CN1558207A - 可自我寻址自我组装的用于分子生物学分析和诊断的微电子系统及装置 - Google Patents

可自我寻址自我组装的用于分子生物学分析和诊断的微电子系统及装置 Download PDF

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CN1558207A
CN1558207A CNA2004100040679A CN200410004067A CN1558207A CN 1558207 A CN1558207 A CN 1558207A CN A2004100040679 A CNA2004100040679 A CN A2004100040679A CN 200410004067 A CN200410004067 A CN 200410004067A CN 1558207 A CN1558207 A CN 1558207A
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place
dna
conjunction
hybridization
binding entity
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Mj
M·J·赫勒
E·杜
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NANOGEN CO Ltd
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NANOGEN CO Ltd
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Abstract

本发明涉及一种用于电子控制含有对某个结合场所特异结合实体和非特异结合实体的溶液中带电结合实体的相互作用的方法。本发明还涉及一种用于电子控制含有对第1和第2结合场所特异结合和非特异结合DNA序列的溶液中DNA杂交的方法。本发明涉及一种用于电子控制含有对第1结合场所和随后第2特异结合场所特异和非特异DNA序列的溶液中DNA杂交的方法。其中，借助于对于上述场所的电势的调控，浓缩结合实体，例如DNA序列，并且保证在上述场所的结合实体，例如DNA序列，的特异性结合。

Description

可自我寻址自我组装的用于分子生物 学分析和诊断的微电子系统及装置
本申请是1994年10月26日递交的、申请号为94194759.9、发明名称与本申请相同的申请的分案申请。
发明领域
本发明有关一种能有效地进行和控制显微形式的多步和多路反应的可自我寻址，自我组装微电子系统的设计、制造和使用。特别地，这些反应包括分子生物学反应，例如核酸杂交、抗体/抗原反应、临床诊断，和生物高分子合成。
发明背景
分子生物学包括核酸和蛋白质分析的各种各样技术，这些大部分技术形成了临床诊断分析的基础。这些技术包括核酸杂交分析，限制性酶分析，基因序列分析，以及核酸和蛋白质的分离和纯化(参见，如J.Sambrook，E.F.Fritsch，和T.Maniatis，分子克隆，实验室手册，第2版，冷泉港实验室印刷，冷泉港，纽约 Molecular Cloning： A Laboratory Manual 2Ed.，Cold Spring Harbor laboratory Press， Cold Spring Harbor New York，1989)。
大多数分子生物学技术牵连到对大量样品进行无数的操作(例如，移液)。这些通常是复杂而耗时的，常需要高度的精确性。许多种技术因缺少灵敏度，特异性或重复性而限制其的应用。例如，因灵敏度和特异性的问题已极大地限制了核酸杂交的应用。
核酸杂交分析通常包括在大量非-目标核酸分子中用探针识别极微量的特异性目标核酸(DNA或RNA)。为了保证高特异性，杂交常在由温度、盐、洗涤剂、溶剂、离液剂和变性剂组合而获得的严格条件下进行。
复合的样品核酸杂交分析已在各种滤膜和固体支持物上进行(参见G.A.Beltz et al，酶学方法，Vol 100，Part B，R.Wu，L.Grossman，K.Moldave，Eds.，Academic Press，New York，19章，pp.266-308，1985)。一种形式，即所谓“斑点”杂交，包括非-共价连接目标DNA到一滤膜上，随后滤膜与放射性同位素标记的探针杂交。“斑点”杂交获得了广泛的使用，并发展了多个改进形式(参见M.L.M.Anderson和B.D.Young，核酸杂交-实用方法，B.D.Hames和S.J.Higgins，Eds.，IRL Press，WashingtonDC，第4章，pp.73-111，1985)。这种技术已经发展成能进行基因组突变的复合分析(D.Nanibhushan和D.Rabin，在EPA 0228075，July 8，1987)和检测重叠克隆以及构建基因组图谱(G.A.Evans，在USP # 5.219.726.June 15，1993)。
