芯片毛细管电泳电化学检测的研究与应用
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摘要
在过去的十几年中，微全分析系统(μ-TAS) 或芯片实验室(lab on a chip)已经发展成为当今世界上最前沿的研究领域之一，它的主要特点是：分析速度快、信息量高、操作费用低、试样消耗小、污染小。
与传统的毛细管电泳类似，芯片毛细管电泳（CE chip）常用的检测方法为激光诱导荧光检测（LIF），主要是因为它的灵敏度较高，但是具有天然荧光的物质较少，常常需要对样品进行衍生。另一方面，电化学检测（ECD）的灵敏度高、选择性易于调变、试样用量少、成本低，特别是包括控制仪器在内的EC装置特有的微型化特点，与微加工技术很匹配。这一传感方式非常符合微流控分析系统的微型化、集成化的要求，成为μ-TAS中非常重要的一类检测方式。
本论文以芯片毛细管电泳电化学检测 (CE – ECD chip) 为研究重点，主要包括以下工作内容：
采用毛细微模塑法（MIMIC）与无电沉积技术，可以直接在玻璃基片上制作出具有特定形状的铜膜电极。该铜膜电极不但可以直接作为工作电极，而且还可以作为铂接地电极的基底。然后将带有分离通道的聚二甲基硅氧烷（PDMS）芯片可逆的与电极板相键合，形成PDMS/玻璃杂化电泳芯片。该芯片制作费用低，时间短，电极形状可以准确控制，而且检测灵敏度高。芯片的有效分离通道长43 mm。在最优化的分析条件下，（30 mmol/L NaOH，检测电为0.7 V，进样与分离场强均为200 V/cm），连续七次进样标准葡萄糖溶液所得迁移时间与电流的相对标准偏差分别为2.2 %，4.4 %。得到葡萄糖的线性响应范围10 μmol/L ~ 1 mmol/L，相关系数为0.997，在信噪比等于3时的检测限是6 μmol/L。在分析健康人与糖尿病人的血浆样品时，测得的葡萄糖浓度与医院里采用酶自动分析仪所得的结果非常接近。证明CE – ECD chip技术在应用于临床样品分析方面显示了良好的选择性、重现性、准确性等优点，对于糖尿病人的诊断和治疗具有很好的应用价值，是一种灵敏、快速、准确的分析技术，具有一定的临床应用前景。
在PMMA上溅射金属Cu，然后利用光刻、湿法腐蚀的办法制出铜电极，与另一片含有微沟道的PMMA基片热键合，制作集成铜电极的塑料电泳芯片。当连续7次进样分析标准葡萄糖溶液时，迁移时间和电化学响应信号的相对标准偏差分别为3.52%和1.12%，重现性较好，说明该芯片微沟道表面特性和电极的电化学特性均较稳定。而且还考察了各种分析条件对氨基酸分离的影响，在优化条件（30 mmol/L NaOH 缓冲溶液中，检测电位为0.7 V，进样与分离电场强度均为50 V/cm）下，精氨酸的线性响应范围为40 μmol/L 到3 mmol/L，检测限为 30 μmol/L（信噪比等于3），同时在3 cm 长的通道内较好地分离了精氨酸与亮氨酸。
For over a decade, the area of micro total analysis systems, also called “lab on a chip”, has been growing rapidly. The numerous advantages of incorporating several previously distinct processes into a miniaturized format include faster analysis time, decreased cost and waste production, portability, disposability.
Capillary electrophoresis microchip (CE chip) is an emerging technology that has generated a great deal of interests in analytical chemistry. Like conventional CE, laser- induced fluorescence (LIF) remains one of the most sensitive detection techniques for CE chip. However, the implementation of LIF can be quite difficult. On the other hand, electrochemical detection (ECD) is relatively simple, inexpensive, applicable to a wide range of analytes, and easily miniaturized.
This thesis is concentrated on the study of CE – ECD chip and its application in analysis of pharmaceuticals and biochemicals as described below.
