CN1353309A - 检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置 - Google Patents
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Abstract
检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置属于毛细管电泳装置,其特征在于,它含有:具有一维、或二维或多维微流体通道和加样用电极孔结构的上层通道层,封闭上层微流体通道以构筑完整的毛细管且为电泳提供所需电压的中层电极层以及为电泳提供稳定温度梯度的加热层,所述上、中、下三层是可导热且相互粘合的。加热层带有相间隔地分成二组或多组各自分别保持恒定温度以便形成稳定的空间温度梯度的温控元件;同时,加热层稳定的温度梯度也可是一种把芯片整体均匀逐渐升温而形成的时间温度梯度。它既有毛细管电泳技术所特有的高速、高效、消耗样品少的优点,又可避免使用变性剂,而用温度来代替,使得检测过程易于控制,梯度也易于实现。
Description
技术领域
一种检测核苷酸和单核苷酸多态性(Single Nucleotide Polymorphism简称SNP)用的毛细管电泳芯片装置属于毛细管电泳芯片装置技术领域。
背景技术
在基因组中普遍存在着核苷酸和单核苷酸多态性(SNP)，据估计人类基因组中有300万个SNP位点。SNP位点在基因组中数量巨大、分布频密且有二态性，这些性质决定了它成为第三代遗传标记。寻找和研究SNP是人类基因组计划的重要内容和目标之一。作为多态性标记，SNP在人类学、医疗诊断。疾病研究、环境易感因子研究、药物筛选以及法医鉴定等方面具有重大意义。对脱氧核糖核酸(DNA)直接测序是检测SNP的最直接的方法，但其工作量大，效率低。目前人们致力于寻找高通量的方法。基于DNA解链动力学的检测方法就是一类高通量的方法，它包括梯度变性胶电泳、恒变性胶电泳、毛细管变性胶电泳和变性高效液相层析。但是在这些方法中都要加入变性剂，而变性剂对电泳、色谱等的影响机制比较复杂，变性剂的选择，电泳或色谱条件的设置以及梯度的实现等都是比较大的技术难题。
发明内容
本发明的目的是提供一种基于高速、高效、消耗样品少的毛细管电泳之上的以温度来替代变性剂的检测核苷酸和单核苷酸多态性使用的毛细管电泳芯片装置。
本发明的特征在于，它含有：具有微流体通道和加样用电极孔结构的上层通道层，封闭上层微流体通道以构筑起完整毛细管且为电泳芯片提供所需电压的中层电极层以及为电泳提供稳定温度梯度的加热层，其中，上、中、下三层是可导热且相互粘合的。所述的微流体通道是一维、或二维、或多维微流体通道中的任何一种。所述的微流体通道的截面宽度或直径在5-200μm之间，微流体通道的深度在5-200μm之间，电泳分离通道的长度在1-30cm之间。所述的中层电极层的材料是金或铂或石墨中的任何一种。所述的中层电极层的上表面涂布着一层聚二甲基硅氧烷(PDMS)。所述的加热层带有相间隔地分成二组或多组且各自分别保持不相同的恒定温度以便形成稳定的空间温度梯度的温控元件。所述加热层的稳定温度梯度是一种把芯片整体均匀逐渐升温而形成的时间温度梯度。
使用证明：它可达到预期目的。
附图说明
图1.本发明提出的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置的原理示意图。
图2.本发明提出的检测核苷酸和单核苷酸多态性用的优选实施例装置的上层通道层的俯视示意图。
图3.本发明提出的检测核苷酸和单核苷酸多态性用的优选实施例装置的中层电极层的俯视示意图。
图4.本发明提出的检测核苷酸和单核苷酸多态性用的优选实施例装置的下层加热层的俯视示意图。
图5.本发明提出的检测核苷酸和单核苷酸多态性用的优选实施例装置中图1A-A向的纵剖视图。
图6.图2中虚线框的俯视放大示意图。
图7.本发明优选实施例装置所用样品的预处理过程示意图。
具体实施方式
请见图1-图6。图1是图2、图3上、下层叠后的原理示意图。1是电极孔，2是第一维电泳分离通道。3是第二维电泳分离通道，它共有50条，每条管宽100μm，间距100μm，深为10μm，电泳分离通道的总长度为30cm，与电极孔1的连接管道宽20μm，4是上层流体通道层，即通道层。本优选实施例装置中，通道层4用聚二甲基硅氧烷(PDMS)制成，也可以用其他硅橡胶、塑料、石英和玻璃中的任何一种，其电泳分离通道和加样用电极孔1的微加工方法有浇铸、模压、蚀刻或光刻，随通道层材料而异。通道层4上的电泳分离通道即微流体通道的横截面呈矩形，也可以是任何其他几何形状。上述电泳分离通道是开放的毛细槽，用一片盖片把毛细槽封闭就形成完整的毛细管。同样，贯穿电泳分离通道的通道层也要加盖片才形成完整的液池结构。5是在中层电极层6上的电极。电极层6可以封闭上层电泳分离通道以形成完整毛细管又带有为电泳提供所需电压的电极。从图1中可知：电极5的裸露部分只在必要处与电泳分离通道中的流体接触，提供所需电压，并能根据计算机控制按程序变换电压。电极层6可以通过在玻璃上沉积金属再蚀刻而成。金属层采用金，也可用铂或石墨中的任何一种，在金属层上利用氧化方法形成绝缘层，只在与通道层4上电极孔1对应位置把金属电极暴露出来，或者直接涂布PDMS层，只在电极孔1的位置裸露金属电极。当通道层4与电极层6粘合后，电极孔1中的溶液与电极层6形成的孔底暴露出的电极接触。这些暴露的电极为电泳提供电泳所需电压。电极5也可设计成针状，从通道层4上面插入电极孔1中与溶液接触，再沿着电泳分离通道对溶液起作用。加热层有加热和冷却两组温控元件。加热元件7保持较高的恒定温度，冷却元件8保持较低的恒定温度，两者间热量通过电极层6的材料玻璃传导，从而在玻璃中形成稳定的空间温度梯度。本实施例中加热和冷却元件用半导体温控元件，也可用电阻。图6是图2中虚线框的俯视放大示意图。9是与电极孔1连接的通道，宽20μm，10是样品。2是第一维电泳分离通道，3是第二维电泳分离通道，箭头表示相应的电泳分离方向。在第一维电泳分离过程中可以防止样品10渗入第二维电泳分离通道3，也可在第二维电泳分离过程中防止第二维电泳分离通道3和连接电极孔1的通道9对第一维电泳分离过程的干扰。它还可使第一维电泳分离得到的区带完整进入第二维电泳分离通道3，而不致同时进入相邻的其他通道。图5是图1的A-A向纵剖视图，其构成已如上述。
