CN1164894A - 自动分子生物学诊断系统 - Google Patents

自动分子生物学诊断系统 Download PDF

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CN1164894A
CN1164894A CN95196089A CN95196089A CN1164894A CN 1164894 A CN1164894 A CN 1164894A CN 95196089 A CN95196089 A CN 95196089A CN 95196089 A CN95196089 A CN 95196089A CN 1164894 A CN1164894 A CN 1164894A
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dna
electrode
electronic installation
holder
control system
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CN1121614C (zh
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M·J·赫彻
E·图
D·D·蒙哥马利
W·F·巴特勒
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Nanogen Inc
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Nanogen Inc
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Abstract

能在微观方式上进行分子诊断、分析、多步骤和多重反应的可自编址、自装配的微电子系统。可主动控制的反应包括核酸杂交、免疫检测、临床诊断和多步骤组合的生物聚合物合成。通过输入/输出装置与用户相连的控制器接口优选地包括一个图像显示器。控制器可与电源和接口相连，接口提供到各独立微位点的选择性连接，提供极性逆转和提供到各独立电极的选择性电压或电流水平。一个用于进行DNA样品制备、杂交、检测和数据分析的组合系统将多个步骤整合到一起。带电物质优选地通过自由电场电泳进行转运。DNA复杂性降低优选地通过将DNA结合到支持物上，由诸如限制性酶等切下未结合部分，再转移切下的片段来完成。有源可编程矩阵装置包括方形矩阵结构，该结构具有扇状分布的电连接和可选的在特异性微位点下的电连接，由此产生了高度自动化的DNA诊断系统。

Description

自动分子生物学诊断系统
发明领域
本发明涉及用于在多重方式(multiplex format)中进行多步骤的分子生物学类型的诊断分析的装置和系统。更具体地说，该分子生物学类型的分析包括各种核酸杂交反应及相关的生物聚合物的合成。此外，也可以进行抗体/抗原反应以及其它的临床诊断。
相关申请资料
本申请是1994年7月7日提交的序列号08/271,882申请的部分继续，而后者又是1993年11月1日提交的序列号07/146,504申请的部分继续，标题均为“用于分子生物学分析和诊断的能自编址和自装配的微电子系统和装置”。
发明背景
分子生物学包括了各种各样的用于分析核酸和蛋白质的技术，许多这样的技术和方法构成了临床诊断试验和检测的基础。这些技术包抬核酸杂交分析，限制性酶分析，基因序列分析，核酸和蛋白质的分离纯化(见，例如J.Sambrook，E.F.Fritsch和T.Maniatis，分子克隆：实验指南，第二版，冷泉港实验室出版社，冷泉港，纽约，1989)。
大多数这类技术涉及到对大量的样品进行大量的操作(例如移液、离心、电泳)。这些操作通常是复杂而耗时的，并通常需要高度的准确性。由于缺乏敏感性、专一性及重现性，许多这类技术在应用时受到局限。例如，上述问题限制了核酸杂交分析在诊断方面的许多应用。
进行一种遗传病或传染病的DNA杂交分析的全过程是很复杂的。概括地讲，全过程可分为许多步骤和分步骤(见图1)。在诊断遗传病的情况下，第一步是得到样品(血液或组织)。依据样品的类型，进行不同的预处理。第二步是裂解或溶解细胞，释放出粗DNA物质及其它细胞组分。通常还需要几个分步骤来去掉细胞碎片及进一步纯化粗DNA。在这一点上，有几种方案供进一步的处理与分析。第一种方案包括使纯化的DNA样品变性，并在多种方式(点印迹、微珠、微量滴定板等)的一种上进行直接杂交。第二种方案是Southen印迹杂交，包括用限制性酶切割DNA，在电泳胶上分离DNA片段，印在一滤膜上，然后用特异性DNA探针杂交印记。此方法有效地降低了基因组DNA样品的复杂性，因而有利于提高了杂交的专一性与灵敏度。不幸的是，此方法既耗时又费力。第三种方案是进行聚合酶链式反应(PCR)或其它的扩增方法。PCR方法扩增(增加)大量的靶DNA序列。靶DNA的扩增有利于克服基因组DNA分析中存在的有关复杂性和灵敏度问题。所有这些方法都是耗时的，相对复杂的，大大增加了诊断试验的费用。在这些样品制备及DNA加工步骤完成以后，进行真正的杂交反应。最后，通过检测和数据处理将杂交结果转变为分析结果。
样品制备和加工步骤典型地独立完成，与其它的杂交主要步骤以及检测和分析区分开来。实际上，包括样品制备和DNA加工的各个分步骤常与其它分步骤分离开来，单独进行操作。就这些分步骤具体而言，样品可通过许多手段获得，例如以全血，组织或其它生物流体样品中得到。在以血液为样品时，首先需加工样品除去红细胞，保留需要的有核细胞(白细胞)。这个方法通常采用密度梯度离心来完成。然后，将细胞裂解或溶解，优选地用超声波、冻融技术或加入细胞裂解剂。通过离心，将粗DNA与细胞碎片分离开来。在杂交反应之前，双链DNA被变性为单链形式。双链DNA的变性通常采用下列技术，包括加热(＞Tm)，改变盐浓度，加碱(NaOH)或加入变性剂(尿素、甲酰胺等)。工作人员建议在电化槽中将DNA变性为单链。该理论呈述如下：在电极的界面处有电子转移到DNA，这有效地削弱了双链结构，使得双链分离。综述见Stanley，“通过电压使DNA变性”，英国专利申请2,247,889,公开于1992年3月18日。
核酸杂交分析通常包括用过量的DNA探针在相对大量的复杂的非靶核酸中检测微量的特异性的靶核酸(DNA或RNA)。在样品制备中，使DNA复杂性降低的分步骤被用来帮助检测低拷贝数(即10,000到100,000)的靶核酸。利用聚合酶链式反应(PCR)扩增靶核酸序列能在一定程度上克服DNA的复杂性(见M.A.Innis等，PCR方案：方法和应用指南，学术出版社，1990)。扩增产生了大量的靶核酸序列，促进了随后的直接探针杂交步骤，但扩增方法费时，繁琐，通常必须在一个相对于其它分步骤独立的基础上进行。进行扩增所用的装置比较大并且很复杂。
实际的杂交反应代表着整个方法中最重要也是最核心的步骤。杂交步骤包括，在一组最适条件下，将制备的DNA样品与专一性报道探针(reporter probe)接触，使探针与靶DNA序列发生杂交。杂交可以以众多方式的任意一种进行。例如，多重样品核酸杂交分析已经在多种滤膜和固体支持物上进行(见G.A.Beltz等，酶学方法，Vol.100，Part B，R.Wu，L.Grossman，K.Moldave编，学术出版社，纽约，第19章，pp.266-308，1985)。一种方式，即所谓“点印迹”杂交，包括靶DNA与滤器非共价连接，然后，再与放射性同位素标记的探针进行杂交。“点印迹”杂交被普遍采用，已有许多版本(见M.L.M.Anderson和B.D.Young，核酸杂交-一种实用方法，B.D.Hames和S.J.Higgins编，IRL出版社，华盛顿特区，第4章，pp.73-111，1985)。它已经被改进，可用于基因组突变的多重分析(D.Nanibhushan和D.Rabin，EPA 0228075，1987年7月8日)，以及重叠克隆的检测和基因组图谱的构建(G.A.Evans，美国专利5,219,726号，1993年6月15日)。
能在微型方式的多路或矩阵装置上进行多重样品核酸杂交分析的新技术正在发展起来(例如，DNA芯片)(见M.Barinaga，253 Science，PP.1487，1991；W.Bains，10 Bio/Technology，PP.757-758，1992)。这些方法通常将专一性DNA序列连接到固体支持物上的一个微小的特殊区域里，例如一个DNA芯片的微孔里。这些杂交方式是传统的“点印迹”和“三明治”杂交系统的微型版本。
这种微型杂交方式可用于完成“通过杂交进行测序”(SBH)(见M.Barinaga，253 Science，PP.1489，1991；W.Bains，10Bio/Technology，PP.757-758，1992)。SBH利用所有可能的n-核苷酸寡聚物(n聚物)来确定一个未知DNA样品中的n聚物，再通过算法分析对其进行排列，得出DNA序列(R.Drmanac和R.Crkvenjakov，南斯拉夫专利申请#570/87，1987；R.Drmanac等，4 Genomics，114，1989；Strezoska等，88美国国家科学院院刊10089，1992；R.Dramanac和R.B.Crkvenjakov，美国专利#5,202,231，1993年4月13日)。
有两种方式可用于SBH。第一种方式包括将所有可能的n聚物在一种支持物上进行排列，然后再与靶序列进行杂交。第二种方式包括将靶序列连到支持物上，后者再依次与所有可能的n聚物进行探针反应。两种方式都有直接探针杂交的基本问题，以及多重杂交带来的额外困难。
Southern在英国专利申请GB 8810400，1988；E.M.Southern等，13 Genomics 1008，1992中提出用第一种方式分析或测序DNA。Southern用PCR扩增基因组DNA，确定了一个已知的单位点突变。Southern还描述了一种在SBH固体支持物上合成一组寡核苷酸的方法。但Southern没有说明对于在一组中的每一种寡核苷酸怎样达到最适的严格条件。
同时，Drmanac等，260 Science 1649-1652，1993，用第二种方式测定了几种短链DNA(116 bp)的序列。将靶DNA连到膜支持物上(“点印迹”方式)。每一种滤膜连续地与272个被标记的10聚物和11聚物的寡核苷酸杂交。要完成对每一种n聚物探针的专一性杂交，需采用范围很宽的一整套严格的条件；洗涤时间从5分钟到过夜不等，温度从0℃到16℃不等。大多数探针需要在16℃洗3小时。为了检测杂交信号，滤膜必须曝光2-18小时。尽管靶序列简单，寡聚物探针组数减少，采用了最严格的条件，但总体假阳性杂交率仍为5％。
有各种方法可用于杂交事件的检测和分析。根据所采用的标记DNA探针的报道基团(荧光团、酶、放射性同位素等)的不同，可用荧光测定，比色法或放射自显影来进行检测和分析。通过观察或测定发出的辐射，如荧光辐射或粒子发射，能得到有关杂交结果的一些情况。即使检测方法具有很高的内在的灵敏度，杂交结果的检测也是困难的，因为存在一些非特异性结合物的背景。许多其它的因素也可降低DNA杂交检测的灵敏度与选择性。
人们已试图将某些操作步骤或分步骤结合起来。例如，已提出将各种不同的微自动系统用于在一支持物上制备成组的DNA探针。例如，Beattie等，1992 San Diego会议：基因识别，1992年11月，用微自动系统将含有特异性DNA序列的微滴放入位于玻璃基质上的各个独立的微型样品池中。
通常，现有技术的方法既费时又费力。例如，PCR扩增过程很费时间，增加了诊断检测的费用。在各过程中或之间需要人类介入的多个步骤不是处于最佳条件，可能存在着污染或操作失误。再者，用于完成每一个独立步骤的众多的机器或复杂的自动化系统，除了最大的实验室外，不论物力财力，对于普通实验室都是无法承受的。
如前所述，为了提供有效地进行多步骤的多样化的分子生物学反应的技术，人们已做了大量的努力。然而，由于前述的众多原因，这些技术是“零碎”的并且有限的。要将这些不同的方法结合在一起形成一个能进行完整的DNA诊断检测的系统是不容易的。尽管人们一直认为需要有这样一个系统，但到目前为止，仍未提出任何满意的解决方法。
发明概述
本发明涉及到一种能自我编址，自我组装的微电子装置和系统的设计，制作和应用，该装置和系统能以微观方式有效地进行受控的多步骤方法和多重反应。这些反应包括，但不限于，大多数的分子生物学方法，如核酸杂交，抗体/抗原反应，及相关的临床诊断。此外，这个要求保护的装置和系统能够进行多步骤的联合的生物聚合物的合成，包括，但不限于，在一给定装置的特异性微位点上合成不同的寡核苷酸或多肽。
这个要求保护的装置和系统的制造利用了微印刷技术与微加工技术。在基本装置的表面有一个可编址的微位点矩阵；对每一个独立的微位点能够电子控制，并指导特异性结合物(如核酸、酶、抗体)转运及连接到它的上面。所有的微位点能够通过其特异性结合物被编址。这个自编址过程依流控或机械部件而需要最少的外部干涉。
这个装置能够控制和有效地进行各种的检测和反应。分析物或反应物可通过自由电场电泳被运送到任何一个特异性微位点上，在那里，这些分析物和反应物被有效地浓缩，并与结合在微位点上的特异性物质发生反应。在杂交分析时，由于杂交反应物在特异性微位点上被浓缩，因而提高了检测特异性分析物或反应物的灵敏度。通过转变微位点的极性，可将任何未结合的分析物或反应物移去。因此，这个装置还能增进反应的专一性。这个用于核酸杂交或其它分析的基本装置还可叫做APEX装置，意思是可编址可编程的电子矩阵(addressable programmableelectronic matrix)。
在本发明的一个方面中，其它的处理步骤或分步骤可以用一个“系统”依次进行。该系统是若干部件的集成排列。每一个部件被适当地设计，按比例缩小，以行使特别的功能。在其最完备的实施方案中，系统能行使各方面的功能，包括样品制备、杂交、检测和分析。在这种最完整的方式中，首先是进行样品的制备，如通过一个电子细胞分选器部件。通常，电子装置特别地具有通过电泳转移带电物体离开或进入部件的能力。随后的DNA加工和复杂性降低可选地由一个粗DNA选择器部件和限制性片段选择器部件来完成。将最后处理的靶DNA转移到分析部件上，在其上以微观多重方式进行电子杂交分析。这个分析部件还可叫做APEX或分析芯片。与之相连的检测和图象分析部件给出结果。
在此系统中，各种材料可通过自由电场电泳、沟流、流控或其它技术在各部件(装置)间转移。可选地装有一个电子试剂分配器，该部件能通过电泳将各试剂提供给该系统的其它加工部件。可选地装有一个废弃物电子处理系统，该系统由一个电极和带电的矩阵材料(matrix material)构成，能吸附带电废弃物。可选地装有一个DNA片段电子贮存系统，该系统能暂时容纳用于以后杂交分析的其它DNA片段。
在本发明的一个方面，基因组DNA复杂性的降低是通过下述步骤实现的，将含有所需目的序列的特异性DNA片段从大量的不含目的序列的DNA物质中分离出来。粗DNA被转移并连接到一支持物上。然后用适当的限制性酶切割结合物。切下的DNA片段被转移到一个能选择性杂交特异性DNA片段的部件上。经过进一步的限制性酶切作用，那些含有待分析靶序列的片段被选择性释放，并被转移到系统的分析部件(APEX芯片)上。这个方法可以重复，用于测定含有其它目的序列的其它片段。
这个装置(或系统)有一个控制器，能分别控制该装置的各个方面。当运用包含有可编址微位点的APEX装置或芯片时，控制器使独立的微位点受电子控制，使其能指示特异性结合物转移并连接到该位点上。该装置能在完全的，精确的电子控制下，优选地是在一个具微处理机的部件控制下进行多步骤的多重反应。在该装置的特异性微位点上，多步骤多重反应的速率、专一性、灵敏度被大大提高。这个控制器通过输入/输出装置如显示器和键盘与用户联系。优选地是有一个图形用户接口，更能方便用户。输入/输出装置连接到一控制器上，后者再依次控制系统的可编址电子位点的电子状态。这个控制器能特异性地指示电源/波形发生器产生不同微位点的电子状态。可选地，在电源/波形发生器与APEX装置或系统之间安装一个接口。这个接口优选地包括一组继电器，这些继电器通过一个多功能输入/输出连接器与控制器相连。这些继电器优选地通过控制连接器的极性，连接存在与否，提供给独立位点的电压或电流量而将电源/波形发生器与APEX装置连接起来。该控制器优选地能控制指示杂交系统的照明源。将一个检测器、图像处理和数据分析系统与APEX装置进行光学连接。在一优选的实施方案中，一个荧光显微镜被用来接收和放大发生在该装置中各微位点上的杂交事件的图像。其发射由一个电荷耦合器件(CCD)阵列或微通道平板检测器进行光学过滤和检测。然后将图像贮存和分析。结果优选地在显示屏上呈现给用户。
本发明的另一方面，形成了具有众多微位点的杂交系统，这些微位点位于包含有电子控制器件的基底的上面。特别地，提供开关电路来为微位点独立地编址。通过相对于样品接触之处的后部建立电子连接。另外，将一个光路例如波导管置于微位点下，使得能从后部接近微位点。如有必要，可通过波导管将光刺激导向微位点。通过后部的波导管可检测发出的辐射。在本发明的另一方面，一个样品容纳系统被置于该系统之上，特别是在杂交矩阵区域。在优选的实施方案中，矩阵杂交区域(包括样品容纳部件)可被改造以便从提供电子控制和检测元件的装置的剩余部分中除去。
在本发明的另一方面，描述了形成矩阵杂交系统的一些改进方法。在一种方法中，一种基质，例如硅，与一绝缘层如厚氧化物一起形成。导电的微位点可通过将金属(如铝或金)沉积在上面而形成，然后通过常规的光刻技术形成图形。可通过如由PECVD形成TEOS来形成一绝缘层。可选地，在TEOS层上形成一个氮化物钝化层。通过氮化物和玻璃可以形成到微电极的开口。可选地利用增粘物如钛钨合金与金属层相连，以增加对氧化物和/或玻璃的粘附。在进一步的改进方法中，通过从下部切去由基底支持的氧化层上的氮化物层，可在电极的上部形成凹孔。
可对独立的微位点进行电子控制，以便控制电压或电流。当其中一个被设定，另一个可被监控。例如，当电压被设定后，可监控电流。电压和/或电流可以为直流方式，或可以随时间变化。例如，可利用脉冲电流或直流偏置。
因此，本发明的一个目的是提供一个生物材料的样品制备、加工、杂交、检测和分析的系统。
本发明的另一个目的是提供一个能将多个步骤或分步骤结合到一起的集成系统。
本发明的另一个目的是提供一个自动DNA诊断系统。
附图简述
图1显示样品制备、杂交、检测及数据分析等各步骤及分步骤的顺序。
图2A和2B为有源可编程矩阵系统的截面图(图2A)和透视图(图2B)。
图3显示位于金属掩膜层上的有源可编程矩阵系统的结构。
图4为有源可编程矩阵系统的详细平面图。
图5为单一微位点和电子连接的透视图。
图6为包括电子细胞分选器矩阵、DNA选择器、限制性片段选择器和杂交矩阵的系统的平面图。
图7为控制系统的框图说明。
图8为带有相关电子装置的有源可编程矩阵系统的截面图。
图9为另一种层状的有源可编程矩阵系统的截面图，该系统具有到达微位点后部的光电通路和生物容纳覆盖物。
图10为安装在配套载体中的APEX系统的透视图。
图11A-G显示制备装置的各加工步骤。
图12为利用多晶硅结构制备的装置的截面图。
图13为利用增粘层制备的装置的截面图。
图14显示在电极上部有一加大的贮存空间的装置。
图15显示适于各种电压电流状况的用户显示器。
图16为DNA纯化系统的截面图。
图17为一种毛细管阵列制造系统和装置的截面图。
图18为一同心结构的微位点的透视图。
发明详述
图2A和2B表明应用本发明设计的一个有源可编程电子矩阵杂交系统的简化形式。通常情况下，由基底10支持着整个矩阵或排列整齐的电子控制的可编址的一系列微位点12。为易于解释，图2A中的各个微位点被标明12A、12B、12C和12D。渗透层14位于独立的电极12之上。渗透层允许相对小的带电物质穿过，但阻止了大的带电物质如DNA与电极12直接接触。这个渗透层14避免了当DNA直接与电极12接触时可能发生的电化学降解。它还能避免DNA牢固地非特异性地吸附到电极上面。附着部位16位于渗透层14之上，为靶物质提供专一性的结合位点，与对应的电极12A-D一致，附着部位16被分别叫做16A、16B、16C和16D。
在操作过程中，样品池18包括了附着部位16上部的空间，样品池中装有待检测、待分析或使用的目的物或非目的物。带电物20，如带电荷的DNA位于样品池18中。在本发明的一个方面，这个有源可编程矩阵系统包含了一个方法，能将带电荷物质20转移到任何一个特异性微位点12上。当一个微位点12被激活后，便产生自由电场，任意一个带电荷的功能化的特异性结合物20能通过电泳转移到电极12上。例如，如果电极12A为正极，电极12D为负极，电泳力线(electrophoretic line offorce)22将在电极12A与12D之间。电泳力线22使得带净负电荷的结合物20向正极12A移动，带净正电荷的带电物质20向负极12D移动。在电泳力的作用下，带净负电荷的已功能化的特异性结合物20向正极移动，与附着层16A接触，并共价连接到附着层16A上。
若要保护不参加反应的附着层如16B和16C，只需对应的电极12B和12C带负电荷即可。这使得电泳力线从附着部位16B发散出来(为简单起见，只讨论16B，对16C而言，结果类似)。电泳力线24将带负电荷的结合物20从附着层16B驱赶向附着层16A。以这种方式，在附着层16周围形成了一个“力场”保护，而此时此刻，该附着层应不与带电荷分子20发生反应。
该系统的一个非常有利的结果是，在与信号附着层16相邻的部位，带电结合物20能被高度浓缩。由透视图2B可见，如果一个微位点26A带正电荷，其它的微位点均带负电荷，则电泳力将使带净负电荷的结合物20向微位点26A移动。在图2A中，用微位点26A来描述一个由附着层16、渗透层14及连于其下的电极12构成的组合。以此种方式，待分析物或反应物能在此装置中的任一个特异性微位点上进行浓缩和反应。当特异性结合物20结合到附着层16以后，位于其下的微电极12将以直流(DC)的方式继续行使其功能。这个独特的性质，使得游离在溶液中的浓度相对稀的带电分析物或反应物分子能在任意一个与其持相反电荷的特异性微位点上以顺序地或平行的方式被迅速转移、浓缩和反应。这种在挑选出的微位点26上浓缩稀分析物或反应物分子的能力大大加速了在这些微位点26上进行的反应的速度。
当目的反应完成以后，电极12可以将其电压逆转，因而在与原先的吸引力相反的方向上产生一个电泳力，这样，可将非特异性的分析物或未反应分子从微位点26上除去。特异性的分析物或反应产物可从任意一微位点26释放出来并转移到其它微位点上进行下一步分析；或在其它可编址的微位点上贮存起来，或将其从系统中完全除去。通过将电场逆转来除去或稀释物质加强了该系统的鉴别能力，使其可将非特异性连接的物质除去。通过控制对非特异性连接在附着层16上的物质的排斥电泳力的数量，可以完成电子实时控制。提高电极12处的电压，使之能产生一个足以除去部分杂交的DNA序列的电场，这样一来，单一错配对的杂交及点突变均可被识别。
在各个不同的附着层16，每步操作可平行进行也可依次进行。例如，参考图2A，一个反应可首先如所示利用电压在附着层16A上发生。电极12A处的电压可被逆转，即变为负极，在相邻电极12B处的电压可被变为正极。以这种方式，可进行一系列的反应。没有特异性地连接到附着层16A上的物质将被电泳力转移到附着层16B。以这种方式，利用浓缩方式使得特异性附着层处具有高浓度，这样会受到正电泳力的作用。被浓缩了的物质再被转移到相邻的或其它的附着层16。也可采用另一种方式，在有一个净电泳力场从电极12发散出来，穿过附着层16，进入样品池18时，可使多重附着层16去除保护。一旦去除了多重附着层16的保护，便可进行多重反应。每一个单独的位点26实际上就是一个独立的生物“试管”，在“试管”中，由一已知附着层16编址的特定的环境不同于其它附着层16周围的环境。
图3为一个有源可编程电子矩阵系统的金属掩膜层的平面图。众多的单个电极30优选地  按一定形式排列。例如，排成一个8×8的电极30矩阵。可以选择装上一个额外的控制或转储缓冲器以帮助产生目的电泳场。电极30和缓冲器32同接触缓冲器34相连。对应于64个电极30和4个缓冲器32，有68个接触缓冲器34。导线36将电极30和缓冲器32分别同接触缓冲器34连接起来。如图所示，采用一个成扇形散开的图形使得电极30和缓冲器32所处的相对密集的部分与金属掩膜的边沿部分36连接起来。
图4为图3金属掩膜的部件分解平面图。形成的金属化系统大体上与金属掩膜图形类似。如图所示，电极30基本上为方形结构。导线36将电极30与接触缓冲器34连接起来(图3)。导线36的宽度优选地为1到20微米。
图5为一个电极50的透视图，电极50直接与导线52相连。渗透层54位于导线50之上，而附着层56位于渗透层之上。
在微型平版印刷产生的装置中的渗透层的厚度可从1个纳米到500个微米不等。优选地是在500纳米到50微米之间。渗透层应该覆盖整个电极表面。渗透层可由任何适宜的材料如多聚物、陶瓷、溶胶-凝胶、多层复合材料、粘土、控孔玻璃等构成。
图6为自动样品制备与制备物杂交的完整系统60。将样品62，如血液或其它生物材料，加入到系统60中。通常需有一个进样口64。当有一个位于上面的生物容纳结构存在时，通常需利用进样口64，因为若不通过进样口64，样品62不能够直接加入系统。
在系统60中，经过电子细胞分选器矩阵部件66，DNA选择器部件64和限制性片段选择器部件70的联合作用，样品得以制备。电子细胞分选器矩阵部件66由位于下面的电极以及渗透层和附着层构成。它们有效地形成了一个附着细胞的位点矩阵。通常独立位点的面积与整个矩阵的面积大于一个分析装置部件上的面积。因此，电子细胞分选器矩阵的大小应加以调整使其适应于来自不同样品和不同大小样品的细胞数量的变化。通常，附着层能为细胞所选择，或为不同类型的细胞单独选择。可任意使一组或一排位点被一种类型的细胞所选择。通过连接特异性抗体或细胞粘合因子到附着层上，可给予细胞选择性。矩阵66由自由电场电泳来操作。
