光微流体生物传感中葡萄球菌肠毒素SEA抗体的固化状态研究
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摘要
基于回音壁谐振模式的光学微腔生物传感器是通过检测固定在微腔表面的生物分子与待测物特异性结合所引起的传感信号变化,对待测物进行微量分析。由于具有体积小、灵敏度高、样品消耗量低、检测无标记等优点,这种传感器近年来受到国内外研究人员越来越多的关注,成为研究热点之一。
微管谐振腔可以将样品输送通道和传感通道合二为一,简化了传感系统,同时具有多路复用的潜力,因此很有发展前景。本文主要针对基于微管的光微流体生物传感器理论模型做了分析研究,并利用时域有限差分算法对微管谐振腔进行了数值模拟,搭建了基于棱镜耦合方法的微管生物传感实验系统,将其用于葡萄球菌肠毒素A(Staphylococcal Enterotoxin A,SEA)抗体在微管内壁固化情况的实验研究中,初步展现了系统在生物传感检测方面的应用,完成的工作主要有以下几点:
1、基于耦合模理论,研究了微管谐振腔的理论模型和微管中光的传输特性;从Maxwell方程出发,推导在柱坐标系下两种不同结构——分别对应于体传感的两层结构和表面传感的三层结构——微管谐振腔中光的电磁场分布表达式,并计算了径向电场在微管内的分布;初步分析了微管谐振腔用于生物传感的两种方式和传感灵敏度。
2、利用基于时域有限差分算法的Fullwave模块,对微管谐振腔进行了数值模拟。研究了光在微管中的传播以及谐振状态,并分别数值分析了微管半径、壁厚等对谐振波长漂移的影响,计算了不同模式数下的体折射率以及表面折射率传感灵敏度。
3、将石英毛细管作为微管谐振腔,采用棱镜耦合方式,激发微管中的WGM模,搭建光微流体生物传感实验系统,研究SEA抗体分子在微管内壁的固化状态。通过检测对应不同浓度SEA抗体溶液的WGM谐振波长漂移量,计算抗体分子固化在微管内壁的表面密度,并与理想表面密度进行比较,初步获得固化系数与SEA抗体溶液浓度的线性关系,为进一步的深入研究奠定了基础。
Optical microcavity biosensor is a kind of sensor which is based on the whispering gallery mode and achieves quantitative analysis. It works mainly by detecting the sensing signal change caused by the specific binding of the analyte to biological molecules immobilizated on the microcavity surface in advance. Due to the small size, high sensitivity, low sample consumption and label-free detection, optical microcavity biosensor has recently attracted increasing attentions.
Owing to the structural feature, microtube simultaneously acts as the light guide channel and fluid transport channel, which simplifies the sensing system, and also has the multiplexing potential. As a result, biosensor based on microtube is very promising. In this paper, the microtube-based optofluidic biosensor is studied theoretically and experimentally and the major work completed is as follows:
1. The theoretical model of the microtube resonator is established by the coupling mode theory, and transmission characteristics of the light propagating in the microtube are studied. Then from the Maxwell’s equations, distribution of the electromagnetic field in the microtube in a cylindrical coordinate system is derived. A brief overview of two different sensing mechanisms for microtube used as a biosensor is given finally.
2. By using the FullWAVE simulation engine based on the finite-difference time-domain algorithm, the microring resonator, a two dimensional model Simplified from the microtube, is simulated and the light propagating states in the microring is studied. Meanwhile, resonance wavelength shift caused by respectively changing different parameters, such as the wall thickness and the effective radius of the microring, is calculated and according to the result, sensitivities with different modes are compared.
3. A optofluidic biosensing experimental system based on microtube immobilizated with staphylococcal enterotoxin A antibodies on its inner wall is built by a prism coupling method, and is applicated in the surface density detection of the SEA antibody. By measuring resonance wavelength shifts corresponding to various concentrations of the antibody solutions injected into the micotube, surface densities can be obtained. Comparing with the ideal and the calculated value, it’s found that only part of SEA antibodies is immobilized and immobilization coefficient k linearly increases with concentrations before saturation concentration. This result is useful for WGM-based optofluidic biosensor development.
微管谐振腔可以将样品输送通道和传感通道合二为一,简化了传感系统,同时具有多路复用的潜力,因此很有发展前景。本文主要针对基于微管的光微流体生物传感器理论模型做了分析研究,并利用时域有限差分算法对微管谐振腔进行了数值模拟,搭建了基于棱镜耦合方法的微管生物传感实验系统,将其用于葡萄球菌肠毒素A(Staphylococcal Enterotoxin A,SEA)抗体在微管内壁固化情况的实验研究中,初步展现了系统在生物传感检测方面的应用,完成的工作主要有以下几点:
1、基于耦合模理论,研究了微管谐振腔的理论模型和微管中光的传输特性;从Maxwell方程出发,推导在柱坐标系下两种不同结构——分别对应于体传感的两层结构和表面传感的三层结构——微管谐振腔中光的电磁场分布表达式,并计算了径向电场在微管内的分布;初步分析了微管谐振腔用于生物传感的两种方式和传感灵敏度。
2、利用基于时域有限差分算法的Fullwave模块,对微管谐振腔进行了数值模拟。研究了光在微管中的传播以及谐振状态,并分别数值分析了微管半径、壁厚等对谐振波长漂移的影响,计算了不同模式数下的体折射率以及表面折射率传感灵敏度。
3、将石英毛细管作为微管谐振腔,采用棱镜耦合方式,激发微管中的WGM模,搭建光微流体生物传感实验系统,研究SEA抗体分子在微管内壁的固化状态。通过检测对应不同浓度SEA抗体溶液的WGM谐振波长漂移量,计算抗体分子固化在微管内壁的表面密度,并与理想表面密度进行比较,初步获得固化系数与SEA抗体溶液浓度的线性关系,为进一步的深入研究奠定了基础。
Optical microcavity biosensor is a kind of sensor which is based on the whispering gallery mode and achieves quantitative analysis. It works mainly by detecting the sensing signal change caused by the specific binding of the analyte to biological molecules immobilizated on the microcavity surface in advance. Due to the small size, high sensitivity, low sample consumption and label-free detection, optical microcavity biosensor has recently attracted increasing attentions.
