CN103616426B - 一种用于快速生化分析的集成式的微流控电化学生物传感系统及其使用方法 - Google Patents

一种用于快速生化分析的集成式的微流控电化学生物传感系统及其使用方法 Download PDF

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CN103616426B
CN103616426B CN201310638228.9A CN201310638228A CN103616426B CN 103616426 B CN103616426 B CN 103616426B CN 201310638228 A CN201310638228 A CN 201310638228A CN 103616426 B CN103616426 B CN 103616426B
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CN103616426A (zh
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樊春海
杨帆
左小磊
黄庆
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Zhejiang Zhenmai Medical Technology Co.,Ltd.
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Shanghai Institute of Applied Physics of CAS
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Abstract

本发明提供一种用于快速生化分析的集成式的微流控电化学生物传感系统及其使用方法，该系统包括：用于依次运输先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液以及电化学检测缓冲溶液的连续进样单元；由一个或多个微通道网络组成的微流控芯片，所述微流控芯片覆盖在电极阵列上形成一个通道系统，所述电极阵列的表面上固定有与所述样品溶液相互作用的捕获探针，所述通道系统与所述连续进样单元连接；以及为所述连续进样单元提供动力的动力系统。本发明创造性地将平面电极阵列，微流控芯片技术以及连续进样单元三种技术结合在一起，提供了一种体积小、成本低、集成式的微流控电化学生物传感系统，具有广阔的应用前景。

Description

一种用于快速生化分析的集成式的微流控电化学生物传感系统及其使用方法
技术领域
本发明涉及微流控电化学生物传感系统领域，更具体地涉及一种用于快速生化分析的集成式的微流控电化学生物传感系统及其使用方法。
背景技术
电化学生物传感器就是利用生物化学反应所特有的专一性，选择性地识别特定的待测物质，并将其生化反应转换成电信号输出的一种装置。电化学检测方法本身具有一些独特的优点，包括：检测快速、灵敏度高、选择性高，仪器简便，易于微型化、集成化、且能耗低，适用于现场检测等。但传统的碳电极或金电极等三电极系统不仅分析通量低，成本也较高，难以满足现阶段的高通量和低成本检测的要求。近来印刷技术、光刻技术的快速发展极大的促进了高通量和一次性电极的开发，但长时间的样品孵育和耗时、繁琐的清洗步骤限制了这类电化学生物传感器进一步的应用。针对以上问题，微流控芯片技术可予以有效解决。
微流控芯片分析是以分析化学和生物化学为基础，以微机电加工技术为依托，以微通道网络结构为特征，把试样的采集、预处理、分离、反应和检测等部分集成在几个平方厘米的范围内，从而快速、高效的完成样品的处理和检测。因微通道的深、宽均在微米级，故可有效的将待检测的目标物和传感界面固定的捕获探针限制在微米尺度范围内相互作用，大大提高了分子间的识别能力。