粗DNA选择器68和限制性片段选择器70能够结合从电子细胞分选器矩阵66来的粗DNA产品，并允许对来自结合物的目的DNA片段进行选择性切割。术语“粗”仅仅用来表示DNA分离或复杂性降低的一个非最终阶段。DNA连接在选择器上，其连接部位不包括目的DNA片段。然后用限制性酶类将目的DNA从结合物上切割下来。这个切下的没有连接的物质被机械地从粗DNA选择器68转移到限制性片段选择器70上。优选地用电泳转移切下的物质。此过程可以重复，方法是将切下的物质连到一个选择器上，用一限制性酶切下处于未连接部位的目的DNA片段。
例如，人DNA含有约100,000个基因。在总DNA中，一个很大的部分由不含目的DNA信息的重复序列组成。借助这些不含信息的重复序列，DNA结合到选择器上。这个结合上的DNA可在含有待分析的目的DNA的未结合部分被切割。然后，将更具特异性的序列再结合到选择器上，可重复此过程。
接着，将限制性片段选择器70的产物提供给APEX芯片72。矩阵72的运作按图2A与2B所述进行。
用于降低DNA复杂性的另一种技术是采用基于DNA的亲和层析。一条单链DNA片段与另一条单链DNA片段的亲和性依赖于它们之间碱基对互补的程度。当层析系统的固定相含有一段特定序列或许多特定序列，流动相中的任一单链DNA将附着在固定相上，其附着量的大小主要依赖于其序列与固定相中的俘获序列配对的程度。这使得层析分离依赖于DNA与固定相中俘获序列的亲和性。
一种利用微位点矩阵的基于互补DNA的亲和层析方法为用一特定序列或一组序列做俘获探针去修饰一系列的位点。这构成了固定相。DNA样品被编址到一个微位点上，然后再依次从一个微位点移到下一个微位点。用电子实时控制来限制在每一个微位点上与俘获探针紧密配对的DNA的量。以这种方式，与俘获探针配对的DNA将被迅速从样品中移去。
在一系列微位点上通过依赖于DNA的亲和层析来连续纯化一种DNA样品的发明可统一为一种连续的模式。图16为该系统的截面图。在此，电极210为一长条形式，被一适当的固定相修饰。流动相被限制在位于固定相上的  通道212里。借助于物质对流，流动相通过固定相。另一种方法是，流动相中的离子可通过电场214的作用在固定相中移动。将独立的单个电极216放在长条电极的两端可建成电场214。将一转换或脉冲电流加在长条电极上可进行电子实时控制。这促使DNA进入或离开固定相。
用于降低DNA复杂性的另一种方法是用一个微孔筛来选择样品的大小。用树枝晶填充任意几何模槽可形成微孔筛。将一些化学物如金属盐、陶瓷材料、单体与多聚物以及其它物质进行电化学降解，可得到树枝晶。通过调节加到电极上的电信号可控制微孔筛的孔径。例如，树枝晶可形成栅栏形结构或分形结构。
在一个APEX装置上形成微孔筛的方法包括形成一个具有相反金属电极的长通道。当这个通道充满了适当的化学物，并将适当的电信号加在电极上，在两电极之间的填隙空间里，将形成树枝晶，由此构成微孔筛。
再回到图6，电子试剂分配系统74用来给系统60提供试剂。如果这些试剂带电荷，优选地通过电泳力来运送。可选地在系统60中装入一电子废弃物处理系统76。该废弃物处理系统76能吸引带电荷的废弃物颗粒，并将其牢牢吸住，从而处理之。还可选地在系统60中装入一DNA片段贮存系统78。该片段贮存系统78能够暂时容纳DNA片段，等待进一步的分析。
系统60可包括上述的部分或全部功能。例如，由DNA选择器68和限制性片段选择器70完成的复杂性降低形式的样品制备，该组合可以与分析矩阵72相连。无论如何，任何或全部上述功能可以根据需要进行组合。
图7为包括控制器在内的整个系统的方框图。通过对电极进行电压控制，或让控制电流通过电极，可使APEX装置中位于下面的电极有源。当APEX装置上每一个电极的电压或电流被独立控制时，可实现全部功能化。这一切由APEX控制系统来完成。
控制器计算机80与用户输入/输出装置相连，如显示器82和输入装置84。显示器82可以是任何形式的常规显示器，如监视器或计算机屏幕。输入84可以是任何常规的用户输入装置如键盘，鼠标或触屏装置。控制器计算机80与电源和波形发生器86相连。控制器80促使电源和波形发生器86向接口88提供电流或电压输出。在优选的实施方案中，电源或波形发生器86能提供准确调控的电压和电流。控制器计算机80通过多功能输入/输出板90给接口88提供控制信号。接口88给APEX系统92的接触器提供简化了的连接。
接口优选地包括有继电器，这些继电器使得在电源和波形发生器86与APEX系统92的专一性电极之间存在选择性连接。在一个实施方案中，接口88由众多的将电源和波形发生器86与APEX系统92的电极连接起来的继电器构成。电源和波形发生器86与APEX系统92电极间的连接可以是选择性的也可是非选择性的。另外，还有一种继电器允许对提供给APEX系统92电极的电压极性进行选择。如果能达到多源水平，例如来自一个多输出电源86，那么连接到APEX系统92电极上的特异性电压水平将被单独设置，使其不同于那些与别的电极相连的电压水平。
因此，如图2A所述，使一些电极(如12B和12C)为负极，但电压低于电极12D，附着层16B和16C将受到局部力场的保护。
接口88能为APEX系统92的各独立电极选择所需的电压。另外，如此不同的电压安排也可以通过一个电压分配器来完成。
在一个优选实施方案中，控制器计算机80为Macintosh Quadra 950。国家仪器公司(National Instruments Corporation)LabVIEW软件被用于为用户提供软件接口，使之能为与APEX相连的装置编程，并能收集和处理测定数据。国家仪器公司NuBus主板被用于提供从Quadra 950计算机到电源装置86的硬件接口，使能提供电压和电流，测定实际电流和电压及检测结果。
用户通过一个由LabVIEW软件创造的Virtual Instrument控制测定。这个Virtual Instrument给用户提供一个友好的用户能够控制的图形表示，及将这些控制应用到APEX装置上进行测定的一些结果的图形表示。用户通过Quadra 950计算机的键盘和鼠标(统称，输入84)与VirtualInstrument相连。Virtual Instrument为国家仪器公司NB-MIO-16XL多功能输入/输出90和与Quadra 950的NuBus数据总线相连的国家仪器公司DMA2800主板提供软件接口。
多功能I/O主板能提供数字和/或模拟信号给外部装置以完成由用户通过Virtual Instrument指定的编程序列。在Quadra 950中，在VirtualInstrument控制下，MIO主板也能数字化和贮存由连接到APEX上的装置产生的信号。DMA2800提供迅速贮存由MIO主板绕过Quadra 950CPU，通过直接存储存取获得的数据的能力。DMA2800也能提供一个GPIB(IEEE 488)接口用于控制符合于IEEE 488通迅和数据转移标准的外部装置，其中包括许多最现代化的仪器。
在这种控制器的优选实施方案中，两个外部装置被用于提供电压或电流给APEX。Keithley 236 Source/Measure Unit电源86作为可精确调控的电压或电流源提供适当的稳定性和可变性。SMU 236提供电压及测定所得电流或提供电流及测定所得电压。这个装置在GPIB控制下由Virtual Instrument编程，通过DMA2800主板控制电流或电压水平和时间依赖性，测定和贮存提供给APEX的实际电压和电流。
发出的电流或电压通过接口88中的一排继电器提供给APEX。这个接口88给在无连接，与正极相连和与负极相连之间的每个电极提供单独的开关。这个优选的实施方案也能提供一个以上的Source/Measure源，可利用来给不同的电极提供不同水平的正和负电压或电流。由一个具有9个16-通道，连接在机壳上的Class 3 Relay Modules，提供总共144个继电器的National Instruments SCXI Chassis提供排列整齐的一组继电器。每个电极需用两个继电器，将它们提供给不与正极或负极相连的电极，或与正极或负极相连的电极。在优选的实施方案中，一大束电缆通过一个Cerprobe探针卡将这些继电器与APEX装置连接起来，这个探针卡使得探针与APEX装置的连接柄机械接触。
控制器计算机80选择性地控制用于DNA杂交检测的荧光发射的光源94。在优选的实施方案中，光源94是一束激光，它在一定波长发生辐射以激发APEX系统92中的荧光标记物。
APEX系统92的输出通过观察途径96到检测器98。这个观察途径96可以是一个物理结合物例如通过一个光导纤维，或可以构成一个光路例如通过一个显微镜。在观察途径中可以利用滤光器来减少检测器里与APEX系统92中荧光标记物的发射光谱不一致的波长下的光照。另外，在激光光源94的发射波长下，需用凹面滤器来减少检测器98的光照。检测器98可任意形成一个APEX系统92的图像，如通过一个冷却的CCD照像机。除此之外，或换一种方式，形成一个光学图像，从APEX系统92发射的荧光辐射可通过常规方法来检测，例如光电二极管或光电倍增管。检测器98的输出被提供给数据处理/分析系统100。该系统监测APEX系统92中被检测的探针的量。可选地将一个专家系统用于分析系统100中。
在优选的实施方案中，一个Data Translation Frame Grabber主板与Quadra 950 NuBus相连，使能俘获图像的记录，这些图像由诸如用于装置中的Optronics冷却的彩色CCD照像机记录。这个CCD照像机通过一个具有合适滤器的显微镜观察APEX装置，提供APEX上的荧光图像。
另一种系统能赋予控制器上述所有的功能，但得运用加入印刷电路板的常规装置和运用常规软件，通过一个类似的用户所需的接口去控制电路板。这种改变了的系统也能将整齐排列的继电器的开关元件加入一位于有源可编程矩阵系统中的半导体装置上。图8为有源可编程矩阵系统的另一种实施方案的截面图。可独立编址的电极102在一支持层104上形成。这个支持层104优选地是一绝缘体。在电极102上优选地放置渗透层106和与独立电极102对应的独立附着层108。一个电子连接物110从电极102的后边穿过支持物104。另外，一个半导体支持物112包括与导体110相连的电路元件114。这个电路元件能在半导体112上面或里面形成。这个电路元件能独立控制从导体110到电极102的电压和/或电流。具体地说，电路元件114能结合在优选的实施方案中整齐排列的继电器的开关元件上。对应于每个电路元件114的多重电流/电压源线116能够为不同的电极102提供不同大小的电流/电压。记忆型地址线118为独立的电路元件114提供方便的激活通路。
波导管用于将发射光导向微位点及将荧光导向检测器。波导管可自由安装，如可在一光导纤维里，或被整合进一单片半导体装置中。波导管可由氧化锌，氧化铟锡这类也能导电的物质组成。波导管既能作为电极，也能作为传送光辐射的工具。波导管可被定位在俘获探针的平面上或其附近，以减少非特异性背景荧光。波导管能结合全息照像光学元件。全息照像光学元件的功能包括(不排除有其它功能)：凹面滤光镜，二色性镜，光谱通带滤光镜，光束分离器，中密度滤光镜，半波片，四分之一波片，起偏镜和透镜。
图9为有源可编程矩阵系统的另一种层状结构的截面图。在第一层，独立电极120在一支持物122上形成，支持物122优选地是绝缘的。在电极120之上优选地形成一渗透层124和对应于独立电极120的独立附着层126。光路128通过支持物122接近电极120。光路128优选地由光导纤维或光导管或结构组成。可选地有一电子结合物130穿过支持物122从后边接近电极120。术语“后边”在此是指与支持物122接触的电极120的一边。在第二层，一个半导体支持物132包括与导体131相连的电路元件133。导体130设计为其上表面与位于第一层后边的导体130的底部紧密配合并形成良好的电接触。电路元件133可在半导体132上面或里面形成。电路元件133可独立控制从联合导体131和130到电极120的电压和/或电流。具体地说，这个电路元件133能结合在优选的实施方案中整齐排列的继电器的开关元件上。这些电路元件可由多重电流/电压源线供应，能被记忆型地址线激活。可选地将一检测器元件134，例如光电二极管，加入到半导体层132上，通过光路135与第一层的光路128连接，使得该检测器元件可监控在第一层附着点126上进行的DNA杂交反应。这些光路可以  为光导纤维或波导管，能加入上述的各种光学元件。可选地将一生物密封容器136置于该结构周围用于装正在分析或测定的生物材料。可选地有一个液体输入口137或光学观察口138。生物密封容器136和任意的端口137和138可与在此描述的任何一种有源可编程矩阵系统相连使用。
图10为有源可编程矩阵系统的装配系统的透视图。将如图3和图4所示结构安装在一片状结构上可形成系统140。片状结构140通过接触缓冲器(图3)之间的导线146相连，片状结构载体144连接缓冲器142。片状结构载体144优选地包括独立的插头147，这些插头通过缓冲器142提供电流到导线146，再到片状结构140上。插头147与插座148相连，后者再依次与控制系统相连。
有源可编程微位点矩阵也可由毛细管构成。图17为该系统及其产物。毛细管矩阵可通过将毛细管堆积成任意几何排列220而形成，或通过加热器222加热熔化，和由拉丝模224拉丝，将这些排列220变成一粘附的整体单元226而形成。另一种方式，由两种不同材料构成，相互以同心圆形式排列的固体棒可用来代管毛细管。图8为这种结构的透视图。在此，构成内核230的物质选择性地从外层物质234蚀刻出来，形成一个贯穿全部或部分装置的洞232。换一种方式，将内核以一定方式蚀刻，使形成一个可控制孔径的玻璃。
独立的毛细管通过插入其中的电线被编址，或通过将毛细管矩阵附加到平版印刷形成的电极的互补矩阵上被编址。另外，固体棒的内核可由一导体物质形成。通过将固体棒矩阵附加到电极的互补矩阵上，或通过在固体棒上平版印刷形成的电极，能形成同内核物质的电连接。
毛细管和蚀刻固体棒内充满一种合适的物质，以形成渗透层。渗透层的表面可通过特定附着化学物而被功能化。
电泳转移的另一种方法是通过物质对流将物质转移到微位点上。能完成该过程的装置为转盘。在此，物质对流通过存在于转盘和溶液之间边界处的流体切力而完成。液体直接从本体溶液流到表面上。一个电极缓中器矩阵被连到一个转盘上，或矩阵中的每个电极可被连到一独立的转盘上。在后一种情况，每一个电极可通过物质对流运输被选择性偏址。在通过物质对流运输将缓冲器编址后，电极可被用于通过电泳除去不需要的物质。
用于形成有源可编程矩阵系统的一优选方法如图11A-G所述。一种半导体150，优选地是p-型，实验级硅，其上形成厚(10,000)的氧化物层152。图11B为在氧化物层152的上面形成一金属层154。所用金属优选地选自下列金属：铝、金、铂、钯、钛、钛/钨。半导体多晶硅也可用来代替这类金属。图11C为在氧化层152上形成图形化的铝156。这种金属可通过任何常规的平版印刷术例如照相平版印刷术形成图形。
图11D为具有一玻璃外壳(例如TEOS)的图11C的结构。TEOS优选地由PECVD技术形成。玻璃优选地在相对高的温度下，如475℃下形成，以提高对金属层156的粘附。然后，在TEOS层158外面包上一氮化物层160。氮化物层160和TEOS层158优选地在图形化电极区域156上面的地方被蚀刻。由此形成一个窗口162，使得可与图形化电极156直接联系。
图11G为将整个结构暴露给氨基丙酸硅宾(APS)的结果。APS 164附着到图形化金属层156上，与氮化物层160无联系。APS层充当DNA俘获探针的附着层。
图12为另一种结构，其中用多晶硅代替通常的金属联系物。结构与图11F的结构类似，但包括一代替铝层156的多晶硅层166。优选步骤的顺序如下。首先，半导体，优选地是p-型的实验级的硅，用厚(10,000)的氧化物进行氧化。形成一个导体多晶硅层，优选地是形成厚达5,000的多晶硅层。然后将多晶硅做出图形，优选地是通过照相平版印刷术用湿蚀刻来做图形。接下来，形成一个玻璃层，例如通过PECVD沉积的TEOS。在475℃形成的大约厚3,000的玻璃层用于提高其粘附性。然后又将玻璃层做出图形，优选地是通过照相平版印刷术用湿蚀刻来做图形。然后在表面形成一金属层，优选地是通过喷镀铝使其达到3,000的厚度。然后将金属层做出图形，优选地是通过照相平版印刷术用湿蚀刻来做图形。接下来，形成氮化物层，优选地通过PECVD在70℃使其厚度为3,000。然后，通过照相平版印刷术用湿蚀刻形成一个通道，使其能与电极接触。
图13为通过应用中间粘附金属如钛钨合金，使得金属导体与位于其下的绝缘层间的粘附性提高的结构。一种半导体170，优选地是硅，其上有氧化层172。由导电金属如金或铝形成的中间电极层176被夹在钛174和钨178之间形成三明治结构。粘附金属层178与外部电极184相连，该电极优选地由铂构成。玻璃层180，例如由TEOS构成，位于外部的氮化物外层182之下。
图14为一改进了的电极阵列的截面图。电极190与一绝缘层192相邻，该绝缘层优选地为氧化物。氮化物层194位于绝缘层192之上。优选地除去氮化物层194的下部，使得绝缘层192从氮化物层的这一侧198受到阻碍。因此，贮存池196被限定，其体积比不具切除区域的类似结构大。
图14所示结构被用于机械握持形成渗透层的材料的接点。这个倒置层俘获渗透层。该设计能统一为具有任意数目的倒置层，使得能形成一种排列，例如蜂巢式的渐减的同心圆，或具有不同半径的同心盘孔。
渗透层(如，图2中的层14)可由下列物质构成，但不局限于此：碳链多聚物，碳硅链多聚物，碳磷链多聚物，碳氮链多聚物，硅链多聚物，聚合物合金，层状多聚物复合物，互穿聚合物材料，陶瓷，控孔玻璃，形成溶胶-凝胶的材料，形成气凝胶的材料，形成水凝胶的材料，多孔石墨，粘土或沸石。
渗透层将结合物与电极表面分开。微位点由微平版印刷术和微机械加工术产生。对微位点表面和位于微位点上的聚合物层表面进行化学修饰，为表面功能基团产生特定的附着位点。
网眼型渗透层包括随机排列的多聚物分子，这些多聚物分子形成网眼状结构，其平均孔径由交联度决定。我们以丙烯酰胺为单体，采用了几种可聚合制剂，已证明了网眼型渗透层的形成。我们用三甘醇二丙烯酸酯，四甘醇二丙烯酸酯和N，N′-甲叉双丙烯酰胺为交联剂。将分子量为330千道尔顿和25千道尔顿的多聚-1-赖氨酸混入丙烯酰胺/共聚物制剂，由此提供了一个将特异性功能基团连到渗透层表面的方法。将混合物浇到微位点表面。然后由紫外光照射进行光聚合。在有些情况下，需加入AuCl4作为光引发剂。聚合物制剂由水和非水溶剂，甲醇，四氢呋喃，乙腈，丙酮，及这些试剂的混合物来调制。
通过连到DNA俘获探针上的氧化核糖核苷与多聚-1-赖氨酸的伯胺之间发生的Schiff碱反应，DNA俘获探针被连到渗透层的表面。这提供了特异性功能基团共价连接到渗透层表面的证据。
通过电泳将氧化了的DNA俘获探针带到表面微位点上。俘获探针由荧光标记物进行标记。由此证明了通过电泳为微位点编址的能力。
连有荧光标记物的氧化俘获探针通过电泳被送到渗透层表面的微位点上。用机械手段将渗透层从微位点下移去。没有观察到有荧光标记的俘获探针存在。这证明了渗透层具有保护DNA不与电极表面接触的能力。
在发生水解出现气泡之前，在一个不被渗透层修饰的金微位点上达到的最大直流电流密度为8毫安/cm2。在发生水解出现气泡之前，在一个被基于丙烯酰胺的渗透层修饰的金微位点上达到的最大直流电流密度为40毫安/cm2。这证明了渗透层具有在水解发生出现气泡前提高最大可及电流密度的能力。
离子交换聚合物三明治渗透层可由一层或几层聚电解质形成。这些聚电解质层可以有相同的电荷，不同的电荷，或可以是带电荷的镶嵌结构。
一个两层的离子交换聚合物三明治层由全氟化磺酸聚电解质(Nafion)下层和多聚-1-赖氨酸上层构成。将Nafion下层浇在微位点上面，让其干燥。然后将下层暴露到1％(重量百分数)的多聚-1-赖氨酸水溶液中。基于赖氨酸的阳离子聚合物紧紧地吸附到阴离子Nafion下层上。多聚-1-赖氨酸层通过Schiff碱反应使得氧化的DNA俘获探针连到渗透层的表面。Nafion下层为阴离子型的，对于带负电荷的离子如DNA具有选择透性。
图15为图形用户接口的实例。窗口200表示显示器的全貌。识别资料202被提供。有源可编程矩阵系统的各种缓冲器可在一长方形的坐标系中被识别。显示物204中的每一个显示出电参数，例如特定缓冲器上的电流或电压。方框204A为一个缓冲器(3，4)上的作为时间函数的电流，其中，电流随时间而变化，在施加电流的过程中改变方向。方框204B表示一个缓冲器(3，5)，在所示的时间段中无电流施加到其上。方框204C表示加到缓冲器(4，4)上随时间变化的电流，其中，不考虑与方框204A中报道的缓冲器相关的时间，电流滞后。方框204D表示一缓冲器(4，5)，没有作为时间函数的电流施加上去。方框204E表示一缓冲器(1，1)，其上的电压具有恒定的负DC值。方框204F表示缓冲器(3，4)上的作为时间函数的电压，该电压具有更大的负DC值。在所有的情况下，方框中虚线表示被编程的电流或电压，实线表示测定的电流或电压。
除了上述的本发明的优选实施方案及其替换方案外，另外几种方案也是可能的。例如，产生离子迁移的电场可被调节，使时间与同时施加的直流偏置或电流一样长。将AC信号加在一直流偏置或电流上可完成三件事：1)减少由于非特异性连接的DNA而产生的背景，2)提供一个电子实时控制的方法，其中，控制变量是交流电流或电压，3)提供空间上的排列DNA分子的方法。
也存在许多其它的荧光检测杂交DNA的方法。大多数转换的技术也包括用能产生可检测信号的报道基团去修饰俘获或目的或报道DNA探针。极少数运用纯物理方法进行测定的技术不需要报道基团。这些可选技术如下所述：(1)线性光学方法，包括荧光、时间调制荧光、荧光猝灭调制、极化选择荧光、吸收、镜反射、折射率的变化、椭圆光度法、表面等离子共振测定、化学发光、斑点干涉仪和磁光Kerr效应；(2)非线性光学方法，包括二次谐波的产生，三次谐波产生、参量混合、光学外差检测、相共振、孤离子减振和光Kerr效应；(3)基于热效应的方法，包括差示扫描量热测定法，多频差示扫描量热测定法，和差示量热分析；(4)基于质量变化的方法，包括晶体微平衡、悬臂微平衡、表面声波和表面Love波；(5)电化学方法，包括电流分析法、电量测定法、伏安法、电化学发光、供体-受体复合物中的电荷转移和表面阻抗光谱学；(6)用标记基团的放射性检测法。
虽然为了清楚和易于理解，已通过说明和实施例对前述发明进行了一定程度的详细阐述，但显然，本领域普通技术人员依据本发明的技术，在不背离其精神或范围的前提下，可对其进行某些改动和修饰。

Claims (54)

1.一种适用于进行分子生物学过程的电子装置，其包括：
具有通常为平面的第一表面的支持物，
许多位于支持物第一表面上的可自编址的电极，这些电极具有与支持物第一表面相邻的接触部分，和
与这些电极相连的分立的电连接装置。
2.权利要求1中的电子装置，其中与电极相连的分立的电连接装置包括位于支持物第一表面上的导线。
3.权利要求1中的电子装置，其中与电极相连的分立的电连接装置是从电极的接触部分延伸到支持物的电子通道。
4.权利要求1中的电子装置，其中的支持物包括绝缘体。
5.权利要求4中的电子装置，其中的绝缘体是氧化物。
6.权利要求1中的电子装置，其中的支持物包括半导体材料。
7.权利要求6中的电子装置，其中包括了半导体的支持物还包括位于其上的氧化物层。
8.权利要求6中的电子装置，其中的控制电子线路包括在半导体材料中，并通过分立的电连接装置与电极相连。
9.权利要求1中的电子装置，其还包括一个与电极相连的光学通路。
10.权利要求9中的电子装置，其中的光学通路是通过支持物形成的，使其能接近电极的接触部分。
11.权利要求9或10中的电子装置，其中的光学通路包括光导纤维。
12.权利要求9或10中的电子装置，其中的光学通路包括光导管。
13.权利要求9中的电子装置，其中的光学通路包括一个开口。
14.权利要求1中的电子装置，其还包括位于电极上面的渗透层。
15.权利要求1中的电子装置，其还包括位于电极上面的附着层。
16.权利要求14中的电子装置，其还包括位于渗透层上面的附着层。
17.权利要求1中的电子装置，其还包括位于支持物上的容器。
18.一个与具有众多电极的有源可编程电子微生物系统共同运作的控制系统，其包括：
适于接收用户输入及提供输出的控制器，所述输出包括控制信号，该控制信号可以在电极处产生独立的电子环境，
与控制器输入相连的用于接受用户指令的输入系统，
能在电极周围提供所需电子环境的发生器，该发生器在控制器输出的控制下进行操作，和
适于将控制系统与有源可编程电子系统相连的接口。
19.权利要求18中的控制系统，其中的发生器包括电源。
20.权利要求19中的控制系统，其中的电源是可调控的电源。
21.权利要求18中的控制系统，其中的发生器包括波形发生器。
22.权利要求18中的控制系统，其中的接口包括继电器系统。
23.权利要求22中的控制系统，其中的接口包括一些能提供从发生器到电极的选择性连接的继电器。
24.权利要求22中的控制系统，其中的接口包括适于改变发生器输出的极性的继电器。
25.权利要求22中的控制系统，其中的接口包括能提供与信号的第一水平或第二水平选择性连接的继电器。
26.权利要求25中的控制系统，其中的信号是预定的电压水平。
27.权利要求25中的控制系统，其中的信号包括预定水平的电流。
28.权利要求18中的控制系统，其中的控制器包括计算机。
29.权利要求18中的控制系统，其中的控制器是基于微信息处理机的。
30.权利要求18中的控制系统，其还包括给用户提供信息的输出系统。
31.权利要求30中的控制系统，其中的输出系统包括显示器。
32.一种在含有DNA的溶液中降低复杂性的方法，其包括下述步骤：
将DNA结合到支持物上，至少使含目的片段的那部分DNA处于未结合状态，