另一种形式，即所谓“夹心”杂交，包括共价连接寡聚核苷酸探针到一固体支持物上并用它们捕获和识别多核酸目标(M.Ranki etal.，Gene，21，pp.77-85，1983；A.M.Palva，T.M.Ranki，和H.E.Soderlund，在UKP Application GB 2156074A，Oct.2，1985，T.M.Ranki和H.E.Soderlund在USP # 4,563,419，January 7，1986；A.D.B.Malcolm和J.A.Langdale，in PCTWO 86/03782，July 3，1986；Y.Stabinsky，in USP # 4,751,177，January 14，1988；T.H.Adams et al.，in PCT WO 90/01564，Feb.22，1990 R.B.Wallace et al.，6 NucleicAcid Res 11，p.3543，1979；和B.J.Connor et al.，80Proc Natl Acad Sci USA pp.278-282，1983)。
应用通用的核酸杂交形式和严格性控制方法，对检测低拷贝数(例如1-100,000)核酸目标仍是困难的即使使用最灵敏的报告基团(酶，荧光团，放射性同位素)等和与其配套的检测系统(荧光计，发光计，光子计数器，闪烁计数器，等等)。
这个困难是由各种与直接探针杂交相关联的本身问题引起的。首先和最严重的困难涉及杂交反应的严格性控制。杂交反应通常在最严格的条件下进行以便获得最高程度的特异性。严格性控制的方法包括初始的在杂交过程以及随后的漂洗过程中应用最适温度、离子强度和变性剂。不幸的是应用这些严格性条件引起用于检测的杂交了的探针/目标复合物的数量显著下降。
第二种困难涉及在大多数样品中DNA的高度复杂性，特别在人类基因组DNA样品中。当一个样品由大量与特异目标序列非常相似的序列所组成时，既使最特异性的探针序列与非-目标序列也会有大量部分杂交。
第三种困难涉及在探针和它的特异目标间的不适合的杂交动力学因素。既使在最佳条件下，大部分杂交反应是在相当低浓度的探针和目标分子间进行的。此外，探针常不得不与互补链竞争目标核酸。
对于大部分现今的杂交形式的第四种困难是高水平的非-特异性背景信号。这是由DNA探针与几乎任何材料的亲和性引起的。
这些问题，或单个或几个组合，在上述杂交形式中导致丧失核酸杂交的灵敏度和/或特异性。这是不幸的因为对大多数基于核酸的临床诊断分析而言检测低拷贝数核酸目标是必须的。
由于识别低拷贝数核酸目标的困难，研究者们极大地依赖于聚合酶链式反应(PCR)来扩增目标核酸序列(参见M.A.Innis et al.，PCR程序：方法和应用的导论，Academic Press，1990)，由PCR反应产生的大量目标核酸序列改进了随后的直接核酸探针技术，虽然其代价是加长了步骤和增加了繁琐性。
在用直接探针识别低拷贝数目标核酸方面与通常出现的困难相反的一个明显例外是原位杂交技术。这个技术使得低拷贝数的独特核酸序列在单个细胞中被识别。在原位杂交形式中，目标核酸被自然地限制在一个细胞(～20-50μm2)或一个细胞核(～10μm2)区域内具有相对高的局部浓度。而且，探针/目标杂交信号被限制在形态上可区分的区域；这使得该形式杂交比在一个固体支持物上杂交更易区别阳性信号与虚假的或非-特异性的信号。
模仿原位杂交，为在显微-形式的多路或矩阵装置(如，DNA芯片)上进行复合样品核酸杂交分析一些新技术发展了起来(参见M.Barinage，253 Science，pp.1489，1991；W.Bains，10 Bio/Technology，pp，757-758，1992)。这些方法通常结合特异的DNA序列到固体支持物非常小的特殊区域上，例如DNA芯片的微井。这些杂交形式是传统的“斑点”和“夹心”杂交体系在显微范围内的改进。
