基于ITO微孔电极的SH-SY5Y细胞行为电化学分析研究
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摘要
细胞是一个能通过与外界进行物质、能量、信息交换的独立生存和自我调节的开放体系,也是生命活动的基本结构和功能单位。生命的实质就是细胞属性的外在体现,它不仅反映了生命活动的多样性和一致性,更体现了生命活动的复杂性。长期以来细胞一直是生命科学研究的核心。由于生物组织的不均匀性,同种细胞在形状、大小、生物活性及其生理状态等方面均有差异。由细胞群体分析获得的统计结果,抹杀了单细胞个体之间的差异,往往无法提供生物学及医学等领域必需的准确信息,而单细胞研究在疾病的早期诊断,揭示不同细胞在化学组成、生理响应等方面的差异性、药物设计和疾病的合理治疗等方面具有不可替代的地位。
细胞也是生命科学与化学的交汇点。现代生命体系的研究已从生物的整体、器官、组织进入到细胞、亚细胞层次,而化学对生命体系的研究也已从原子、分子、大分子聚集体,走向细胞。二十一世纪分析化学与生物学之间的渗透交叉,使对生命奥秘的探索更加深入,也促进了分析方法的快速发展。
本论文以电化学方法为基础,以神经母细胞瘤细胞(SH-SY5Y cell)为研究对象,在研制了ITO(Indium Tin Oxide)微孔电极、ITO阵列微孔电极和改进了碳纤维微电极的基础上,对SH-SY5Y单细胞、多细胞在不同条件下的胞吐及SH-SY5Y细胞“失巢凋亡”进行了研究。
第一章绪论
首先介绍了细胞分析特别是单细胞分析的意义与发展概况,重点关注了细胞通讯中胞吐现象的研究。对常见的单细胞分析手段如图像分析、毛细管电泳分析、微电极电化学分析、微流控分析进行了简要综述。最后阐述了本论文主要的研究目的、对象、研究方法和研究手段。
第二章ITO微孔电极、阵列微孔电极的制备与表征
ITO微电极与传统微电极相比,其突出优势在于在具备良好的电化学特性的同时,还具备优良的光学特性。本研究采用ITO与紫外光刻技术构建了一种新型ITO微孔电极和ITO阵列微孔电极,将该电极用于神经递质的测定,取得较好的效果。与传统的方法相比,ITO微孔电极不仅可以用电化学的方法监测细胞胞吐,而且还可与荧光或者化学发光等方法联用,实现同时运用多种手段对细胞的生理现象进行研究的目的。
第三章ITO微孔电极上不同形态SH-SY5Y细胞胞吐的研究
在细胞信号转导的众多形式中,以释放特定生化或化学信息为手段的细胞胞吐等细胞通讯方式,在生命的进程中具有尤其重要的地位。本章利用ITO微孔电极,成功地对SH-SY5Y单细胞、多细胞的胞吐进行了直接和实时的监测,并对不同形态的SH-SY5Y单细胞胞吐的情形进行了比较,发现具有突出的SH-SY5Y细胞的胞吐活性明显高于球形SH-SY5Y细胞,并对此展开了初步讨论。
第四章ITO微孔电极上不同刺激剂SH-SY5Y细胞胞吐响应时间和机理研究
细胞胞吐是真核细胞所具有的一种极为复杂的机能活动。对细胞胞吐的机制进行深入研究,将为我们对生命的理解提供直接的依据。分别使用高钾,尼古丁、亚硝基降烟碱等溶液为刺激剂,对SH-SY5Y细胞进行刺激,实验结果表明,不同刺激剂下SH-SY5Y细胞的胞吐发生时间存在明显差异,表明不同刺激下的胞吐对应着不同的胞吐机制。
研究神经递质和激素的分泌调控,阐明某些对胞吐活动具有干预作用的胞外因素,将为细胞胞吐机制的探索提供实践例证。
第五章碳纤维微电极的制备及初步用于SECM和对细胞胞吐的实时监测
自Wightman等将碳纤维微电极应用于单细胞的测试以来,多数单细胞实验的测定均以碳纤维微电极为实验工具,碳纤维微电极的稳定性以及灵敏度等直接影响着实验结果。碳纤维微电极的制备也一直在实验的过程中占有重要地位,碳纤维微电极的制备过程具有操作繁琐、效率低、需要显微操作、以及电极容易泄漏等不足。我们优化了制做流程,避免了在制备过程中的显微操作,使碳纤维微电极的制备更加简便、快捷。
用此方法制备的碳纤维微电极经电化学表征和在SECM等实验中的应用,取得较好的实验效果。将碳纤维微电极与ITO微孔电极同时应用于细胞胞吐的监测中,通过比较实验数据发现,两种电极在应用中各有能够发挥自身优势的领域：ITO电极由于与细胞接触近,接触面较大,能够监测到较多的胞吐事件,而碳纤维微电极可以区分细胞表面不同的胞吐活性区域。
第六章基于电化学阻抗法实时监测SH-SY5Y细胞生理活动
大多数哺乳动物细胞在体内和体外生长时需要附着于一定的底物,细胞与底物粘附后将逐渐伸展而形成一定的形态。细胞能否生长的关键取决于尽早地使细胞粘附贴壁,如细胞不能及时粘附贴壁、或者贴壁被破坏,细胞将不能维持正常的生理进程以至于凋亡。研究细胞粘附现象,对研究多个生理学和病理学进程的重要组成部分,例如伤口愈合、炎症、血管天生和癌症有重要的意义。三氧化二砷传统上是一种毒性试剂,研究发现其对肝癌、白血病、神经母细胞瘤的治疗有疗效。如能在肿瘤细胞贴壁潜伏期通过控制外界条件,如调整培养基成分、加入抗肿瘤药物等影响细胞的粘附及生长,将对癌症的治疗等有着重要的意义。
以往的细胞测试方法都是基于终点测验,不能实时监测细胞状态的变化。我们将ITO阵列微孔电极用于细胞生理功能的无标记、实时的监测,对三氧化二砷作用于SH-SY5Y细胞的粘附贴壁效果进行研究。实验结果表明,一定浓度的三氧化二砷对细胞的粘附和贴壁有着明显的影响,对SH-SY5Y细胞的增殖有着明显的抑制作用。本实验中使用ITO阵列微孔电极,避免了传统EIS法中电极中贵金属的使用,而且由于ITO又具有优越的透光性,可使电化学阻抗测量与其他光学表征手段联合使用,为将来复合功能细胞传感器的研制提供思路。
