摘要
表面等离子体共振(Surface Plasmon Resonance,SPR)生物传感器凭借其实时监测、灵敏度高、无标记等优点在环境检测、食品安全等方面得到了广泛应用。目前,对SPR高通量检测的需求日益增多。点阵SPR成像(SPRi)传感器是实现SPR高通量检测的关键。本项目的任务是研制一台点阵SPRi传感器,本论文的主要内容和成果主要包括：
1.在SPR偏振控制金膜消光方法的基础上,针对其不足之处,提出了SPR偏振控制棱镜消光方法,建立了对应的理论模型,通过实验验证了该理论构思。
2.通过理论模型对传感器主要光学元件参数进行了仿真分析和优化,并设计了点阵SPRi传感器。其特点是入射光是一个包含S偏振分量和P偏振分量的线偏振光,用1/4波片和检偏器对反射光的偏振态进行调制,可以有效抑制背景光,得到一个高对比度的图像。
3.提出了自参考方法、希尔伯特黄变换(Hilbert-Huang Transform, HHT)方法和变长度移动平均滤波方法的SPR数据联用处理方法：自参考方法抑制基线漂移,通过参比通道来消除外界温度和整体光强波动导致的漂移；HHT方法剔除高频噪声的同时能够保留信号的能量；变长度移动平均滤波可以进一步改善基线噪声,同时保留重要的SPR高频特征。该联用方法将基线漂移降低了一个数量级,提高了传感器的检出限。
4.编写了点阵SPRi的分析处理软件,搭建了点阵SPRi传感器系统；进行了传感器基本性能指标的测试。传感器的测量范围约为0.022RIU,分辨率为10-5RIU,能检测到的最小光强变化为0.18灰度值比特,多次测量结果重复性为0.8053%。并对BSA生物分子进行了生物测量实验。
目前该传感器设置了35个测量点,具有实现高通量检测的潜力。
Surface Plasmon Resonance (SPR) bio-sensors have been widely applied in the areas of environment monitoring and food safety for its real-time, label-free measurement and high sensitivity. The need of high-througput SPR system is rising. Array SPR imaging sensor is key to perform SPR highthrougput detection. The aim of the project is to build an array SPRi sensor. In this assay, an array SPR imaging sensor has been built and tested,including:
1. Based on SPR gold film polarization control method, a contrast-enhancing prism polarization control method is proposed. A theoretical model was established and the theory was proved by experiment.
2. The primary optical parameter have been analyzed and optimized. The array SPRi sensor has been designed. The linear light contains both transverse-electric (TE) and transverse-magnetic (TM) waves. The polarization of the reflected light is modulated by1/4waveplate and analyzer. The background signal is suppressed to get a high contrast imaging.
3. Combined methods to improve the performance of the surface plasmon resonance array sensor are proposed. A self-reference method is adpoted to suppress the baseline drift. The Hilbert-Huang transform-based signal post-processing algorithm is employed to reduce high-frequency noise. An adaptive moving-average method was used to reduce noise while preserving important high-frequency signal characteristics. The combined methods improve the baseline drift by an order of magnitude and achieve a higher limit of detection.
4. An analysis software for the array SPR imaging sensor is developed. With the array SPRi sensing system, the basic performance of the sensor is tested. The dynamic range is about0.022RIU and the resolution is10-5RIU. The smallest change of light that can be detected is0.18greyscale bit and the repeatability is0.8053%. The measurement of BS A has been performed.
Now the sensor can perform detection up to35spots, which has potiential for higer throuput and resolution.
引文
1. Wood, R., XLⅡ. On a remarkable case of uneven distribution of light in a diffraction grating spectrum. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science, 1902.4(21):p.396-402.
2. Otto, A., Excitation of nonradiative surface plasma waves in silver by the method of frustrated total reflection. Zeitschrift fur Physik, 1968.216(4):p.398-410.
3. E, K., Determination of optical constants of metals by excitation of surface plasmons. Zeitschrift fur Physik, 1971.241(4):p.313-317.
4. Liedberg, B., C. Nylander, I. Lunstrom, Surface plasmon resonance for gas detection and biosensing. Sensors and Actuators, 1983.4:p.299-304.
5. Murakami, K., P.R. Gordon-Weeks, S.P. Rose, Isolation of Postsynaptic Densities from Day-Old Chicken Brain. Journal of Neurochemistry, 1986.46(2):p.340-348.