The pattern of the microelectrodes for CE – ECD chip was directly made on the surface of a microscope slide through the micromolding in capillaries (MIMIC) techniques and electroless deposition procedure. The copper microelectrode is fabricated by selective electroless deposition. And the fabrication of decoupler is platinum electrochemical deposition on metal film formed by electroless deposition. The whole chip was built by reversibly sealing the slide to the poly(dimethylsiloxane) (PDMS) layer with electrophoresis microchannels at room temperature. The fabrication of a hybrid chip device is simple, rapid and costless compared with the conventional method of glucose detection using glucose oxidase. Factors influencing the performance, including the detection potential, separation field strength, buffer concentration, were studied. The electrodes exhibited good stability and durability in the analytical procedures. Under optimized detection conditions, （30 mM NaOH, separation field strength of 200 V/cm and detection potential at 0.7 V）， seven consecutive injections of glucose
were performed. The relative standard deviation (RSD) of the migration time was 2.2 %, with that of the peak height was 4.4 %. And the glucose responded linearly from 10 μmol/L to 1 mmol/L. Furthermore, the glucose in human plasma from healthy individuals and diabetics was successfully determined, which was close to those got with HITACHI 7020 Automatic Analyzer in Jilin University Hospital. This work gives a newly alternative way to the quick determination of glucose in real sample with high sensitivity. So the miniaturized CE–ECD analysis system has the application prospect and attraction for clinical bioassays.
Cu is sputtered onto PMMA, and copper electrodes are formed by photolithograph and wet etching; an electrophoresis chip is fabricated by thermally bonding the PMMA with copper electrodes to a PMMA substrate with microchannels. When seven consecutive injections of standard glucose were performed, the relative RSD of the migration time was 3.52 %, with that of the peak height was 1.12 %. Furthermore, factors influencing the performance, including the detection potential, separation field strength were studied. Under optimized detection conditions, (30 mmol/L NaOH buffer, 0.7 V detection potential and 50 V/cm separation field strength), arginine responded linearly from 40 μmol/L to 3 mmol/L. The arginine and leucine got fast and good separation by 30 mm-long channel.
与传统的毛细管电泳类似，芯片毛细管电泳（CE chip）常用的检测方法为激光诱导荧光检测（LIF），主要是因为它的灵敏度较高，但是具有天然荧光的物质较少，常常需要对样品进行衍生。另一方面，电化学检测（ECD）的灵敏度高、选择性易于调变、试样用量少、成本低，特别是包括控制仪器在内的EC装置特有的微型化特点，与微加工技术很匹配。这一传感方式非常符合微流控分析系统的微型化、集成化的要求，成为μ-TAS中非常重要的一类检测方式。
本论文以芯片毛细管电泳电化学检测 (CE – ECD chip) 为研究重点，主要包括以下工作内容：
采用毛细微模塑法（MIMIC）与无电沉积技术，可以直接在玻璃基片上制作出具有特定形状的铜膜电极。该铜膜电极不但可以直接作为工作电极，而且还可以作为铂接地电极的基底。然后将带有分离通道的聚二甲基硅氧烷（PDMS）芯片可逆的与电极板相键合，形成PDMS/玻璃杂化电泳芯片。该芯片制作费用低，时间短，电极形状可以准确控制，而且检测灵敏度高。芯片的有效分离通道长43 mm。在最优化的分析条件下，（30 mmol/L NaOH，检测电为0.7 V，进样与分离场强均为200 V/cm），连续七次进样标准葡萄糖溶液所得迁移时间与电流的相对标准偏差分别为2.2 %，4.4 %。得到葡萄糖的线性响应范围10 μmol/L ~ 1 mmol/L，相关系数为0.997，在信噪比等于3时的检测限是6 μmol/L。在分析健康人与糖尿病人的血浆样品时，测得的葡萄糖浓度与医院里采用酶自动分析仪所得的结果非常接近。证明CE – ECD chip技术在应用于临床样品分析方面显示了良好的选择性、重现性、准确性等优点，对于糖尿病人的诊断和治疗具有很好的应用价值，是一种灵敏、快速、准确的分析技术，具有一定的临床应用前景。
在PMMA上溅射金属Cu，然后利用光刻、湿法腐蚀的办法制出铜电极，与另一片含有微沟道的PMMA基片热键合，制作集成铜电极的塑料电泳芯片。当连续7次进样分析标准葡萄糖溶液时，迁移时间和电化学响应信号的相对标准偏差分别为3.52%和1.12%，重现性较好，说明该芯片微沟道表面特性和电极的电化学特性均较稳定。而且还考察了各种分析条件对氨基酸分离的影响，在优化条件（30 mmol/L NaOH 缓冲溶液中，检测电位为0.7 V，进样与分离电场强度均为50 V/cm）下，精氨酸的线性响应范围为40 μmol/L 到3 mmol/L，检测限为 30 μmol/L（信噪比等于3），同时在3 cm 长的通道内较好地分离了精氨酸与亮氨酸。