从未结合的DNA切下结合的DNA，和
从剩余的结合的DNA中移去切下的DNA。
33.权利要求32中的在含有DNA的溶液中降低复杂性的方法，其中的结合是通过将DNA与互补DNA杂交来完成的。
34.权利要求32中的降低复杂性的方法，其中的切割是用限制性酶来完成的。
35.权利要求32中的在含有DNA的溶液中降低复杂性的方法，其中切下的DNA是通过电泳力移走的。
36.一个能进行分子生物学反应的系统，其包括：
能接受包含待分析物的样品的输入装置，
样品制备单元，和
有源可编程电子装置，包括众多的可独立编址的电极。
37.权利要求36中的系统，其中的有源可编程矩阵包括电极阵列。
38.权利要求36中的系统，其中的有源可编程电极还包括一个位于电极上面的附着层。
39.权利要求38中的系统，其中的附着层包括俘获序列。
40.权利要求36中的系统，其还包括被有效定位的检测器，用于监控有源的可编程的装置。
41.权利要求40中的系统，其中的检测器包括成像系统。
42.权利要求41中的系统，其中的成像系统包括CCD照相机。
43.权利要求40中的系统，其还包括适于接收检测系统输出的分析系统。
44.权利要求36中的系统，其中的样品制备单元包括细胞分选器。
45.权利要求36中的系统，其中的样品制备单元包括DNA选择器。
46.权利要求36中的系统，其中的样品制备单元包括限制性片段选择器。
47.权利要求36中的系统，其中的样品制备单元包括扩增系统。
48.权利要求47中的系统，其中的扩增单元利用了聚合酶链式反应。
49.权利要求36中的系统，其还包括试剂传送系统。
50.权利要求49中的系统，其中的试剂传送系统是电子试剂传送系统。
51.权利要求49中的系统，其中的试剂传送系统是流体试剂传送系统。
52.权利要求36中的系统，其还包括废弃物处理系统。
53.权利要求52中的系统，其中的废弃物处理系统是电子废弃物处理系统。
54.权利要求52中的系统，其中的废弃物处理系统是流体废弃物处理系统。
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100387990C (zh) * 2002-05-21 2008-05-14 索尼株式会社 生物测定方法、生物测定设备和生物测定衬底
CN103289893A (zh) * 2003-02-26 2013-09-11 凯利达基因组股份有限公司 通过杂交进行的随机阵列dna分析
US8840848B2 (en) 2010-07-23 2014-09-23 Beckman Coulter, Inc. System and method including analytical units
US8973736B2 (en) 2011-11-07 2015-03-10 Beckman Coulter, Inc. Magnetic damping for specimen transport system
CN104569368A (zh) * 2013-10-11 2015-04-29 三星Sds株式会社 生物样本分析系统和方法
US9046506B2 (en) 2011-11-07 2015-06-02 Beckman Coulter, Inc. Specimen container detection
US9446418B2 (en) 2011-11-07 2016-09-20 Beckman Coulter, Inc. Robotic arm
US9482684B2 (en) 2011-11-07 2016-11-01 Beckman Coulter, Inc. Centrifuge system and workflow
US9506943B2 (en) 2011-11-07 2016-11-29 Beckman Coulter, Inc. Aliquotter system and workflow
US9910054B2 (en) 2011-11-07 2018-03-06 Beckman Coulter, Inc. System and method for processing samples
CN110823835A (zh) * 2019-12-16 2020-02-21 长沙学院 一种波导耦合长程表面等离子共振传感器及其测量方法
CN112654431A (zh) * 2018-04-02 2021-04-13 生物动力学公司 介电材料

Families Citing this family (598)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081226B1 (en) * 1996-06-04 2006-07-25 University Of Utah Research Foundation System and method for fluorescence monitoring
US6197508B1 (en) 1990-09-12 2001-03-06 Affymetrix, Inc. Electrochemical denaturation and annealing of nucleic acid
US6048690A (en) * 1991-11-07 2000-04-11 Nanogen, Inc. Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis
US6051380A (en) * 1993-11-01 2000-04-18 Nanogen, Inc. Methods and procedures for molecular biological analysis and diagnostics
US6017696A (en) 1993-11-01 2000-01-25 Nanogen, Inc. Methods for electronic stringency control for molecular biological analysis and diagnostics
US5849486A (en) 1993-11-01 1998-12-15 Nanogen, Inc. Methods for hybridization analysis utilizing electrically controlled hybridization
US6569382B1 (en) * 1991-11-07 2003-05-27 Nanogen, Inc. Methods apparatus for the electronic, homogeneous assembly and fabrication of devices
US5605662A (en) 1993-11-01 1997-02-25 Nanogen, Inc. Active programmable electronic devices for molecular biological analysis and diagnostics
US6652808B1 (en) * 1991-11-07 2003-11-25 Nanotronics, Inc. Methods for the electronic assembly and fabrication of devices
US5587128A (en) * 1992-05-01 1996-12-24 The Trustees Of The University Of Pennsylvania Mesoscale polynucleotide amplification devices
US6045996A (en) * 1993-10-26 2000-04-04 Affymetrix, Inc. Hybridization assays on oligonucleotide arrays
US6129828A (en) 1996-09-06 2000-10-10 Nanogen, Inc. Apparatus and methods for active biological sample preparation
US6287517B1 (en) 1993-11-01 2001-09-11 Nanogen, Inc. Laminated assembly for active bioelectronic devices
US20040077074A1 (en) * 1993-11-01 2004-04-22 Nanogen, Inc. Multi-chambered analysis device
US6207373B1 (en) 1998-02-25 2001-03-27 Nanogen, Inc. Methods for determining nature of repeat units in DNA
US7172864B1 (en) * 1993-11-01 2007-02-06 Nanogen Methods for electronically-controlled enzymatic reactions
US5965452A (en) * 1996-07-09 1999-10-12 Nanogen, Inc. Multiplexed active biologic array
US6068818A (en) * 1993-11-01 2000-05-30 Nanogen, Inc. Multicomponent devices for molecular biological analysis and diagnostics
US6375899B1 (en) 1993-11-01 2002-04-23 Nanogen, Inc. Electrophoretic buss for transport of charged materials in a multi-chamber system
US7314708B1 (en) * 1998-08-04 2008-01-01 Nanogen, Inc. Method and apparatus for electronic synthesis of molecular structures
US6309602B1 (en) 1993-11-01 2001-10-30 Nanogen, Inc. Stacked, reconfigurable system for electrophoretic transport of charged materials
US6254827B1 (en) 1993-11-01 2001-07-03 Nanogen, Inc. Methods for fabricating multi-component devices for molecular biological analysis and diagnostics
US6315953B1 (en) * 1993-11-01 2001-11-13 Nanogen, Inc. Devices for molecular biological analysis and diagnostics including waveguides
US6468742B2 (en) 1993-11-01 2002-10-22 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip
US7582421B2 (en) * 1993-11-01 2009-09-01 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip
US6225059B1 (en) 1993-11-01 2001-05-01 Nanogen, Inc. Advanced active electronic devices including collection electrodes for molecular biological analysis and diagnostics
US6319472B1 (en) 1993-11-01 2001-11-20 Nanogen, Inc. System including functionally separated regions in electrophoretic system
US6331274B1 (en) 1993-11-01 2001-12-18 Nanogen, Inc. Advanced active circuits and devices for molecular biological analysis and diagnostics
US6638482B1 (en) 1993-11-01 2003-10-28 Nanogen, Inc. Reconfigurable detection and analysis apparatus and method
US6306348B1 (en) * 1993-11-01 2001-10-23 Nanogen, Inc. Inorganic permeation layer for micro-electric device
US6726880B1 (en) 1993-11-01 2004-04-27 Nanogen, Inc. Electronic device for performing active biological operations and method of using same
US7101661B1 (en) 1993-11-01 2006-09-05 Nanogen, Inc. Apparatus for active programmable matrix devices
US5824473A (en) * 1993-12-10 1998-10-20 California Institute Of Technology Nucleic acid mediated electron transfer
US6071699A (en) 1996-06-07 2000-06-06 California Institute Of Technology Nucleic acid mediated electron transfer
EP0750680B1 (en) 1994-03-15 1999-01-13 Scientific Generics Ltd Electrochemical denaturation of double-stranded nucleic acid
US5976896A (en) * 1994-06-06 1999-11-02 Idexx Laboratories, Inc. Immunoassays in capillary tubes
US6379897B1 (en) * 2000-11-09 2002-04-30 Nanogen, Inc. Methods for gene expression monitoring on electronic microarrays
US6403367B1 (en) * 1994-07-07 2002-06-11 Nanogen, Inc. Integrated portable biological detection system
US7857957B2 (en) * 1994-07-07 2010-12-28 Gamida For Life B.V. Integrated portable biological detection system
US6071394A (en) 1996-09-06 2000-06-06 Nanogen, Inc. Channel-less separation of bioparticles on a bioelectronic chip by dielectrophoresis
US5544268A (en) 1994-09-09 1996-08-06 Deacon Research Display panel with electrically-controlled waveguide-routing
US5620850A (en) 1994-09-26 1997-04-15 President And Fellows Of Harvard College Molecular recognition at surfaces derivatized with self-assembled monolayers
SE9404166D0 (sv) * 1994-11-30 1994-11-30 Pharmacia Biotech Ab Multifunctional surfaces
US6140045A (en) * 1995-03-10 2000-10-31 Meso Scale Technologies Multi-array, multi-specific electrochemiluminescence testing
US6066448A (en) * 1995-03-10 2000-05-23 Meso Sclae Technologies, Llc. Multi-array, multi-specific electrochemiluminescence testing
US6673533B1 (en) 1995-03-10 2004-01-06 Meso Scale Technologies, Llc. Multi-array multi-specific electrochemiluminescence testing
US6207369B1 (en) * 1995-03-10 2001-03-27 Meso Scale Technologies, Llc Multi-array, multi-specific electrochemiluminescence testing
US5932100A (en) * 1995-06-16 1999-08-03 University Of Washington Microfabricated differential extraction device and method
US6454945B1 (en) * 1995-06-16 2002-09-24 University Of Washington Microfabricated devices and methods
US6524532B1 (en) * 1995-06-20 2003-02-25 The Regents Of The University Of California Microfabricated sleeve devices for chemical reactions
US6521181B1 (en) * 1995-06-20 2003-02-18 The Regents Of The University Of Calfornia Microfabricated electrochemiluminescence cell for chemical reaction detection
US6387625B1 (en) 1995-06-27 2002-05-14 The University Of North Carolina At Chapel Hill Monolayer and electrode for detecting a label-bearing target and method of use thereof
US6361951B1 (en) 1995-06-27 2002-03-26 The University Of North Carolina At Chapel Hill Electrochemical detection of nucleic acid hybridization
US5968745A (en) * 1995-06-27 1999-10-19 The University Of North Carolina At Chapel Hill Polymer-electrodes for detecting nucleic acid hybridization and method of use thereof
US6180346B1 (en) 1995-06-27 2001-01-30 The Universtiy Of North Carolina At Chapel Hill Electropolymerizable film, and method of making and use thereof
US6346387B1 (en) 1995-06-27 2002-02-12 Xanthon, Inc. Detection of binding reactions using labels detected by mediated catalytic electrochemistry
US6127127A (en) * 1995-06-27 2000-10-03 The University Of North Carolina At Chapel Hill Monolayer and electrode for detecting a label-bearing target and method of use thereof
US6132971A (en) * 1995-06-27 2000-10-17 The University Of North Carolina At Chapel Hill Microelectronic device
US5849208A (en) * 1995-09-07 1998-12-15 Microfab Technoologies, Inc. Making apparatus for conducting biochemical analyses
JP3574457B2 (ja) * 1995-09-12 2004-10-06 エーザイ株式会社 電気化学発光検出方法と装置
US6048734A (en) 1995-09-15 2000-04-11 The Regents Of The University Of Michigan Thermal microvalves in a fluid flow method
US20040086917A1 (en) * 1995-09-27 2004-05-06 Nanogen, Inc. Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis
US5876995A (en) 1996-02-06 1999-03-02 Bryan; Bruce Bioluminescent novelty items
EP1726958A3 (en) * 1996-04-25 2007-07-11 BioArray Solutions Ltd. Light-controlled electrokinetic assembly of particles near surfaces
US6958245B2 (en) 1996-04-25 2005-10-25 Bioarray Solutions Ltd. Array cytometry
ES2288760T3 (es) * 1996-04-25 2008-01-16 Bioarray Solutions Ltd. Ensamblaje electrocinetico controlado por luz de particulas proximas a superficies.
US7041510B2 (en) 1996-04-25 2006-05-09 Bioarray Solutions Ltd. System and method for programmable illumination pattern generation
US6387707B1 (en) 1996-04-25 2002-05-14 Bioarray Solutions Array Cytometry
GB9608644D0 (en) 1996-04-26 1996-07-03 Scient Genarics Ltd Nucleic acid manipulation
US6054277A (en) * 1996-05-08 2000-04-25 Regents Of The University Of Minnesota Integrated microchip genetic testing system
US6048691A (en) * 1996-05-13 2000-04-11 Motorola, Inc. Method and system for performing a binding assay
US6355436B1 (en) 1996-05-17 2002-03-12 L'ecole Centrale De Lyon Method for analyzing biological substances in a conductive liquid medium
ZA975891B (en) * 1996-07-05 1998-07-23 Combimatrix Corp Electrochemical solid phase synthesis of polymers
US7169556B2 (en) * 1996-07-29 2007-01-30 Nanosphere, Inc. Nanoparticles having oligonucleotides attached thereto and uses therefor