Each cell is an independent self-adjusting system, and it interacts and exchanges substance, energy, and message with the surrounding environment. Cell is both the basic constitution and functional unit of biological activities. Life is the external realization of cell's property. Cell embodies such characteristics as diversity, homogeneity and complexity of biological activities. For this reason, cell has long been the core of biosciences. Due to the variation of biological tissues, the same type of cells may differ in shape, size, biological activity, and physiological state. Statistical results obtained from experiments on cell colony often failed to provide the desired accurate message for biology and medicine because differences among individual cells are not under consideration. In contrast, studies on single cells could reveal the differences of cells in chemical components and physiological reaction, and are indispensable for early diagnosis of disease, prescription of drugs, and proper treatment.
Cell is also the crosspoint between bioscience and chemistry study. Biological researches have progressed from biological body as a whole, over organs, tissues, into cells and subcellular fractions, while chemical researches into biological system have been pushed forward from atom, over molecule, macromolecule, molecular aggregate, to cell. Nowadays the interaction and overlapping between chemistry and biology propelled exploration into the mystery of biological activities, and promoted the fast development of analytical methods.
In this dissertation, SH-SY5Y cells were chosen as the object of study, and electrochemical method was the fundamental approach. Indium Tin Oxide (ITO) micro-pore electrode and ITO array micro-pore electrode were fabricated, and improvements were made on traditional carbon fiber microelectrode. Then using the electrodes, the author made studies about SH-SY5Y single cell and multi-cell exocytoses under different conditions, and about the anoikis of SH-SY5Y cells
Chapter1Introduction
The significance and overall development of cell analysis, in particular, single cell analysis, were first introduced. In the matter of cellular communication, emphasis was put on studies related to cell exocytosis.
Next, the author briefly reviewed the conventional means of single cell analysis, namely, image analysis, capillary electrophoresis, microelectrode electrochemical analysis, microfluidics. Finally, the author presented the purpose of study, object of study, research methods and devices.