显微-形式的杂交能用于进行“杂交测序”(SBH)(参见M.Barinaga，253 Science，pp.1489，1991；W.Bains，10 Bio/Technology，pp，757-758，1992)。 SBH应用所有可能的n-核苷酸寡聚体(n-mers)来鉴别在一未知DNA样品中的n-mers，随后通过规则系统分析线性排列产生DNA序列(R.Drmanac和R.Crkvenjakov，Yugoslav Patent Kpplication # 570/87，1987R.Drmanac et al.，4 Genomics，114，1989：Strezoska etal.，88 Proc.Natl.Acad.Sci，UAS 10089 1991；和R.DrmanacR.B.Crkvenjakov，USP # 5，202，231，April 13，1993)。
有两种形式可进行SBH。第一种形式包括在一个支持物上形成一个所有可能n-mers的列阵，然后用其与目标序列杂交。第二种形式包括结合目标序列到一个支持物上，随后用所有可能的n-mers来标记。两种形式都具有直接探针杂交的基本困难和涉及多路杂交的额外困难。
在UKP Application GB 8810400，1988；和B.Genomics1008，1992年中，Southern提出应用第一种形式来分析或测定DNA序列。Southern应用PCR扩增的基因组DNA鉴定了一个已知单点突变。Southern也描述了一种为进行SBH而在一个固体支持物上合成寡聚核苷酸列阵的方法。然而，Southern没有讲述如何获得列阵中每一个寡聚核苷酸的最适的严格性条件。
在364 Nature，pp.555-556，1993中，Fodor等人应用1,0248-mer的寡聚核苷酸列阵在一个固体支持物上测定了DNA序列。在这例中，目标DNA是仅含有核苷酸A和C并荧光标记的单链12-mer寡聚核苷酸。1pmol(～6×1011分子)的12-mer目标序列对与列阵上8-mer寡聚体杂交是必须的。该结果显示了多个错配合。象Southern一样，Fodor et al.，没有讲述直接探针杂交的基本困难，例如多路杂交的严格性控制。这些困难，与需要大量简单12-mer目标一起，表明这一SBH形式的严重局限性。
同时，在260 Science 1649-1652，1993中，Drmanac等人应用第二种形式为数种短(116bp)的DNA序列测序。目标DNA被结合到膜支持物上(“斑点”形式)。每一个滤膜顺序地与272个标记过的10-mer和11-mer寡聚核苷酸杂交。大范围的严格性条件被用来获得每一个n-mer探针的特异性杂交；漂洗时间从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℃漂洗3小时。滤膜必须曝光2到18小时以便识别杂交信号。尽管是简单目标序列，降低了寡聚体探针量，和使用现有的最严格条件，总的假阳性杂交率是5％。
在251 Science 767-773，1991中，Fodor等人应用照相平版印刷技术在一个基质上合成寡聚核苷酸。在USP # 5,143,854 Sept.1，1992中，Pirrung等人讲述了在硅基质上以列阵方式大范围照相平版印刷固相合成多肽。
另一种矩阵杂交方法，Beattie et al.，在1992年圣地亚哥会议：基因识别Nov.1992中，应用一种微机器人体系在一种玻璃基质上存放含有特异性DNA序列的微滴于单个微加工的样品并中。每个样品中杂交反应是由询问微型电极测定固定装置来识别，而该固定装置排在每个微井四周并带有交流(AC)电场。
不管那种形式，现今显微范围DNA杂交和SBH方法都没能克服与直接探针杂交反应联系着的本身物理困难。它们需要非常高水平的相对短的单链目标序列或PCR扩增的DNA，并产生高水平的虚假阳性杂交信号，既使是在最严格条件下。在应用短寡聚核苷酸序列的多路形式例子中，不可能用任何传统的方法获得对于每个序列最适的严格条件，因为用于这些形式的列阵或装置不能在单个场所相对于另一场所改变或调整温度、离子强度，或变性剂。因此，一个共同的严格条件必须用于所有装置上的序列。这导致了大量非-特异性和部分杂交并严重地限制了该装置的应用。这一困难随着列阵中不同序列数目的增多和序列长度的下降而更加复杂。这对于SBH是特别的困难，它需要大量短寡聚核苷酸探针。
不同大小，电荷或构象的核酸常规是通过电泳技术分离，电泳技术能通过电场中它们的不同迁移率来区别杂交核酸。脉冲场电泳使用在介质(如，凝胶)四周安排复合电极来分离那些由传统凝胶电泳系统不能解决的非常大的DNA片段(参见R.Anand和E.M.Southern核酸凝胶电泳-实用方法2nd.D.Rickwood和B.D.Hames Eds.IRL Press，New York，pp.101-122，1990)。
在USP # 4,908,112，March 13，1990中，Pace讲述了使用微加工技术制造硅基质上的毛细管凝胶电泳系统。复合电极被用于该系统中用来在装置中移动分子通过分离介质。
