便携式生物化学发光测量平台的研究
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摘要
生物化学发光免疫分析法(Chemiluminescence Immunoassay, CLIA)是建立在放射免疫分析技术(Radio Immunoassay, RIA)理论的基础上,以标记发光剂为示踪物信号建立起来的一种非放射标记免疫分析法,具有灵敏度高、线性范围宽、易操作、易于实现自动化等优点。经过三十多年的发展,以光电倍增管(Photomultiplier tube, PMT)为核心部件的生物化学发光测量仪已经成为成熟的医疗诊断设备。通用型生物化学发光测量仪设备价格昂贵、体积笨重、功耗巨大,难以普及推广到家庭和个人,而随着近年来光电器件研究的进展,实现生物化学发光测量仪的微型化、便携化具备了一定的条件。
本课题是便携式生物化学发光测量仪的预研项目,通过对生物化学发光(Biochemical luminescence, BCL)测量领域的调研和研究,提出了基于固态光电传感器的生物化学发光测量仪的设计方案,设计并研制出了用于实验和验证的生物化学发光测量系统硬件平台,为便携式生物化学发光测量仪的研制,提供了技术基础。
本文的工作主要体现在以下几个方面:
1.调研了生物化学发光测量与光子测量与计数领域的前沿研究现状,对应用于生物化学发光测量领域的光电倍增管、电荷耦合器件(Charge-Coupled Device,CCD)、雪崩击穿光电二极管(avalanche Photodiode, APD)、硅光电倍增管(Silicon Photomultiplier, SiPM)等光电传感器进行了调研,提出了基于APD与SiPM的便携式生物化学发光测量系统设计方案。
2.设计并研制出了基于光电倍增管的前端光子信号测量单元,为生物化学发光测量系统的研究提供了一个实验和验证的传感器平台。
3.设计了基于ARM+FPGA的生物化学发光测量系统的后端数据采集与处理平台,完成了底层软件系统的开发。作为后端数据采集与处理的实验与验证平台,设计并实现了基于32位DSP处理器的高速信号采集系统。
4.完成了整个生物化学发光测量平台的基础功能测试,为本项目后续的研究工作提供了基本的平台。
Based on the theory of RIA technology, chemiluminescence immunoassay is a kind of non-radioactive immunoassay. With advantages of high sensitivity, wide linear range, easy to use and easy to realize automation, chemiluminescence immunoassay uses the marked brightening agent as Signal tracer. After 30 years research and development, it has become a mature immune analysis technique. But the General purpose Chemiluminescence instrument is too expensive, bulky size, great power to promote universal access to families and individuals. Compared to the professional-grade large-scale medical equipment in hospitals, Portable personal medical diagnostic equipment has its advantage of convenience. In recent years,with the progress of optoelectronic devices, luminescence measuring instrument has a certain condition to achieve miniaturization and portable.
With the work of investigation and research in the field of chemiluminescence, a forward-looking thinking and design for chemiluminescence detecting system based on solid-state photoelectric sensor was made, a chemiluminescence system hardware platform for Authentication was designed and build. This work provides the basis for the further research of portable-chemiluminescence instrument. The research work of this paper lies in the following areas:
1. In the filed of chemiluminescence and photo detecting and counting, the cutting-edge research was studied. Researched several photoelectric sensors such as PMT, CCD, avalanche photodiode (APD), silicon photodiode tube (SiPM), and so on. Give out a portable chemiluminescence detecting system design.
2. Designed and developed a front-end module of photon signal acquisition for chemiluminescence detecting system based on the photomultiplier tube. This provides a verification of the sensor platform for the research and development of chemiluminescence instrument.
3. Designed and implemented back-end signal processing platform based on ARM + FPGA for biochemiluminescence detecting system, and developed the Underlying software system. Also, Designed and developed a high-speed signal acquisition system based on 32-bit DSP.
4. Realized the functional verification of the entire chemiluminesecnce system. The work made a theoretical basis and experimental platform for the further research.