For over a decade, the area of micro total analysis systems, also called “lab on a chip”, has been growing rapidly. The numerous advantages of incorporating several previously distinct processes into a miniaturized format include faster analysis time, decreased cost and waste production, portability, disposability.
Capillary electrophoresis microchip (CE chip) is an emerging technology that has generated a great deal of interests in analytical chemistry. Like conventional CE, laser- induced fluorescence (LIF) remains one of the most sensitive detection techniques for CE chip. However, the implementation of LIF can be quite difficult. On the other hand, electrochemical detection (ECD) is relatively simple, inexpensive, applicable to a wide range of analytes, and easily miniaturized.
This thesis is concentrated on the study of CE – ECD chip and its application in analysis of pharmaceuticals and biochemicals as described below.
The pattern of the microelectrodes for CE – ECD chip was directly made on the surface of a microscope slide through the micromolding in capillaries (MIMIC) techniques and electroless deposition procedure. The copper microelectrode is fabricated by selective electroless deposition. And the fabrication of decoupler is platinum electrochemical deposition on metal film formed by electroless deposition. The whole chip was built by reversibly sealing the slide to the poly(dimethylsiloxane) (PDMS) layer with electrophoresis microchannels at room temperature. The fabrication of a hybrid chip device is simple, rapid and costless compared with the conventional method of glucose detection using glucose oxidase. Factors influencing the performance, including the detection potential, separation field strength, buffer concentration, were studied. The electrodes exhibited good stability and durability in the analytical procedures. Under optimized detection conditions, （30 mM NaOH, separation field strength of 200 V/cm and detection potential at 0.7 V）， seven consecutive injections of glucose
were performed. The relative standard deviation (RSD) of the migration time was 2.2 %, with that of the peak height was 4.4 %. And the glucose responded linearly from 10 μmol/L to 1 mmol/L. Furthermore, the glucose in human plasma from healthy individuals and diabetics was successfully determined, which was close to those got with HITACHI 7020 Automatic Analyzer in Jilin University Hospital. This work gives a newly alternative way to the quick determination of glucose in real sample with high sensitivity. So the miniaturized CE–ECD analysis system has the application prospect and attraction for clinical bioassays.
Cu is sputtered onto PMMA, and copper electrodes are formed by photolithograph and wet etching; an electrophoresis chip is fabricated by thermally bonding the PMMA with copper electrodes to a PMMA substrate with microchannels. When seven consecutive injections of standard glucose were performed, the relative RSD of the migration time was 3.52 %, with that of the peak height was 1.12 %. Furthermore, factors influencing the performance, including the detection potential, separation field strength were studied. Under optimized detection conditions, (30 mmol/L NaOH buffer, 0.7 V detection potential and 50 V/cm separation field strength), arginine responded linearly from 40 μmol/L to 3 mmol/L. The arginine and leucine got fast and good separation by 30 mm-long channel.
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