Owing to the structural feature, microtube simultaneously acts as the light guide channel and fluid transport channel, which simplifies the sensing system, and also has the multiplexing potential. As a result, biosensor based on microtube is very promising. In this paper, the microtube-based optofluidic biosensor is studied theoretically and experimentally and the major work completed is as follows:
1. The theoretical model of the microtube resonator is established by the coupling mode theory, and transmission characteristics of the light propagating in the microtube are studied. Then from the Maxwell’s equations, distribution of the electromagnetic field in the microtube in a cylindrical coordinate system is derived. A brief overview of two different sensing mechanisms for microtube used as a biosensor is given finally.
2. By using the FullWAVE simulation engine based on the finite-difference time-domain algorithm, the microring resonator, a two dimensional model Simplified from the microtube, is simulated and the light propagating states in the microring is studied. Meanwhile, resonance wavelength shift caused by respectively changing different parameters, such as the wall thickness and the effective radius of the microring, is calculated and according to the result, sensitivities with different modes are compared.
3. A optofluidic biosensing experimental system based on microtube immobilizated with staphylococcal enterotoxin A antibodies on its inner wall is built by a prism coupling method, and is applicated in the surface density detection of the SEA antibody. By measuring resonance wavelength shifts corresponding to various concentrations of the antibody solutions injected into the micotube, surface densities can be obtained. Comparing with the ideal and the calculated value, it’s found that only part of SEA antibodies is immobilized and immobilization coefficient k linearly increases with concentrations before saturation concentration. This result is useful for WGM-based optofluidic biosensor development.
引文
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[2]Clark L C, Lyon C, Electrode system for continuous monitoring in cardiovaseular surgery.Ann.N.Y.Aead.Sei.,1962,102:29~45
[3]Updike S J, Hicks G P, The enzyme electrode, Nature, 1967, Vol.214(92):986~988.
[4]韩雪清,杨泽晓,林祥梅,极具应用前景的生物学检测技术—生物传感器,中国生物工程杂志,2008,Vol.28(5):141~14
[5] Gomes S A S S, Nogueira J M F, Rebelo M J F, An amPerometric biosensor for Polyphenolic compounds in red wine, Biosensors and Bioelectronies, 2004, 20:1211~1216
[6]Kroger S, Piletsky S, Turner A P F, Biosensors for marine pollution research, monitoring and control, Marine Pollution Bulletin, 2002, 45(12-jan), 24-34
[7]Ulber R, Frerichs J G, Beutel S, Optical sensor systems for bioprocess monitoring. Anal Bioanal Chem. 2003 Jun;376(3):342-8
[8]O’Neil P M, Fletcher J E, Srafford C G, et al Use of an optical biosensor to measure prostate-specific antigen in whole blood, Sensors and Actuators B: Chemical, 1995, 29:79~83
[9]葛晶,使用SPR生物传感器快速检测大肠杆菌的研究:[硕士毕业论文],上海:复旦大学,2005
[10]王锋,樊先平,王民权,光学生物传感器的研究进展,材料导报,2004,7(18):1~4
[11]Ye Fang, Non-Invasive Optical Biosensor for Probing Cell Signaling, sensor, 2007, 7:2316~2329
[12]江俊峰,?李海伟,刘铁根等,基于空心光纤构建微管生物传感器的实验研究,中国激光,2010,37(6):1421~1425
[13]Vollmer, F, et al, Protein detection by optical shift of a resonant microcavity. Applied Physics Letters, 2002. 80(21): 4057-4059
[14]S. Arnold, M. Khoshsima, I. Teraoka, S. Holler, et al, Shift of whispering-gallery modes in microspheres by protein adsorption. Opt. Lett. ,2003, 28(4):272~274
[15]M. Noto, M. Khoshsima, D. Keng, I. Teraoka, et al, Molecular weight dependence of a whispering gallery mode biosensor,?Appl. Phys. Lett. 2005, 87, 223901
[16]Ren, H.C., et al., High-Q microsphere biosensor analysis for adsorption of rodlike bacteria. Optics Express, 2007. 15(25):17410-17423
[17]Vollmer, F., S. Arnold, and D. Keng, Single virus detection from the reactive shift of a whispering-gallery mode. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(52): 20701-20704
[18]M. Noto, D. Keng, I. Teraoka, et al, Detection of Protein Orientation on the Silica Microsphere Surface using ? Transverse Electric/Transverse Magnetic Whispering Gallery Modes, Bio. Phys. J., 2007, 92, 4466-4472
[19]Teraoka, I. and S. Arnold,. Enhancing the sensitivity of a whispering-gallry mode microsphere sensor by a hight-refractive-index surface layer.Journal of the Optical Society of America B-Optical Physics, 2006. 23(7): 1434-1441
[20]Gaathon, O., et al., Enhancing sensitivity of a whispering gallery mode biosensor by subwavelength confinement. Applied Physics Letters, 2006. 89(22)
[21]R.W.Boyd, J.E.Heebner. Sensitive disk resonator photonic biosensor. Appl,Opt,2001, 40: 5742~5747
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