US5874046A (en) * 1996-10-30 1999-02-23 Raytheon Company Biological warfare agent sensor system employing ruthenium-terminated oligonucleotides complementary to target live agent DNA sequences
US7160678B1 (en) 1996-11-05 2007-01-09 Clinical Micro Sensors, Inc. Compositions for the electronic detection of analytes utilizing monolayers
US7045285B1 (en) 1996-11-05 2006-05-16 Clinical Micro Sensors, Inc. Electronic transfer moieties attached to peptide nucleic acids
US7381525B1 (en) 1997-03-07 2008-06-03 Clinical Micro Sensors, Inc. AC/DC voltage apparatus for detection of nucleic acids
US7014992B1 (en) 1996-11-05 2006-03-21 Clinical Micro Sensors, Inc. Conductive oligomers attached to electrodes and nucleoside analogs
WO1998022819A1 (de) * 1996-11-16 1998-05-28 Nmi Naturwissenschaftliches Und Medizinisches Institut An Der Universität Tübingen In Reutlingen Stiftung Bürgerlichen Rechts Mikroelementenanordnung, verfahren zum kontaktieren von in einer flüssigen umgebung befindlichen zellen und verfahren zum herstellen einer mikroelementenanordnung
GB2319771B (en) * 1996-11-29 2001-09-26 Imperial College Process
US6054325A (en) * 1996-12-02 2000-04-25 Glaxo Wellcom Inc. Method and apparatus for transferring and combining distinct chemical compositions with reagents
US6083761A (en) * 1996-12-02 2000-07-04 Glaxo Wellcome Inc. Method and apparatus for transferring and combining reagents
US6706473B1 (en) 1996-12-06 2004-03-16 Nanogen, Inc. Systems and devices for photoelectrophoretic transport and hybridization of oligonucleotides
CA2271717A1 (en) 1996-12-12 1998-06-18 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
US6046004A (en) * 1997-02-27 2000-04-04 Lorne Park Research, Inc. Solution hybridization of nucleic acids with antisense probes having modified backbones
US6251591B1 (en) 1997-02-27 2001-06-26 Lorne Park Research, Inc. Quantitative method for detecting nucleotide concentration
US20030027126A1 (en) 1997-03-14 2003-02-06 Walt David R. Methods for detecting target analytes and enzymatic reactions
US7622294B2 (en) 1997-03-14 2009-11-24 Trustees Of Tufts College Methods for detecting target analytes and enzymatic reactions
US6235471B1 (en) 1997-04-04 2001-05-22 Caliper Technologies Corp. Closed-loop biochemical analyzers
US6391622B1 (en) 1997-04-04 2002-05-21 Caliper Technologies Corp. Closed-loop biochemical analyzers
WO1998048275A1 (de) * 1997-04-22 1998-10-29 Thomas Schalkhammer Cluster verstärkter optischer sensor
EP1003904B1 (en) 1997-05-23 2007-07-11 BioArray Solutions Ltd. Color-encoding and in-situ interrogation of matrix-coupled chemical compounds
US6156273A (en) 1997-05-27 2000-12-05 Purdue Research Corporation Separation columns and methods for manufacturing the improved separation columns
JP4124830B2 (ja) 1997-06-12 2008-07-23 クリニカル・マイクロ・センサーズ・インコーポレイテッド 分析物の検出のための電気的方法
WO1999000657A1 (en) * 1997-06-26 1999-01-07 Perseptive Biosystems, Inc. High density sample holder for analysis of biological samples
US6258534B1 (en) 1998-03-02 2001-07-10 Bbi Bioseq, Inc. Pressure-controlled nucleic acid hybridization
FR2765967B1 (fr) * 1997-07-11 1999-08-20 Commissariat Energie Atomique Dispositif d'analyse a puce comprenant des electrodes a chauffage localise
US5989402A (en) 1997-08-29 1999-11-23 Caliper Technologies Corp. Controller/detector interfaces for microfluidic systems
AU9127898A (en) * 1997-09-02 1999-03-22 Isis Pharmaceuticals, Inc. Compositions and methods for the identification and quantitation of deletion sequence oligonucleotides in synthetic oligonucleotide preparations
US6988176B2 (en) 1997-09-12 2006-01-17 Hitachi, Ltd. Method and apparatus for data duplexing in storage unit system
DE19741738A1 (de) * 1997-09-22 1999-03-25 Hoechst Ag Linker-Nucleosid, seine Herstellung und Verwendung
DE19741715A1 (de) * 1997-09-22 1999-03-25 Hoechst Ag Pentopyranosyl-Nucleosid, seine Herstellung und Verwendung
US5945286A (en) * 1997-10-23 1999-08-31 Motorola, Inc. Electrochemical-based molecular detection apparatus and method
AU753505B2 (en) 1997-10-30 2002-10-17 Cold Spring Harbor Laboratory Probe arrays and methods of using probe arrays for distinguishing DNA
US6203758B1 (en) * 1997-11-10 2001-03-20 Bio-Pixel Ltd. Micro-circuit system with array of functionalized micro-electrodes
DE19750237A1 (de) * 1997-11-13 1999-05-20 Roche Diagnostics Gmbh Verfahren zum Nachweis von Nukleinsäuren aus mehreren Proben
DE19753598C1 (de) * 1997-12-03 1999-07-01 Micronas Intermetall Gmbh Vorrichtung zum Messen physiologischer Parameter
US20020144905A1 (en) 1997-12-17 2002-10-10 Christian Schmidt Sample positioning and analysis system
US7244349B2 (en) * 1997-12-17 2007-07-17 Molecular Devices Corporation Multiaperture sample positioning and analysis system
DE59801410D1 (de) 1997-12-17 2001-10-11 Ecole Polytech Positionierung und elektrophysiologische charakterisierung einzelner zellen und rekonstituierter membransysteme auf mikrostrukturierten trägern
US6093302A (en) * 1998-01-05 2000-07-25 Combimatrix Corporation Electrochemical solid phase synthesis
US20030050437A1 (en) * 1998-01-05 2003-03-13 Montgomery Donald D. Electrochemical solid phase synthesis
US6893877B2 (en) 1998-01-12 2005-05-17 Massachusetts Institute Of Technology Methods for screening substances in a microwell array
DE69930726T2 (de) * 1998-01-12 2007-01-25 Massachusetts Institute Of Technology, Cambridge Verfahren und vorrichtung zur mikrotestdurchführung
CA2319170A1 (en) 1998-01-27 1999-07-29 Clinical Micro Sensors, Inc. Amplification of nucleic acids with electronic detection
US20050053962A1 (en) * 1998-01-27 2005-03-10 Gary Blackburn Amplification of nucleic acids with electronic detection
US6224830B1 (en) * 1998-01-30 2001-05-01 The Governors Of The University Of Alberta Absorbance cell for microfluid devices
US6287776B1 (en) 1998-02-02 2001-09-11 Signature Bioscience, Inc. Method for detecting and classifying nucleic acid hybridization
NZ506204A (en) * 1998-02-20 2003-06-30 Nanogen Inc Advanced active devices and methods for molecular biological analysis and diagnostics
WO1999049019A2 (en) 1998-03-27 1999-09-30 Prolume, Ltd. Luciferases, fluorescent proteins, nucleic acids encoding the luciferases and fluorescent proteins and the use thereof in diagnostics
DE19815901A1 (de) 1998-04-08 1999-10-14 Aventis Res & Tech Gmbh & Co Verfahren zur Herstellung von Pentopyranosyl-Nucleosiden
US6350618B1 (en) * 1998-04-27 2002-02-26 Corning Incorporated Redrawn capillary imaging reservoir
US6884626B1 (en) 1998-04-27 2005-04-26 Corning Incorporated Redrawn capillary imaging reservoir
EP0955084B1 (en) * 1998-04-27 2006-07-26 Corning Incorporated Method of depositing an array of biological samples using a redrawn capillary reservoir
US7875440B2 (en) 1998-05-01 2011-01-25 Arizona Board Of Regents Method of determining the nucleotide sequence of oligonucleotides and DNA molecules
US6780591B2 (en) 1998-05-01 2004-08-24 Arizona Board Of Regents Method of determining the nucleotide sequence of oligonucleotides and DNA molecules
US6048695A (en) * 1998-05-04 2000-04-11 Baylor College Of Medicine Chemically modified nucleic acids and methods for coupling nucleic acids to solid support
ATE407220T1 (de) 1998-05-06 2008-09-15 Clinical Micro Sensors Inc Elekronische verfahren zur erkennung von analyten mit hilfe von einfachschichten
EP1080229A4 (en) 1998-05-20 2005-07-13 Nano-Technologies L Integrated NANOMETRIC SCALE DEVICES CHEMICALLY ASSEMBLED
US6664103B2 (en) 1998-05-20 2003-12-16 Integrated Nano-Technologies, Llc Chemically assembled nano-scale circuit elements
US6255050B1 (en) 1998-05-22 2001-07-03 Lorne Park Research, Inc. Dynamic hybridization system
AU747464B2 (en) 1998-06-08 2002-05-16 Caliper Technologies Corporation Microfluidic devices, systems and methods for performing integrated reactions and separations
US6274089B1 (en) * 1998-06-08 2001-08-14 Caliper Technologies Corp. Microfluidic devices, systems and methods for performing integrated reactions and separations
US7344499B1 (en) 1998-06-10 2008-03-18 Georgia Tech Research Corporation Microneedle device for extraction and sensing of bodily fluids
AU767122B2 (en) * 1998-06-10 2003-10-30 Georgia Tech Research Corporation Microneedle devices and methods of manufacture and use thereof
US6503231B1 (en) * 1998-06-10 2003-01-07 Georgia Tech Research Corporation Microneedle device for transport of molecules across tissue
GB9812783D0 (en) 1998-06-12 1998-08-12 Cenes Ltd High throuoghput screen
US6270730B1 (en) * 1998-06-16 2001-08-07 Northwest Engineering Inc. Multi-well rotary synthesizer
US6251595B1 (en) 1998-06-18 2001-06-26 Agilent Technologies, Inc. Methods and devices for carrying out chemical reactions
US6761816B1 (en) * 1998-06-23 2004-07-13 Clinical Micro Systems, Inc. Printed circuit boards with monolayers and capture ligands
US7087148B1 (en) 1998-06-23 2006-08-08 Clinical Micro Sensors, Inc. Binding acceleration techniques for the detection of analytes
US20050244954A1 (en) * 1998-06-23 2005-11-03 Blackburn Gary F Binding acceleration techniques for the detection of analytes
US6290839B1 (en) 1998-06-23 2001-09-18 Clinical Micro Sensors, Inc. Systems for electrophoretic transport and detection of analytes
EP1090293B2 (en) 1998-06-24 2019-01-23 Illumina, Inc. Decoding of array sensors with microspheres
US6762061B1 (en) 1998-07-03 2004-07-13 Corning Incorporated Redrawn capillary imaging reservoir
DE19837387A1 (de) * 1998-08-18 2000-02-24 Aventis Res & Tech Gmbh & Co 3'-Desoxypentopyranosyl-Nucleinsäure, ihre Herstellung und Verwendung
US6271042B1 (en) * 1998-08-26 2001-08-07 Alpha Innotech Corporation Biochip detection system
US6740518B1 (en) 1998-09-17 2004-05-25 Clinical Micro Sensors, Inc. Signal detection techniques for the detection of analytes
US6136171A (en) * 1998-09-18 2000-10-24 The University Of Utah Research Foundation Micromachined electrical field-flow fractionation system
US6169394B1 (en) 1998-09-18 2001-01-02 University Of The Utah Research Foundation Electrical detector for micro-analysis systems
US6703228B1 (en) 1998-09-25 2004-03-09 Massachusetts Institute Of Technology Methods and products related to genotyping and DNA analysis
EP1001037A3 (en) * 1998-09-28 2003-10-01 Whitehead Institute For Biomedical Research Pre-selection and isolation of single nucleotide polymorphisms
FR2784751B1 (fr) 1998-10-20 2001-02-02 Mesatronic Boitier de logement d'une puce electronique a sondes biologiques
AU1241000A (en) * 1998-10-27 2000-05-15 Clinical Micro Sensors, Inc. Detection of target analytes using particles and electrodes
US6156478A (en) * 1998-10-30 2000-12-05 3M Innovative Properties Company Photocurable and photopatternable hydrogel matrix based on azlactone copolymers
US6187540B1 (en) 1998-11-09 2001-02-13 Identigene, Inc. Method of newborn identification and tracking
US7135283B1 (en) 1998-11-17 2006-11-14 Nanogen, Inc. Topoisomerase type II gene polymorphisms and their use in identifying drug resistance and pathogenic strains of microorganisms
US6503750B1 (en) * 1998-11-25 2003-01-07 The Regents Of The University Of California PCR thermocycler
