微电极阵列细胞芯片的设计及其对心肌细胞生理特性的研究
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摘要
细胞传感器作为一类以活体细胞为一级传感单元、换能器为二级传感单元的器件,具有高灵敏度、低成本、高通量检测等特点,是环境毒性研究、食品安全、药物筛选等领域研究的有效手段并在近年来逐渐实现产业化。微电极阵列(Microelectrode Arrays, MEAs)是以检测电兴奋类细胞如心肌细胞、神经网络等的电生理活动的一类细胞传感器。它因无损检测、响应速度快、制备工艺简单、可扩展性强等特点而具有广泛的应用前景。本论文基于微电极阵列,针对心肌细胞的特性扩展了其设计和功能,开发了具有多功能共同分析的细胞传感器平台,并研究了心肌细胞的生理特性及基于此的药物毒性研究。所设计的平台亦可推广用于其它类型细胞的研究。
本论文的主要内容和创新点在于：
一.深入分析微电极阵列胞外场电位的检测机理,并应用于实际细胞芯片的设计。
本文基于金属电极-电解液双电层模型和离子通道模型,系统地研究了细胞与微电极耦合的点接触模型。采用仿真软件工具对胞内外场电位的关系进行了深入的分析,阐述了细胞-微电极的界面特性对分析细胞胞内外电位的影响。基于该模型的分析结果设计的细胞芯片表现出良好的生物相容性和稳定性。细胞芯片成功记录了心肌细胞、海马区神经元以及嗅觉细胞的胞外场电位信号,实际检测结果与模型仿真结果具有较高的一致性。
二.本文首次提出了设计小同尺度的电极阵列芯片实现对心肌细胞兴奋-收缩偶联以整体进行分析的方法。
根据心肌细胞的生长特点,将电极尺寸从微米级扩展至毫米级,从而在用微米级电极检测细胞兴奋电位的同时,使用毫米级的电极可同时检测细胞的收缩电位,其幅度及持续时间和面积呈正相关,并采用常规的微管抑制剂验证了该方法的正确性。在此基础上,基于电极-电解液双电层的检测机理,分析了机械搏动引起了双电层电荷的排布变化,从而影响了电极电位的变化。根据该分忻结果,将微米尺寸电极和大面积电极共同设计并采用统一电学方式检测,实现了心肌细胞兴奋-收缩偶联的整体研究,弥补了传统方式膜片钳-荧光染色等方法的不足；该方法可进一步扩展成以兴奋-收缩偶联机制为靶点的心脏药物研究手段。
三.提出了细胞电生理和形态多功能检测的方法,设计了结合微电极阵列和细胞阻抗电极复合细胞芯片,并共同完成了基于该复合细胞芯片检测的自动分析仪的设计制作,建立了药物分析的研究平台。
将微电极阵列和检测细胞-电极阻抗的叉指电极对集成于同一芯片内,在一次实验中同时记录细胞的胞外电生理和形态的变化。芯片应用于蒽环类抗癌药物阿霉素的心脏毒性研究,将分析结果和传统心肌细胞研究方法及临床出现的症状进行对比分析,证明了平台的有效性,提出了将长时程检测中出现的症状按时间点排布,得到的药物作用时间谱可直观地描绘其诱发的心脏毒性的症状变化过程。
共同设计了基于复合细胞芯片自动分析仪的设计制作；实现了细胞生理多参数的自动化分析；初步探索了心脏毒性的检测和评价方法。
Cell-based biosensors (CBBs), taking live cells and transducers as primary and secondary sensing elements respectively, exhibit the characteristics of high sensitivity, low cost and high-throughput detection. They have been widely applied in the fields of environmental toxicity, food safety and pharmacological screening, and gradually commercialized. Microelectrode arrays (MEAs), a type of cell-based biosensors, are specially to detect the extracellular electrophysiological activities of electrigenic cells including cardiomyocytes and neuronal networks. With outstanding qualities such as non-invasiveness to cells, fast response, uncomplicated fabrication process and scalability, it has been a research hotspot. In this paper, we designed some chips with multiple functions based on microelectrode arrays to study the cardiac physiology and exploit the drug-induced cardiotoxicity. These chips can also be used to study other types of cells.
