微型电化学生物传感器的设计及其在细胞生化参数检测中的应用研究
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摘要
活体细胞对外界刺激如药物、环境因素变化和受体作用等产生响应,会引起细胞代谢等功能性变化,外在表现为生化参数的改变。利用微型化电化学生物传感器,可以将细胞培养在传感器表而,细胞内的生理变化引起胞外环境的变化,胞外的电解质溶液与传感器之间形成电化学池,从而将这些参数的变化通过二级换能器转换为电信号输出,最终实现定量化监测和细胞水平的分析。将传感器微型化和建立良好的细胞-芯片耦合是关键问题所在。鉴于此,采用微机械加工技术开展的基于细胞传感器的微电极阵列、叉指型阻抗传感器、场效应传感器等具有良好的生物相容性,得到了广泛的研究,并已在药物筛选、环境监测等领域得到了初步应用。
本文从微型电化学生物传感器的设计和制备等关键技术入手,对基于电解质/金属-绝缘层-半导体(Electrolyte/metal-insulator-silicon, EIS/MIS)结构和和光伏检测技术的传感器、金微电极、碳微电极等传感器进行了研究,实现了离体原代肾细胞在传感器表而的良好耦合以及胞外酸化率、胞外氧化还原电位检测、葡萄糖溶液浓度检测,为EIS/MIS结构半导体器件拓展了新的生物学应用领域。此外,本文将碳微加工(Carbon micro-electromechanical systems, C-MEMS)工艺用于碳微电极的制备,实现了碳电极的微型化,成功应用于胰岛素溶液的检测,为细胞分泌的研究提供了一种新的可行性方法。本论文的主要内容和贡献如下
1.提出了一种新的有效的细胞胞外氧化还原电位检测的方法
细胞胞外氧化还原电位(Extracellular redox potential, ERP)反应了细胞外微环境的氧化还原状态,与细胞的增殖、分化、凋亡及癌细胞侵蚀都有着密切的关系。本文采用基于MIS结构的传感器和流动注射微腔体联用的方法,为细胞水平的氧化还原电位测试提供了一个可行的解决方案。测试无需添加其他氧化还原介质。研究表明,线粒体电子传递链对ERP有较大的影响。
2.提出了一种从细胞释放H+和自由电子活性两种角度研究细胞生命代谢活动的集成传感器的设计和可行性
本文提出了同时检测胞外酸化率和胞外氧化还原电位的一种集成传感器的设计,该集成传感器的性能可与单独的EIS、MIS传感器相媲美。此外,本文对正常生理状态下的细胞酸化率和ERP两种参数进行了初步的研究,获得了与单独测试类似的结果,验证了该设计的可行性。该设计有望应用于揭示细胞代谢机理的研究和药物分析测试中。
3.研制了一种新的电位型葡萄糖传感器
本文将PPy-GOD (Polypyrrole-glucose oxidase)超薄膜修饰在MIS结构传感器上获得了比使用同种修饰薄膜的其他类型传感器更高的灵敏度。MIS传感器所采用的光伏检测技术与流动注射微腔体联用,有利于提高传感器本身的灵敏度和响应时间。
4.提出了将C-MEMS工艺制备碳微电极用于胰岛素的检测
采用C-MEMS工艺将光刻胶热解制备的碳微电极具有较好的电化学性能,在其表面电沉积纳米RuOx颗粒之后实现了胰岛素的电化学检测,这是继玻碳电极、碳糊电极、碳纤维微电极之后,首次将C-MEMS应用于胰岛素测试的研究。采用C-MEMS工艺的优势在于,可根据实际检测需要灵活设计电极的结构和尺(?),有利于胰岛素传感器的微型化和集成化。
Living cells can respond to external stimuli, such as drugs and environmental change, or receptor functions. This induces the functional change of cell metabolism and variations in biochemical parameters, which can be detected using micro fabricated electrochemical biosensors. Cells are generally cultured on the sensor surface, and the extracellular electrolyte together with the sensor form a micro electrochemical cell, thus the biochemical parameter change induced by the physiological state of cells can be output as a physical electric signal through the transformation of transducers. By doing this, the quantitative detection and analysis in cellular level can be realized. The miniaturization of sensors and the cell-chip coupling are the key issues. In view of this the micro-electromechanical systems (MEMS) technologies are widely applied in the construction of cell-based biosensor, such as microelectrode array (MEA), interdigitated electrodes (IDE) and field effect transistor (FET). With good biocompatibility, these cell-based biosensors have been widely studied and preliminary applications have been achieved in drug screening, and environmental monitoring.
