细胞捕获、操控及光学检测平台研究
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摘要
细胞研究对癌症、艾滋病等重大疾病的研究十分重要,提供一种方便、快捷的细胞捕获和检测方法将促进细胞生物学的发展。将MEMS技术用于细胞生物学基础研究以及小型化生物仪器研究意义重大。
本文利用MEMS技术制做了一种基于微磁珠技术的细胞捕获芯片,提出了一种基于悬臂梁控制、电容式力学检测的细胞操作平台,并开发了一种用于细胞生长环境检测的光学检测系统,其内容主要包括：
1.介绍磁珠捕获理论,提出MEMS芯片结构模型,并使用仿真软件模拟了芯片工作性能；使用MEMS制作加工细胞捕获芯片,采用结肠癌细胞以及CD4细胞对芯片功能进行测试,并得到结肠癌细胞在0.1 ml/h流速下捕获效率达到92.3%。
2.使用MEMS工艺制作加工用于细胞微操控力检测的MEMS电容,使用仿真软件模拟其力学、电学性能,并搭建了微电容测量电路。
3.利用单片机、Arduino开发板、VB程序以及LED和PD等搭建用于细胞生长环境微光检测的小型化透射光检测系统；对系统进行环境测试和蓝光信号测试,并使用黄色染料进行了浓度测试。
本文提出的细胞捕获芯片具有微量化以及便于操作等优点；采用MEMS电容式力敏传感器控制微力、将悬臂梁用于细胞微操作的平台易于细胞研究；而基于LED和PD的细胞环境检测平台研究能够推动细胞检测设备往小型化发展。本文的研究对细胞生物学基础研究及临床检测的发展有重要的意义。
Cell research is an important part in disease research such as cancer and AIDS. It will help to develop cell biology to give a convenient and fast cell capturing and detecting method. It is meaningful to use the MEMS technology to research cell biology and biological device miniaturization.
This paper uses MEMS technology to fabricate a kind of cell capture chip based on immunomagnetic bead technology, proposes a platform which uses MEMS cantilever to manipulate cell and uses capacitance micro-force sensor to test force, and develops a kind of optical detection system for detecting cell growing condition. The main contents include as following:
1. Magnetic capture theory, Bio-MEMS chip's performance simulation and its fabrication process is introduced, and this chip's function test using cancer cells and CD4 cells is discussed. The cancer cells'capture efficient is 92.3% at the 0.1ml/h rate.
2. The fabrication of MEMS capacitance which is used to test cell's micro control force is introduced. Their mechanical and electrical properties simulation and the canpacitance test circuit is discussed.
3. The optical detection system for cells growing condition test by Micro Computer Unit, Arduino development board, VB, LED and PD is set up. The environment test, blue light test and yellow dye solution test is discussed.
This MEMS cell capture chip needs only small volume of sample, and is operated easily. The cell manipulation platform composed of MEMS cantilever and capacitance micro-force sensor is useful for cell research. And the optical detection system for cell's growing condition test could promote the miniaturization of biological testing equipment.
本文利用MEMS技术制做了一种基于微磁珠技术的细胞捕获芯片,提出了一种基于悬臂梁控制、电容式力学检测的细胞操作平台,并开发了一种用于细胞生长环境检测的光学检测系统,其内容主要包括：
1.介绍磁珠捕获理论,提出MEMS芯片结构模型,并使用仿真软件模拟了芯片工作性能；使用MEMS制作加工细胞捕获芯片,采用结肠癌细胞以及CD4细胞对芯片功能进行测试,并得到结肠癌细胞在0.1 ml/h流速下捕获效率达到92.3%。
2.使用MEMS工艺制作加工用于细胞微操控力检测的MEMS电容,使用仿真软件模拟其力学、电学性能,并搭建了微电容测量电路。
3.利用单片机、Arduino开发板、VB程序以及LED和PD等搭建用于细胞生长环境微光检测的小型化透射光检测系统；对系统进行环境测试和蓝光信号测试,并使用黄色染料进行了浓度测试。
本文提出的细胞捕获芯片具有微量化以及便于操作等优点；采用MEMS电容式力敏传感器控制微力、将悬臂梁用于细胞微操作的平台易于细胞研究；而基于LED和PD的细胞环境检测平台研究能够推动细胞检测设备往小型化发展。本文的研究对细胞生物学基础研究及临床检测的发展有重要的意义。
Cell research is an important part in disease research such as cancer and AIDS. It will help to develop cell biology to give a convenient and fast cell capturing and detecting method. It is meaningful to use the MEMS technology to research cell biology and biological device miniaturization.