电极表面的快速分子识别是实现现场高效电化学生物传感的基础。Soh等人（Swensen,J.S.;Xiao,Y.;Ferguson,B.S.;Lubin,A.A.;Lai,R.Y.;Heeger,A.J.;Plaxco,K.W.;Soh,H.T.,Continuous,Real-TimeMonitoringofCocaineinUndilutedBloodSerumviaaMicrofluidic,ElectrochemicalAptamer-BasedSensor.JACS,2009,131,4262-4266）通过光刻技术制备了平面金电极，构建微流控E-DNA传感器。但光刻技术制备电极成本高，难以批量生产。另外，Rusling等人（Chikkaveeraiah,B.V.;Mani,V.;Patel,V.;Gutkind,J.S.;Rusling,J.F.,Microfluidicelectrochemicalimmunoarrayforultrasensitivedetectionoftwocancerbiomarkerproteinsinserum.Biosens.Bioelectron.,2011,26,4477-4483）利用印刷电极阵列与微通道结构在机械螺丝和有机玻璃夹具的固定下完成了芯片传感器的可逆封合，虽然实现了超灵敏的标志物检测，但每次样品测试均要重新组装和拆卸传感器件，并重复沿微通道插入对电极和参比电极，该工作量大，繁琐。虽然有报道毛细作用力驱动的单电极式微流控电化学传感器，但该作用力无法一次完成多种溶液的输送，也很难进行多元检测（Lillehoj,P.B.;Wei,F.;Ho,C.-M.,Aself-pumpinglab-on-a-chipforrapiddetectionofbotulinumtoxin.LabChip,2010,10,2265-2270）。如何实现高效的分子识别和快速的完成多种溶液的传递依然是一个严峻的挑战。近来，Sia等（Chin,C.D.;Laksanasopin,T.;Cheung,Y.K.;Steinmiller,D.;Linder,V.;Parsa,H.;Wang,J.;Moore,H.;Rouse,R.;Umviligihozo,G.;Karita,E.;Mwambarangwe,L.;Braunstein,S.L.;vandeWijgert,J.;Sahabo,R.;Justman,J.E.;El-Sadr,W.;Sia,S.K.,Microfluidics-baseddiagnosticsofinfectiousdiseasesinthedevelopingworld.Nat.Med.,2011,17,1015-1019）通过引入气体间隔的溶液区带和微流控芯片完成了传染性疾病的快速检测，但该方法主要通过银增强的信号来定性的分析了疾病情况，而临床及现场检测更多的需要定量的分析疾病标志物。
发明内容
本发明的目的是提供一种用于快速生化分析的集成式的微流控电化学生物传感系统及其使用方法，从而解决现有技术不能快速地完成多种溶液的传递，微流控芯片的微通道网络层和电极阵列层需要借助辅助设备固定，并且无法实现定量分析疾病标记物的缺陷，以及现有技术的电化学生物传感系统仅限于光刻技术制备的平面电极阵列，造成成本较高的缺陷。
为了解决上述技术问题，本发明采用以下技术方案：
提供一种用于快速生化分析的集成式的微流控电化学生物传感系统，包括：用于依次运输先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液以及电化学检测缓冲溶液的连续进样单元；由一个或多个微通道网络组成的微流控芯片，所述微流控芯片覆盖在电极阵列上形成一个通道系统，所述电极阵列的表面上固定有与所述样品溶液相互作用的捕获探针，所述通道系统与所述连续进样单元连接；以及为所述连续进样单元提供动力的动力系统。
其中，所述连续进样单元在动力系统的作用下，将先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液以及电化学检测缓冲溶液依次连续地通入所述微流控芯片的微通道网络，并与固定在所述电极阵列表面的捕获探针相互作用，产生可供电化学设备检测的信号，一次性读出不同捕获探针修饰的电极阵列表面的电化学信号。
所述微流控芯片与电极阵列通过等离子体清洗以及加热键合处理后形成无漏液的可逆或不可逆所述通道系统。
所述加热键合处理的条件是37℃下恒温30min以上。
所述电极阵列是由丝网印刷技术制备的碳电极阵列或金电极阵列，或者是在碳电极表面直接电化学沉积纳米金属颗粒制备的电极阵列或由光刻技术制备的平面电极阵列。
所述电极阵列表面固定的捕获探针包括抗体、抗原、核酸或核酸适配体。
所述连续进样单元由具有贯穿通道的小管形成，所述先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液和电化学检测缓冲溶液彼此之间通过空气泡间隔依次通过所述贯穿通道通入所述微流控芯片的微通道网络。