AU1742300A (en) * 1998-12-02 2000-06-19 Nanogen, Inc. Apparatus and methods for transport of charged biological materials
US6438497B1 (en) 1998-12-11 2002-08-20 Symyx Technologies Method for conducting sensor array-based rapid materials characterization
JP2002532717A (ja) * 1998-12-11 2002-10-02 サイミックス テクノロジーズ、インク 迅速な物質特性評価のためのセンサ配列に基づくシステム及びその方法
US6477479B1 (en) 1998-12-11 2002-11-05 Symyx Technologies Sensor array for rapid materials characterization
US20030032029A1 (en) * 1998-12-21 2003-02-13 Nanogen, Inc. Three dimensional apparatus and method for integrating sample preparation and multiplex assays
US6833267B1 (en) 1998-12-30 2004-12-21 Clinical Micro Sensors, Inc. Tissue collection devices containing biosensors
US7595189B2 (en) * 1999-01-08 2009-09-29 Applied Biosystems, Llc Integrated optics fiber array
JP4454155B2 (ja) 1999-01-08 2010-04-21 アプライド バイオシステムズ， エルエルシー 化学種を接触させるためのファイバーアレイならびにファイバーアレイを使用および作製する方法
US20050026209A1 (en) * 1999-01-08 2005-02-03 Vann Charles S. Optical fiber bundle for detecting binding of chemical species
US6053030A (en) * 1999-01-22 2000-04-25 Bacou Usa Safety, Incorporated Instrument information and identification system and method
US6294063B1 (en) * 1999-02-12 2001-09-25 Board Of Regents, The University Of Texas System Method and apparatus for programmable fluidic processing
US6251685B1 (en) 1999-02-18 2001-06-26 Agilent Technologies, Inc. Readout method for molecular biological electronically addressable arrays
EP1157264B1 (en) * 1999-02-26 2004-04-21 EXACT Sciences Corporation Biochemical purification devices with immobilized capture probes and their uses
WO2000053625A2 (en) * 1999-03-11 2000-09-14 Combimatrix Corporation Microarrays of peptide affinity probes for analyzing gene products and methods for analyzing gene products
CN1181337C (zh) 2000-08-08 2004-12-22 清华大学 微流体系统中实体分子的操纵方法及相关试剂盒
TW496775B (en) 1999-03-15 2002-08-01 Aviva Bioscience Corp Individually addressable micro-electromagnetic unit array chips
CN1185492C (zh) 1999-03-15 2005-01-19 清华大学 可单点选通式微电磁单元阵列芯片、电磁生物芯片及应用
US6306578B1 (en) * 1999-03-19 2001-10-23 Genencor International, Inc. Multi-through hole testing plate for high throughput screening
CN1192116C (zh) * 1999-03-30 2005-03-09 内诺金有限公司 通过在半导体微芯片上进行电斑点印迹检测法分辩单核苷酸多态性
EP1173613A2 (en) * 1999-04-02 2002-01-23 Mosaic Technologies Methods of detecting microorganism using immobilized probes
US6531302B1 (en) * 1999-04-12 2003-03-11 Nanogen/Becton Dickinson Partnership Anchored strand displacement amplification on an electronically addressable microchip
US6238868B1 (en) * 1999-04-12 2001-05-29 Nanogen/Becton Dickinson Partnership Multiplex amplification and separation of nucleic acid sequences using ligation-dependant strand displacement amplification and bioelectronic chip technology
WO2000061805A1 (en) * 1999-04-12 2000-10-19 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip
CA2369016A1 (en) * 1999-04-12 2000-10-19 Nanogen/Becton Dickinson Partnership Amplification and separation of nucleic acid sequences using strand displacement amplification and bioelectronic microchip technology
US6326173B1 (en) * 1999-04-12 2001-12-04 Nanogen/Becton Dickinson Partnership Electronically mediated nucleic acid amplification in NASBA
US7312087B2 (en) * 2000-01-11 2007-12-25 Clinical Micro Sensors, Inc. Devices and methods for biochip multiplexing
US20020177135A1 (en) * 1999-07-27 2002-11-28 Doung Hau H. Devices and methods for biochip multiplexing
US20040053290A1 (en) * 2000-01-11 2004-03-18 Terbrueggen Robert Henry Devices and methods for biochip multiplexing
US6942771B1 (en) * 1999-04-21 2005-09-13 Clinical Micro Sensors, Inc. Microfluidic systems in the electrochemical detection of target analytes
US6238909B1 (en) * 1999-05-04 2001-05-29 Motorola, Inc. Method and apparatus for obtaining electric field-enhanced bioconjugation
US20030096321A1 (en) * 1999-05-19 2003-05-22 Jose Remacle Method for the identification and/or the quantification of a target compound obtained from a biological sample upon chips
US20020051971A1 (en) * 1999-05-21 2002-05-02 John R. Stuelpnagel Use of microfluidic systems in the detection of target analytes using microsphere arrays
US8080380B2 (en) * 1999-05-21 2011-12-20 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US8481268B2 (en) 1999-05-21 2013-07-09 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US6743211B1 (en) * 1999-11-23 2004-06-01 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
US6611707B1 (en) 1999-06-04 2003-08-26 Georgia Tech Research Corporation Microneedle drug delivery device
IL130326A0 (en) * 1999-06-07 2000-06-01 Yeda Res & Dev A sensor based on molecular controlled semiconductor resistor
WO2000077253A1 (fr) * 1999-06-16 2000-12-21 Hitachi, Ltd. Appareil et procede d'examen des genes
US7501245B2 (en) 1999-06-28 2009-03-10 Helicos Biosciences Corp. Methods and apparatuses for analyzing polynucleotide sequences
US6818395B1 (en) 1999-06-28 2004-11-16 California Institute Of Technology Methods and apparatus for analyzing polynucleotide sequences
US6303316B1 (en) 1999-07-02 2001-10-16 Conceptual Mind Works, Inc. Organic semiconductor recognition complex and system
JP2001033458A (ja) * 1999-07-26 2001-02-09 Fuji Photo Film Co Ltd マイクロアレイおよびそれを用いた分析方法
EP1218541B1 (en) 1999-07-26 2008-12-10 Clinical Micro Sensors, Inc. Sequence determination of nucleic acids using electronic detection
US20040185462A1 (en) * 1999-08-06 2004-09-23 Tum Gene, Inc. Method of and detecting apparatus and detecting chip for single base substitution SNP and point mutation of genes
CA2381750A1 (en) * 1999-08-13 2001-02-22 Nanogen, Inc. Microelectronic molecular descriptor array devices, methods, procedures, and formats for combinatorial selection of intermolecular ligand binding structures and for drug screening
US20020132371A1 (en) * 1999-09-27 2002-09-19 Kreimer David I. Amplification of analyte detection by substrates having particle structures with receptors
US20030232388A1 (en) * 1999-09-27 2003-12-18 Kreimer David I. Beads having identifiable Raman markers
US20040023293A1 (en) * 1999-09-27 2004-02-05 Kreimer David I. Biochips for characterizing biological processes
JP5181157B2 (ja) 1999-09-30 2013-04-10 ハミダ・フォー・ライフ・ベスローテン・フェンノートシャップ マイクロエレクトロニックアレイ上の生体分子付着部位
US6875619B2 (en) 1999-11-12 2005-04-05 Motorola, Inc. Microfluidic devices comprising biochannels
JP3548159B2 (ja) * 1999-11-12 2004-07-28 クリニカル・マイクロ・センサーズ・インコーポレイテッド 被検体検出のための結合促進法
US6361958B1 (en) * 1999-11-12 2002-03-26 Motorola, Inc. Biochannel assay for hybridization with biomaterial
US6451191B1 (en) 1999-11-18 2002-09-17 3M Innovative Properties Company Film based addressable programmable electronic matrix articles and methods of manufacturing and using the same
JP2001153870A (ja) * 1999-11-25 2001-06-08 Hitachi Software Eng Co Ltd ハイブリダイゼーション装置、ケース、支持体、及び、標識試薬
US6303082B1 (en) * 1999-12-15 2001-10-16 Nanogen, Inc. Permeation layer attachment chemistry and method
US6284117B1 (en) 1999-12-22 2001-09-04 Nanogen, Inc. Apparatus and method for removing small molecules and ions from low volume biological samples
DE10000629C5 (de) * 2000-01-10 2010-06-02 november Aktiengesellschaft, Gesellschaft für Molekulare Medizin Verfahren zur Identifizierung einer auf einen festen Körper aufgebrachten Markierung
AU2001232779A1 (en) * 2000-01-24 2001-07-31 Nanogen, Inc. Systems and devices for photoelectrophoretic transport and hybridization of oligonucleotides
EP1990428B1 (en) 2000-02-07 2010-12-22 Illumina, Inc. Nucleic acid detection methods using universal priming
US8076063B2 (en) * 2000-02-07 2011-12-13 Illumina, Inc. Multiplexed methylation detection methods
US7582420B2 (en) 2001-07-12 2009-09-01 Illumina, Inc. Multiplex nucleic acid reactions
EP1255865B1 (en) 2000-02-07 2007-04-18 Illumina, Inc. Nucleic acid detection method using universal priming
US7361488B2 (en) * 2000-02-07 2008-04-22 Illumina, Inc. Nucleic acid detection methods using universal priming
US7611869B2 (en) * 2000-02-07 2009-11-03 Illumina, Inc. Multiplexed methylation detection methods
US7955794B2 (en) 2000-09-21 2011-06-07 Illumina, Inc. Multiplex nucleic acid reactions
EP1257668B1 (en) 2000-02-16 2008-10-29 Illumina, Inc. Parallel genotyping of multiple patient samples
US6824669B1 (en) * 2000-02-17 2004-11-30 Motorola, Inc. Protein and peptide sensors using electrical detection methods
JP2004507207A (ja) * 2000-02-18 2004-03-11 サイエンス　アプリケイションズ　インターナショナル　コーポレイション サンプル中の生物学的実体を検出するための方法
US20020151040A1 (en) 2000-02-18 2002-10-17 Matthew O' Keefe Apparatus and methods for parallel processing of microvolume liquid reactions
CA2400644C (en) 2000-02-18 2009-07-14 Board Of Trustees Of The Leland Stanford Junior University Apparatus and methods for parallel processing of micro-volume liquid reactions
AU2001243487A1 (en) * 2000-03-08 2001-09-17 Imagene Technology, Inc Lateral flow pcr with amplicon concentration and detection
US7041206B2 (en) * 2000-03-09 2006-05-09 Clinical Analysis Corporation Medical diagnostic system
US7485454B1 (en) 2000-03-10 2009-02-03 Bioprocessors Corp. Microreactor
US6537433B1 (en) * 2000-03-10 2003-03-25 Applera Corporation Methods and apparatus for the location and concentration of polar analytes using an alternating electric field
US6569383B1 (en) * 2000-03-11 2003-05-27 Intrinsic Bioprobes, Inc. Bioactive chip mass spectrometry
US7109315B2 (en) * 2000-03-15 2006-09-19 Bruce J. Bryan Renilla reniformis fluorescent proteins, nucleic acids encoding the fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
JP2003529772A (ja) * 2000-03-30 2003-10-07 インフィネオン テクノロジーズ アクチエンゲゼルシャフト バイオセンサー、バイオセンサーアレイ、バイオセンサーの電極の製造方法、バイオセンサーの製造方法
US7001792B2 (en) 2000-04-24 2006-02-21 Eagle Research & Development, Llc Ultra-fast nucleic acid sequencing device and a method for making and using the same
US6413792B1 (en) 2000-04-24 2002-07-02 Eagle Research Development, Llc Ultra-fast nucleic acid sequencing device and a method for making and using the same
US8232582B2 (en) 2000-04-24 2012-07-31 Life Technologies Corporation Ultra-fast nucleic acid sequencing device and a method for making and using the same
US7455966B1 (en) 2000-05-01 2008-11-25 Science Applications International Corporation System and method for detecting a biological entity in a water sample
AU6114501A (en) * 2000-05-03 2001-11-12 Jen Gau Jr Biological identification system with integrated sensor chip
DE10028257A1 (de) * 2000-06-09 2001-12-20 Alpha Technology Ges Fuer Ange Analysechip für elektrofokussiertes Spotten
WO2001096024A2 (en) * 2000-06-14 2001-12-20 Board Of Regents, The University Of Texas System Apparatus and method for fluid injection
EP1164201A1 (en) * 2000-06-14 2001-12-19 Facultés Universitaires Notre-Dame de la Paix Reverse detection for identification and/or quantification of nucleotide target sequences on biochips
US6602400B1 (en) 2000-06-15 2003-08-05 Motorola, Inc. Method for enhanced bio-conjugation events
CN1741036A (zh) 2000-06-19 2006-03-01 科雷洛吉克系统公司 构造分类属于不同状态的生物样本的模型的方法
ES2259666T3 (es) 2000-06-21 2006-10-16 Bioarray Solutions Ltd Analisis molecular de multiples analitos usando series de particulas aleatorias con especificidad de aplicacion.