在USP 5,126,022 June 30，1992中，Soane和Soane讲述了大量电极能被用来控制混合物中带电分子通过细管中凝胶分离介质的线性移动。电极必须被安装在细管中以便控制分子在分离介质中的移动和定位。
在26 IEEE在工业应用中的反作用6，pp，1165-1172，1990中，Washizu，M.和Kurosawa O.，应用高频交流(AC)电场来使DNA分子定向在微加工电极间产生的电场线上，然而，使用直流(DC)电场限制了他们的工作。在静电杂志25卷109-123页，1990中，Washizu描述了应用介电电泳来操作细胞和生物分子。细胞能融合以及生物分子能沿着由微电极结构闻AC电压产生的电场线定向。然而，介电电泳过程需要非常高频(1MHz)AC电压和一种低电导率介质。虽然这些技术能沿着AC电场线使不同大小的DNA分子定向，但它们不能区别相同大小的杂交复合物。
从上述讨论中已很明显，花费了极大的努力来提供有效的技术以实施多步，多路分子生物学反应。然而，正如上述的种种原因，这些技术已被证明是欠缺的。尽管对有效技术有长期熟知的需求，但满意的方案还没有被提出来。
本发明的摘要
本发明涉及设计、制造，和使用一种可自我寻址自我组装的微电子系统和装置，它能有效地进行显微形式的被控制的多步和多路反应。这些反应包括，但不局限于，大多数分子生物学过程，例如核酸杂交，抗体/抗原反应，和有关的临床诊断学。此外，权利要求的装置能进行多步组合的生物高分子合成，包括，但不局限于，在特定微场所合成不同的寡聚核苷酸或多肽。
权利要求的装置是应用微平版印刷和微机械技术制造的。装置在其表面具有一个可寻址的微场所的矩阵；每单个微场所能够电子地控制和引导特异性结合实体(例如，核酸，抗体)的转移和结合于其自身。所有微场所能被它们特异的结合实体寻址。应用这一装置，在最小外界干预下这系统能被自我组装。
这装置能控制和有效地进行各种测定和反应。分析物或反应物通过自由场电泳被转移到任何特定的微场所上，在这儿分析物或反应物有效地浓缩并在所说的微场所与特异的结合实体反应。检测特异分析物或反应物的灵敏度因浓缩效应而提高了。任何未结合的分析物或反应物能通过反向微场所的极性而被移走。这样，装置也提高了测定和反应的特异性。
装置为特定微场所上的杂交反应提供独立的严格性控制。这样矩阵上所有的微场所在同一时间里能有不同的严格性条件，允许复合杂交在最适条件下进行。
通过使用辅助的光学(荧光或紫外分光光度计)成像识别系统或集成的传感元件，装置也促进在每个微场所上检测杂交复合物。
此外，装置积极的特性允许复杂的多步反应在最少外部物理操作下进行。如需要的话，被特异结合实体寻址的主装置能被电子地复制或拷贝成另一个基础装置。
这样，权利要求的装置能用完全的和精确的电子控制，最好使用微处理机，进行多步和多路反应。多步和多路反应的速率，特异性和灵敏度在权利要求的装置的特定微场所上极大地提高。
本发明克服了在本说明书背景中描述的多样品杂交的列阵和装置具有的限制性。以前的方法和装置相对于实际的杂交过程功能上是被动的。虽然复杂的照相平版印刷技术被用于制造列阵，或微电子传感元件被组装进用于检测，但以前的装置不控制或影响实际杂交过程。它们不被设计成能主动地克服任何与杂交反应联系着的固有物理困难。
本发明可应用符合于本发明目标的任何大小或形状的微场所。在本发明优选的实施方案中，亚-毫米级的微场所被选用。
“特异的结合实体”一词通常表示一种能通过共价键或非-共价键与其它分子特异性亲和结合的生物或合成的分子。优选地，一种特异结合实体含有(或自然地或通过化学修饰)一种功能的化学基团(伯胺、巯基、醛基，等等)，一种共同序列(核酸)，一种抗原表位(抗体)，半抗原或一种配体，这些成份允许结合实体共价反应或非-共价结合到微场所表面的共同功能基团上。特异结合实体包括，但不局限于：脱氧核糖核酸(DNA)、核糖核酸(RNA)，合成的寡聚核苷酸、抗体、蛋白质、肽、凝集素、修饰的多糖，合成的复合大分子，具功能的纳米结构，合成高分子，修饰/封闭的核苷酸/核苷，修饰/封闭的氨基酸、荧光团、生色团、配体、螯合物和半抗原。
“严格性控制”一词表示区别特异和非-特异结合相互作用的能力。
因此，首先，本发明特征地描述一种带有可电子地自我寻址微场所列阵的装置。每个微场所包含由基质支撑着的基础直流(DC)微电极。每个微场所表面有一种用于小的相反离子自由经过的渗透层，和一种用于共价结合特异结合实体的粘附层。
“列阵”或“矩阵”是表示装置上场所的一种排列。场所能排列成二维列阵、三维列阵、或其它矩阵形式。场所的数量可从几个到至少数十万个。