图7为本发明优选实施例装置所用样品的预处理过程原理示意图。11是PCR聚合酶链式反应过程，12是变性、复性过程。其中，B代表AGCT中任一碱基，B*表示该位点为SNP点，″+″、″-″用以区分DNA的两条链。图7为存在SNP的情况，得到相同长度的4种DNA片段，有的存在错配。若不存在SNP，则只能有一种DNA片段。现结合该图简要描述用本发明检测SNP的过程。对于可能存在SNP位点的待分析样品进行预处理，使得DNA在存在SNP位点的地方发生错配，具体方法见图7。第一维电泳使不同长度的DNA片段得到有效分离，但是存在SNP位点的DNA和与其长度相同的DNA片段仍然存在于同一区带中。在第一维电泳分离时，第二维电泳分离通道两端加一定电压，防止样品扩散到第二维电泳分离通道3中。第二维电泳分离通道3是一排阵列。第一维电泳分离出的各区带通过电压控制进入第二维阵列电泳通道3中继续进行电泳，在这个电泳过程中，加热层在电泳前进方向提供了逐渐升高的温度梯度。有错配的DNA解链温度较无错配的低，在电泳前进不断升温的过程中，首先解链，从而受到更大的阻滞力，与其他尚未解链的相同长度的DNA片段分离。只要系统分辨率足够高，就可以把尚未解链的相同长度的DNA片段分离。若只分离得到1条区带，就可以断定无SNP位点，若分离得到多于一条区带，则可以断定存在SNP。综合以上信息还可以指出SNP存在于哪一段DNA限制性片段上。
温度梯度也可以考虑在时间上实现温度梯度。在第二维电泳分离时，对电泳芯片均匀加热，控制好升温速率，可以达到与前述相同的目的。只要分离通道足够长，电泳分离效率足够高，也可用普通毛细管作一维电泳分离。分离出不同长度的DNA片段，然后采用时间温度梯度继续电泳。
由此可见，本申请既有毛细管电泳技术所特有的高速、高效、消耗样品少的优点，又可避免使用变性剂，使检测过程易于控制，其梯度也易于实现。
Claims (7)
1、一种检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，含有电泳芯片，其特征在于，它含有：具有微流体通道和加样用电极孔结构的上层通道层，封闭上层微流体通道以构成起完整毛细管且为电泳芯片提供所需电压的中层电极层以及为电泳提供稳定温度梯度的加热层，其中，上、中、下三层是可导热且相互粘合的。
2、根据权利要求1所述的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，其特征在于：所述的微流体通道是一维、或二维、或多维微流体通道中的任何一种。
3、根据权利要求1所述的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，其特征在于：所述的微流体通道的截面宽度或直径在5-200μm之间，微流体通道的深度在5-200μm之间，电泳分离通道的长度在1-30cm之间。
4、根据权利要求1所述的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，其特征在于：所述中层电极层的材料是金或铂或石墨中的任何一种。
5、根据权利要求1所述的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，其特征在于：所述的中层电极层的上表面涂布着一层聚二甲基硅氧烷(PDMS)。
6、根据权利要求1所述的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，其特征在于：所述的加热层带有相间隔地分成二组或多组且各自分别保持不同的恒定温度以便形成稳定的空间温度梯度的温控元件。
7、根据权利要求1所述的检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置，其特征在于：所述加热层的稳定温度梯度是一种把芯片整体均匀逐渐升温而形成的时间温度梯度。
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011398310A CN1164939C (zh) | 2001-11-30 | 2001-11-30 | 检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置 |
| US10/500,180 US7527719B2 (en) | 2001-11-30 | 2002-11-29 | Capillary electrophoresis chip apparatus for detecting nucleotide polymorphism and single nucleotide polymorphism |
| AU2002349465A AU2002349465A1 (en) | 2001-11-30 | 2002-11-29 | Capillary electrophoresis chip apparatus for detecting polymorphism of nucleotide and mononucleotide |
| PCT/CN2002/000857 WO2003058227A1 (en) | 2001-11-30 | 2002-11-29 | Capillary electrophoresis chip apparatus for detecting polymorphism of nucleotide and mononucleotide |