This paper uses MEMS technology to fabricate a kind of cell capture chip based on immunomagnetic bead technology, proposes a platform which uses MEMS cantilever to manipulate cell and uses capacitance micro-force sensor to test force, and develops a kind of optical detection system for detecting cell growing condition. The main contents include as following:
1. Magnetic capture theory, Bio-MEMS chip's performance simulation and its fabrication process is introduced, and this chip's function test using cancer cells and CD4 cells is discussed. The cancer cells'capture efficient is 92.3% at the 0.1ml/h rate.
2. The fabrication of MEMS capacitance which is used to test cell's micro control force is introduced. Their mechanical and electrical properties simulation and the canpacitance test circuit is discussed.
3. The optical detection system for cells growing condition test by Micro Computer Unit, Arduino development board, VB, LED and PD is set up. The environment test, blue light test and yellow dye solution test is discussed.
This MEMS cell capture chip needs only small volume of sample, and is operated easily. The cell manipulation platform composed of MEMS cantilever and capacitance micro-force sensor is useful for cell research. And the optical detection system for cell's growing condition test could promote the miniaturization of biological testing equipment.
引文
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[2]I Nicoletti, G Migliorati, MC Pagliacci, et al. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. Journal of Immunological Methods, 1991,139(2):271-279
[3]Chih-Ming Ho, Yu-Chong Tai. MICRO-ELECTRO-MECHANICAL-SYSTEMS (MEMS) AND FLUID FLOWS. Annual Review of Fluid Mechanics,1998,30:579-612
[4]Tai-Ran Hsu. MEMS& microsystems:design and manufacture.2nd Edition, Hoboken:New Jersey. 2008
[5]徐辉,张国亮,张凤宝.免疫磁性微球的研究进展.化学工业与工程,2003,20(1)：27-32
[6]潘欣欣.基于磁珠技术的微流控生物芯片系统的研究[硕士论文].上海：上海交通大学.2007.
[7]Yasser H.Anis, James K.Mills, William L. Cleghorn. Visual Measurement of MEMS Microassembly Forces Using Template Matching. Proceeding of the 2006 IEEE International Conference on Robotics & Automation,2006
[8]Michael A. Greminger, Bradley J. Nelson. Vision-Based Force Measurement. IEEE Transactions on pattern analysis and machine intelligence,2004,26(3):290-298
[9]Xiaoye Wang, G.K. Ananthasuresh, James P.Ostrowski. Vision-based Sensing of Forces in Elastic Objects. Sensors and Acutators,2001,94:142-156
[10]Xiaoye Wang, G.K. Ananthasuresh, James P.Ostrowski. Vision-based Extraction of Geometry and Forces from Fabricated Micro Devices. Technical Proceeding of the MSM 2000 International Conference,2000
[11]Michael A. Greminger, Ge Yang, Bradley J.Nelson. Sensing Nanonewton Level Forces by Visually Tracking Structural Deformations. Proceedings of the 2002 IEEE International Conference on Robotics & Automation,2002
[12]Y.H. Anis, J.K. Mills, W.L. Cleghorn. Vision-Based mearsurement of microassembly forces. Journal of Micromechanics and Microengineering,2006,16:1639-1652
[13]Y.H. Anis, J.K. Mills, W.L. Cleghorn. Zero-crossing edge detection for visual force measurement in assembly of MEMS devices. Micromachining and Microfabrication Process Technology XI, Proc. Of SPIE 2006,6109(61090H):1-12
[14]肖丽君.基于微流控的细胞分离芯片的研究[硕士论文].上海：上海交通大学.2010.