6. Fang, S., H.J. Lee, A.W. Wark, R.M. Corn, Attomole microarray detection of microRNAs by nanoparticle-amplified SPR imaging measurements of surface polyadenylation reactions. Journal of the American Chemical Society, 2006.128(43):p.14044-14046.
7. Sendroiu, I.E., L.K. Gifford, A. Luptak, R.M. Corn, Ultrasensitive DNA microarray biosensing via in situ RNA transcription-based amplification and nanoparticle-enhanced SPR imaging. Journal of the American Chemical Society, 2011.133(12):p.4271-4273.
8. Hall, W.P., S.N. Ngatia, R.P. Van Duyne, LSPR Biosensor Signal Enhancement Using Nanoparticle- Antibody Conjugates. The Journal of Physical Chemistry C, 2011.115(5):p. 1410-1414.
9. Takei, H., N. Bessho, A. Ishii, T. Okamoto, A. Beyer, H. Vieker, A. Golzhauser, Enhanced infrared LSPR sensitivity of cap-shaped gold nanoparticles coupled to a metallic film. Langmuir, 2014.30(8):p.2297-2305.
10. 包宇,毛燕,王伟,李正刚,牛利,表面等离子体共振光谱技术与电化学方法联用及其应用.电化学,2013.19(1)：p.17-28.
11. Sriwichai, S., A. Baba, S. Deng, C. Huang, S. Phanichphant, R. C. Advincula, Nanostructured ultrathin films of alternating sexithiophenes and electropolymerizable polycarbazole precursor layers investigated by electrochemical surface plasmon resonance (EC-SPR) spectroscopy. Langmuir, 2008.24(16):p.9017-9023.
12. 詹舒越,董联红,王晓萍,基于表面等离子体共振技术的液相色谱检测器研究.现代科学仪器,2009(5)：p.11-13.
13. 刘钰,徐抒平,唐彬,徐蔚青,表面等离子体共振与表面增强拉曼散射相关性研究.光散射学报,2010.22(1)：p.29-33.
14. Meyer, S.A., E.C. Le Ru, P.G. Etchegoin, Combining surface plasmon resonance (SPR) spectroscopy with surface-enhanced Raman scattering (SERS). Analytical chemistry, 2011. 83(6):p.2337-2344.
15. Boecker, D., A. Zybin, V. Horvatic, C. Grunwald, K. Niemax, Differential surface plasmon resonance imaging for high-throughput bioanalyses. Analytical chemistry, 2007.79(2):p. 702-709.
16. Piliarik, M.,J. Homola, Self-referencing SPR imaging for most demanding high-throughput screening applications. Sensors and Actuators B:Chemical, 2008.134(2):p.353-355.
17. Beusink, J.B., A. Lokate, G.A. Besselink, G.J. Pruijn, R. Schasfoort, Angle-scanning SPR imaging for detection of biomolecular interactions on microarrays. Biosensors and Bioelectronics, 2008.23(6):p.839-844.
18. Scarano, S., C. Scuffi, M. Mascini, M. Minunni, Surface plasmon resonance imaging (SPRi)-based sensing: A new approach in signal sampling and management. Biosensors and Bioelectronics, 2010.26(4):p.1380-1385.
19. Abbas, A., M.J. Linman, Q. Cheng, Patterned resonance plasmonic microarrays for high-performance SPR imaging. Analytical chemistry, 2011.83(8):p.3147-3152.
20. 梁金庆,图像SPR分析仪及其微阵列芯片的研制[硕士学位论文],北京中国科学院研究生院(电子学研究所),2006.
21. 梁金庆,崔大付,蔡浩原,王军波,王于杰,利用图像SPR分析仪检测多组分蛋白芯片.传感器与微系统,2006.25(10)：p.57-59.
22. 申刚义,韩志强,刘巍,陈义,彩色表面等离子体共振成像初探.高等学校化学学报,2007.28(9)：p.1651-1653.
23. 张轶鸣,陈畯,廖滔,许吉英,陈义,固定光路可变焦宽调角表而等离子共振成像装置.高等学校化学学报,2012.33(2)：p.251-256.
24. Liu, L., S. Ma, Y. Ji, X. Chong, Z. Liu, Y. He, J. Guo, A two-dimensional polarization interferometry based parallel scan angular surface plasmon resonance biosensor. Review of Scientific Instruments, 2011.82(2):p.023109-023109-8.
