臺灣博碩士論文加值系統

本論文研究適用於水中環境的矽基片B型抗諧振反射光波導(ARROW-B)表面電漿子共振(SPR)生化感測元件。由於此生物感測器具有免標定、即時偵測以及對於金表面所固定的生物分子層之折射率變化具有高靈敏度等特性，因此能夠應用在即時感測表面生物分子之交互作用。此生物感測元件的設計，使用模擬分析光場在元件中的傳播特性，使其在水環境下具有最佳化的感測靈敏度。由於B型抗諧振反射光波導擁有較大的入射導光區，所以能夠有效和單模光纖相匹配。在感測區前後的光場傳播區設計具上下對稱的光波導隔離層，使元件能穩定導光而不受外界環境影響。並且於感測區附加液體流道設計，幫助生物分子附著於感測區表面進行反應。本感測元件應用於免疫分析與蛋白質&;#37238;活性之即時檢測，於免疫分析之即時檢測使用老鼠免疫球蛋白G型與抗老鼠免疫球蛋白G型抗體，在蛋白質&;#37238;活性之即時檢測則使用胰蛋白&;#37238;、基質金屬蛋白&;#37238;2型與7型，檢測結果證實本元件之有效性。

In this study, a Si-based ARROW-B SPR biosensor used in aqueous environment has been investigated. The ARROW-B SPR biosensor was proposed to provide a label-free, real-time detection, and highly surface-sensitive platform to detect the bimolecular interactions. Modal characteristics of ARROW-B were analyzed with simulation and the devices were designed for obtaining optimum sensitivity in aqueous environment. The ARROW-B waveguide with a thick guiding region provides efficient coupling with a single-mode fiber. The waveguide in the front and the rear of the SPR sensing region have a symmetric cladding structure which can improve the immunity against environmental changes and elimmate the effect on the light propagation characteristics. The sensing region was configured with a liquid flow channel which assists bioagents in attaching to the surface for reaction. The sensors were applied in real-time detections of immunoassay and proteinase activity. In the experiments, the real-time immunoassay detection for mouse IgG and anti-mouse IgG antibody as well as the proteinase activity detection for trypsin, MMP2, and MMP7 were performed, which have verified the feasibility of devices.

1 Introduction 1
2 Methods for Analysis 4
2.1 Transfer Matrix Method[8] . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Normalization of Guided Modes [10] . . . . . . . . . . . . . . . . . . . . . 8
2.3 Eigenmode Expansion Analysis [10] . . . . . . . . . . . . . . . . . . . . . 9
3 ARROW-B Waveguides 12
3.1 Characteristics of an ARROW-B . . . . . . . . . . . . . . . . . . . . . . 13
3.2 Design of an ARROW-B Structure . . . . . . . . . . . . . . . . . . . . . 16
3.3 Design of an ARROW-B Structure in the Propagation Region . . . . . . 19
4 SPR Sensor Based on an ARROW-B structure 24
4.1 Surface Plasmon Wave . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.1.1 Principle of SPR . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.1.2 Derivation of SPR . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.2 Design of an ARROW-B Structure in the Sensing Region . . . . . . . . . 30
4.2.1 Au-coated ARROW-B SPR Sensors . . . . . . . . . . . . . . . . . 30
4.2.2 Au-coated ARROW-B SPR Sensor with HSQ Bu¤er Layer . . . . 31
4.2.3 Au-coated ARROW-B SPR Sensor with Si3N4 Adjusting Layer . . 32
5 Fabrication Process of ARROW-B SPR Sensor Chips 35
5.1 Layout of an ARROW-B SPR Sensor . . . . . . . . . . . . . . . . . . . . 35
5.2 Fabrication Process of the ARROW-B SPR Sensor Chips . . . . . . . . . 38
6 Real-Time Detection Using ARROW-B SPR Biosensors 46
6.1 Optical Measurement System and Fluid Flow System . . . . . . . . . . . 46
6.2 Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
6.3 Feasibility Demonstration of Sensor Chips . . . . . . . . . . . . . . . . . 51
6.4 Detection of Immunoassay for Goat Anti-Mouse IgG Antibody . . . . . . 53
6.5 Detection of Proteinase Activity . . . . . . . . . . . . . . . . . . . . . . . 55
7 Conclusion 61
Bibliography 63