所述动力系统由连接在微流控芯片的下游的注射泵或注射器形成，提供作为流体驱动力的真空负压，以实现连续进样单元内不同功能溶液的自动传送。
还提供一种用于快速生化分析的集成式的微流控电化学生物传感系统的使用方法，包括：提供如上所述的微流控电化学生物传感系统；将动力系统连接在所述微流控芯片的下游，通过所述连续进样单元将先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液和电化学检测缓冲溶液依次连续地通入所述微流控芯片的微通道网络，并与固定在所述电极阵列表面的捕获探针相互作用，实现连续的捕获和清洗，快速形成供检测的电化学信号，通过电化学工作站一次性读出不同捕获探针修饰的电极阵列表面的电化学信号。
所述先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液和电化学检测缓冲溶液之间依次由长度为0.5cm以上的空气泡间隔开，防止交叉污染。
所述动力系统由连接在微流控芯片的下游的注射泵或注射器形成，所述注射泵或注射器通过一段形变能力强的橡胶小管与所述微流控芯片的出口端连接形成真空负压系统。
本发明创造性地将平面电极阵列，微流控芯片技术以及连续进样单元三种技术结合在一起形成了一种可同时检测多种疾病标志物的微尺度电化学传感方法。电化学分析和微流控芯片实际上是属于两个不同的研究领域。电化学分析领域多强调电极界面的设计和调控，在样品的操纵、连续进样或连续清洗等方面研究不多。而微流控领域则强调流体的可控操纵和芯片微通道的设计以匹配或满足相应的检测手段。尽管集成电化学检测的微流控芯片早有报道，但多集中在玻璃或硅基底的光刻平面微电极的基础上，主要原因是这种光刻平面微电极能够与芯片微通道相匹配，且易于键合。但是这种光刻技术制备电极成本高，难以批量生产。此外，这类集成电化学检测的微流控芯片主要靠毛细作用力或微泵提供动力进行多次繁琐的进样和清洗程序。而本申请中的电极阵列则不仅适用已经成功商业化的一类宏观的如塑料基底的印刷电极而言，而且还可扩展到光刻技术制备的平面宏观电极。我们成功将市场无穷大的印刷电极同新的微流控技术结合并集成一次性连续进样单元，具有明显的创新和应用前景。
本发明相对现有技术具有的有益效果如下：
1）可快速并一次性完成多种溶液的运输，使其依次流经微尺度传感界面，提高分子识别效率，操作简单，速度快，大大简化了电化学生物传感器的操作步骤；
2）微流控芯片的微通道网络和电极阵列层之间通过处理实现了无漏液的封接，无需任何辅助设备固定，降低了器件制备难度，提高了器件制备的重复性和稳定性；
3）可实现多种不同目标物的不同浓度的定量检测，试剂消耗量少，分析速度快；
4）提供了一种体积小、成本低、集成式的微流控电化学生物传感系统，具有广阔的应用前景。
附图说明
图1是根据本发明的一个优选实施例的微流控电化学生物传感系统的立体结构示意图；
图2是如图1所示的微流控电化学生物传感系统的剖面图；
图3是基于单个三电极体系的微流控电化学生物传感器的形成的流程示意图；
图4是基于4个三电极体系的微流控电化学生物传感器的形成的流程示意图；
图5是基于印刷电极阵列和聚二甲基硅氧烷微通道的微流控电化学生物传感器的表面处理和键合过程示意图；
图6A和图6B是单个三电极体系和微流控芯片的微通道网络键合后检测500ng/mLPSA的电流结果比较图；
图7是不同浓度的人类流感病毒H1N1裂解疫苗在单个三电极体系的微流控电化学生物传感器上检测的结果图；
图8是不同浓度的人类前列腺癌标志物PSA在如图1所示的微流控电化学生物传感系统的检测的结果图；
图9是不同浓度的人类肝癌标志物AFP在如图1所示的微流控电化学生物传感系统的检测的结果图。
具体实施方式
以下结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围。
如图1-图2所示，是根据本发明的一个优选实施例的微流控电化学生物传感系统，该系统包括：用于运输不同功能溶液的连续进样单元1，由四个微通道网络21组成的微流控芯片2，通过所述微流控芯片2覆盖的电极阵列3，以及连接在微流控芯片2下游的动力系统4。
其中，连续进样单元1由透明的塑料小管11形成，提供一贯穿通道供各种功能溶液依次通入微流控芯片2的微通道网络21，各种功能溶液通过空气泡13彼此间隔形成不同的功能溶液区带12。优选地，空气泡13的长度需保持在0.5厘米以上，以防止进样和上样过程中因压力的快速变化导致空气泡13被挤压或溶液的不连续分散以至前后溶液混合，形成交叉污染。