25. 刘俊锋,SPR微阵列相位检测图像信息采集系统研究[硕士学位论文],北京清华大学,2005.
26. 耿俊清,章恩耀,余兴龙,成像式SPR传感测量中的图像处理方法.光学技术,2007.33(5)：p.673-675.
27. 张玮,邓焱,王大千,丁丽丽,余兴龙,制冷双CCD采集系统在SPR成像中的应用.仪器仪表学报,2011.32(8)：p.1751-1756.
28. 余兴龙,王大千,张玮,罗昭锋,邓焱,丁丽丽,欧惠超,闫硕,章恩耀,SPR双分差动干涉成像生物分子相互作用分析仪.清华大学学报：自然科学版,2013(2)：p.160-166.
29. 张玮,邓焱,王大千,余兴龙,基于变曝光时是图像采集法提高SPR相位成像检测灵敏度.清华大学学报：自然科学版,2011.51(4)：p.433-438.
30. 周超,表面等离子体子共振成像系统的研制和应用[博十学位论文],杭州浙江大学,2013.
31. 赵晓君,陈焕文,表面等离子体子共振传感器Ⅰ：基本原理.分析仪器,2000(4)：p.1-8.
32. Homola, J., Electromagnetic theory of surface plasmons, Berlin Heidelberg:Springer, 2006. p. 3-44.
33. 郁道银,谈恒英,工程光学.北京机械工业出版社.2006.
34. Huang, Z., X. Wang, S. Zhan, X. Liu, Contrast-enhancing polarization control method for surface plasmon imaging sensor. Optical Engineering, 2012.51(9):p.094402-1-094402-8.
35. Homola, J.,M. Piliarik, Surface plasmon resonance (SPR) sensors, Berlin Heidelberg: Springer, 2006. p.45-67.
36. Weber, M.J., Handbook of optical materials. California CRC press. 2002.
37. Jung, L.S., C.T. Campbell, T.M. Chinowsky, M.N. Mar, S.S. Yee, Quantitative interpretation of the response of surface plasmon resonance sensors to adsorbed films. Langmuir, 1998. 14(19):p.5636-5648.
38. Shumaker-Parry, J.S.,C.T. Campbell, Quantitative methods for spatially resolved adsorption/desorption measurements in real time by surface plasmon resonance microscopy. Analytical chemistry, 2004.76(4):p.907-917.
39. Homola, J.,S.S. Yee, Novel polarization control scheme for spectral surface plasmon resonance sensors. Sensors and Actuators B: Chemical, 1998.51(1):p.331-339.
40. Lee, J.-Y.,S.-K. Tsai, Measurement of refractive index variation of liquids by surface plasmon resonance and wavelength-modulated heterodyne interferometry. Optics Communications, 2011.284(4): p.925-929.
41. Wilkop, T., Z. Wang, Q. Cheng, Analysis of μ-contact printed protein patterns by SPR imaging with a LED light source. Langmuir, 2004.20(25):p.11141-11148.
42. Yanase, Y, A. Araki, H. Suzuki, T. Tsutsui, T. Kimura, K. Okamoto, T. Nakatani, T. Hiragun, M. Hide, Development of an optical fiber SPR sensor for living cell activation. Biosensors and Bioelectronics, 2010.25(5):p.1244-1247.
43. Slavik, R.,J. Homola, Ultrahigh resolution long range surface plasmon-based sensor. Sensors and Actuators B: Chemical, 2007.123(1):p.10-12.
44. Vala, M., K. Chadt, M. Piliarik, J. Homola, High-performance compact SPR sensor for multi-analyte sensing Sensors and Actuators B: Chemical, 2010.148(2):p.544-549.
45. Wartmann, R., Double-sided telecentric measurement objective, US, US5708532 A,1998.
46. Jo, B.-H., L.M. Van Lerberghe, K.M. Motsegood, D.J. Beebe, Three-dimensional micro-channel fabrication in polydimethylsiloxane (PDMS) elastomer. Microelectromechanical Systems, Journal of, 2000.9(1):p.76-81.
47. Eddings, M.A., M.A. Johnson, B.K. Gale, Determining the optimal PDMS-PDMS bonding technique for microfluidic devices. Journal of Micromechanics and Microengineering, 2008. 18(6):p.067001.