本课题是便携式生物化学发光测量仪的预研项目,通过对生物化学发光(Biochemical luminescence, BCL)测量领域的调研和研究,提出了基于固态光电传感器的生物化学发光测量仪的设计方案,设计并研制出了用于实验和验证的生物化学发光测量系统硬件平台,为便携式生物化学发光测量仪的研制,提供了技术基础。
本文的工作主要体现在以下几个方面:
1.调研了生物化学发光测量与光子测量与计数领域的前沿研究现状,对应用于生物化学发光测量领域的光电倍增管、电荷耦合器件(Charge-Coupled Device,CCD)、雪崩击穿光电二极管(avalanche Photodiode, APD)、硅光电倍增管(Silicon Photomultiplier, SiPM)等光电传感器进行了调研,提出了基于APD与SiPM的便携式生物化学发光测量系统设计方案。
2.设计并研制出了基于光电倍增管的前端光子信号测量单元,为生物化学发光测量系统的研究提供了一个实验和验证的传感器平台。
3.设计了基于ARM+FPGA的生物化学发光测量系统的后端数据采集与处理平台,完成了底层软件系统的开发。作为后端数据采集与处理的实验与验证平台,设计并实现了基于32位DSP处理器的高速信号采集系统。
4.完成了整个生物化学发光测量平台的基础功能测试,为本项目后续的研究工作提供了基本的平台。
Based on the theory of RIA technology, chemiluminescence immunoassay is a kind of non-radioactive immunoassay. With advantages of high sensitivity, wide linear range, easy to use and easy to realize automation, chemiluminescence immunoassay uses the marked brightening agent as Signal tracer. After 30 years research and development, it has become a mature immune analysis technique. But the General purpose Chemiluminescence instrument is too expensive, bulky size, great power to promote universal access to families and individuals. Compared to the professional-grade large-scale medical equipment in hospitals, Portable personal medical diagnostic equipment has its advantage of convenience. In recent years,with the progress of optoelectronic devices, luminescence measuring instrument has a certain condition to achieve miniaturization and portable.
With the work of investigation and research in the field of chemiluminescence, a forward-looking thinking and design for chemiluminescence detecting system based on solid-state photoelectric sensor was made, a chemiluminescence system hardware platform for Authentication was designed and build. This work provides the basis for the further research of portable-chemiluminescence instrument. The research work of this paper lies in the following areas:
1. In the filed of chemiluminescence and photo detecting and counting, the cutting-edge research was studied. Researched several photoelectric sensors such as PMT, CCD, avalanche photodiode (APD), silicon photodiode tube (SiPM), and so on. Give out a portable chemiluminescence detecting system design.
2. Designed and developed a front-end module of photon signal acquisition for chemiluminescence detecting system based on the photomultiplier tube. This provides a verification of the sensor platform for the research and development of chemiluminescence instrument.
3. Designed and implemented back-end signal processing platform based on ARM + FPGA for biochemiluminescence detecting system, and developed the Underlying software system. Also, Designed and developed a high-speed signal acquisition system based on 32-bit DSP.
4. Realized the functional verification of the entire chemiluminesecnce system. The work made a theoretical basis and experimental platform for the further research.
引文
[1]魏继峰.光子成像技术及其新进展.激光与光电子学进展,2007年7月.
[2]王栩,林金明.化学发光免疫分析技术新进展.分析实验室,2007年6月.
[3] Khaled Salama, Helmy Eltoukhy, Arjang Hassibi, etc.Modeling and simulation of luminescence detection platforms.biosensors and bioelectronics, Jun 2004.
[4]罗丽容.化学发光成像分析法定量检测人尿液中β-人绒毛膜促性腺激素.分析化学,2005年第9期.
[5]马晓燠,饶长辉,张学军.三种光电器件用于天体光度测量时的性能比较.光学学报,2007年第五期.
[6]莫建华.基于CMOS的μTAS荧光检测系统的开发. 2005年浙江大学硕士学位论文.
[7]张灿林,陈钱,周蓓蓓.高灵敏度电子倍增CCD的发展现状.红外技术,2007年第四期.