参见图3-图4，优选地，微流控芯片2由四个蛇形微通道网络21制成，电极阵列3由四个三电极体系的印刷电极组成，具体为工作电极31，对电极32，参比电极33，以及电极印刷银导线34（参见图1）。图5示出了该微流控芯片2与电极阵列3的表面处理和键合过程。具体为：首先，同时对含有微通道网络21的微流控芯片2（由聚二甲基硅氧烷（PDMS）制成）和被PDMS框选择性保护的电极阵列3进行等离子体处理；之后，移除保护电极阵列的表面抗体活性的PDMS框，使PDMS通道层和电极阵列层对齐加热键合。由于经等离子体处理后的芯片表面和电极阵列表面均产生了大量的含氧官能团，界面的含氧基团可以发生交联反应而形成不可逆的芯片键合，使得所述微流控芯片与电极阵列形成无漏液的可逆或不可逆系统，而无需机械螺丝和上下夹板任何外界的作用力。其中，所述加热键合处理的条件优选是37℃下恒温30min以上。
动力系统4作为连续进样单元1的动力源连接于微流控芯片2的下游，本优选实施例中选用一次性的注射器41，在使用时通过将注射器41的推柄拉至一定高度后用小木条或金属棒固定，从而在整个流道中形成真空负压，该负压作为流体驱动力进而实现连续进样单元1中各种功能溶液区带12的自动传送。为了保证真空负压的顺利形成，注射器41通过一段形变能力强且口径匹配的活塞式橡胶小管42与微流控芯片2的出口端连接。其中，活塞式橡胶小管42设计有可调的阀门43，从而控制整个流道的开和关。而注射器41与橡胶小管42，橡胶小管42与微流控芯片2的出口端之间进一步通过合适的小管连接。
实施例1
本实施例是采用单个三电极单元和微通道网络键合前后形成的微流控电化学生物传感系统（图3）用于人类前列腺癌标志物PSA的检测。具体步骤如下：将20μLTMB溶液（3,3',5,5'-四甲基联苯胺盐酸盐）分别滴加在三电极表面（Normal）和覆盖有PDMS的微通道内（Channel），然后将电极分别连接到电化学工作站进行循环伏安检测，获得图6A的实验结果。
通过1mL规格注射器连续手动抽取辣根过氧化物酶标记亲和素（avidin-HRP）、水、缓冲液（0.01M磷酸盐，0.14MNaCl，2.7mMKCl，pH7.2）、生物素标记PSA（biotin-PSA）和500ng/mLPSA溶液区带，各溶液区带之间间隔有0.5-1cm长的空气泡，其中各溶液区带体积在1-20μL；分别将制备好的微流控芯片、连续进样单元、动力系统连接成整体，注射泵的抽取流速调节到10-20μL/min，当看到连续进样单元内的溶液区带开始流向微流控芯片时，暂停抽取，快速调节流速到2-5μL/min。在溶液区带连续流通的过程中，电极界面固定的PSA-Ab（单克隆抗体）依次结合样品区带中的500ng/mLPSA、10-20μg/mL生物素标记的二抗biotin-PSA，形成夹心结构后与信号探针溶液区带中的avidin-HRP偶联。经缓冲溶液和水洗脱掉未结合的探针复合物后，直接在进样口滴加10μLTMB溶液，无动力进样，将电极连接到电化学工作站进行安培检测，HRP酶催化TMB溶液中的H2O2循环放大电化学信号，获得图6B的实验结果。
实施例2
本实施例还是采用单个三电极单元和微通道网络键合前后形成的微流控电化学生物传感系统（图3）用于人类流感病毒H1N1裂解疫苗的检测，步骤如下，通过1mL规格注射器连续手动抽取H1N1-HRP、水、缓冲液（0.01M磷酸盐，0.14MNaCl，2.7mMKCl，pH7.2）、和一定浓度的H1N1裂解疫苗溶液区带，各溶液区带之间间隔有0.5-1cm长的空气泡，其中各溶液区带体积在1-20μL；分别将制备好的微流控芯片、连续进样单元、动力系统连接成整体，注射泵的抽取流速调节到10-20μL/min，当看到传送单元内的溶液区带开始流向微流控芯片时，暂停抽取，快速调节流速到2-5μL/min。在溶液区带连续流通的过程中，电极界面固定的H1N1-77（H1N1抗体）依次结合样品区带中的0-500ng/mLH1N1、10μg/mLHRP标记的二抗HRP-H1N1（探针溶液），形成夹心结构。经缓冲溶液和水洗脱掉未结合的探针复合物后，直接在进样口滴加10μLTMB溶液，无动力进样，将电极连接到电化学工作站进行安培检测，HRP酶催化TMB溶液中的H2O2循环放大电化学信号，获得图7的实验结果。
实施例3
