes of single-channel and two-channel sound detectors are fabricated as pulse measurement devices; they are useful tool and objective reference for Traditional Chinese Medicine pulse diagnosis. A simple high sensitivity condenser microphone is used as receiver. With commercial LabVIEW software program, we have designed highly sensitive pulse diagnosis detector. By the vibration signals of pulse and performing Fourier Transform, we cannot only obtain the signals of health conditions of individuals, but also provide a real-time and reliable data for TCM pulse diagnosis. Most importantly, these are non-contact, harmless, and reusable measurement devices; the patients do not need to waste time for waiting and the doctors can do immediate and efficient diagnosis for the patients who are not able to move or to be moved physically. This study designs and fabricates a simple and low cost pulse measurement based on a commercial laptop. The measurement results demonstrate that pulse signals are acquired correctly and two-channel sound detectors can successfully acquire vibration signals of pulse. As a result, these non-contact pulse measurement devices can promote the development of Traditional Chinese Medicine and reduce the cost for disease diagnosis.

並列關鍵字

Sensors ； Biomedical ； Label-Free ； Real-Time ； Non-Contact ； Lamellar grating ； fundamental mode ； sub-wavelength ； TE polarization

參考文獻

[2] Xudong Fan, et al, “Sensitive optical biosensors for unlabeled targets: A review”, analytica chimica acta, 6 2 0, P.P. 8–26, 2 0 0 8.

[3] R. Narayana swamy, O.S. Wolfbeis, “Optical Sensors: Industrial, Environmental and Diagnostic Applications”, Springer, New York, 2004.

[4] W.E. Moerner, “New directions in single-molecule imaging and analysis”, Proc. Natl. Acad. Sci., 104, P.P. 12596, 2007.

[5] Jiří Homola, “Present and future of surface plasmon resonance biosensors”, Anal Bioanal Chem, 377, P.P. 528–539, 2003.

[7] B. Liedberg, C. Nylander, I. Lunstrom, “Surface plasmon resonance for gas detection and biosensing”, Sens. Actuators, P.P. 4299, 1983.