在第二方面，本发明特征地描述一种用于转移结合实体到装置的任何微场所上的方法。当被活化时，一个微场所能影响任何带电具功能的特异结合实体自由场电泳转移直接到它本身上。一旦结合到特定微场所上，这具功能的特异结合实体立即变成共价地结合到那个特定微场所表面的粘附层上。其它微场所能通过保持它们在与带电分子相反电势上而同时被保护。这一过程能迅速地重复直至所有微场所被它们特异结合实体寻址。
“带电具功能的特异结合实体”一词表示一种被化学地活化(即，能够共价地结合到场所上)和带有一个净电荷(或正电或负电)的特异结合实体。
在第三方面，本发明特征地描述一种在装置的任何特定微场所上浓缩和反应分析物或反应物的方法。在特异结合实体结合到粘附层以后，每个微场所的基础微电极继续以直流(DC)方式起作用。这种独特的特性允许那些自由存在溶液中的相对稀的带电分析物或反应分子以连续的或平行的方式在任何保持与分析或反应分子相反电荷的特定微场所上被快速地转移、浓缩、和反应。特定的微场所能被保护或掩盖起来，通过保持它们在与分析或反应分子相同电荷情况下。这种在选择的微场所上浓缩稀的分析或反应分子的能力在这些微场所上极大地加速反应速率。
当所需的反应完成后，微电极的电势能被反转以便从这些微场所上移去非-特异性分析物或未反应的分子。
特异的分析物或反应产物可以从任何微场所上释放出并转移到其它场所上进一步分析：或贮存在其它可寻址的场所上；或从本系统中完全移走。
在这特异微场所上分析物随后的分析也通过这种从这些场所上排斥非-特异性实体的能力极大地被改进。
在第四方面，本发明特征地描述了一种增进核酸杂交反应的严格性控制的方法，包括下列步骤：
—在进行杂交的特定微场所上快速地浓缩稀的目标DNA和/或探针DNA序列；
—从已发生杂交的特定微场所上快速地移走非-特异地结合的目标DNA序列；
—从已发生杂交的特定微场所上快速地移走竞争的互补目标DNA序列；
—提高电势以便移走部分杂交的DNA序列(多于一个碱基错配)；
—调节电势以便增进单个错配杂交的分辨能力(例如，识别点突变)；
—应用独立的电势控制到在同一批溶液中发生的单个杂交反应上；和
—使用电势控制以便增进未-扩增目标DNA序列杂交到捕获寡聚核苷酸探针的列阵上。
在第五方面，本发明特征地描述一种在微场所上合成生物高分子的方法。
在第六方面，本发明特征地描述一种复制主装置的方法。
在第七方面，本发明特征地描述数种方法用于应用自我寻址的带配套的光学，光电子或电子检测系统的微电子学装置或自我寻址的带一体化的光学、光电子或电子检测系统的微电子学装置检测和分析已在已寻址的微场所上发生的反应。
图的简要描述
图1是应用微平版印刷技术制造的三个可自我寻址的微场所的横截面。
图2是一个微平版印刷地制造的微场所的横截面。
图3是一个可自我寻址的64微场所芯片的图解代表，该芯片是实际被制造，由寡聚核苷酸寻址的，和经测试的。
图4表明特定结合化学过程，该过程允许快速共价结合特异性寡聚核苷酸到一个微场所的粘附表层。
图5是一幅微机械加工的96微场所装置的放大图解图。
图6是微机械加工的装置的横截面。
图7是表明装置用来在特定微场所电子地浓缩分析物或反应分子的原理。
图8表明用三个特异寡聚核苷酸结合实体(SSO-A，SSO-B，和SSO-C)来自我引导组装一个装置。
图9表明一种用在含有特异DNA捕获序列微场所上浓缩的样品/目标DNA进行的电子控制的杂交过程。
图10表明一种电子引导的系列杂交过程。
图11表明为确定单点突变的电子严格性控制(ESC)的杂交过程。
图12表明一种不使用标记的DNA探针而检测杂交的DNA的方案，即，电子控制的染料识别过程。
图13表明一种电子控制复制装置的方案。
图14表明一种电子引导组合性合成寡聚核苷酸的方案。
本发明的详细描述
本发明的装置和有关的方法允许一些重要的分子生物学和诊断反应能在完全电子控制下进行。本发明的基本思想是一种带有特殊设计的可寻址的微场所的微电子装置。每个微场所具有能共价结合特异结合实体的衍生表面层(即，粘附层)，一种渗透层，和一种基础的直流(DC)微电极。在基本的微电子结构初期制造后，装置能够自我引导用特异结合实体来寻址每个特定的微场所。自我寻址的装置随后能在它的任何微场所上主动地进行多步，组合的和多路反应。装置能够电子地引导和控制快速移动和浓缩分析物和反应物到或离开任何它的微场所。装置电子地控制各种反应动力学方面的能力提供了多个新的和重要的优越性和改进。
本发明的思想和实施方案分三部分描述。第一部分，“基本装置的设计和制造”描述基本基础的微电子学装置的设计和应用微平版印刷和微加工技术制造该装置。第二部分，“该装置自我引导的寻址”描述装置的自我寻址和自我装配，特别是快速转移和结合特异结合实体到每个微场所上。第三部分“装置的应用”描述装置如何提供各种多步，组合的，和多路反应的电子控制。这部分也描述装置的各种使用和应用。