Chapter2The Fabrication and characterizing of the ITO micro-pore electrode and array micro-pore electrode
Compared with traditional electrodes, ITO micropore electrode was characterized by its good electrochemical property and fine photological property. The author manufactured a new type of ITO micro-pore electrochemical sensor and ITO array micro-pore electrode, using ITO and UV-light photolithography technology. When the electrode was applied to the assay of neurotransmitter, the desired result was achieved. Different from the conventional method, ITO micro-pore electrode can be used in monitoring cell exocytosis with electrochemical method. It can also collaborate with other methods like fluorescence and chemiluminescence and be used for studying cell's physiological activity.
Chapter3Exocytosis of SH-SY5Y single cell with different shapes cultured on the ITO Micro-pore electrode
Among the different forms of cell signal transmission, cells or neuronal communication, particularly through the release of specific biochemical or chemical messengers via exocytosis plays crucial roles in biological process. Using ITO micro-pore electrode, the author successfully conducted immediate and real-time monitoring of both single cell and multi-cell exocytosis. Then a comparison was made between different shapes of SH-SY5Y single cell exocytosis. The finding was that cells having clear process are more active than those having spherical shape. With regard to this phenomenon, discussion followed afterwards.
Chapter4The study on response time and mechanism of SH-SY5Y cell exocytosis with various stimulant
One of the prerequisites for cell existence is reacting properly to external stimulation. The biological state of cells depends, to a large extent, on their procedural reaction to a series of ultra-cell signals. Exocytosis is the complicated physiological activity possessed by eukaryon. Researches into mechanism of exocytosis provide people with rationale for understanding life. When SH-SY5Y cells were experimented on, high potassium, nicotine and nitroso nornicotine were used respectively as stimulants. Experimental results showed that the timing for exocytosis caused by various stimulants differed greatly. In other words, exocytoses caused by different stimulants have to do with different mechanisms of exocytosis.
Chapter5Fabrication of carbon fiber microelectrode and application to SECM and to the real-time monitoring of cell exocytosis
Carbon fiber microelectrode, first employed by Wightman on testing single cell, has been widely used in experiments of single cell testing. The stability and sensitivity of carbon fiber microelectrode exerted immediate influence on experimental results, and its fabrication also played important roles in the experimental process. Traditional fabrication process of carbon fiber microelectrode had drawbacks like complex operation, low efficiency, operation under microscope, and possible leakage of electrode. In our experiments, new fabrication procedure has been employed, and the technology has been improved. In the process of fabrication, microscopy operation was no longer needed. Thus, the fabrication of carbon fiber electrode has turned out to be more convenient, economical and easier to handle.
Characteristics of the carbon fiber microelectrode were confirmed electrochemically and when it was applied to SECM, desired results were obtained. When carbon fire microelectrode and ITO micro-pore electrode were used separately to monitor exocytosis, experimental data revealed that they had different advantages. ITO micro-pore electrode could closely approach the cell, so the larger interface enabled detection of more exocytotic events. Meanwhile, carbon fiber microelectrode could detect active exocytotic regions over the cell surface.
Chapter6The real-time monitoring of the physiological activity of SH-SY5Y cells based on electrochemical impedance spectrum
Most of the mammalian cells needed bind to certain substrate when growing in vitro and in vivo. This agglutination between cell and substrate will make cells extend gradually and grow into certain shapes. The growth of cells depended largely on their possible and early binding to the substrate. If they failed to immediately agglutinate the substrate or if their binding was interfered with, cells were unable to maintain normal physiological process and would die. Therefore, studies on cell binding were of significance for researches into physiological and pathological processes, such as wound healing, inflammation, cancerization. Arsenic trioxide, a type of toxic reagent, has been found having curative effects on the treatment of liver cancer, leukemia, and neuroblastoma. If external conditions like ingredients of culture medium, addition of antitumor medicine during incubation period can be changed, the conglutination and growth of tumor cells will be impeded, which will be of great significance to cancer treatment.
Previous cell testing methods were all terminal test, unable to monitor the real-time alteration of cells'condition. A new type of ITO array micro-pore electrochemical sensor has been fabricated based on ITO and UV light photolithography technology and has been used in the label-free and real-time monitoring of cell's physiological function. Studies have also been made on the degree to which arsenic trioxide affected agglutination of SH-SY5Y cells. The experimental results showed that arsenic trioxide of a certain concentration had distinct influence on the conglutination of the SH-SY5Y cells and greatly inhibited the proliferation of the SH-SY5Y cells.