[15]UJAM L.B, CLEMMITT R.H, CLARKE S.A, et al. Isolation of monocytes from human peripheral blood using immuno-affinity expanded-bed adsorption. Biotechnology and bioengineering,2003, 83(5):554-566.
[16]Sunitha Nagrath, Lecia V. Sequist, Shyamala Maheswaran, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. NATURE,2007,450(20):1235-1239
[17]Andre A. Adams, Paul I. Okagbare, Juan Feng, et al. Highly Efficient Circulating Tumor Cell Isolation from Whole Blood and Label-Free Enumeration Using Polymer-Based Microfluidics with an Integrated Conductivity Sensor. J Am Chem Soc,2008,130(27):8633-8641
[18]James V. Green, Milica Radisic, Shashi K. Murthy. Deterministic Lateral Displacement as a Means to Enrich Large Cells for Tissue Engineering. Anal. Chem.,2009,81(21):9178-9182
[19]David W. Inglis, John A. Davis, Robert H. Austin, etc. Critical particle size for fractionation by deterministic lateral displacement. Lab on a Chip,2006,6:65-5658
[20]Masumi Yamada, Megumi Nakashima, Minoru Seki. Pinched Flow Fractionation:Continuous Size Separation of Particles Utilizing a Laminar Flow Profile in a Pinched Microchannel. Anal. Chem.,2004,76 (18):5465-5471
[21]Yong Lak Joo, Eric S.G. Shaqfeh. A purely elastic instability in Dean and Taylor-Dean flow. Phys. Fluids A,1992,4(3):524-543
[22]SIN A, MURTHY S K, REVZIN A, et al. Enrichment using antibody-coated microfluidic chambers in shear flow:Model mixtures of human lymphocytes [J]. Biotechnology and bioengineering,2005,91(7):816-826
[23]Xuanhong Cheng, Daniel Irimia, Meredith Dixon, et al. A microfluidic device for practical label-free CD4+T cell counting of HIV-infected subjects. Lab on a Chip,2007,7(2):170-178
[24]徐勇,霍梅.免疫磁珠分离及流式细胞仪分选纯化外周血CD34+/CD90+干细胞.临床检验杂志,2004,22(4)：246-248
[25]William Liu, Nikolai Dechev, Ian G.Foulds, et al. A novel permalloy based magnetic single cell micro array. Lab Chip,2009,9(16):2381-2390
[26]潘欣欣,陈翔,陈迪等.新型纳米磁色谱微流体芯片.功能材料与器件学报,2008,14(2)：441-443
[27]王聿估,陈翔,潘欣欣等.集成高梯度磁场分离结构的微流控芯片快速制作法.功能材料与器件学报,2008,14(4)：441-443
[28]Yan-Jun Liu, Shi-Shang Guo, Zhi-Ling Zhang, Wei-Hua Huang, Damien Baigl, Min Xie, Yong Chen, Dai-Wen Pang. A micropillar-integrated smart microfluidic device for specific capture and sorting of cells. Electrophoresis,2007,28:4713-4722
[29]Sung-Pil Chang, Mark G Allen. Capacitive pressure sensors with stainless steel diaphragm and substrate. Journal of micromechanics and microengineering,2004,14 (2004):612-618
[30]Sung-Pil Chang, Mark G. Allen. Demonstration for integrating capacitive pressure sensors with read-out circuitry on stainless steel substrate. Sensors and Actuators A,2004,116 (2004):195-204
[31]Raquel G. Bolea, Antonio Luque, Jose Manuel Quero. Capacitive Pressure Sensor and Characterization as RF MEMS Device. Industrial Electronics,2007,3267-3272
[32]方东明,付世,周勇等.静电驱动可调微机械电容.半导体学报,2007,28(9)：1454-1458
[33]靖向萌,陈迪,张晔等.三维微弹簧型MEMS探卡的设计和制备.传感技术学报,2006,19(5)：1484-1487
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