US9709559B2 (en) 2000-06-21 2017-07-18 Bioarray Solutions, Ltd. Multianalyte molecular analysis using application-specific random particle arrays
JP4382265B2 (ja) * 2000-07-12 2009-12-09 日本電気株式会社 酸化シリコン膜の形成方法及びその形成装置
KR101054732B1 (ko) * 2000-07-18 2011-08-05 더 유나이티드 스테이츠 오브 아메리카 애즈 리프리젠티드 바이 더 세크레터리 오브 더 디파트먼트 오브 헬쓰 앤드 휴먼 써비시즈 생물학적 데이터의 숨겨진 패턴에 근거한 생물학적 상태의 식별 방법
US7501284B2 (en) * 2000-07-31 2009-03-10 Applera Corporation Apparatus and method for specific release of captured extension products
US6544477B1 (en) 2000-08-01 2003-04-08 Regents Of The University Of Minnesota Apparatus for generating a temperature gradient
US7270730B2 (en) * 2000-08-04 2007-09-18 Essen Instruments, Inc. High-throughput electrophysiological measurement system
US7067046B2 (en) * 2000-08-04 2006-06-27 Essen Instruments, Inc. System for rapid chemical activation in high-throughput electrophysiological measurements
AU2001286784A1 (en) * 2000-08-25 2002-03-04 Genome Therapeutics Corporation Device for rapid dna sample processing with integrated liquid handling, thermocycling, and purification
US6610499B1 (en) 2000-08-31 2003-08-26 The Regents Of The University Of California Capillary array and related methods
JP4193345B2 (ja) * 2000-09-07 2008-12-10 横河電機株式会社 生体高分子の遺伝子配列を計測するための測定装置
US6780584B1 (en) * 2000-09-27 2004-08-24 Nanogen, Inc. Electronic systems and component devices for macroscopic and microscopic molecular biological reactions, analyses and diagnostics
CN100495030C (zh) 2000-09-30 2009-06-03 清华大学 多力操纵装置及其应用
DE10049901C2 (de) * 2000-10-10 2003-01-02 Aventis Res & Tech Gmbh & Co Vorrichtung und Verfahren zur elektrisch beschleunigten Immobilisierung und zur Detektion von Molekülen
US20030045005A1 (en) * 2000-10-17 2003-03-06 Michael Seul Light-controlled electrokinetic assembly of particles near surfaces
AU2002241803A1 (en) * 2000-10-20 2002-06-18 The Board Of Trustees Of The Leland Stanford Junior University Transient electrical signal based methods and devices for characterizing molecular interaction and/or motion in a sample
DE10054487A1 (de) * 2000-11-03 2002-05-23 Eppendorf Ag Verfahren und Vorrichtung zum Temperieren von Proben
US20020150887A1 (en) * 2000-11-09 2002-10-17 National Institute Of Advanced Industrial Science And Technology Methods and nucleic acid probes for molecular genetic analysis of polluted environments and environmental samples
WO2002043828A2 (en) * 2000-11-28 2002-06-06 Nanogen, Inc. Microtiter plate format device and methods for separating differently charged molecules using an electric field
US7776571B2 (en) * 2000-12-12 2010-08-17 Autogenomics, Inc. Multi-substrate biochip unit
EP1345646A2 (en) 2000-12-14 2003-09-24 Georgia Tech Research Corporation Microneedle devices and production thereof
WO2002050584A2 (en) * 2000-12-21 2002-06-27 Biovalve Technologies, Inc. Microneedle array systems
US20020123134A1 (en) * 2000-12-26 2002-09-05 Mingxian Huang Active and biocompatible platforms prepared by polymerization of surface coating films
AU2002243360A1 (en) * 2000-12-26 2002-08-06 C. Frederick Battrell Microfluidic cartridge with integrated electronics
US20020127855A1 (en) * 2001-01-04 2002-09-12 Sauer Jon Robert Method for fabricating a pattern in a mask on a surface of an object and product manufactured thereby
US20030132117A1 (en) * 2002-01-14 2003-07-17 Andras Guttman Thin film electrophoresis apparatus and method
DE10102063A1 (de) * 2001-01-17 2002-07-25 Alpha Technology Ges Fuer Ange Analysechip mit mehreren funktionalen Ebenen für elektrofokussiertes Spotten
US6707548B2 (en) 2001-02-08 2004-03-16 Array Bioscience Corporation Systems and methods for filter based spectrographic analysis
US6692700B2 (en) 2001-02-14 2004-02-17 Handylab, Inc. Heat-reduction methods and systems related to microfluidic devices
GB0103765D0 (en) * 2001-02-15 2001-04-04 Affitech As Assay
DE10109777A1 (de) * 2001-03-01 2002-09-19 Infineon Technologies Ag Verfahren zum Erfassen von makromolekularen Biopolymeren mittels mindestens einer Einheit zum Immobilisieren von makromolekularen Biopolymeren
US20060108218A1 (en) * 2001-03-05 2006-05-25 Clinical Analysis Corporation Test cell for use with medical diagnostic instrument
GB0105831D0 (en) * 2001-03-09 2001-04-25 Toumaz Technology Ltd Method for dna sequencing utilising enzyme linked field effect transistors
US8114591B2 (en) 2001-03-09 2012-02-14 Dna Electronics Ltd. Sensing apparatus and method
CA2440754A1 (en) * 2001-03-12 2002-09-19 Stephen Quake Methods and apparatus for analyzing polynucleotide sequences by asynchronous base extension
US20020151041A1 (en) * 2001-03-15 2002-10-17 Kreimer David I. Enhancing surfaces for analyte detection
US6852287B2 (en) 2001-09-12 2005-02-08 Handylab, Inc. Microfluidic devices having a reduced number of input and output connections
US7270786B2 (en) 2001-03-28 2007-09-18 Handylab, Inc. Methods and systems for processing microfluidic samples of particle containing fluids
US7323140B2 (en) * 2001-03-28 2008-01-29 Handylab, Inc. Moving microdroplets in a microfluidic device
US7010391B2 (en) * 2001-03-28 2006-03-07 Handylab, Inc. Methods and systems for control of microfluidic devices
US6575188B2 (en) 2001-07-26 2003-06-10 Handylab, Inc. Methods and systems for fluid control in microfluidic devices
US7829025B2 (en) 2001-03-28 2010-11-09 Venture Lending & Leasing Iv, Inc. Systems and methods for thermal actuation of microfluidic devices
US7192557B2 (en) * 2001-03-28 2007-03-20 Handylab, Inc. Methods and systems for releasing intracellular material from cells within microfluidic samples of fluids
US8895311B1 (en) 2001-03-28 2014-11-25 Handylab, Inc. Methods and systems for control of general purpose microfluidic devices
US20020172938A1 (en) * 2001-04-04 2002-11-21 Cuomo Jerome J. Adsorbing and non-adsorbing surfaces for biological materials
DE10117772C2 (de) * 2001-04-09 2003-04-03 Advalytix Ag Mischvorrichtung und Mischverfahren für die Durchmischung kleiner Flüssigkeitsmengen
US20040058437A1 (en) * 2001-04-10 2004-03-25 Rodgers Seth T. Materials and reactor systems having humidity and gas control
US20040058407A1 (en) * 2001-04-10 2004-03-25 Miller Scott E. Reactor systems having a light-interacting component
JP2004530044A (ja) * 2001-04-12 2004-09-30 アストラゼネカ アクチボラグ 微細工学的反応装置
EP1384067B1 (en) * 2001-05-02 2007-07-18 Applera Corporation Concentration and purification of analytes using electric fields
DE10122659A1 (de) * 2001-05-10 2002-12-05 Infineon Technologies Ag Biochip-Anordnung
US20050009101A1 (en) * 2001-05-17 2005-01-13 Motorola, Inc. Microfluidic devices comprising biochannels
US7214300B2 (en) * 2001-06-04 2007-05-08 Epocal Inc. Integrated electrokinetic devices and methods of manufacture
WO2002099386A2 (en) * 2001-06-07 2002-12-12 Proligo Llc Microcalorimetric detection of analytes and binding events
US6824974B2 (en) * 2001-06-11 2004-11-30 Genorx, Inc. Electronic detection of biological molecules using thin layers
US20040048241A1 (en) * 2001-06-11 2004-03-11 Freeman Beverly Annette Methods for attaching molecules
US7262063B2 (en) 2001-06-21 2007-08-28 Bio Array Solutions, Ltd. Directed assembly of functional heterostructures
CA2764307C (en) 2001-06-29 2015-03-03 Meso Scale Technologies, Llc. Assay plates, reader systems and methods for luminescence test measurements
US6893822B2 (en) 2001-07-19 2005-05-17 Nanogen Recognomics Gmbh Enzymatic modification of a nucleic acid-synthetic binding unit conjugate
US20030022150A1 (en) * 2001-07-24 2003-01-30 Sampson Jeffrey R. Methods for detecting a target molecule
US6890409B2 (en) * 2001-08-24 2005-05-10 Applera Corporation Bubble-free and pressure-generating electrodes for electrophoretic and electroosmotic devices
US10539561B1 (en) * 2001-08-30 2020-01-21 Customarray, Inc. Enzyme-amplified redox microarray detection process
US20050032060A1 (en) * 2001-08-31 2005-02-10 Shishir Shah Arrays comprising pre-labeled biological molecules and methods for making and using these arrays
US7198754B2 (en) * 2001-08-31 2007-04-03 Kabushiki Kaisha Toshiba Biological material detection element, biological material detection method and apparatus, charged material moving apparatus
WO2003021230A2 (en) * 2001-09-05 2003-03-13 Essen Instruments, Inc. High-throughput electrophysiological measurement system
DE10145700A1 (de) * 2001-09-17 2003-04-10 Infineon Technologies Ag Biochip-Anordnung, Sensor-Anordnung und Verfahren zum Betreiben einer Biochip-Anordnung
WO2003024507A2 (en) * 2001-09-19 2003-03-27 Biovalve Technologies, Inc. Microneedles, microneedle arrays, and systems and methods relating to same
EP1471953B1 (en) * 2001-09-21 2011-02-16 Valeritas, Inc. Gas pressure actuated microneedle arrays, and systems and methods relating to same
EP1469903A2 (en) * 2001-09-28 2004-10-27 BioValve Technologies, Inc. Microneedle with membrane
CA2500452A1 (en) * 2001-09-28 2003-04-03 Biovalve Technologies, Inc. Switchable microneedle arrays and systems and methods relating to same
US7439346B2 (en) * 2001-10-12 2008-10-21 Perkinelmer Las Inc. Nucleic acids arrays and methods of use therefor
US20030073071A1 (en) * 2001-10-12 2003-04-17 Jurgen Fritz Solid state sensing system and method for measuring the binding or hybridization of biomolecules
JP2005519634A (ja) 2001-10-12 2005-07-07 スペクトラル ジェノミクス、インク． 核酸組成物及びアレイ及びそれらを用いる方法
EP2722395B1 (en) 2001-10-15 2018-12-19 Bioarray Solutions Ltd Multiplexed analysis of polymorphic loci by concurrent interrogation and enzyme-mediated detection
WO2003039753A1 (en) * 2001-11-05 2003-05-15 President And Fellows Of Harvard College System and method for capturing and positioning particles
US20030175947A1 (en) * 2001-11-05 2003-09-18 Liu Robin Hui Enhanced mixing in microfluidic devices
JP3758183B2 (ja) * 2001-11-08 2006-03-22 横河電機株式会社 バイオチップおよびそれを用いた遺伝子配列測定装置
US6960298B2 (en) * 2001-12-10 2005-11-01 Nanogen, Inc. Mesoporous permeation layers for use on active electronic matrix devices
US20030113832A1 (en) * 2001-12-14 2003-06-19 Lauf Robert J. Apparatus and method for assaying electrophysiological effects
US6866762B2 (en) * 2001-12-20 2005-03-15 Board Of Regents, University Of Texas System Dielectric gate and methods for fluid injection and control
JP3786881B2 (ja) * 2002-02-01 2006-06-14 富士写真フイルム株式会社 リセプター・リガンド会合反応方法
US6887362B2 (en) * 2002-02-06 2005-05-03 Nanogen, Inc. Dielectrophoretic separation and immunoassay methods on active electronic matrix devices
US7504364B2 (en) * 2002-03-01 2009-03-17 Receptors Llc Methods of making arrays and artificial receptors
GB0205455D0 (en) 2002-03-07 2002-04-24 Molecular Sensing Plc Nucleic acid probes, their synthesis and use
DE10214719A1 (de) * 2002-04-03 2003-11-20 Infineon Technologies Ag Sensor zur qualitativen und quantitativen Bestimmung von (bio)organischen Oligomeren und Polymeren, Analyseverfahren hierzu sowie Verfahren zur Herstellung des Sensors
US20050026134A1 (en) * 2002-04-10 2005-02-03 Bioprocessors Corp. Systems and methods for control of pH and other reactor environment conditions
CA2481411C (en) 2002-04-19 2016-06-14 Diversa Corporation Phospholipases, nucleic acids encoding them and methods for making and using them
US7226771B2 (en) 2002-04-19 2007-06-05 Diversa Corporation Phospholipases, nucleic acids encoding them and methods for making and using them
JP4228114B2 (ja) * 2002-05-07 2009-02-25 独立行政法人科学技術振興機構 微小物体の回収方法及び装置
US6841379B2 (en) 2002-05-15 2005-01-11 Beckman Coulter, Inc. Conductive microplate
GB0211564D0 (en) 2002-05-21 2002-06-26 Tournaz Technology Ltd Reference circuit
JP4628095B2 (ja) * 2002-05-29 2011-02-09 オウトジエノミクス・インコーポレーテツド 統合されたマイクロアレイシステムおよびその製造方法
AU2003249681A1 (en) * 2002-05-31 2003-12-19 Diversa Corporation Multiplexed systems for nucleic acid sequencing
DE50305588D1 (de) 2002-06-24 2006-12-14 Siemens Ag Biosensor-array und verfahren zum betreiben eines biosensor-arrays
DE10228124A1 (de) * 2002-06-24 2004-01-29 Infineon Technologies Ag Biosensor-Array und Verfahren zum Betreiben eines Biosensor-Arrays
DE10228125A1 (de) * 2002-06-24 2004-01-22 Infineon Technologies Ag Biosensor-Array und Verfahren zum Betreiben eines Biosensor-Arrays
US20040005572A1 (en) * 2002-07-05 2004-01-08 Rosner S. Jeffrey Electronically readable microarrays
US20040011650A1 (en) * 2002-07-22 2004-01-22 Frederic Zenhausern Method and apparatus for manipulating polarizable analytes via dielectrophoresis
US7601493B2 (en) * 2002-07-26 2009-10-13 Nanogen, Inc. Methods and apparatus for screening and detecting multiple genetic mutations
AR040711A1 (es) * 2002-07-29 2005-04-13 Us Agriculture Un metodo para verificacion de calidad/control de calidad para proceso de bioensayo de alto rendimiento
US7153687B2 (en) * 2002-08-13 2006-12-26 Hong Kong Dna Chips Limited Apparatus and methods for detecting DNA in biological samples
US7267751B2 (en) * 2002-08-20 2007-09-11 Nanogen, Inc. Programmable multiplexed active biologic array
US8277753B2 (en) * 2002-08-23 2012-10-02 Life Technologies Corporation Microfluidic transfer pin
US20050037381A1 (en) * 2002-09-16 2005-02-17 Receptors Llc Artificial receptors, building blocks, and methods
CA2503905A1 (en) * 2002-09-16 2004-03-25 Plexxikon, Inc. Crystal structure of pim-1 kinase
US20050170385A1 (en) * 2002-09-16 2005-08-04 Receptors Llc Artificial receptors including gradients
US20050037429A1 (en) * 2003-03-28 2005-02-17 Receptors Llc Artificial receptors including reversibly immobilized building blocks and methods
US20050136483A1 (en) * 2003-09-03 2005-06-23 Receptors Llc Nanodevices employing combinatorial artificial receptors
WO2005003326A2 (en) * 2003-03-28 2005-01-13 Receptors Llc. Artificial receptors including reversibly immobilized building blocks and methods
US20060051802A1 (en) * 2002-09-16 2006-03-09 Receptors Llc Artificial receptors, building blocks, and methods
US20040137481A1 (en) * 2002-09-16 2004-07-15 Receptors Llc Artificial receptor building blocks, components, and kits
AU2003267583A1 (en) * 2002-09-19 2004-04-08 The Chancellor, Master And Scholars Of The University Of Oxford Molecular arrays and single molecule detection
US6911132B2 (en) * 2002-09-24 2005-06-28 Duke University Apparatus for manipulating droplets by electrowetting-based techniques
US7329545B2 (en) 2002-09-24 2008-02-12 Duke University Methods for sampling a liquid flow
US20040259105A1 (en) * 2002-10-03 2004-12-23 Jian-Bing Fan Multiplex nucleic acid analysis using archived or fixed samples
US20040072334A1 (en) * 2002-10-15 2004-04-15 The Regents Of The University Of California Thermal cycler
US20090209030A1 (en) * 2002-10-15 2009-08-20 Benett William J Thermal Cycler
US20040147045A1 (en) * 2002-10-29 2004-07-29 Gentel Biosurfaces, Inc. Signal molecule arrays
US7000870B2 (en) * 2002-11-07 2006-02-21 Aerion Corporation Laminar flow wing for transonic cruise
WO2004047007A1 (en) 2002-11-15 2004-06-03 Bioarray Solutions, Ltd. Analysis, secure access to, and transmission of array images
TW200409821A (en) * 2002-12-03 2004-06-16 Ind Tech Res Inst Microarray biochip reactor
US20040121339A1 (en) * 2002-12-19 2004-06-24 Jizhong Zhou Special film-coated substrate for bio-microarray fabrication and use thereof
CA2521999A1 (en) 2002-12-20 2004-09-02 Biotrove, Inc. Assay apparatus and method using microfluidic arrays
US7887752B2 (en) * 2003-01-21 2011-02-15 Illumina, Inc. Chemical reaction monitor
US20050048573A1 (en) * 2003-02-03 2005-03-03 Plexxikon, Inc. PDE5A crystal structure and uses
US20040157220A1 (en) 2003-02-10 2004-08-12 Purnima Kurnool Methods and apparatus for sample tracking
US20050170431A1 (en) * 2003-02-28 2005-08-04 Plexxikon, Inc. PYK2 crystal structure and uses
CN104388449A (zh) 2003-03-06 2015-03-04 维莱尼姆公司 淀粉酶、编码它们的核酸及其制备和应用方法
CA2889013C (en) 2003-03-07 2018-07-17 Dsm Ip Assets B.V. Hydrolases, nucleic acids encoding them and methods for making and using them
US7147764B2 (en) * 2003-03-28 2006-12-12 Applera Corporation Dual electrode injection of analyte into a capillary electrophoretic device
MXPA05010681A (es) 2003-04-04 2005-12-15 Diversa Corp Liasas de pectato, acidos nucleicos que las codifican, y metodos para hacerlas y usarlas.
RU2390561C2 (ru) 2003-05-23 2010-05-27 Колд Спринг Харбор Лэборетери Виртуальные наборы фрагментов нуклеотидных последовательностей
EP1628748A2 (en) * 2003-06-05 2006-03-01 Bioprocessors Corporation Reactor with memory component
CN108486086A (zh) 2003-07-02 2018-09-04 维莱尼姆公司 葡聚糖酶，编码它们的核酸以及制备和使用它们的方法
US20050079548A1 (en) * 2003-07-07 2005-04-14 Plexxikon, Inc. Ligand development using PDE4B crystal structures
US7731906B2 (en) 2003-07-31 2010-06-08 Handylab, Inc. Processing particle-containing samples
CA2534336A1 (en) * 2003-08-01 2005-02-10 Correlogic Systems, Inc. Multiple high-resolution serum proteomic features for ovarian cancer detection
WO2005021714A2 (en) 2003-08-11 2005-03-10 Diversa Corporation Laccases, nucleic acids encoding them and methods for making and using them
US20050164300A1 (en) * 2003-09-15 2005-07-28 Plexxikon, Inc. Molecular scaffolds for kinase ligand development
US7316320B2 (en) * 2003-09-18 2008-01-08 Intel Corporation Sorting charged particles
WO2005029705A2 (en) 2003-09-18 2005-03-31 Bioarray Solutions, Ltd. Number coding for identification of subtypes of coded types of solid phase carriers
ES2375962T3 (es) 2003-09-22 2012-03-07 Bioarray Solutions Ltd Polielectrolito inmovilizado en superficie con múltiples grupos funcionales capaces de unirse covalentemente a biomoléculas.