本实施例采用四个三电极单元和微通道网络键合形成的微流控电化学生物传感系统（图4）用于人类前列腺癌标志物PSA和人类肝癌标志物AFP的同时检测，步骤如下，通过1mL规格注射器连续手动抽取avidin-HRP、水、缓冲液（0.01M磷酸盐，0.14MNaCl，2.7mMKCl，pH7.2）、biotin-PSA与biotin-AFP的混合物和一定浓度的PSA和AFP抗原混合物溶液区带，区带之间间隔有0.5-1cm长的空气泡，其中各溶液区带体积在1-20μL；分别将制备好的微流控芯片、连续进样单元、动力系统连接成整体，注射泵的抽取流速调节到10-20μL/min，当看到传送单元内的溶液区带开始流向微流控芯片时，暂停抽取，快速调节流速到2-5μL/min。在溶液区带连续流通的过程中，电极界面固定的PSA-Ab和AFP-Ab（单克隆抗体）依次结合样品区带中的0-100ng/mLPSA和0-500ng/mLAFP、10-20μg/mL生物素标记的二抗biotin-PSA和12.5-25μg/mL生物素标记的二抗biotin-AFP，形成夹心结构后与信号探针溶液区带中的avidin-HRP偶联。经缓冲溶液和水洗脱掉未结合的探针复合物后，直接在进样口滴加20μLTMB溶液，无动力进样，将电极连接到电化学工作站进行安培检测，HRP酶催化TMB溶液中的H2O2循环放大电化学信号，获得图8图9的实验结果。
以上所述的，仅为本发明的较佳实施例，并非用以限定本发明的范围，本发明的上述实施例还可以做出各种变化。即凡是依据本发明申请的权利要求书及说明书内容所作的简单、等效变化与修饰，皆落入本发明专利的权利要求保护范围。本发明未详尽描述的均为常规技术内容。

Claims (7)

1.一种用于快速生化分析的集成式的微流控电化学生物传感系统，其特征在于，包括：
用于依次运输通过空气泡间隔的先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液以及电化学检测缓冲溶液的连续进样单元；
由多个蛇形微通道网络组成的微流控芯片，所述微流控芯片覆盖在三电极体系的电极阵列上形成一个通道系统，所述电极阵列的表面上固定有与所述样品溶液相互作用的捕获探针，所述通道系统与所述连续进样单元连接，所述微流控芯片与电极阵列通过等离子体清洗以及加热键合处理后形成无漏液的可逆或不可逆的所述通道系统；以及
为所述连续进样单元提供动力的动力系统，所述动力系统由连接在微流控芯片的下游的注射泵或注射器形成，提供作为流体驱动力的真空负压。
2.根据权利要求1所述的微流控电化学生物传感系统，其特征在于，所述加热键合处理的条件是37℃下恒温30min以上。
3.根据权利要求1所述的微流控电化学生物传感系统，其特征在于，所述电极阵列是由丝网印刷技术制备的碳电极阵列或金电极阵列，或者是在碳电极表面直接电化学沉积纳米金属颗粒制备的电极阵列或由光刻技术制备的平面电极阵列。
4.根据权利要求1所述的微流控电化学生物传感系统，其特征在于，所述电极阵列表面固定的捕获探针包括抗体、抗原、核酸或核酸适配体。
5.根据权利要求1所述的微流控电化学生物传感系统，其特征在于，所述连续进样单元由具有贯穿通道的小管形成，所述先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液和电化学检测缓冲溶液彼此之间通过空气泡间隔依次通过所述贯穿通道通入所述微流控芯片的微通道网络。
6.一种用于快速生化分析的集成式的微流控电化学生物传感系统的使用方法，其特征在于，包括：
提供如权利要求1-5中任意一项所述的微流控电化学生物传感系统；
将动力系统连接在所述微流控芯片的下游，通过所述连续进样单元将先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液和电化学检测缓冲溶液依次连续地通入所述微流控芯片的微通道网络，并与固定在所述电极阵列表面的捕获探针相互作用，实现连续的捕获和清洗，快速形成供检测的电化学信号，通过电化学工作站一次性读出不同捕获探针修饰的电极阵列表面的电化学信号。
7.根据权利要求6所述的使用方法，其特征在于，所述先导洗脱液，样品溶液，样品洗脱液，信号探针溶液，信号探针洗脱液和电化学检测缓冲溶液之间依次由长度为0.5cm以上的空气泡间隔开，防止交叉污染。
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