48. Wang, Z., T. Wilkop, D. Xu, Y. Dong, G. Ma, Q. Cheng, Surface plasmon resonance imaging for affinity analysis of aptamer-protein interactions with PDMS microfluidic chips. Analytical and bioanalytical chemistry, 2007.389(3):p.819-825.
49. Zhan, S., X. Wang, Z. Luo, H. Zhou, H. Chen, Y. Liu, Study on design and application of fully automatic miniature surface plasmon resonance concentration analyzer. Sensors and Actuators B:Chemical, 2011.153(2):p.427-433.
50. 董联红,SPR检测仪监控与分析软件设计[硕士学位论文],杭州浙江大学,2012.
51. Zhan, S., X. Wang, Y. Liu, Fast centroid algorithm for determining the surface plasmon resonance angle using the fixed-boundary method. Measurement Science and Technology, 2011.22(2):p.025201.
52. Piliarik, M.,J. Homola, Surface plasmon resonance (SPR) sensors: approaching their limits? Optics Express, 2009.17(19):p.16505-16517.
53. Nenninger, G.G., M. Piliarik, J. Homola, Data analysis for optical sensors based on spectroscopy of surface plasmons. Measurement Science and Technology, 2002.13(12):p. 2038.
54. Thirstrup, C.,W. Zong, Data analysis for surface plasmon resonance sensors using dynamic baseline algorithm. Sensors and Actuators B: Chemical, 2005.106(2):p.796-802.
55. Owega, S.,D. Poitras, Local similarity matching algorithm for determining SPR angle in surface plasmon resonance sensors. Sensors and Actuators B:Chemical, 2007.123(1):p. 35-41.
56. Stenberg, E., B. Persson, H. Roos, C. Urbaniczky, Quantitative determination of surface concentration of protein with surface plasmon resonance using radiolabeled proteins. Journal of Colloid and Interface Science, 1991.143(2):p.513-526.
57. Kolomenskii, A. A., P. Gershon, H. Schuessler, Sensitivity and detection limit of concentration and adsorption measurements by laser-induced surface-plasmon resonance. Applied Optics, 1997.36(25):p.6539-6547.
58. 赵光灿,多通道表面等离子体共振传感器设计[硕上学位论文],杭州浙江大学,2010.
59. 郦雅平,王晓萍,赵光灿,詹舒越,刘玉玲,SPR光谱信号的一阶矩数据分析方法.浙江大学学报：工学版,2011(12)：p.2269-2273.
60. Huang, Z.,X. Wang, Noise reduction in the surface plasmon resonance array sensor. Optical Engineering, 2013.52(4):p.044403-044403.
61. Huang, N.E.,S.S. Shen, Hilbert-Huang transform and its applications. Vol.5. Singapore World Scientific.2005.
62. Chen, H.,X. Wang, Study on the performance promotion of the surface plasmon resonance analytical system. Instrumentation Science & Technology, 2012.40(2-3):p.226-237.
63. 谭善义,多分辨希尔伯特-黄(Hilbert-Huang)变换方法的研究[博上学位论文],重庆重庆大学,2001.
64. Datig, M.,T. Schlurmann, Performance and limitations of the Hilbert-Huang transformation (HHT) with an application to irregular water waves. Ocean Engineering, 2004.31(14):p. 1783-1834.
65. 杨培杰,印兴耀,张广智,希尔伯特-黄变换地震信号时频分析与属性提取.地球物理学进展,2007.22(5)：p.1585-1590.
66. 刘庆敏,杨午阳,田连玉,徐云泽,李琳,希尔伯特-黄变换在地震资料去噪中的应用.新疆石油地质,2009.30(3)：p.333-336.
67. 韩松,何利铨,孙斌,姜浩,彭小俊,基于希尔伯特-黄变换的电力系统低频振荡的非线性非平稳分析及其应用.电网技术,2008.32(4)：p.56-60.
68. 李天云,程思勇,杨梅,基于希尔伯特-黄变换的电力系统谐波分析.中国电机工程学报,2008.28(4)：p.109-113.
69. Zhidong, Z., Z. Zhijin, C. Yuquan. Time-frequency analysis of heart sound based on HHT [Hilbert-Huang transform].2005:IEEE.