JP4321854B2 (ja) * 2003-10-02 2009-08-26 ソニー株式会社 ハイブリダイゼーションその他の相互作用検出部と該検出部を備えるｄｎａチップその他のバイオアッセイ用基板
US7390622B2 (en) 2003-10-16 2008-06-24 Hai Kang Life Corporation Limited Apparatus and methods for detecting nucleic acid in biological samples
EP1692298A4 (en) 2003-10-28 2008-08-13 Bioarray Solutions Ltd OPTIMIZATION OF GENE EXPRESSION ANALYSIS USING IMMOBILIZED CATCHES
ES2533876T3 (es) 2003-10-29 2015-04-15 Bioarray Solutions Ltd Análisis multiplexado de ácidos nucleicos mediante fragmentación de ADN bicatenario
JP2007515947A (ja) * 2003-10-30 2007-06-21 タフツ−ニュー イングランド メディカル センター 羊水中の無細胞胎児ｄｎａを使用する出生前診断
US7981362B2 (en) * 2003-11-04 2011-07-19 Meso Scale Technologies, Llc Modular assay plates, reader systems and methods for test measurements
US7169560B2 (en) 2003-11-12 2007-01-30 Helicos Biosciences Corporation Short cycle methods for sequencing polynucleotides
AU2004316286A1 (en) 2003-11-20 2005-09-09 Biowarn, Llc Methodology and apparatus for the detection of biological substances
ATE447044T1 (de) 2003-12-15 2009-11-15 Geneohm Sciences Inc Kohlenstoffelektrodenoberfläche zur bindung von dna- und proteinmolekülen daran
US20070066641A1 (en) * 2003-12-19 2007-03-22 Prabha Ibrahim Compounds and methods for development of RET modulators
PL1696920T3 (pl) * 2003-12-19 2015-03-31 Plexxikon Inc Związki i sposoby opracowywania modulatorów Ret
WO2005075971A1 (en) * 2004-02-02 2005-08-18 Agilent Technologies Inc. Charged particle reduction in analyte processing
EP2248911A1 (en) 2004-02-19 2010-11-10 Helicos Biosciences Corporation Methods and kits for analyzing polynucleotide sequences
CA2559171A1 (en) 2004-03-12 2005-09-29 Biotrove, Inc. Nanoliter array loading
US20050224094A1 (en) * 2004-03-31 2005-10-13 Davis Randall W Apparatus and methods for isolating bioreactive materials on a microarray substrate surface
KR100613612B1 (ko) * 2004-04-27 2006-08-18 삼성전자주식회사 인덕턴스 소자 및 캐패시턴스 소자를 이용한 바이오결합검출 장치 및 방법
US8852862B2 (en) 2004-05-03 2014-10-07 Handylab, Inc. Method for processing polynucleotide-containing samples
AU2005241080B2 (en) 2004-05-03 2011-08-11 Handylab, Inc. Processing polynucleotide-containing samples
US7534336B2 (en) * 2004-05-04 2009-05-19 Palo Alto Research Center Incorporated Continuous flow particle concentrator
US7491307B2 (en) * 2004-05-04 2009-02-17 Palo Alto Research Center Incorporated Portable bioagent concentrator
EP1742627A4 (en) 2004-05-06 2009-08-26 Plexxikon Inc PDE4B HEMMER AND ITS USE
EP1766061B1 (en) * 2004-05-20 2013-07-17 Quest Diagnostics Investments Incorporated Single label comparative hybridization
WO2006007207A2 (en) 2004-05-25 2006-01-19 Helicos Biosciences Corporation Methods and devices for nucleic acid sequence determination
US7476734B2 (en) 2005-12-06 2009-01-13 Helicos Biosciences Corporation Nucleotide analogs
US8974652B2 (en) * 2004-05-28 2015-03-10 Board Of Regents, The University Of Texas System Programmable fluidic processors
US7338763B2 (en) 2004-06-02 2008-03-04 Eppendorf Array Technologies S.A. Method and kit for the detection and/or quantification of homologous nucleotide sequences on arrays
JP2008504845A (ja) * 2004-06-07 2008-02-21 バイオプロセッサーズ コーポレイション リアクター環境条件の制御
ES2540728T3 (es) 2004-06-16 2015-07-13 Dsm Ip Assets B.V. Método para la decoloración enzimática de feofitina
WO2006009797A1 (en) * 2004-06-17 2006-01-26 Plexxikon, Inc. Azaindoles modulating c-kit activity and uses therefor
US7498342B2 (en) * 2004-06-17 2009-03-03 Plexxikon, Inc. Compounds modulating c-kit activity
US20060014155A1 (en) * 2004-07-16 2006-01-19 Wisconsin Alumni Research Foundation Methods for the production of sensor arrays using electrically addressable electrodes
DE602004030678D1 (de) * 2004-07-19 2011-02-03 St Microelectronics Srl Vorrichtung zur Detektion von biologischen Molekülen mit erhöhter Detektionsgeschwindigkeit und Verfahren zur schnellen Detektion von Biomolekülen
US7848889B2 (en) 2004-08-02 2010-12-07 Bioarray Solutions, Ltd. Automated analysis of multiplexed probe-target interaction patterns: pattern matching and allele identification
US20060105453A1 (en) 2004-09-09 2006-05-18 Brenan Colin J Coating process for microfluidic sample arrays
EP1623996A1 (en) * 2004-08-06 2006-02-08 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Improved method of selecting a desired protein from a library
US7605168B2 (en) * 2004-09-03 2009-10-20 Plexxikon, Inc. PDE4B inhibitors
US7504365B2 (en) * 2004-09-03 2009-03-17 Receptors Llc Combinatorial artificial receptors including tether building blocks
WO2006029383A2 (en) * 2004-09-11 2006-03-16 Receptors Llc Combinatorial artificial receptors including peptide building blocks
US7828954B2 (en) * 2004-09-21 2010-11-09 Gamida For Life B.V. Electrode based patterning of thin film self-assembled nanoparticles
US7524672B2 (en) * 2004-09-22 2009-04-28 Sandia Corporation Microfluidic microarray systems and methods thereof
US7314542B2 (en) * 2004-09-23 2008-01-01 Nanogen, Inc. Methods and materials for optimization of electronic transportation and hybridization reactions
US7592139B2 (en) 2004-09-24 2009-09-22 Sandia National Laboratories High temperature flow-through device for rapid solubilization and analysis
WO2007044029A2 (en) * 2004-12-03 2007-04-19 Nano Science Diagnostic, Inc. Method and apparatus for low quantity detection of bioparticles in small sample volumes
US7220549B2 (en) 2004-12-30 2007-05-22 Helicos Biosciences Corporation Stabilizing a nucleic acid for nucleic acid sequencing
DE602006018861D1 (de) * 2005-01-27 2011-01-27 Quest Diagnostics Invest Inc Schnelle komparative genomhybridisierung
US7482120B2 (en) 2005-01-28 2009-01-27 Helicos Biosciences Corporation Methods and compositions for improving fidelity in a nucleic acid synthesis reaction
EP1859330B1 (en) * 2005-01-28 2012-07-04 Duke University Apparatuses and methods for manipulating droplets on a printed circuit board
US20070003996A1 (en) * 2005-02-09 2007-01-04 Hitt Ben A Identification of bacteria and spores
CA2614769A1 (en) 2005-03-10 2006-09-21 Verenium Corporation Lyase enzymes, nucleic acids encoding them and methods for making and using them
BRPI0609140A2 (pt) 2005-03-15 2010-02-17 Verenium Corp celulases, ácidos nucléicos que codificam eles e métodos para a produção e uso deles
US7785862B2 (en) * 2005-04-07 2010-08-31 454 Life Sciences Corporation Thin film coated microwell arrays
US7682816B2 (en) 2005-04-07 2010-03-23 454 Life Sciences Corporation Thin film coated microwell arrays and methods of using same
WO2006124628A2 (en) * 2005-05-12 2006-11-23 Correlogic Systems, Inc. A model for classifying a biological sample in relation to breast cancer based on mass spectral data
AU2006272951A1 (en) 2005-05-17 2007-02-01 Plexxikon, Inc. Pyrrol (2,3-b) pyridine derivatives protein kinase inhibitors
US8486629B2 (en) 2005-06-01 2013-07-16 Bioarray Solutions, Ltd. Creation of functionalized microparticle libraries by oligonucleotide ligation or elongation
EP2278303A3 (en) * 2005-06-10 2012-02-22 Life Technologies Corporation Method and system for multiplex genetic analysis
SG162795A1 (en) 2005-06-15 2010-07-29 Callida Genomics Inc Single molecule arrays for genetic and chemical analysis
DK1893612T3 (da) * 2005-06-22 2011-11-21 Plexxikon Inc Pyrrol [2,3-B]pyridin-derivater som proteinkinasehæmmere
US7666593B2 (en) 2005-08-26 2010-02-23 Helicos Biosciences Corporation Single molecule sequencing of captured nucleic acids
US7681738B2 (en) * 2005-09-12 2010-03-23 Palo Alto Research Center Incorporated Traveling wave arrays, separation methods, and purification cells
US20070231794A1 (en) * 2005-09-21 2007-10-04 Combimatrix Corporation Process to detect binding events on an electrode microarray using enzymes
US7960104B2 (en) 2005-10-07 2011-06-14 Callida Genomics, Inc. Self-assembled single molecule arrays and uses thereof
US8076074B2 (en) 2005-11-29 2011-12-13 Quest Diagnostics Investments Incorporated Balanced translocation in comparative hybridization
US20090305248A1 (en) * 2005-12-15 2009-12-10 Lander Eric G Methods for increasing accuracy of nucleic acid sequencing
EP2216403A3 (en) 2006-02-02 2010-11-24 Verenium Corporation Esterases and related nucleic acids and methods
NZ595498A (en) 2006-02-10 2013-05-31 Verenium Corp Cellulolytic enzymes, nucleic acids encoding them and methods for making and using them
ES2682284T3 (es) 2006-02-14 2018-09-19 Bp Corporation North America Inc. Xilanasas, ácidos nucleicos que las codifican y métodos para elaborarlas y usarlas
SG10201405158QA (en) * 2006-02-24 2014-10-30 Callida Genomics Inc High throughput genome sequencing on dna arrays
CN101432439B (zh) * 2006-02-24 2013-07-24 考利达基因组股份有限公司 Dna阵列上的高通量基因组测序
EP2316962B1 (en) 2006-03-07 2014-07-09 Cargill, Incorporated Aldolases, nucleic acids encoding them and methods for making and using them
CA2645225A1 (en) 2006-03-07 2007-09-13 Verenium Corporation Aldolases, nucleic acids encoding them and methods for making and using them
US7397546B2 (en) * 2006-03-08 2008-07-08 Helicos Biosciences Corporation Systems and methods for reducing detected intensity non-uniformity in a laser beam
US20080309926A1 (en) * 2006-03-08 2008-12-18 Aaron Weber Systems and methods for reducing detected intensity non uniformity in a laser beam
US10900066B2 (en) 2006-03-24 2021-01-26 Handylab, Inc. Microfluidic system for amplifying and detecting polynucleotides in parallel
US8088616B2 (en) 2006-03-24 2012-01-03 Handylab, Inc. Heater unit for microfluidic diagnostic system
JP5415253B2 (ja) 2006-03-24 2014-02-12 ハンディラブ・インコーポレーテッド 微小流体サンプルを処理するための一体化システム及びその使用方法
US11806718B2 (en) 2006-03-24 2023-11-07 Handylab, Inc. Fluorescence detector for microfluidic diagnostic system
US7998708B2 (en) 2006-03-24 2011-08-16 Handylab, Inc. Microfluidic system for amplifying and detecting polynucleotides in parallel
US8883490B2 (en) 2006-03-24 2014-11-11 Handylab, Inc. Fluorescence detector for microfluidic diagnostic system
US20070232556A1 (en) * 2006-03-31 2007-10-04 Montine Thomas J Methods and compositions for the treatment of neurological diseases and disorders
US7856272B2 (en) * 2006-04-28 2010-12-21 Flint Hills Scientific, L.L.C. Implantable interface for a medical device system
AU2007254191B2 (en) * 2006-05-16 2013-01-10 Fluidigm Corporation PCR-free sample preparation and detection systems for high speed biologic analysis and identification
US20100216657A1 (en) * 2006-05-16 2010-08-26 Arcxis Biotechnologies, Inc. Pcr-free sample preparation and detection systems for high speed biologic analysis and identification
US11001881B2 (en) 2006-08-24 2021-05-11 California Institute Of Technology Methods for detecting analytes
EP2489745B1 (en) * 2006-06-05 2017-01-11 California Institute Of Technology Real time micro arrays
WO2008014485A2 (en) * 2006-07-28 2008-01-31 California Institute Of Technology Multiplex q-pcr arrays
US11525156B2 (en) 2006-07-28 2022-12-13 California Institute Of Technology Multiplex Q-PCR arrays
EP2444413A1 (en) 2006-08-04 2012-04-25 Verenium Corporation Methods for oil or gas well drilling, washing and/or fracturing
US11560588B2 (en) 2006-08-24 2023-01-24 California Institute Of Technology Multiplex Q-PCR arrays
US7687103B2 (en) * 2006-08-31 2010-03-30 Gamida For Life B.V. Compositions and methods for preserving permeation layers for use on active electronic matrix devices
WO2008030763A2 (en) * 2006-09-05 2008-03-13 Nanogen, Inc. Fluorescent cartridge for calibration of a microarray reader
BRPI0716872A2 (pt) 2006-09-21 2015-06-16 Verenium Corp Fosfolipases, ácidos nucléicos codificando-as e métodos para fabricação e uso delas
EP2617819B1 (en) 2006-09-21 2016-04-27 BASF Enzymes LLC Phytases, nucleic acids encoding them and methods for making and using them
EP2089410A4 (en) * 2006-10-11 2011-08-03 Arcxis Biotechnologies Inc DISPOSABLE MICRO-PURIFICATION CARDS, METHODS AND SYSTEMS THEREOF
EP1912067A1 (en) * 2006-10-12 2008-04-16 Eppendorf Array Technologies S.A. Method for quantification of a target compound obtained from a biological sample upon chips
US7910354B2 (en) * 2006-10-27 2011-03-22 Complete Genomics, Inc. Efficient arrays of amplified polynucleotides
US8618248B2 (en) 2006-10-31 2013-12-31 President And Fellows Of Harvard College Phosphopeptide compositions and anti-phosphopeptide antibody compositions and methods of detecting phosphorylated peptides
US20080221832A1 (en) * 2006-11-09 2008-09-11 Complete Genomics, Inc. Methods for computing positional base probabilities using experminentals base value distributions
US20090111705A1 (en) * 2006-11-09 2009-04-30 Complete Genomics, Inc. Selection of dna adaptor orientation by hybrid capture
WO2008061165A2 (en) 2006-11-14 2008-05-22 Handylab, Inc. Microfluidic cartridge and method of making same
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9433880B2 (en) * 2006-11-30 2016-09-06 Palo Alto Research Center Incorporated Particle separation and concentration system
US10052571B2 (en) * 2007-11-07 2018-08-21 Palo Alto Research Center Incorporated Fluidic device and method for separation of neutrally buoyant particles
US8276760B2 (en) 2006-11-30 2012-10-02 Palo Alto Research Center Incorporated Serpentine structures for continuous flow particle separations
US8931644B2 (en) * 2006-11-30 2015-01-13 Palo Alto Research Center Incorporated Method and apparatus for splitting fluid flow in a membraneless particle separation system
US9862624B2 (en) * 2007-11-07 2018-01-09 Palo Alto Research Center Incorporated Device and method for dynamic processing in water purification
US9486812B2 (en) * 2006-11-30 2016-11-08 Palo Alto Research Center Incorporated Fluidic structures for membraneless particle separation
PL3101128T3 (pl) 2006-12-21 2019-09-30 Basf Enzymes Llc Amylazy i glukoamylazy, kwasy nukleinowe kodujące te związki oraz sposoby wytwarzania tych związków oraz stosowania ich
PE20081581A1 (es) * 2006-12-21 2008-11-12 Plexxikon Inc COMPUESTOS PIRROLO[2,3-b]PIRIDINAS COMO MODULADORES DE QUINASA
EP2094701A2 (en) 2006-12-21 2009-09-02 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
WO2008079909A1 (en) * 2006-12-21 2008-07-03 Plexxikon, Inc. Pyrrolo [2,3-b] pyridines as kinase modulators
NZ610301A (en) 2007-01-30 2015-03-27 Bp Corp North America Inc Enzymes for the treatment of lignocellulosics, nucleic acids encoding them and methods for making and using them
WO2008100941A2 (en) * 2007-02-12 2008-08-21 Correlogic Systems Inc. A method for calibrating an analytical instrument
CN103555735B (zh) 2007-04-27 2016-03-09 加利福尼亚大学董事会 植物co2传感器、编码它们的核酸以及制造和使用它们的方法
CA2691980C (en) * 2007-06-29 2022-05-10 Correlogic Systems, Inc. Predictive markers for ovarian cancer
USD621060S1 (en) 2008-07-14 2010-08-03 Handylab, Inc. Microfluidic cartridge
WO2009012185A1 (en) 2007-07-13 2009-01-22 Handylab, Inc. Polynucleotide capture materials, and methods of using same
US9618139B2 (en) 2007-07-13 2017-04-11 Handylab, Inc. Integrated heater and magnetic separator
US8182763B2 (en) 2007-07-13 2012-05-22 Handylab, Inc. Rack for sample tubes and reagent holders
US8287820B2 (en) 2007-07-13 2012-10-16 Handylab, Inc. Automated pipetting apparatus having a combined liquid pump and pipette head system
US20090136385A1 (en) 2007-07-13 2009-05-28 Handylab, Inc. Reagent Tube
US8133671B2 (en) 2007-07-13 2012-03-13 Handylab, Inc. Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples
US9186677B2 (en) 2007-07-13 2015-11-17 Handylab, Inc. Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples
US8105783B2 (en) 2007-07-13 2012-01-31 Handylab, Inc. Microfluidic cartridge
MX2010000617A (es) 2007-07-17 2010-05-17 Plexxikon Inc Compuestos y metodos para modulacion de cinasa, e indicaciones de estos.
US7507539B2 (en) * 2007-07-30 2009-03-24 Quest Diagnostics Investments Incorporated Substractive single label comparative hybridization
US8268246B2 (en) * 2007-08-09 2012-09-18 Advanced Liquid Logic Inc PCB droplet actuator fabrication
DE102007042986A1 (de) * 2007-09-10 2009-04-23 Siemens Ag Medizinisches Gerät und Verfahren zum Betreiben eines medizinischen Geräts
CN110577945A (zh) 2007-10-03 2019-12-17 维莱尼姆公司 木聚糖酶、编码它们的核酸以及其制备和应用方法
WO2009052214A2 (en) * 2007-10-15 2009-04-23 Complete Genomics, Inc. Sequence analysis using decorated nucleic acids
US8518640B2 (en) * 2007-10-29 2013-08-27 Complete Genomics, Inc. Nucleic acid sequencing and process
US7897344B2 (en) * 2007-11-06 2011-03-01 Complete Genomics, Inc. Methods and oligonucleotide designs for insertion of multiple adaptors into library constructs
US8415099B2 (en) 2007-11-05 2013-04-09 Complete Genomics, Inc. Efficient base determination in sequencing reactions
US8381169B2 (en) * 2007-10-30 2013-02-19 International Business Machines Corporation Extending unified process and method content to include dynamic and collaborative content
WO2009061840A1 (en) * 2007-11-05 2009-05-14 Complete Genomics, Inc. Methods and oligonucleotide designs for insertion of multiple adaptors employing selective methylation
US20090137925A1 (en) * 2007-11-23 2009-05-28 Divya Cantor Impedance Spectroscopy Cervix Scanning Apparatus and Method
WO2009073629A2 (en) 2007-11-29 2009-06-11 Complete Genomics, Inc. Efficient shotgun sequencing methods
US8592150B2 (en) 2007-12-05 2013-11-26 Complete Genomics, Inc. Methods and compositions for long fragment read sequencing
CN104651381A (zh) 2008-01-03 2015-05-27 巴斯夫酶有限责任公司 转移酶和氧化还原酶、编码它们的核酸以及其制备和应用方法
WO2009094583A1 (en) * 2008-01-23 2009-07-30 Complete Genomics, Inc. Methods and compositions for preventing bias in amplification and sequencing reactions
WO2009097368A2 (en) 2008-01-28 2009-08-06 Complete Genomics, Inc. Methods and compositions for efficient base calling in sequencing reactions
CN102037351A (zh) 2008-04-03 2011-04-27 加利福尼亚大学董事会 分离并离析细胞、囊泡、纳米颗粒和生物标记的离体多维系统
US20090255801A1 (en) * 2008-04-11 2009-10-15 Haas Alfred M Programmable Electrode Arrays and Methods for Manipulating and Sensing Cells and Substances Using Same
US20090270273A1 (en) * 2008-04-21 2009-10-29 Complete Genomics, Inc. Array structures for nucleic acid detection
WO2009137369A1 (en) * 2008-05-03 2009-11-12 Tufts Medical Center, Inc. Neonatal salivary genomics
US8039817B2 (en) 2008-05-05 2011-10-18 Illumina, Inc. Compensator for multiple surface imaging
USD618820S1 (en) 2008-07-11 2010-06-29 Handylab, Inc. Reagent holder
USD787087S1 (en) 2008-07-14 2017-05-16 Handylab, Inc. Housing
US8153391B2 (en) 2008-08-29 2012-04-10 Bunge Oils, Inc. Hydrolases, nucleic acids encoding them and methods for making and using them
US8357503B2 (en) 2008-08-29 2013-01-22 Bunge Oils, Inc. Hydrolases, nucleic acids encoding them and methods for making and using them
US8198062B2 (en) 2008-08-29 2012-06-12 Dsm Ip Assets B.V. Hydrolases, nucleic acids encoding them and methods for making and using them
USD838288S1 (en) * 2009-02-24 2019-01-15 Tixtrack, Inc. Display screen or portion of a display screen with a computer generated venue map and a pop-up window appearing in response to an electronic pointer
ES2661310T3 (es) * 2009-03-09 2018-03-28 Bioatla, Llc Proteínas mirac
WO2010114928A2 (en) * 2009-04-03 2010-10-07 F.Hoffmann-La Roche Ag Compositions and uses thereof
MX355638B (es) 2009-05-21 2018-03-26 Verenium Corp Fitasas, ácidos nucléicos que las codifican, y métodos de hacerlas y usarlas.