(1)基本装置的设计和制造
为了使装置能进行多步和多路反应，它的主要电子元件在水溶液中必须能保持活性操作状态。为满足这一需求，每个微场所必须具有一个基础的功能DC方式微电极。其它为设计和制造装置的考虑包括，但不局限于，材料的相容性，特异结合实体的特性和随后反应物和分析物的特性，和微场所的数置。
“一种功能的D C方式微电极”是表示一种微电极偏压或是正电或是负电，并以直流电方式(或是连续的或是脉冲的)运行。它能影响或引起带电的特异结合实体反应物或分析物自由场电泳式移动到或离开装置上任何场所，或在样品溶液中。
在本发明范围内，分子的自由场电泳式移动不取决于由绝缘材料为界或限制的所产生的电场。
一个装置可被设计成仅含有二个可寻址微场所或含有数十万个微场所。一般来说，一种带有大量微场所的复杂装置是应用微平版印刷技术制造的。制造是在硅或其它合适基质材料例如玻璃、二氧化硅、塑料或陶瓷材料上进行的。这些微电子“芯片”的设计能被认为是大范围列阵或多路分析装置。一种带有少量微场所的装置能应用微加工技术而制造。
可寻址微场所可为任何形状，优选地园形、方形、或长方形。一个可寻址微场所的大小可为任何大小，优选地从亚-微米(～0.5μm)到几厘米(cm)的范围，5μm到100μm是使用微平版印刷技术制造的装置的最优选的大小范围，而100μm到5毫米是使用微加工技术制造的装置最优选的大小范围。制造小于微平版印刷方法分辨力的微场所将需要诸如电子束平版印刷、离子束平版印刷，或分子束外延技术。显微场所是分析和诊断类型应用所必须的，同时，较大的可寻址场所(例如，大于2mm)是制备范围生物高分子合成所必须的。
在通过使用微平版印刷和/或微加工技术微场所制造后，化学技术被用来构建特殊的粘附和渗透层，它们能允许在微场所下面的DC方式微电极：(1)影响或引起特异(带电)的结合实体从任何场所的自由场电泳式移动；(2)浓缩和共价结合特异结合实体到特定的微场所的经特别修饰过的表面上；和(3)在结合特异结合实体以后继续以DC方式主动地发挥功能以便其它反应物和分析物能被转移到或离开微场所。
设计参数(微平版印刷)
图1表明使用微平版印刷技术制造的一种自我寻址的微场所的基本设计。三个微场所(10)(ML-1，ML-2，ML-3)在沉积在绝缘层/基础材料的金属位点形成(12)的表层上。该金属位点(12)作为基础微电极结构(10)。一种绝缘材料把金属位点(12)之间相互隔离开。绝缘材料包括，但不局限于，二氧化硅、玻璃、防染剂、橡胶、塑料、或陶瓷材料。
图2表明形成在微平版印刷制造的金属位点(12)之上一个独立的微场所(10)的基本特征。该可寻址的微场所是在金属位点(12)之上形成，并包含一个氧化层(20)，一个渗透层(22)，一个粘附层(24)，和一个结合实体层(26)。金属氧化层提供共价结合渗透层的基础。渗透层提供了位于金属表面和粘附/结合实体层之间的空间并允许溶剂分子，小相反离子，和气体自由地进入或离开金属表面。微平版印刷技术制造的装置渗透层的厚度可从大约1纳米(nm)到10微米(μm)范围，从2nm到1μm是最优选的。粘附层提供了共价结合结合实体的基础。微平版印刷技术制造的装置粘附层的厚度能从0.5nm到1μm的范围，1nm到200nm是最优选的。在一些情况下，渗透层和粘附层能从相同材料形成。特异结合实体共价结合到粘附层上，形成特异结合实体层。特异结合实体层通常是单层的特异结合分子。然而，在一些情况下结合实体层能有几层或甚至多层结合分子。
渗透和粘附层的一定设计和功能方面是通过特异结合实体分子的物理(例如，大小和形状)和化学特性支配的，它们也在一定程度上被随后转移和结合到微场所上的反应和分析分子的物理和化学特性所支配。例如，寡聚核苷酸结合实体能被结合到一种类型的微场所表面上而不引起DC方式功能的丧失，即，基础的微电极仍能引起其它分析分子的快速自由场电泳式转移到或离开寡聚核苷酸结合实体结合着的表面。然而，如果大球形蛋白质结合实体(如，抗体)结合到相同类型的表面，它们可有效地绝缘这表面而引起DC方式功能的降低或完全丧失。粘附层合适的修饰将不得不进行以便或降低大结合实体(例如，大球形蛋白)的数目或在表面结合实体间提供空间。
微场所闻空间的决定是由制造的难易，微场所闻检测分辨力的要求，和装置上需要的微场所数量。然而，微场所闻特点空间，或微场所的特别安排或地形对于装置的功能不是必须的，其中微场所(即，基础微电极)的任何组合能在装置所有区域内操作。这既不必包装装置也不必用绝缘边界限制微场所。这是因为复杂的电场形式或绝缘边界对在任何电极间的空间或介质内选择地移动、分离、停留或定向特异的分子是不需要的。装置通过结合特异结合分子和随后的分析物和反应物到可寻址微场所的表面来完成这些。自由场电泳式推进力提供了在装置上任何和所有场所闻快速和直接转移任何带电分子。