[8] Ude Lu, Ben C.-P.Hu,Yu-Chuan Shih,Yuh-Shyong Yang,Chung-Yu Wu,Chiun-Jye Yuan, Ming-Dou Ker, Tung-Kung Wu, Yaw-Kuen Li,You-Zung Hsieh,Wensyang Hsu,Chin-Teng Lin. CMOS Chip as Luminescent Sensor for Biochemical Reactions.IEEE SENSORS JOURNAL,Jun 2003.
[9] Application Form For Innovators’Challenge Competition stanfod 2007.
[10] Gerralt A. de Vree, G.A.Westra, A.H. Moody, I.van der Have, F.Ligtvoet, K.M.Beekman. Electronics for a Photon-counting Gamma Camera based on an Electron-multiplying CCD.Nuclear Science Symposium Conference Record, Oct 2004.
[11]段帷,赵昭旺.基于EMCCD的成像系统的构建.天文研究与技术,2006年第四期.
[12] Smith D.R,Ingley R, Holland A.D. Proton irradiation of EMCCDs.Electron Devices,Feb 2006.
[13] Soesbe T.C, Lewis M.A, Richer E, Slavine N.V, Antich P.P. Development and Evaluation of an EMCCD Based Gamma Camera for Preclinical SPECT Imaging. Nuclear Science,Oct 2007.
[14]王俊生,许文海,黎坚,邢达,陈维山.高灵敏延迟荧光探测植物光合速率检测系统.光电工程,2007年3月.
[15]潘建国,阙沛文,雷华明.基于FPGA的高速大容量数据采集系统设计.电子测量技术, 2008年9月.
[16]张鹏飞,周金运.单光子探测器及其发展.传感器世界, 2003年10期.
[17]上海科端生物科技.化学发光仪和弱光检测. 2005年.
[18] J. C. Jacksona, J. Westa, A. M. Moloneyb, D. O'Connella, A. P. Morrisonb, A. Mathewson. A novel flipchipped integrated single photon detection platform for proteomics.Optics and PhotonicsTechnologies and Applications, 2003.
[19] E.Levin, E. Shelegeda, V. E. Shubin, D. A. Shushakov,Constantin Sitarsky,S. Vinogradov. Advances in the development of solid state photomultipliers formedical imaging.Medical Imaging,2008.
[20] William G.Lawrence,Gyula Varadi,Gerald.Entine,Edward Podniesinski,Paul K.Wallace. A Comparison of Avalanche Photodiode and Photomultiplier Tube Detectors for Flow Cytometry.Imaging, Manipulation,and Analysis of Biomolecules, 2008.
[21] WU Qing-Lin,LIU Yun,HAN Zheng-Fu,CHEN Wei,DAI Yi-Min, WEI Guo,GUO Guang-Can. Single photon detector module based on avalanche photodiodes.International Symposium on Photoelectronic Detection and Imaging, 2007.
[22] Sergey V.Polyakov, V.Schettinib,I.P.Degiovanni,G.Brida, Alan Migdalla. Multiplexed PhotonCounting Detectors. Quantum Sensing and Nanophotonic Devices,2008.
[23] I.Rech,I Labanca,M.Ghioni,S.Cova. Modified single photon counting modules for optimal timing performance. REVIEW OF SCIENTIFIC INSTRUMENTS,2006.
[24] Jeffrey A.Mendenhall,Lawrence M.Candell,Pablo I.Hopman,George Zogbi,Don M.Boroson,David O.Caplan,Constantine J.Digenis,David R.Hearn,Ryan C. ShoupDesign of an Optical Photon Counting Array Receiver System for Deep-Space Communications.Digital Object Identifier,2007.
[25]何瑾,刘铁根,孟卓,杨莉君.弱光强信号检测系统前级放大电路的设计.科学技术与工程,2007年5月.
[26]霍戌文,李伟,李进,陈科.光电探测微信号放大器设计.浙江理工大学学报,2005年9月.
[27] [日]冈村迪夫. OP放大电路设计—从重视再现性设计的基础到实际应用.科学出版社,2005年出版.
[28]李建新,王应宗.光电倍增管单光子探测器的噪声特性研究.延安大学学报,2006年3月.