The work mainly consisted of three parts as follows:
Firstly, we systematically explored the extracellular detection mechanism of microelectrode array and achieved the design.
Based on the electrochemical attributes of metal-electrolyte interface and ion-channel model, the point-contact model was built up to simulate the relationship between transmembrane action potential and extracellular field potential by software tool. According to the simulation result, we achieved chip design and found it with good biocompatibility and stability. It successfully recorded the extracellular field potential of cardiomyocytes hippocampal neurons and olfactory epithelium. The experimental results showed high fitness with the simulated result.
Secondly, we firstly designed the chip of multi-scale electrode array (MSEA) to detect the cardiac excitation-contraction coupling as a whole system.
Based on the special attributes of cardiomyocytes, we changed the common microelectrode array and expanded the diameter of electrodes from several tens micrometers to millimeter scale. It is observed that the general microelectrodes could detect the extracellular field potentials, as well as the millimeter scale electrode can detect the mechanical contraction whose amplitude and time duration showed positive relationship with electrode area. Furthermore, the contractile detection was confirmed by a type of microtubule inhibitor. The generation mechanism of hump was analyzed and it resulted from the change of electrode half-cell potential due to the mechanical perturbation on the charge in double electric layers.
According to the study, the MSEA integrated with micro-and milli-scale electrodes could detect the extracellular field potential and mechanical contraction synchronously in electric way. It could be a platform for cardiac pharmacology screening targeted with the excitation-contraction coupling.
Thirdly, we raised the method of jointly studying the extracellular field potential and physical state.
Based on the method, the cell chip integrated with microelectrode array and interdigitated electrodes was designed. To avoid the electric disturbance between these two types of sensors, the whole recording process was scheduled in a time-switch way. The chip was used to recording the extracellular field potential and cell-electrode impedance change of cardiomyocytes under the treatment of anthracycline anticancer drug doxorubicin. The analysis showed that most of the symptoms extracted from the recording results by chip ExCell occurred in the clinical treatment of histological results, which proved the validity of the designed chip. Additionally, we proposed the temporal spectrum of the symptoms of drug-induced cardiotoxicity, which could clearly map the changing process of the symptoms when drugs acting on cardiomyocytes.
Correspondingly, we built up a multi-function automatic analyzing system based on the integrated chip. With these work, it explored the methods of detection and evaluation on cardiotoxicity preliminary.
本论文的主要内容和创新点在于：
一.深入分析微电极阵列胞外场电位的检测机理,并应用于实际细胞芯片的设计。
本文基于金属电极-电解液双电层模型和离子通道模型,系统地研究了细胞与微电极耦合的点接触模型。采用仿真软件工具对胞内外场电位的关系进行了深入的分析,阐述了细胞-微电极的界面特性对分析细胞胞内外电位的影响。基于该模型的分析结果设计的细胞芯片表现出良好的生物相容性和稳定性。细胞芯片成功记录了心肌细胞、海马区神经元以及嗅觉细胞的胞外场电位信号,实际检测结果与模型仿真结果具有较高的一致性。
二.本文首次提出了设计小同尺度的电极阵列芯片实现对心肌细胞兴奋-收缩偶联以整体进行分析的方法。
根据心肌细胞的生长特点,将电极尺寸从微米级扩展至毫米级,从而在用微米级电极检测细胞兴奋电位的同时,使用毫米级的电极可同时检测细胞的收缩电位,其幅度及持续时间和面积呈正相关,并采用常规的微管抑制剂验证了该方法的正确性。在此基础上,基于电极-电解液双电层的检测机理,分析了机械搏动引起了双电层电荷的排布变化,从而影响了电极电位的变化。根据该分忻结果,将微米尺寸电极和大面积电极共同设计并采用统一电学方式检测,实现了心肌细胞兴奋-收缩偶联的整体研究,弥补了传统方式膜片钳-荧光染色等方法的不足；该方法可进一步扩展成以兴奋-收缩偶联机制为靶点的心脏药物研究手段。
三.提出了细胞电生理和形态多功能检测的方法,设计了结合微电极阵列和细胞阻抗电极复合细胞芯片,并共同完成了基于该复合细胞芯片检测的自动分析仪的设计制作,建立了药物分析的研究平台。
将微电极阵列和检测细胞-电极阻抗的叉指电极对集成于同一芯片内,在一次实验中同时记录细胞的胞外电生理和形态的变化。芯片应用于蒽环类抗癌药物阿霉素的心脏毒性研究,将分析结果和传统心肌细胞研究方法及临床出现的症状进行对比分析,证明了平台的有效性,提出了将长时程检测中出现的症状按时间点排布,得到的药物作用时间谱可直观地描绘其诱发的心脏毒性的症状变化过程。
共同设计了基于复合细胞芯片自动分析仪的设计制作；实现了细胞生理多参数的自动化分析；初步探索了心脏毒性的检测和评价方法。