ITO array micro-pore electrode used in our experiments did not contain any noble metal which was the component of traditional EIS method. Since ITO was characterized by good transmission of light, it was likely to combine electrochemical impedance measurement with other photological characterization measures, which throwed light on the development of cell sensor with compound functions.
细胞也是生命科学与化学的交汇点。现代生命体系的研究已从生物的整体、器官、组织进入到细胞、亚细胞层次,而化学对生命体系的研究也已从原子、分子、大分子聚集体,走向细胞。二十一世纪分析化学与生物学之间的渗透交叉,使对生命奥秘的探索更加深入,也促进了分析方法的快速发展。
本论文以电化学方法为基础,以神经母细胞瘤细胞(SH-SY5Y cell)为研究对象,在研制了ITO(Indium Tin Oxide)微孔电极、ITO阵列微孔电极和改进了碳纤维微电极的基础上,对SH-SY5Y单细胞、多细胞在不同条件下的胞吐及SH-SY5Y细胞“失巢凋亡”进行了研究。
第一章绪论
首先介绍了细胞分析特别是单细胞分析的意义与发展概况,重点关注了细胞通讯中胞吐现象的研究。对常见的单细胞分析手段如图像分析、毛细管电泳分析、微电极电化学分析、微流控分析进行了简要综述。最后阐述了本论文主要的研究目的、对象、研究方法和研究手段。
第二章ITO微孔电极、阵列微孔电极的制备与表征
ITO微电极与传统微电极相比,其突出优势在于在具备良好的电化学特性的同时,还具备优良的光学特性。本研究采用ITO与紫外光刻技术构建了一种新型ITO微孔电极和ITO阵列微孔电极,将该电极用于神经递质的测定,取得较好的效果。与传统的方法相比,ITO微孔电极不仅可以用电化学的方法监测细胞胞吐,而且还可与荧光或者化学发光等方法联用,实现同时运用多种手段对细胞的生理现象进行研究的目的。
第三章ITO微孔电极上不同形态SH-SY5Y细胞胞吐的研究
在细胞信号转导的众多形式中,以释放特定生化或化学信息为手段的细胞胞吐等细胞通讯方式,在生命的进程中具有尤其重要的地位。本章利用ITO微孔电极,成功地对SH-SY5Y单细胞、多细胞的胞吐进行了直接和实时的监测,并对不同形态的SH-SY5Y单细胞胞吐的情形进行了比较,发现具有突出的SH-SY5Y细胞的胞吐活性明显高于球形SH-SY5Y细胞,并对此展开了初步讨论。
第四章ITO微孔电极上不同刺激剂SH-SY5Y细胞胞吐响应时间和机理研究
细胞胞吐是真核细胞所具有的一种极为复杂的机能活动。对细胞胞吐的机制进行深入研究,将为我们对生命的理解提供直接的依据。分别使用高钾,尼古丁、亚硝基降烟碱等溶液为刺激剂,对SH-SY5Y细胞进行刺激,实验结果表明,不同刺激剂下SH-SY5Y细胞的胞吐发生时间存在明显差异,表明不同刺激下的胞吐对应着不同的胞吐机制。
研究神经递质和激素的分泌调控,阐明某些对胞吐活动具有干预作用的胞外因素,将为细胞胞吐机制的探索提供实践例证。
第五章碳纤维微电极的制备及初步用于SECM和对细胞胞吐的实时监测
自Wightman等将碳纤维微电极应用于单细胞的测试以来,多数单细胞实验的测定均以碳纤维微电极为实验工具,碳纤维微电极的稳定性以及灵敏度等直接影响着实验结果。碳纤维微电极的制备也一直在实验的过程中占有重要地位,碳纤维微电极的制备过程具有操作繁琐、效率低、需要显微操作、以及电极容易泄漏等不足。我们优化了制做流程,避免了在制备过程中的显微操作,使碳纤维微电极的制备更加简便、快捷。
用此方法制备的碳纤维微电极经电化学表征和在SECM等实验中的应用,取得较好的实验效果。将碳纤维微电极与ITO微孔电极同时应用于细胞胞吐的监测中,通过比较实验数据发现,两种电极在应用中各有能够发挥自身优势的领域：ITO电极由于与细胞接触近,接触面较大,能够监测到较多的胞吐事件,而碳纤维微电极可以区分细胞表面不同的胞吐活性区域。
第六章基于电化学阻抗法实时监测SH-SY5Y细胞生理活动
大多数哺乳动物细胞在体内和体外生长时需要附着于一定的底物,细胞与底物粘附后将逐渐伸展而形成一定的形态。细胞能否生长的关键取决于尽早地使细胞粘附贴壁,如细胞不能及时粘附贴壁、或者贴壁被破坏,细胞将不能维持正常的生理进程以至于凋亡。研究细胞粘附现象,对研究多个生理学和病理学进程的重要组成部分,例如伤口愈合、炎症、血管天生和癌症有重要的意义。三氧化二砷传统上是一种毒性试剂,研究发现其对肝癌、白血病、神经母细胞瘤的治疗有疗效。如能在肿瘤细胞贴壁潜伏期通过控制外界条件,如调整培养基成分、加入抗肿瘤药物等影响细胞的粘附及生长,将对癌症的治疗等有着重要的意义。
以往的细胞测试方法都是基于终点测验,不能实时监测细胞状态的变化。我们将ITO阵列微孔电极用于细胞生理功能的无标记、实时的监测,对三氧化二砷作用于SH-SY5Y细胞的粘附贴壁效果进行研究。实验结果表明,一定浓度的三氧化二砷对细胞的粘附和贴壁有着明显的影响,对SH-SY5Y细胞的增殖有着明显的抑制作用。本实验中使用ITO阵列微孔电极,避免了传统EIS法中电极中贵金属的使用,而且由于ITO又具有优越的透光性,可使电化学阻抗测量与其他光学表征手段联合使用,为将来复合功能细胞传感器的研制提供思路。
Each cell is an independent self-adjusting system, and it interacts and exchanges substance, energy, and message with the surrounding environment. Cell is both the basic constitution and functional unit of biological activities. Life is the external realization of cell's property. Cell embodies such characteristics as diversity, homogeneity and complexity of biological activities. For this reason, cell has long been the core of biosciences. Due to the variation of