| EP02782653A EP1464955A4 (en) | 2001-11-30 | 2002-11-29 | CAPILLARY ELECTROPHORESIS CHIP APPARATUS FOR DETECTION OF POLYMORPHISMS OF NUCLEOTIDES AND MONONUCLEOTIDES |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB011398310A CN1164939C (zh) | 2001-11-30 | 2001-11-30 | 检测核苷酸和单核苷酸多态性用的毛细管电泳芯片装置 |
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| CN1353309A true CN1353309A (zh) | 2002-06-12 |
| CN1164939C CN1164939C (zh) | 2004-09-01 |
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| US (1) | US7527719B2 (zh) |
| EP (1) | EP1464955A4 (zh) |
| CN (1) | CN1164939C (zh) |
| AU (1) | AU2002349465A1 (zh) |
| WO (1) | WO2003058227A1 (zh) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851680A (zh) * | 2010-06-01 | 2010-10-06 | 厦门大学 | 生物芯片高通量杂交的方法 |
| CN101670998B (zh) * | 2009-09-16 | 2011-10-26 | 哈尔滨工业大学 | 点面电极系统及利用该系统进行微流体驱动的方法 |
| CN1767898B (zh) * | 2003-01-31 | 2011-11-16 | 惠普开发有限公司 | 具有薄膜电子装置的微流体装置 |
| CN102883868A (zh) * | 2010-04-14 | 2013-01-16 | 道达尔公司 | 用于运输包含碳氢化合物的流体的管道及此类管道的生产方法 |
| CN102928495A (zh) * | 2012-11-22 | 2013-02-13 | 谭啸 | 匀速升温-变性梯度凝胶多功能电泳系统 |
| US9020333B2 (en) | 2010-04-14 | 2015-04-28 | Total Sa | Line for transporting a fluid containing a hydrocarbon, and method for producing such a line |
| CN112771364A (zh) * | 2018-09-27 | 2021-05-07 | 京瓷株式会社 | 粒子分离测量设备以及粒子分离测量装置 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1756952A (zh) * | 2002-12-20 | 2006-04-05 | 东北大学 | 精确控制的恒温器 |
| US9393566B2 (en) | 2008-06-23 | 2016-07-19 | Canon U.S. Life Sciences, Inc. | System and method for temperature referencing for melt curve data collection |
| WO2016138208A1 (en) * | 2015-02-27 | 2016-09-01 | Waters Technologies Corporation | Spatial temperature gradients in liquid chromatography |
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| US3502558A (en) * | 1967-11-03 | 1970-03-24 | Us Army | Method of depositing gelatin |
| US6001229A (en) | 1994-08-01 | 1999-12-14 | Lockheed Martin Energy Systems, Inc. | Apparatus and method for performing microfluidic manipulations for chemical analysis |
| US5641400A (en) | 1994-10-19 | 1997-06-24 | Hewlett-Packard Company | Use of temperature control devices in miniaturized planar column devices and miniaturized total analysis systems |
| JP2937064B2 (ja) * | 1995-02-28 | 1999-08-23 | 株式会社島津製作所 | キャピラリ電気泳動チップ |
| US6045676A (en) * | 1996-08-26 | 2000-04-04 | The Board Of Regents Of The University Of California | Electrochemical detector integrated on microfabricated capilliary electrophoresis chips |
| WO1999014368A2 (en) * | 1997-09-15 | 1999-03-25 | Whitehead Institute For Biomedical Research | Methods and apparatus for processing a sample of biomolecular analyte using a microfabricated device |