70. Huang, N.E., Z. Shen, S.R. Long, M.C. Wu, H.H. Shih, Q. Zheng, N.-C. Yen, C.C. Tung, H.H. Liu, The empirical mode decomposition and the Hilbert spectrum for nonlinear and non-stationary time series analysis. Proceedings of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences, 1998.454(1971):p.903-995.
71. Chan, D.S.K., Adaptive linear filter for real time noise reduction in surface plasmon resonance systems, US, US8045173 B2,2011.
72. Huang, Z., X. Hong, L. Dong, S. Zhan, X. WANG, X. Liu, Study on calibration method for performance index of SPR sensor. Optoelectronics Letters, 2013.9(5):p.329-332.
73. Homola, J., Surface plasmon resonance based sensors. Vol.4. Berlin Heidelberg Springer. 2006.
74. 云自厚,欧阳律,张晓彤,液相色谱检测方法.北京化学工业出版社.2005.
75. Naya, M., N. Mori, T. Kimura, H. Ohtsuka, T. Kubo, H. Shimizu, Extremely high signal-to-noise ratio surface plasmon resonance sensor using a monolithic prism sensor chip. Journal of Nanophotonics, 2007.1(1):p.011596-011596-9.
76. Shin, Y.-B., H.M. Kim, Y. Jung, B.H. Chung, A new palm-sized surface plasmon resonance (SPR) biosensor based on modulation of a light source by a rotating mirror. Sensors and Actuators B: Chemical, 2010.150(1):p.1-6.
77. Hooper, I., M. Rooth, J. Sambles, Dual-channel differential surface plasmon ellipsometry for bio-chemical sensing. Biosensors and Bioelectronics, 2009.25(2): p.411-417.
78. Lee, J.-Y., H.-C. Shih, C.-T. Hong, T.K. Chou, Measurement of refractive index change by surface plasmon resonance and phase quadrature interferometry. Optics Communications, 2007.276(2):p.283-287.
79. 宝清,现代传感器技术基础.北京：中国铁道出版社.2001.
80. 陈悦,崔大付,蔡浩原,王军波,王于杰,小型SPR生物传感器的研制.传感器与微系统,2007.25(12)：p.79-81.
81. 郝鹏,吴一辉,庄须叶,SPR传感芯片的理论与实验研究.传感技术学报,2008.21(2)：p.211-214.
82. Johnston, K., S. Shen, S.S. Yee, Optical lightpipe sensor based on surface plasmon resonance, US, US5822073 A, 1998.
83. 李海波,徐抒平,刘钰,菅晓光,徐蔚青,波长型SPR检测仪的灵敏度探讨.高等学校化学学报,2010(011)：p.2157-2161.
84. Homola, J., Surface plasmon resonance sensors for detection of chemical and biological species. Chemical reviews, 2008.108(2):p.462.
85. 郝鹏,吴一辉,基于噪声分析的波长表面等离子体共振分析仪的数据处理.光学精密工程,2009.17(9)：p.2159.
86. Masadome, T., Y. Asano, T. Imato, S. Ohkubo, T. Tobita, H. Tabei, Y. Iwasaki, O. Niwa, Y. Fushinuki, Preparation of refractive index matching polymer film alternative to oil for use in a portable surface-plasmon resonance phenomenon-based chemical sensor method. Analytical and bioanalytical chemistry, 2002.373(4-5):p.222-226.
87. Lim, T.-k., M. Oyama, K. Ikebukuro, I. Karube, Detection of Atrazine Based on the SPR Determination of P450 mRNA Levels in Saccharomyces c erevisiae. Analytical chemistry, 2000.72(13):p.2856-2860.
88. 曾捷,梁大开,曾振武,杜燕,基于SPR光谱分析的液体折射率测量研究.光谱学与光谱分析,2006.26(4)：p.723-727.
89. 王晓雷,李伟,胡建东,张润娜,赵向阳,涂洪涛,李伟华,表面等离子共振生物传感系统构建及应用研究.化学通报,2008.71(1)：p.62-67.
90. 白泽生,刘竹琴,徐红,几种液体的折射率与其浓度关系的经验公式.延安大学学报：自然科学版,2004.23(1)：p.33-36.
91. 张志伟,尹卫峰,温廷敦,朱林泉,张记龙,溶液浓度与其折射率关系的理论和实验研究.中北大学学报(自然科学版),2009.30(3)：p.281-285.