[1] K. Nakatani, S. Sando, I. Saito, "Scanning of guanine-guanine mismatches in DNA by synthetic ligands using surface plasmon resonance," Nat. Biotechnol., vol. 19, pp. 51–55, 2001.
[2] J. M. McDonnell, "Surface plasmon resonance: towards an understanding of the mechanisms of biological molecular recognition," Curr. Opin. Chem. Biol., vol. 5, pp. 572–577, 2001.
[3]Ying Sun, Xia Liu, Daqian Song, Yuan Tian, Shuyun Bi, and Hanqi Zhang, "Sensitivity enhancement of wavelength modulation surface plasmon resonance biosensor by improving the baseline solution," Analytica Chimica Acta, vol. 569, pp. 21--26, 2006.
[4] Shuyan Gao, Naoto Koshizaki, Hideo Tokuhisa, Emiko Koyama, Takeshi Sasaki, JaeKwan Kim, Joonghyun Ryu, Deok-Soo Kim, and Yoshiki Shimizu, "Highly Stable Au Nanoparticles with Tunable Spacing and Their Potential Application in Surface Plasmon Resonance Biosensors,"”Adv.Funct.Mater., pp. 78–86, 2010.
[5] R.W. Wood, "On a remarkable case of uneven distribution of light in a di¤raction grating spectrum,"”Phil.Magm., pp. 396–402, 1902.
[6] J. Homola, S. S. Yee, and G. Gauglitz, "Surface plasmon resonance sensors: review,"”Sensors and Actuators B, vol. 54, pp. 3–15, 1999.
[7] H. Raether, "Surface plasmons on smooth and rough surfaces and on gratings," Springer-Verlag, Berlin, 1988.
[8] A.D. Boardman, "Electromagnetic surface modes," Wiley, Chichester, 1982.
[9] C. K. Chen, P. Berini, D. Feng, S. Tanev, and V. P. Tzolov,“"Effcient and accurate numerical analysis of multilayer planar optical waveguides in lossy anisotropic media,"”IEEE Photonics Technology Letters, vol.7, no. 8, pp. 260–272.
[10] C. C. Cheng, "Design of ARROW-B SPR sensors in aqueous environment,"”Master Thesis, Institute of Electronics, National Chiao Tung University, Hsinchu Taiwan, R.O.C., 2002.
[11] J. J. Deng, "The analysis and design of antiresonant reffecting optical waveguide devices with discontinuities,"”Ph. D. Dissertation, Institute of Electronics, National Chaio Tung University, Hsinchu, Taiwan, R. O. C., 2000.
[12] T. Baba and Y. Kokubun, "Dispersion and radiation loss characteristics of antiresonant reffecting optical waveguides - numerical results and analytical expressions,"”IEEE Journal of Quantum Electronics, vol. 28, no. 7, pp. 1689–1700, 1992.
[13] J. L. Archambault, R. J. Black, S. Lacroix, and J. Bures, "Loss calculations for antiresonant waveguides,"”J. Lightwave Technol., vol. 11, no. 3, pp. 416–423, 1993.
[14] Y. Kokubun and T. Baba, "Scattering loss of antiresonant reffecting optical waveguide,"”J. Lightwave Technol., vol. 9, no. 5, pp. 590–597, 1991.
[15] T. Baba and Y. Kokubun, "New polarization-insensitive antiresonant reffecting optical waveguide,"”IEEE Photon. Technol. Lett., vol. 1. no. 8, pp. 232–234, 1989.
[16] W. Z. Chang, "Investigation on ARROW-B SPR sensors in aqueous environment,"”Master Thesis, Institute of Electronics, National Chiao Tung University, Hsinchu, Taiwan, R.O.C., 2001.
[17] C.C. Yang, W.C. Chen, "The structures and properties of hydrogen silsesquioxane (HSQ) films produced by thermal curing,"”Journal of Materials Chemistry, vol. 12, pp. 1138–1141, 2002.
[18] H. Raether, "Surface plasmons on smooth and rough surfaces and on gratings," Springer-Verlag, Berlin, 1988.
[19] P.E. Laibinis, G.M. Whitesides, D.L. Allara, "Comparison of the structures and wetting properties of self-assembled monolayers of n-alkanethiols on the coinage metal surfaces, copper, silver, and gold,"”Journal of the American
[20] H. de Bruijn, R. Kooyman, and J. Greve, "Choice of metal and wavelength for surface plasmon resonance sensors: Some Considerations,"”Applied Optics, 31(4):440–442,1992.
[21] M. Mrksich, J. R. Grunwell, and G. M. Whitesides, "Biospecifc Absorption of Car-bonic Anhydrase to Self-AssembledMonolayers of Alkanethiolates That Present Ben-zenesulfonamide Groups on Gold,"”J.Am.Chem.Soc., 117:12009–12010, 1995.
[22] C. Pale-Grosdemange, E. S. Simon, K. L. Prime, and G. M. Whitesides, "Formation of Self-assembled Monolayers by Chemisorption of Derivatives of Oligo (ethylene glycol) of structure HS(CH2)11(OCH2CH2)mOH on gold,"”J.Am.Chem.Soc., 113:12–20,1991.
[23] C. D. Bain, E. B. Troughton,Y. T. Tao, J. Evall, and G. M. Whitesides, "Formation of Monolayer Films by the Spontaneous Assembly of Organic Thiols from Solution onto Gold,"”J. Am. Chem. Soc., 111:321–335, 1989.
[24] G. G. Nenninger, P. Tobiska, J. Homola, and S. S. Yee, "Long-range surface plasmons for high-resolution surface plasmon resonance sensors," Sensors and Actuators B, vol. 74, pp. 145–151, 2001.
[25] J. Ctyroky, J. Homola, and M. Skalsky, "Tuning of spectral operation range of a waveguide surface plasmon resonance sensor,"”Electron. Lett., vol. 33, no. 14, pp, 1246-1248, 1997.
[26] K. Y. Tsai, "Design and fabrication of ARROW-B SPR biochemical sensors in aqueous environment," Master Thesis, Institute of Electronics, National Chiao Tung University, Hsinchu, Taiwan, R.O.C., 2002.
[27] L. C. Junqueira, J. Carneiro, "Basic Histology," McGraw-Hill, 2003.
[28] Anti-mouse IgG (fab specifc), product no. A2179, SIGMA.
[29] Akihiko YAMAMOTO, Seiji TANO, Minoru SHIRAGA, Hirohisa OGAWA, Hisatsugu GOTO, Toyokazu MIKI, Helong ZHANG and Saburo SONE, "A third-
generation matrix metalloproteinase (MMP) inhibitor (ONO-4817) combined with docataxel suppresses progression of lung micrometastasis of MMP-expressing tumor cells in nude mice,"”Int. J. Cancer, vol. 103, pp. 822–828, 2003.