臺灣博碩士論文加值系統

本論文研究一種適用於水中環境的B型抗諧振反射光波導 (ARROW-B) 結構之表面電漿子共振(SPR)感測器的製程，並應用於蛋白酶的活性即時檢測。B型抗諧振反射光波導的入射導光區較大，能有效和單模光耦合。在感測區前後的光場傳播區使用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，附加液體的流道，能應用於即時感測表面生物分子之交互作用。利用設計與製造之感測器測知，186.88nM的ONO-4817即可完全抑制0.5μl濃度為0.1μg/μl之基質金屬蛋白酶的活性。

In this thesis, the fabrication process of ARROW-B SPR sensors used in aqueous environment has been investigated. The sensors are used for real-time detection of proteinase activity. ARROW-B waveguide with a thick guiding region provides efficient coupling with a single-mode fiber. The waveguides in front and rear of the SPR sensing region have symmetric cladding structure to improve the immunity against environmental changes, and the sensing region is configured with a liquid flow channel which enables biomolecules to adhere to the Au surface. Then we apply the sensors in real-time detection of the degradation of gelatin by MMP2. We could tell from the SPR curve that ONO-4817 of 186.88 nM could totally inhibit the activity of 0.5 μl MMP2 of 0.1 μg/μl.

Contents i
List of Tables iii
List of Figures iv
1 Introduction ...1
2 Methods for Analysis ...4
2.1 TransferMatrixMethod ...4
2.2 Normalization ofGuidedModes ...8
2.3 Eigenmode ExpansionAnalysis ...9
3 ARROW-BWaveguide 12
3.1 Characteristics of anARROW-B...14
3.2 Design of anARROW-B Structure in the Sensing Region . . . . . . . . . . . .. . .16
3.3 Design of an ARROW-B Structure in the Propagation Region . . . . . . . .. . .. . .. 19
4 SPR Sensor Based on an ARROW-B structure 23
4.1 Surface PlasmonWave ...23
4.1.1 Physical Properties of SPW...23
4.1.2 Au-coated ARROW-B SPRSensors 28
4.1.3 Au-coated ARROW-B SPR Sensor with MgF2 Buffer Layer and Si3N4 Adjusting Layer . . . . 29
4.1.4 Au-coated ARROW-B SPR Sensor with Si3N4 Adjusting Layer . . . . .. . .. . .. . .. . .29
5 Fabrication Process of ARROW-B SPR Sensor Chips .....36
5.1 Design of layout for the ARROW-B SPRSensor Chips...36
5.2 Fabrication Process of the ARROW-B SPRSensor Chips.40
6 Real-Time Detection Using ARROW-B SPR Biosensors ....47
6.1 OpticalMeasurement Systemand Circulating-Flow System..47
6.2 Digesting characteristics of gelatin by trypsin ...50
6.2.1 Reagents andMethods . . . . . .. . . . . . . . . 50
6.2.2 Feasibility Demonstration of Sensor Chips . .. . 54
6.2.3 Measurement andDiscussion . . . . . . . . . . . .56
7 Conclusion ... 61
Bibliography ... 63

[1] Rebecca J. Green, Richard A. Frazier, Kevin M. Shakesheff, Martyn C. Davies,Clive J. Roberts, Saul J.B. Tendler, “Surface plasmon resonance analysis of dynamic biological interactions with biomaterials,” Biomaterials, vol. 21, pp. 1823-1835, 2000.
[2] H. Raether, Surface plasmons on smooth and rough surfaces and on gratings, Springer-Verlag, Berlin, 1988.
[3] J. Homola, S.S. Yee, and G. Gauglitz, “Surface plasmon resonance sensors: review,” Sensors and Actuators B, vol. 54, pp. 3-15, 1999.
[4] A.D. Boardman, Electromagnetic surface modes, Wiley, Chichester, 1982.
[5] J. M. McDonnell, “Surface plasmon resonance: towards an understanding of the mechanisms of biological molecular recognition,” Current Opinion in Chemical Biology, vol. 5, pp. 572-577, 2001.
[6] C. K. Chen, P. Berini, D. Feng, S. Tanev, and V. P. Tzolov, “Efficient and accurate numerical analysis of multilayer planar optical waveguides in lossy anisotropic media,” IEEE Photonics Technology Letters, vol.7, no. 8, pp. 260-272.
[7] 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.
[8] J. J. Deng, “The analysis and design of antiresonant reflecting optical waveguide devices with discontinuities,” Ph. D. Dissertation, Institute of Electronics, National Chaio Tung University, Hsinchu, Taiwan, R. O. C., 2000.
[9] T. Baba and Y. Kokubun, “New polarization-insensitive antiresonant reflecting optical waveguide,” IEEE Photon. Technol. Lett., vol. 1. no. 8, pp. 232-234, 1989.
[10] 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.
[11] Y. Kokubun and T. Baba, “Scattering loss of antiresonant reflecting optical waveguide,” J. Lightwave Technol., vol. 9, no. 5, pp. 590-597, 1991.
[12] T. Baba and Y. Kokubun, “Dispersion and radiation loss characteristics of antiresonant reflecting optical waveguides—numerical results and analytical expressions,” IEEE J. of Quantum Electron., vol. 28. no. 7, pp. 1689-1700, 1992.
[13] 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.
[14] H. E. Brujin, R. P. H. Kooyman, and J. Greve, “Choice of metal and wavelength for surface plasmon resonance sensors: some considerations,” Appl. Opt., vol. 31, pp. 440-442, 1992.
[15] T. Wink, S. J. van Zuilen, A. Bult, and W. P. van Bennekom, “Self-assembled
monolayers for biosensors,” Analyst, vol. 122, pp. 43-50, 1997.
[16] 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. 64
[17] 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.
[18] X. Liu, D. Song, Q. Zhang, Y. Tian, Z. Liu, and H. Zhang, “Characterization of drugbinding levels to serum albumin using a wavelength modulation surface Plasmon resonance sensor,” Sensors and Actuators B, vol. 117, pp. 188-195, 2006.
[19] D. G. Hong, T. W. Kim, K. B. Kim, J. S. Yuk, and K. S. Ha, “Development of an immunosensor with angular interrogation-based SPR spectroscopy,” Meas. Sci. Technol., vol. 18, pp. 1367-1371, 2007.
[20] H. Nakagawa, I. Saito, T. Chinzei, Y. Nakaoki, and Y. Iwata, “Themerits/demerits of biochemical reaction measurements by SPR reflectance signal at a fixed angle,” Sensors and Actuators B, vol. 108, pp. 772-777, 2004.
[21] Akihiko YAMAMOTO, Seiji TANO, Minoru SHIRAGA, Hirohisa OGAWA, Hisatsugu GOTO, Toyokazu MIKI, Helong ZHANG and Saburo SONE, “A thirdgeneration 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.
[22] A.Yamada, A. Uegaki,T. Nakamura and K. Ogawa, “ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs,” Inflamm. res, vol. 49, pp. 144-146, 2000.
[23] I. Craig and J. A. McLaughlin, “SPR and AFM study of engineered biomolecule immobilisation techniques,” Proceedings of the 28th IEEE EMBC conference, pp. 6728-6731, 2006.