biological tissues, the same type of cells may differ in shape, size, biological activity, and physiological state. Statistical results obtained from experiments on cell colony often failed to provide the desired accurate message for biology and medicine because differences among individual cells are not under consideration. In contrast, studies on single cells could reveal the differences of cells in chemical components and physiological reaction, and are indispensable for early diagnosis of disease, prescription of drugs, and proper treatment.
Cell is also the crosspoint between bioscience and chemistry study. Biological researches have progressed from biological body as a whole, over organs, tissues, into cells and subcellular fractions, while chemical researches into biological system have been pushed forward from atom, over molecule, macromolecule, molecular aggregate, to cell. Nowadays the interaction and overlapping between chemistry and biology propelled exploration into the mystery of biological activities, and promoted the fast development of analytical methods.
In this dissertation, SH-SY5Y cells were chosen as the object of study, and electrochemical method was the fundamental approach. Indium Tin Oxide (ITO) micro-pore electrode and ITO array micro-pore electrode were fabricated, and improvements were made on traditional carbon fiber microelectrode. Then using the electrodes, the author made studies about SH-SY5Y single cell and multi-cell exocytoses under different conditions, and about the anoikis of SH-SY5Y cells
Chapter1Introduction
The significance and overall development of cell analysis, in particular, single cell analysis, were first introduced. In the matter of cellular communication, emphasis was put on studies related to cell exocytosis.
Next, the author briefly reviewed the conventional means of single cell analysis, namely, image analysis, capillary electrophoresis, microelectrode electrochemical analysis, microfluidics. Finally, the author presented the purpose of study, object of study, research methods and devices.
Chapter2The Fabrication and characterizing of the ITO micro-pore electrode and array micro-pore electrode
Compared with traditional electrodes, ITO micropore electrode was characterized by its good electrochemical property and fine photological property. The author manufactured a new type of ITO micro-pore electrochemical sensor and ITO array micro-pore electrode, using ITO and UV-light photolithography technology. When the electrode was applied to the assay of neurotransmitter, the desired result was achieved. Different from the conventional method, ITO micro-pore electrode can be used in monitoring cell exocytosis with electrochemical method. It can also collaborate with other methods like fluorescence and chemiluminescence and be used for studying cell's physiological activity.