[29]陈凯,杨振萍.确定单光子计数系统中最佳甄别电压的实验研究.物理实验,2007年11月.
[30]张雪皎,万钧力.单光子探测器件的发展与应用.激光杂志,2007年第五期.
[31]王海科,吕云鹏.光电倍增管特性及应用.仪器仪表与分析监测,2005年第1期.
[32]闯恩华,郭旭.基于光子计数技术的测量系统研究.上海电机学院学报,2007年4月.
[33]朱勇,欧阳俊.单光子计数系统的设计与实现.仪器仪表学报,2007年4月.
[34]黄宇红.单光子计数实验系统及其应用.实验科学与技术,2006年2月.
[35] S.Cova, M.Ghioni, A. Lacaita, C. Samori, F. Zappa. Avalanche photodiodes and quenching circuits for singlephoton detection. APPLIED OPTICS,April 1996.
[36] Vinit H.Dhulla,Georgiy Gudkov,Dmitri Gavrilov,Andrey Stepukhovich,Andriy Tsupryk,OlgaKosobokova,Anatoly Borodin,Boris Gorbovitski,Vera Gorfinkel. Single Photon Counting Module Based on LargeArea APD and Novel Logic Circuit for Quench and Reset Pulse Generation.Digital Object Identifier,2007.
[37] K. Yamamoto, K. Yamamura, K. Sato, S. Kamakura, T. Ota, H. Suzuki, S. Ohsuka. Development of Multi-Pixel Photon Counter (MPPC). Nuclear Science Symposium Conference Record,2007.
[2]王栩,林金明.化学发光免疫分析技术新进展.分析实验室,2007年6月.
[3] Khaled Salama, Helmy Eltoukhy, Arjang Hassibi, etc.Modeling and simulation of luminescence detection platforms.biosensors and bioelectronics, Jun 2004.
[4]罗丽容.化学发光成像分析法定量检测人尿液中β-人绒毛膜促性腺激素.分析化学,2005年第9期.
[5]马晓燠,饶长辉,张学军.三种光电器件用于天体光度测量时的性能比较.光学学报,2007年第五期.
[6]莫建华.基于CMOS的μTAS荧光检测系统的开发. 2005年浙江大学硕士学位论文.
[7]张灿林,陈钱,周蓓蓓.高灵敏度电子倍增CCD的发展现状.红外技术,2007年第四期.
[8] Ude Lu, Ben C.-P.Hu,Yu-Chuan Shih,Yuh-Shyong Yang,Chung-Yu Wu,Chiun-Jye Yuan, Ming-Dou Ker, Tung-Kung Wu, Yaw-Kuen Li,You-Zung Hsieh,Wensyang Hsu,Chin-Teng Lin. CMOS Chip as Luminescent Sensor for Biochemical Reactions.IEEE SENSORS JOURNAL,Jun 2003.
[9] Application Form For Innovators’Challenge Competition stanfod 2007.
[10] Gerralt A. de Vree, G.A.Westra, A.H. Moody, I.van der Have, F.Ligtvoet, K.M.Beekman. Electronics for a Photon-counting Gamma Camera based on an Electron-multiplying CCD.Nuclear Science Symposium Conference Record, Oct 2004.
[11]段帷,赵昭旺.基于EMCCD的成像系统的构建.天文研究与技术,2006年第四期.
[12] Smith D.R,Ingley R, Holland A.D. Proton irradiation of EMCCDs.Electron Devices,Feb 2006.
[13] Soesbe T.C, Lewis M.A, Richer E, Slavine N.V, Antich P.P. Development and Evaluation of an EMCCD Based Gamma Camera for Preclinical SPECT Imaging. Nuclear Science,Oct 2007.
[14]王俊生,许文海,黎坚,邢达,陈维山.高灵敏延迟荧光探测植物光合速率检测系统.光电工程,2007年3月.
[15]潘建国,阙沛文,雷华明.基于FPGA的高速大容量数据采集系统设计.电子测量技术, 2008年9月.