随着微场所的数目增加超过数百，微场所间的基础电路的复杂性增加了。在这种情况下微场所的分组形式不得不改变并有比例地增加空间距离，或多层电路能被制造入基本装置中。
除了已被特异结合实体寻址的微场所以外，一个装置将包含一些未-被寻址的，或简易的微场所它们起其它的功能。这些微场所能被用于贮存试剂，暂时地保留反应物或分析物和为多余反应物、分析物或样品中其它干扰成份，作为处理单元。其它未被寻址的微场所能用于与已寻址的微场所一起去影响或干扰在这些特定微场所上发生的反应。这些微场所增加了装置内活性和控制。这也是可能的即微场所在两个分离的装置间相互作用和转移分子。这提供一种机理即把从一个贮存装置上的结合实体或反应物加样到一个工作装置上，和拷贝或复制一个装置。
图3显示一个含有64可寻址微场所(30)的矩阵型装置。64微场所的装置是一种方便的设计，它适合标准微电子芯片包装元件。这种装置是在约1.5cm×1.5cm的硅芯片基质上制造，带有大约750μm×750μm含有64个微场所的中心区域。每个微场所(32)大约50μm见方并与相邻微场所向相距50μm。连接每个单独基础微电极的电路沿着金属接触垫(300μm见方)的外周(10mm×10mm)走线(34)。在带有微场所的区域和接触垫之间形成抬高的内周，产生一个能装下大约2到10微升(μl)样品溶液的腔。该“芯片”能被放置在一个标准铅块包装中，并且芯片的接触垫(34)与铅块包装的管脚用线相连。包装了的芯片能随后插入到一个微处理机上控制DC电源输出和插入到能控制和操纵装置的万用表仪器上。
制造过程(微平版印刷)
微平版印刷制造步骤
通常微平版印刷或照相平版印刷技术可用于制造具有大量小微场所的复杂“芯片”类型的装置。虽然装置的制造不需要复杂的照相平版印刷，但材料的选择和电子装置能在水溶液中主动地起作用的条件必须需要特别的考虑。
图3所示的64微场所装置能使用相对简单的蒙片设计和标准的微平版印刷技术来制造。一般地，基底的基质材料可以是1到2厘米见方的硅晶片或大约0.5毫米厚的芯片。硅芯片第1步复盖一层1到2微米厚二氧化硅(SiO2)绝缘层，它可用等离子体增强的化学蒸气沉积(PECVD)而形成。
在下步，通过真空蒸发而沉积一层0.2到0.5微米金属层(例如，铝)。除铝以外，用于电路的合适金属包括金、银、锡、铜、铂、钯、碳和各种合金。为了保证极好地粘附到绝缘材料(SiO2)上一些特殊的技术被用于各种不同的金属。
下步该芯片复盖一层正电的光致抗蚀剂(Shipley，MicropositA2 1350 J)，用线路模型蒙片(光场)，曝光和冲洗。光溶的抗蚀剂被冲走，并且暴露的铝被蚀刻。抗蚀剂的小岛现在被移走，留下铝线路模型在芯片上。这包括一个外周的金属接触垫，相连的线路(电线)和作为可寻址微场所基础的中心列阵的微电极。
使用PECVD，芯片被先复盖1层0.2到0.4微米SiO层，然后是0.1到0.2微米氮化硅(Si3N4)层。芯片随后复盖正电的光致抗蚀剂，为接触垫和微电极场所蒙片，曝光，并冲洗。光溶的抗蚀剂被移走，SiO2和Si3N4层被蚀刻以便暴露铝接触垫和微电极。周围的岛式抗蚀剂然后被移走，在接触垫和微电极间的连接线由SiO2和Si3N4层保持相互绝缘。
SiO2和Si3N4层为装置的功能提供了重要的特性。首先，第二个SiO2层具有更好地接触并增进了铝线路的密封性。也可能应用抗蚀剂材料绝缘和密封。这个防止当微电极工作时由电解影响导致的线路逐渐损害。最终的Si3N4表层复盖的应用是因为该层与随后的用于修饰供粘附特异结合实体的微电极表面的试剂具有极低的反应性。
渗透和粘附层形成步骤
在这时装置上的微电极场所已准备好用特殊的渗透和粘附层来修饰。这代表了本发明的最重要部分，并且是本装置主动功能化的核心。目标是在微电极上构建一个带有选择扩散特性的中间渗透层和一个带有最佳结合特性的粘附表层。粘附层必须具有从每平方微米(μm2)105到107功能化的场所用于最佳结合特异结合实体。然而，结合特异的结合实体不应复盖表面或使表面绝缘而阻止下面的微电极起作用。一个具功能的装置需要实际金属微电极表面的部分区域(～5％到25％)保持与溶剂(H2O)分子接触，并允许相反离子(例如，Na+和Cl-)和电解气体(例如，O2和H2)的扩散发生。
中间的渗透层也必须允许扩散的发生。此外，渗透层必须具有一种孔限特性它限制或阻止较大结合实体，反应物，和分析物与微电极表面的物理接触。这渗透层保持活性的微电极表面物理地与微场所的结合实体层一定距离。