Cell-based biosensors (CBBs), taking live cells and transducers as primary and secondary sensing elements respectively, exhibit the characteristics of high sensitivity, low cost and high-throughput detection. They have been widely applied in the fields of environmental toxicity, food safety and pharmacological screening, and gradually commercialized. Microelectrode arrays (MEAs), a type of cell-based biosensors, are specially to detect the extracellular electrophysiological activities of electrigenic cells including cardiomyocytes and neuronal networks. With outstanding qualities such as non-invasiveness to cells, fast response, uncomplicated fabrication process and scalability, it has been a research hotspot. In this paper, we designed some chips with multiple functions based on microelectrode arrays to study the cardiac physiology and exploit the drug-induced cardiotoxicity. These chips can also be used to study other types of cells.
The work mainly consisted of three parts as follows:
Firstly, we systematically explored the extracellular detection mechanism of microelectrode array and achieved the design.
Based on the electrochemical attributes of metal-electrolyte interface and ion-channel model, the point-contact model was built up to simulate the relationship between transmembrane action potential and extracellular field potential by software tool. According to the simulation result, we achieved chip design and found it with good biocompatibility and stability. It successfully recorded the extracellular field potential of cardiomyocytes hippocampal neurons and olfactory epithelium. The experimental results showed high fitness with the simulated result.
Secondly, we firstly designed the chip of multi-scale electrode array (MSEA) to detect the cardiac excitation-contraction coupling as a whole system.
Based on the special attributes of cardiomyocytes, we changed the common microelectrode array and expanded the diameter of electrodes from several tens micrometers to millimeter scale. It is observed that the general microelectrodes could detect the extracellular field potentials, as well as the millimeter scale electrode can detect the mechanical contraction whose amplitude and time duration showed positive relationship with electrode area. Furthermore, the contractile detection was confirmed by a type of microtubule inhibitor. The generation mechanism of hump was analyzed and it resulted from the change of electrode half-cell potential due to the mechanical perturbation on the charge in double electric layers.
According to the study, the MSEA integrated with micro-and milli-scale electrodes could detect the extracellular field potential and mechanical contraction synchronously in electric way. It could be a platform for cardiac pharmacology screening targeted with the excitation-contraction coupling.
Thirdly, we raised the method of jointly studying the extracellular field potential and physical state.
Based on the method, the cell chip integrated with microelectrode array and interdigitated electrodes was designed. To avoid the electric disturbance between these two types of sensors, the whole recording process was scheduled in a time-switch way. The chip was used to recording the extracellular field potential and cell-electrode impedance change of cardiomyocytes under the treatment of anthracycline anticancer drug doxorubicin. The analysis showed that most of the symptoms extracted from the recording results by chip ExCell occurred in the clinical treatment of histological results, which proved the validity of the designed chip. Additionally, we proposed the temporal spectrum of the symptoms of drug-induced cardiotoxicity, which could clearly map the changing process of the symptoms when drugs acting on cardiomyocytes.
Correspondingly, we built up a multi-function automatic analyzing system based on the integrated chip. With these work, it explored the methods of detection and evaluation on cardiotoxicity preliminary.
引文
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