| US6261431B1 (en) * | 1998-12-28 | 2001-07-17 | Affymetrix, Inc. | Process for microfabrication of an integrated PCR-CE device and products produced by the same |
| JP2000227414A (ja) | 1999-02-08 | 2000-08-15 | Shimadzu Corp | マイクロチップ電気泳動用のチップユニット |
| AU3963300A (en) * | 1999-03-30 | 2000-10-16 | Institut Fur Mikrotechnik Mainz Gmbh | Electrophoresis chip and device for operating an electrophoresis chip |
| US20010025792A1 (en) * | 2000-03-14 | 2001-10-04 | Shaorong Liu | Pseudoradial electrophoresis chip |
| AU2001249236A1 (en) * | 2000-03-17 | 2001-10-03 | Spectrumedix Corporation | Electrophoresis microchip and system |
| US6939451B2 (en) * | 2000-09-19 | 2005-09-06 | Aclara Biosciences, Inc. | Microfluidic chip having integrated electrodes |
| CN1131428C (zh) * | 2001-04-23 | 2003-12-17 | 清华大学 | 用于化学分析的毛细管电泳芯片的制备方法 |
-
2001
- 2001-11-30 CN CNB011398310A patent/CN1164939C/zh not_active Expired - Fee Related
-
2002
- 2002-11-29 AU AU2002349465A patent/AU2002349465A1/en not_active Abandoned
- 2002-11-29 WO PCT/CN2002/000857 patent/WO2003058227A1/zh not_active Application Discontinuation
- 2002-11-29 EP EP02782653A patent/EP1464955A4/en not_active Withdrawn
- 2002-11-29 US US10/500,180 patent/US7527719B2/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1767898B (zh) * | 2003-01-31 | 2011-11-16 | 惠普开发有限公司 | 具有薄膜电子装置的微流体装置 |
| CN101670998B (zh) * | 2009-09-16 | 2011-10-26 | 哈尔滨工业大学 | 点面电极系统及利用该系统进行微流体驱动的方法 |
| CN102883868A (zh) * | 2010-04-14 | 2013-01-16 | 道达尔公司 | 用于运输包含碳氢化合物的流体的管道及此类管道的生产方法 |
| US9020333B2 (en) | 2010-04-14 | 2015-04-28 | Total Sa | Line for transporting a fluid containing a hydrocarbon, and method for producing such a line |
| US9046207B2 (en) | 2010-04-14 | 2015-06-02 | Total Sa | Line for transporting a fluid containing a hydrocarbon, and method for producing such a line |
| CN101851680A (zh) * | 2010-06-01 | 2010-10-06 | 厦门大学 | 生物芯片高通量杂交的方法 |
| CN102928495A (zh) * | 2012-11-22 | 2013-02-13 | 谭啸 | 匀速升温-变性梯度凝胶多功能电泳系统 |
| CN112771364A (zh) * | 2018-09-27 | 2021-05-07 | 京瓷株式会社 | 粒子分离测量设备以及粒子分离测量装置 |
| CN112771364B (zh) * | 2018-09-27 | 2024-04-26 | 京瓷株式会社 | 粒子分离设备以及粒子分离测量装置 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002349465A1 (en) | 2003-07-24 |
| US7527719B2 (en) | 2009-05-05 |
| EP1464955A1 (en) | 2004-10-06 |
| CN1164939C (zh) | 2004-09-01 |
| EP1464955A4 (en) | 2007-09-12 |
| WO2003058227A1 (en) | 2003-07-17 |
| US20050161335A1 (en) | 2005-07-28 |
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