Based on the important techniques in the sensor design and fabrication, the electrolyte/metal-insulator-silicon (EIS/MIS) structured sensor, gold microelectrode and carbon microelectrode have been studied in this thesis. Good coupling of primary kidney cells on the EIS/MIS sensor surface are demonstrated in vitro, and the detection of cells acidification rate, the extracellular redox potential (ERP) are successfully realized. The MIS sensor can also be applied for the construction of potentiometric glucose sensor with high sensitivity, which expands the applications of MIS sensor in biology. Besides, the carbon micro-electromechanical systems (C-MEMS) technology is successfully used for the fabrication of carbon microelectrode, which facilitates the miniaturization of carbon electrode. Then the carbon microelectrode is applied for insulin detection, which provides a new potential, feasible way for the study of exocytosis. The major contents and contributions of this thesis are given as follows:
1. A new effective method for ERP detection is studied
The ERP value, which reflects the redox state of extracellular environment, has close relationship with cell proliferation, differentiation, apoptosis and cancer erosion. Based on the MIS sensor and the micro chamber with flow injection system, this thesis provides a feasible solution for ERP detection without addition of other redox mediators. It is found that the mitochondrial electron transport chain has important effect on ERP detection.
2. An integrated sensor for simultaneous detection of acidification rate and ERP is demonstrated to be feasible
This thesis proposes an integrated sensor design for the simultaneous detection of the two parameters. The integrated sensor has comparable performance with separate EIS or MIS sensor. The study of the two parameters under physiological state is primarily carried out, which demonstrates the feasibility of the sensor design. This design has potential application in revealing the cell metabolism mechanism and drug analysis and testing.
3. A new type potentiometric glucose sensor with high sensitivity is developed
An ultra thin polypyrrole-glucose oxidase (PPy-GOD) film is modified on the MIS sensor surface, and much higher sensitivity for glucose detection is obtained in comparison with other types of sensor with the same PPy-GOD film. The application of photovoltage technology and the micro chamber with flow injection system, contribute to the improved sensor sensitivity and response time.
4. Carbon microelectrode fabricated with C-MEMS technology is applied for insulin detection
The carbon microelectrode fabricated through the pyrolysis of photoresist with C-MEMS technology has good electrochemical performance. After electrodeposition of nano RuOx particles on the carbon surface, insulin oxidation is electro-catalyzed and its electrochemical detection is achieved. This is the first application of C-MEMS technology for insulin detection after glassy carbon, carbon paste and carbon fiber electrode. C-MEMS technology has the advantages of flexible design of the electrode structure and dimensions, which is propitious to the miniaturization and integration of insulin sensor.
本文从微型电化学生物传感器的设计和制备等关键技术入手,对基于电解质/金属-绝缘层-半导体(Electrolyte/metal-insulator-silicon, EIS/MIS)结构和和光伏检测技术的传感器、金微电极、碳微电极等传感器进行了研究,实现了离体原代肾细胞在传感器表而的良好耦合以及胞外酸化率、胞外氧化还原电位检测、葡萄糖溶液浓度检测,为EIS/MIS结构半导体器件拓展了新的生物学应用领域。此外,本文将碳微加工(Carbon micro-electromechanical systems, C-MEMS)工艺用于碳微电极的制备,实现了碳电极的微型化,成功应用于胰岛素溶液的检测,为细胞分泌的研究提供了一种新的可行性方法。本论文的主要内容和贡献如下
1.提出了一种新的有效的细胞胞外氧化还原电位检测的方法
细胞胞外氧化还原电位(Extracellular redox potential, ERP)反应了细胞外微环境的氧化还原状态,与细胞的增殖、分化、凋亡及癌细胞侵蚀都有着密切的关系。本文采用基于MIS结构的传感器和流动注射微腔体联用的方法,为细胞水平的氧化还原电位测试提供了一个可行的解决方案。测试无需添加其他氧化还原介质。研究表明,线粒体电子传递链对ERP有较大的影响。
2.提出了一种从细胞释放H+和自由电子活性两种角度研究细胞生命代谢活动的集成传感器的设计和可行性
本文提出了同时检测胞外酸化率和胞外氧化还原电位的一种集成传感器的设计,该集成传感器的性能可与单独的EIS、MIS传感器相媲美。此外,本文对正常生理状态下的细胞酸化率和ERP两种参数进行了初步的研究,获得了与单独测试类似的结果,验证了该设计的可行性。该设计有望应用于揭示细胞代谢机理的研究和药物分析测试中。
3.研制了一种新的电位型葡萄糖传感器
本文将PPy-GOD (Polypyrrole-glucose oxidase)超薄膜修饰在MIS结构传感器上获得了比使用同种修饰薄膜的其他类型传感器更高的灵敏度。MIS传感器所采用的光伏检测技术与流动注射微腔体联用,有利于提高传感器本身的灵敏度和响应时间。
4.提出了将C-MEMS工艺制备碳微电极用于胰岛素的检测
采用C-MEMS工艺将光刻胶热解制备的碳微电极具有较好的电化学性能,在其表面电沉积纳米RuOx颗粒之后实现了胰岛素的电化学检测,这是继玻碳电极、碳糊电极、碳纤维微电极之后,首次将C-MEMS应用于胰岛素测试的研究。采用C-MEMS工艺的优势在于,可根据实际检测需要灵活设计电极的结构和尺(?),有利于胰岛素传感器的微型化和集成化。