[16]张鹏飞,周金运.单光子探测器及其发展.传感器世界, 2003年10期.
[17]上海科端生物科技.化学发光仪和弱光检测. 2005年.
[18] J. C. Jacksona, J. Westa, A. M. Moloneyb, D. O'Connella, A. P. Morrisonb, A. Mathewson. A novel flipchipped integrated single photon detection platform for proteomics.Optics and PhotonicsTechnologies and Applications, 2003.
[19] E.Levin, E. Shelegeda, V. E. Shubin, D. A. Shushakov,Constantin Sitarsky,S. Vinogradov. Advances in the development of solid state photomultipliers formedical imaging.Medical Imaging,2008.
[20] William G.Lawrence,Gyula Varadi,Gerald.Entine,Edward Podniesinski,Paul K.Wallace. A Comparison of Avalanche Photodiode and Photomultiplier Tube Detectors for Flow Cytometry.Imaging, Manipulation,and Analysis of Biomolecules, 2008.
[21] WU Qing-Lin,LIU Yun,HAN Zheng-Fu,CHEN Wei,DAI Yi-Min, WEI Guo,GUO Guang-Can. Single photon detector module based on avalanche photodiodes.International Symposium on Photoelectronic Detection and Imaging, 2007.
[22] Sergey V.Polyakov, V.Schettinib,I.P.Degiovanni,G.Brida, Alan Migdalla. Multiplexed PhotonCounting Detectors. Quantum Sensing and Nanophotonic Devices,2008.
[23] I.Rech,I Labanca,M.Ghioni,S.Cova. Modified single photon counting modules for optimal timing performance. REVIEW OF SCIENTIFIC INSTRUMENTS,2006.
[24] Jeffrey A.Mendenhall,Lawrence M.Candell,Pablo I.Hopman,George Zogbi,Don M.Boroson,David O.Caplan,Constantine J.Digenis,David R.Hearn,Ryan C. ShoupDesign of an Optical Photon Counting Array Receiver System for Deep-Space Communications.Digital Object Identifier,2007.
[25]何瑾,刘铁根,孟卓,杨莉君.弱光强信号检测系统前级放大电路的设计.科学技术与工程,2007年5月.
[26]霍戌文,李伟,李进,陈科.光电探测微信号放大器设计.浙江理工大学学报,2005年9月.
[27] [日]冈村迪夫. OP放大电路设计—从重视再现性设计的基础到实际应用.科学出版社,2005年出版.
[28]李建新,王应宗.光电倍增管单光子探测器的噪声特性研究.延安大学学报,2006年3月.
[29]陈凯,杨振萍.确定单光子计数系统中最佳甄别电压的实验研究.物理实验,2007年11月.
[30]张雪皎,万钧力.单光子探测器件的发展与应用.激光杂志,2007年第五期.
[31]王海科,吕云鹏.光电倍增管特性及应用.仪器仪表与分析监测,2005年第1期.
[32]闯恩华,郭旭.基于光子计数技术的测量系统研究.上海电机学院学报,2007年4月.
[33]朱勇,欧阳俊.单光子计数系统的设计与实现.仪器仪表学报,2007年4月.
[34]黄宇红.单光子计数实验系统及其应用.实验科学与技术,2006年2月.
[35] S.Cova, M.Ghioni, A. Lacaita, C. Samori, F. Zappa. Avalanche photodiodes and quenching circuits for singlephoton detection. APPLIED OPTICS,April 1996.
[36] Vinit H.Dhulla,Georgiy Gudkov,Dmitri Gavrilov,Andrey Stepukhovich,Andriy Tsupryk,OlgaKosobokova,Anatoly Borodin,Boris Gorbovitski,Vera Gorfinkel. Single Photon Counting Module Based on LargeArea APD and Novel Logic Circuit for Quench and Reset Pulse Generation.Digital Object Identifier,2007.
[37] K. Yamamoto, K. Yamamura, K. Sato, S. Kamakura, T. Ota, H. Suzuki, S. Ohsuka. Development of Multi-Pixel Photon Counter (MPPC). Nuclear Science Symposium Conference Record,2007.