US9524369B2 (en) 2009-06-15 2016-12-20 Complete Genomics, Inc. Processing and analysis of complex nucleic acid sequence data
US8329724B2 (en) 2009-08-03 2012-12-11 Hoffmann-La Roche Inc. Process for the manufacture of pharmaceutically active compounds
CN102630250A (zh) 2009-09-25 2012-08-08 基因诊断测试公司 用于检测与癌症和其他疾病相关的染色体异常的多重(+/-)链阵列和测试
UA111708C2 (uk) 2009-10-16 2016-06-10 Бандж Ойлз, Інк. Спосіб рафінування олії
UA109884C2 (uk) 2009-10-16 2015-10-26 Поліпептид, що має активність ферменту фосфатидилінозитол-специфічної фосфоліпази с, нуклеїнова кислота, що його кодує, та спосіб його виробництва і застосування
US20120277112A1 (en) 2009-10-19 2012-11-01 Stichting Het Nederlands Kanker Instituut Predicting response to anti-cancer therapy via array comparative genomic hybridization
WO2011048495A1 (en) 2009-10-19 2011-04-28 Stichting Het Nederlands Kanker Instituut Predicting benefit of anti-cancer therapy via array comparative genomic hybridization
WO2011048498A2 (en) 2009-10-19 2011-04-28 Stichting Het Nederlands Kanker Instituut Differentiation between brca2-associated tumours and sporadic tumours via array comparative genomic hybridization
NZ629615A (en) 2009-11-06 2016-01-29 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor
US8974651B2 (en) 2010-04-17 2015-03-10 C.C. Imex Illuminator for visualization of fluorophores
US20140018251A1 (en) 2010-09-20 2014-01-16 Stichting Het Nederlands Kanker Instituut Methods for Predicting Response to Anti-Cancer Therapy in Cancer Patients
WO2012051055A2 (en) 2010-10-06 2012-04-19 Bp Corporation North America Inc. Variant cbh i polypeptides
EP2661485A4 (en) 2011-01-06 2018-11-21 Meso Scale Technologies, LLC Assay cartridges and methods of using the same
JP5941069B2 (ja) 2011-02-07 2016-06-29 プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． キナーゼ調節のための化合物および方法、ならびにそれに対する適応症
AR085279A1 (es) 2011-02-21 2013-09-18 Plexxikon Inc Formas solidas de {3-[5-(4-cloro-fenil)-1h-pirrolo[2,3-b]piridina-3-carbonil]-2,4-difluor-fenil}-amida del acido propano-1-sulfonico
CN106190806B (zh) 2011-04-15 2018-11-06 贝克顿·迪金森公司 扫描实时微流体热循环仪和用于同步的热循环和扫描光学检测的方法
RU2631487C2 (ru) 2011-05-17 2017-09-22 Плексксикон Инк. Модуляция киназ и показания к её применению
KR102121853B1 (ko) 2011-09-30 2020-06-12 벡톤 디킨슨 앤드 컴퍼니 일체화된 시약 스트립
USD692162S1 (en) 2011-09-30 2013-10-22 Becton, Dickinson And Company Single piece reagent holder
CN104040238B (zh) 2011-11-04 2017-06-27 汉迪拉布公司 多核苷酸样品制备装置
US8986523B2 (en) 2012-01-19 2015-03-24 International Business Machines Corporation Biosensor capacitor
CN107881219B (zh) 2012-02-03 2021-09-10 贝克顿·迪金森公司 用于分子诊断测试分配和测试之间兼容性确定的外部文件
US8932815B2 (en) 2012-04-16 2015-01-13 Biological Dynamics, Inc. Nucleic acid sample preparation
WO2013158686A1 (en) 2012-04-16 2013-10-24 Biological Dynamics, Inc. Nucleic acid sample preparation
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
JP6430406B2 (ja) * 2013-02-07 2018-11-28 コーニンクレッカ フィリップス エヌ ヴェＫｏｎｉｎｋｌｉｊｋｅ Ｐｈｉｌｉｐｓ Ｎ．Ｖ． ヌクレオチド配列の処理
US9267171B2 (en) 2013-02-28 2016-02-23 New York University DNA photolithography with cinnamate crosslinkers
US9069358B2 (en) 2013-06-24 2015-06-30 Biolytic Lab Performance, Inc. System for controlling and optimizing reactions in solid phase synthesis of small molecules
US9352315B2 (en) 2013-09-27 2016-05-31 Taiwan Semiconductor Manufacturing Company, Ltd. Method to produce chemical pattern in micro-fluidic structure
US20150273231A1 (en) * 2014-03-31 2015-10-01 Electronics And Telecommunications Research Institute Plasma system
US9835587B2 (en) 2014-04-01 2017-12-05 C.C. Imex Electrophoresis running tank assembly
JP2017512483A (ja) 2014-04-08 2017-05-25 バイオロジカル ダイナミクス，インク． 生体物質の単離のための改良された装置
ES2913205T3 (es) 2014-05-13 2022-06-01 Bioatla Inc Proteínas biológicas activas condicionalmente
AU2015308818B2 (en) 2014-08-28 2021-02-25 Bioatla Llc Conditionally active chimeric antigen receptors for modified T-cells
US11111288B2 (en) 2014-08-28 2021-09-07 Bioatla, Inc. Conditionally active chimeric antigen receptors for modified t-cells
JP2017532019A (ja) 2014-09-03 2017-11-02 バイオアトラ、エルエルシー 同じ真核細胞産生宿主における条件的活性型生物学的タンパク質の発見及び作製
CA3225013A1 (en) 2015-02-24 2016-09-01 Bioatla, Llc Conditionally active proteins
US9708647B2 (en) 2015-03-23 2017-07-18 Insilixa, Inc. Multiplexed analysis of nucleic acid hybridization thermodynamics using integrated arrays
US10160755B2 (en) 2015-04-08 2018-12-25 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10829484B2 (en) 2015-07-28 2020-11-10 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9499861B1 (en) 2015-09-10 2016-11-22 Insilixa, Inc. Methods and systems for multiplex quantitative nucleic acid amplification
RU2018123825A (ru) 2015-12-07 2020-01-15 Плексксикон Инк. Соединения и способы для модуляции киназ, и показания для этого
WO2017100454A1 (en) 2015-12-09 2017-06-15 Intuitive Biosciences, Inc. Automated silver enhancement system
WO2017155858A1 (en) 2016-03-07 2017-09-14 Insilixa, Inc. Nucleic acid sequence identification using solid-phase cyclic single base extension
AU2017237187B2 (en) 2016-03-24 2022-12-08 Biological Dynamics, Inc. Disposable fluidic cartridge and components
IL308504A (en) 2016-05-13 2024-01-01 Bioatla Llc Antibodies, Antibody Fragments and Their Immunomodules Against ROR2 and Their Uses
US9976902B1 (en) 2016-05-25 2018-05-22 J.A. Woolam Co., Inc. Method to analyze spectroscopic ellipsometry data of porous samples utilizing the anisotropic Bruggeman-effective medium theory
TW201815766A (zh) 2016-09-22 2018-05-01 美商普雷辛肯公司 用於ｉｄｏ及ｔｄｏ調節之化合物及方法以及其適應症
WO2018136202A2 (en) 2016-12-23 2018-07-26 Plexxikon Inc. Compounds and methods for cdk8 modulation and indications therefor
US10818379B2 (en) 2017-05-08 2020-10-27 Biological Dynamics, Inc. Methods and systems for analyte information processing
US10428067B2 (en) 2017-06-07 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation
EP3727693A4 (en) 2017-12-19 2021-08-25 Biological Dynamics, Inc. METHODS AND DEVICES FOR DETECTION OF MULTIPLE ANALYTES FROM A BIOLOGICAL SAMPLE
CN109945776B (zh) * 2019-02-01 2021-05-25 天津大学 一种电化学中基于荧光颗粒标记与主动光学测量的位移/应变测量方法
CN113924041A (zh) 2019-03-14 2022-01-11 因斯利克萨公司 基于时间门控的荧光检测的方法和系统
JP2022552194A (ja) 2019-10-10 2022-12-15 １８５９，インク． マイクロ流体スクリーニングのための方法およびシステム

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5036087A (zh) * 1973-07-13 1975-04-04
US3995190A (en) * 1974-09-19 1976-11-30 Butler, Binion, Rice, Cook & Knapp Mobile ion film memory
US4283773A (en) * 1977-08-30 1981-08-11 Xerox Corporation Programmable master controller communicating with plural controllers
FI63596C (fi) * 1981-10-16 1983-07-11 Orion Yhtymae Oy Mikrobdiagnostiskt foerfarande som grundar sig pao skiktshybridisering av nukleinsyror och vid foerfarandet anvaenda kombinationer av reagenser
US4580895A (en) * 1983-10-28 1986-04-08 Dynatech Laboratories, Incorporated Sample-scanning photometer
EP0143623A3 (en) * 1983-11-25 1987-09-23 Mars Incorporated Automatic test equipment
FI71768C (fi) * 1984-02-17 1987-02-09 Orion Yhtymae Oy Foerbaettrade nykleinsyrareagenser och foerfarande foer deras framstaellning.
US5118605A (en) * 1984-10-16 1992-06-02 Chiron Corporation Polynucleotide determination with selectable cleavage sites
US4584075A (en) * 1984-11-26 1986-04-22 Ionics Incorporated Process and apparatus for electrically desorbing components selectively sorbed on an electrolytically conducting barrier
GB8432118D0 (en) * 1984-12-19 1985-01-30 Malcolm A D B Sandwich hybridisation technique
US4594135A (en) * 1985-02-20 1986-06-10 Ionics Incorporated Process and apparatus for electrically desorbing components selectively sorbed on granules
US5096807A (en) * 1985-03-06 1992-03-17 Murex Corporation Imaging immunoassay detection system with background compensation and its use
US4751177A (en) * 1985-06-13 1988-06-14 Amgen Methods and kits for performing nucleic acid hybridization assays
US4816418A (en) * 1985-07-22 1989-03-28 Sequoia-Turner Corporation Method and apparatus for performing automated, multi-sequential immunoassays
EP0213825A3 (en) * 1985-08-22 1989-04-26 Molecular Devices Corporation Multiple chemically modulated capacitance
US4822566A (en) 1985-11-19 1989-04-18 The Johns Hopkins University Optimized capacitive sensor for chemical analysis and measurement
EP0228075B1 (en) * 1986-01-03 1991-04-03 Molecular Diagnostics, Inc. Eucaryotic genomic dna dot-blot hybridization method
US5125748A (en) * 1986-03-26 1992-06-30 Beckman Instruments, Inc. Optical detection module for use in an automated laboratory work station
YU57087A (en) * 1987-04-01 1990-08-31 Centar Za Genticko Inzenjerstv Process for obtaining genome by hebridization and oligonucleotidic tests
US5202231A (en) * 1987-04-01 1993-04-13 Drmanac Radoje T Method of sequencing of genomes by hybridization of oligonucleotide probes
US5114674A (en) 1987-05-01 1992-05-19 Biotronic Systems Corporation Added array of molecular chains for interfering with electrical fields
US4787963A (en) * 1987-05-04 1988-11-29 Syntro Corporation Method and means for annealing complementary nucleic acid molecules at an accelerated rate
JP2682859B2 (ja) 1987-07-27 1997-11-26 コモンウェルス サイエンティフィック アンド インダストリアル リサーチ オーガニゼーション レセプター膜
GB8810400D0 (en) * 1988-05-03 1988-06-08 Southern E Analysing polynucleotide sequences
US4908112A (en) * 1988-06-16 1990-03-13 E. I. Du Pont De Nemours & Co. Silicon semiconductor wafer for analyzing micronic biological samples
US5075077A (en) * 1988-08-02 1991-12-24 Abbott Laboratories Test card for performing assays
WO1990001564A1 (en) * 1988-08-09 1990-02-22 Microprobe Corporation Methods for multiple target analyses through nucleic acid hybridization
WO1990002327A1 (en) * 1988-08-18 1990-03-08 AUSTRALIAN MEMBRANE AND BIOTECHNOLOGY RESEARCH INSTITUTE LTD., Commonwealth Scientific and Industrial Research Organization Improvements in sensitivity and selectivity of ion channel membrane biosensors
US5096669A (en) * 1988-09-15 1992-03-17 I-Stat Corporation Disposable sensing device for real time fluid analysis
US5063081A (en) * 1988-11-14 1991-11-05 I-Stat Corporation Method of manufacturing a plurality of uniform microfabricated sensing devices having an immobilized ligand receptor
US5200051A (en) * 1988-11-14 1993-04-06 I-Stat Corporation Wholly microfabricated biosensors and process for the manufacture and use thereof
US5219726A (en) * 1989-06-02 1993-06-15 The Salk Institute For Biological Studies Physical mapping of complex genomes
US5143854A (en) * 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
US5126022A (en) * 1990-02-28 1992-06-30 Soane Tecnologies, Inc. Method and device for moving molecules by the application of a plurality of electrical fields
US5166063A (en) 1990-06-29 1992-11-24 Eli Lilly And Company Immobolization of biomolecules by enhanced electrophoretic precipitation
GB2247889A (en) * 1990-09-12 1992-03-18 Scient Generics Ltd DNA denaturation by an electric potential
WO1992004470A1 (en) 1990-09-12 1992-03-19 Scientific Generics Limited Electrochemical denaturation of double-stranded nucleic acid
US5227265A (en) * 1990-11-30 1993-07-13 Eastman Kodak Company Migration imaging system
US5605662A (en) * 1993-11-01 1997-02-25 Nanogen, Inc. Active programmable electronic devices for molecular biological analysis and diagnostics
US5846708A (en) * 1991-11-19 1998-12-08 Massachusetts Institiute Of Technology Optical and electrical methods and apparatus for molecule detection
JPH05236997A (ja) 1992-02-28 1993-09-17 Hitachi Ltd ポリヌクレオチド捕捉用チップ
US5304487A (en) * 1992-05-01 1994-04-19 Trustees Of The University Of Pennsylvania Fluid handling in mesoscale analytical devices
US5312527A (en) 1992-10-06 1994-05-17 Concordia University Voltammetric sequence-selective sensor for target polynucleotide sequences
CA2170264A1 (en) * 1993-09-10 1995-03-16 Michael W. Konrad Optical detection of position of oligonucleotides on large dna molecules

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100387990C (zh) * 2002-05-21 2008-05-14 索尼株式会社 生物测定方法、生物测定设备和生物测定衬底
CN103396933B (zh) * 2003-02-26 2016-04-20 凯利达基因组股份有限公司 通过杂交进行的随机阵列dna分析
CN103289893A (zh) * 2003-02-26 2013-09-11 凯利达基因组股份有限公司 通过杂交进行的随机阵列dna分析
CN103289893B (zh) * 2003-02-26 2015-11-18 凯利达基因组股份有限公司 通过杂交进行的随机阵列dna分析
US8840848B2 (en) 2010-07-23 2014-09-23 Beckman Coulter, Inc. System and method including analytical units
US8932541B2 (en) 2010-07-23 2015-01-13 Beckman Coulter, Inc. Pipettor including compliant coupling
US8956570B2 (en) 2010-07-23 2015-02-17 Beckman Coulter, Inc. System and method including analytical units
US8962308B2 (en) 2010-07-23 2015-02-24 Beckman Coulter, Inc. System and method including thermal cycler modules
US8996320B2 (en) 2010-07-23 2015-03-31 Beckman Coulter, Inc. System and method including analytical units
US9519000B2 (en) 2010-07-23 2016-12-13 Beckman Coulter, Inc. Reagent cartridge
US9285382B2 (en) 2010-07-23 2016-03-15 Beckman Coulter, Inc. Reaction vessel
US9046455B2 (en) 2010-07-23 2015-06-02 Beckman Coulter, Inc. System and method including multiple processing lanes executing processing protocols
US9140715B2 (en) 2010-07-23 2015-09-22 Beckman Coulter, Inc. System and method for controlling thermal cycler modules
US9274132B2 (en) 2010-07-23 2016-03-01 Beckman Coulter, Inc. Assay cartridge with reaction well
US8973736B2 (en) 2011-11-07 2015-03-10 Beckman Coulter, Inc. Magnetic damping for specimen transport system
US9046506B2 (en) 2011-11-07 2015-06-02 Beckman Coulter, Inc. Specimen container detection
US9446418B2 (en) 2011-11-07 2016-09-20 Beckman Coulter, Inc. Robotic arm
US9482684B2 (en) 2011-11-07 2016-11-01 Beckman Coulter, Inc. Centrifuge system and workflow
US9506943B2 (en) 2011-11-07 2016-11-29 Beckman Coulter, Inc. Aliquotter system and workflow
US9910054B2 (en) 2011-11-07 2018-03-06 Beckman Coulter, Inc. System and method for processing samples
US10048284B2 (en) 2011-11-07 2018-08-14 Beckman Coulter, Inc. Sample container cap with centrifugation status indicator device
US10274505B2 (en) 2011-11-07 2019-04-30 Beckman Coulter, Inc. Robotic arm
CN104569368A (zh) * 2013-10-11 2015-04-29 三星Sds株式会社 生物样本分析系统和方法
CN112654431A (zh) * 2018-04-02 2021-04-13 生物动力学公司 介电材料
CN110823835A (zh) * 2019-12-16 2020-02-21 长沙学院 一种波导耦合长程表面等离子共振传感器及其测量方法
CN110823835B (zh) * 2019-12-16 2022-02-25 长沙学院 一种波导耦合长程表面等离子共振传感器及其测量方法

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