Living cells can respond to external stimuli, such as drugs and environmental change, or receptor functions. This induces the functional change of cell metabolism and variations in biochemical parameters, which can be detected using micro fabricated electrochemical biosensors. Cells are generally cultured on the sensor surface, and the extracellular electrolyte together with the sensor form a micro electrochemical cell, thus the biochemical parameter change induced by the physiological state of cells can be output as a physical electric signal through the transformation of transducers. By doing this, the quantitative detection and analysis in cellular level can be realized. The miniaturization of sensors and the cell-chip coupling are the key issues. In view of this the micro-electromechanical systems (MEMS) technologies are widely applied in the construction of cell-based biosensor, such as microelectrode array (MEA), interdigitated electrodes (IDE) and field effect transistor (FET). With good biocompatibility, these cell-based biosensors have been widely studied and preliminary applications have been achieved in drug screening, and environmental monitoring.
Based on the important techniques in the sensor design and fabrication, the electrolyte/metal-insulator-silicon (EIS/MIS) structured sensor, gold microelectrode and carbon microelectrode have been studied in this thesis. Good coupling of primary kidney cells on the EIS/MIS sensor surface are demonstrated in vitro, and the detection of cells acidification rate, the extracellular redox potential (ERP) are successfully realized. The MIS sensor can also be applied for the construction of potentiometric glucose sensor with high sensitivity, which expands the applications of MIS sensor in biology. Besides, the carbon micro-electromechanical systems (C-MEMS) technology is successfully used for the fabrication of carbon microelectrode, which facilitates the miniaturization of carbon electrode. Then the carbon microelectrode is applied for insulin detection, which provides a new potential, feasible way for the study of exocytosis. The major contents and contributions of this thesis are given as follows:
1. A new effective method for ERP detection is studied
The ERP value, which reflects the redox state of extracellular environment, has close relationship with cell proliferation, differentiation, apoptosis and cancer erosion. Based on the MIS sensor and the micro chamber with flow injection system, this thesis provides a feasible solution for ERP detection without addition of other redox mediators. It is found that the mitochondrial electron transport chain has important effect on ERP detection.
2. An integrated sensor for simultaneous detection of acidification rate and ERP is demonstrated to be feasible
This thesis proposes an integrated sensor design for the simultaneous detection of the two parameters. The integrated sensor has comparable performance with separate EIS or MIS sensor. The study of the two parameters under physiological state is primarily carried out, which demonstrates the feasibility of the sensor design. This design has potential application in revealing the cell metabolism mechanism and drug analysis and testing.
3. A new type potentiometric glucose sensor with high sensitivity is developed
An ultra thin polypyrrole-glucose oxidase (PPy-GOD) film is modified on the MIS sensor surface, and much higher sensitivity for glucose detection is obtained in comparison with other types of sensor with the same PPy-GOD film. The application of photovoltage technology and the micro chamber with flow injection system, contribute to the improved sensor sensitivity and response time.
4. Carbon microelectrode fabricated with C-MEMS technology is applied for insulin detection
The carbon microelectrode fabricated through the pyrolysis of photoresist with C-MEMS technology has good electrochemical performance. After electrodeposition of nano RuOx particles on the carbon surface, insulin oxidation is electro-catalyzed and its electrochemical detection is achieved. This is the first application of C-MEMS technology for insulin detection after glassy carbon, carbon paste and carbon fiber electrode. C-MEMS technology has the advantages of flexible design of the electrode structure and dimensions, which is propitious to the miniaturization and integration of insulin sensor.
引文
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