Chapter3Exocytosis of SH-SY5Y single cell with different shapes cultured on the ITO Micro-pore electrode
Among the different forms of cell signal transmission, cells or neuronal communication, particularly through the release of specific biochemical or chemical messengers via exocytosis plays crucial roles in biological process. Using ITO micro-pore electrode, the author successfully conducted immediate and real-time monitoring of both single cell and multi-cell exocytosis. Then a comparison was made between different shapes of SH-SY5Y single cell exocytosis. The finding was that cells having clear process are more active than those having spherical shape. With regard to this phenomenon, discussion followed afterwards.
Chapter4The study on response time and mechanism of SH-SY5Y cell exocytosis with various stimulant
One of the prerequisites for cell existence is reacting properly to external stimulation. The biological state of cells depends, to a large extent, on their procedural reaction to a series of ultra-cell signals. Exocytosis is the complicated physiological activity possessed by eukaryon. Researches into mechanism of exocytosis provide people with rationale for understanding life. When SH-SY5Y cells were experimented on, high potassium, nicotine and nitroso nornicotine were used respectively as stimulants. Experimental results showed that the timing for exocytosis caused by various stimulants differed greatly. In other words, exocytoses caused by different stimulants have to do with different mechanisms of exocytosis.
Chapter5Fabrication of carbon fiber microelectrode and application to SECM and to the real-time monitoring of cell exocytosis
Carbon fiber microelectrode, first employed by Wightman on testing single cell, has been widely used in experiments of single cell testing. The stability and sensitivity of carbon fiber microelectrode exerted immediate influence on experimental results, and its fabrication also played important roles in the experimental process. Traditional fabrication process of carbon fiber microelectrode had drawbacks like complex operation, low efficiency, operation under microscope, and possible leakage of electrode. In our experiments, new fabrication procedure has been employed, and the technology has been improved. In the process of fabrication, microscopy operation was no longer needed. Thus, the fabrication of carbon fiber electrode has turned out to be more convenient, economical and easier to handle.
Characteristics of the carbon fiber microelectrode were confirmed electrochemically and when it was applied to SECM, desired results were obtained. When carbon fire microelectrode and ITO micro-pore electrode were used separately to monitor exocytosis, experimental data revealed that they had different advantages. ITO micro-pore electrode could closely approach the cell, so the larger interface enabled detection of more exocytotic events. Meanwhile, carbon fiber microelectrode could detect active exocytotic regions over the cell surface.
Chapter6The real-time monitoring of the physiological activity of SH-SY5Y cells based on electrochemical impedance spectrum
Most of the mammalian cells needed bind to certain substrate when growing in vitro and in vivo. This agglutination between cell and substrate will make cells extend gradually and grow into certain shapes. The growth of cells depended largely on their possible and early binding to the substrate. If they failed to immediately agglutinate the substrate or if their binding was interfered with, cells were unable to maintain normal physiological process and would die. Therefore, studies on cell binding were of significance for researches into physiological and pathological processes, such as wound healing, inflammation, cancerization. Arsenic trioxide, a type of toxic reagent, has been found having curative effects on the treatment of liver cancer, leukemia, and neuroblastoma. If external conditions like ingredients of culture medium, addition of antitumor medicine during incubation period can be changed, the conglutination and growth of tumor cells will be impeded, which will be of great significance to cancer treatment.
Previous cell testing methods were all terminal test, unable to monitor the real-time alteration of cells'condition. A new type of ITO array micro-pore electrochemical sensor has been fabricated based on ITO and UV light photolithography technology and has been used in the label-free and real-time monitoring of cell's physiological function. Studies have also been made on the degree to which arsenic trioxide affected agglutination of SH-SY5Y cells. The experimental results showed that arsenic trioxide of a certain concentration had distinct influence on the conglutination of the SH-SY5Y cells and greatly inhibited the proliferation of the SH-SY5Y cells.
ITO array micro-pore electrode used in our experiments did not contain any noble metal which was the component of traditional EIS method. Since ITO was characterized by good transmission of light, it was likely to combine electrochemical impedance measurement with other photological characterization measures, which throwed light on the development of cell sensor with compound functions.
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