就原始装置功能而言，本设计允许电泳式转移所需的电解反应在微电极表面发生，但避免了对结合实体，反应物，和分析物的不利电化学影响。
衍生金属微电极表面的一种优选的步骤是应用氨基丙基三乙氧基硅烷(APS)。APS容易与金属和硅表面的氧化物和/或羟基团起反应。APS提供一种组合的渗透层和粘附层，并带有伯胺基团用于随后共价结合结合实体。就表面结合位点而言，APS在略氧化的铝表面产生一个相对高水平的功能化激活(即，大量伯胺基团)在SiO2表面产生一个中等水平的功能化激活，和产生非常有限的功能化激活的Si3N4表面。
APS反应的进行是通过用溶于甲苯的10％APS溶液在50℃处理整个装置(即，芯片)表面30分钟。芯片然后在甲苯，乙醇中冲洗，然后在50℃干燥1小时。微电极金属表面即被大量伯胺基团(105到106每平方微米)所功能活化。现在结合实体能被共价地结合到衍生的微电极表面。
APS步骤对结合寡聚核苷酸结合实体工作很好。图4表明结合3′-末端醛基衍生的寡聚核苷酸(40)到一个APS功能化激活的表面(42)的机制。虽然这代表了优选的方法的一个方面，多个类型结合实体共价的和非-共价的结合各种各样的其它结合反应是可能的。
设计和制造(微加工)
这部分描述如何使用微加工技术(例如，钻孔，铣削，等)或非一平版印刷技术来制造装置。通常，这些装置比那些由微平版印刷技术生产的装置具有相对较大的微场所(＞100微米)。这些装置能用于分析应用，以及制备类型的应用，例如生物高分子合成。大的可寻址场所能以三维方式制造(例如，管状或园筒状)以便携带大量结合实体。这种装置可应用各种材料制造，包括，但不局限于，塑料、橡胶、硅、玻璃(例如，微槽的，毛细管，等等)，或陶瓷。在微加工装置的情况下，连续的线路和较大的电极结构能应用对那些本领域的技术人员熟知的标准线路板印刷技术被印刷在材料上。
可寻址的微场所装置应用微加工技术能相对简单地被制造。图5一个代表性96微场所装置的图解。这种微场所装置是从一个适合的材料坯(2cm×4cm×1cm)通过穿过材料钻96个等比例相隔的于(直径1mm)而制造的。一个电极线路板(52)是在塑料材料坯的薄片上形成的，它准确地安置在微场所元件的上部(54)。在线路板的下部含有单根电线(印刷线路)到每个微场所上(55)。短的铂电极结构(～3-4mm)(62)被设计成延伸进入单个微场所腔(57)。印刷的线路电线用合适的防水绝缘材料覆盖。印刷线路电线会聚到一个孔中，它允许连接到多路开关控制器(56)和DC电源(58)上。装置是部分浸没并在一个共同的缓冲液贮槽(59)中工作。
虽然由微加工和微平版印刷技术制造的装置的微场所的初始功能是相同的，但它们的设计是不同的。由微平版印刷制造的装置，其渗透和粘附层是直接在基础金属微电极上形成的。由微加工技术制造的装置，其渗透和粘附层由在单个腔或槽(57)中的缓冲液从它们单个金属电极结构(62)上物理地分离开(见图6)。在微加工的装置中渗透和粘附层能应用功能化的亲水凝胶，膜，或其它合适的多孔材料而形成。
一般地说，组合的渗透和粘附层的厚度从10μm到10mm。例如，一种26％到35％聚丙烯酰胺(带有0.1％聚赖氨酸)的修饰的亲水凝胶，能被用来部分填充装置上每个独立的微场所腔。这种浓度的凝胶形成一种理想的渗透层并带有从2nm到3nm的孔径限度。结合到凝胶中的聚赖氨酸为随后粘附特异结合实体提供伯胺功能基团。这种类型的凝胶渗透层允许电极以DC方式主动地起功能。当电极被激活时，这凝胶渗透层允许小的相反离子通过，但较大的特异结合实体分子在外部表面被浓缩。在这儿它们共价地结合到外层伯胺基团上，有效地成为粘附层。
为形成渗透和粘附层的另一种技术是将一种多孔膜材料结合入每个微场所腔的基部。膜的外表面随后用化学功能基团衍生以形成粘附层。进行这种方法的合适技术和材料对于本领域的技术人员是熟知的。
上述关于装置设计和制造的描述不应被认为是对基本装置其它变型或形式的限制。多个带有较大量或较小量可寻址微场所装置的变型是为了不同的分析和制备应用被预想的。带有较大量可寻址场所的装置变型是为了制备生物高分子合成的应用预想的。一些变型也被期望作为电子地可寻址的和可控制的试剂分配器为与其它装置一起使用，包括那些由微平版印刷技术生产的装置。
(2)装置的自我引导的寻址
权利要求的装置能够用一个特异结合实体电子地自我寻址每个微场所。装置本身直接影响或引起转移和粘附特异结合实体到特定微场所上。装置自我装配自己以无需外界过程，机械加工，或在一个特定微场所放置一个特异结合实体。这种自我寻址过程既快速又特异，并能以系列或平行的方式进行。
装置能通过保持选择的微场所以DC方式并与特异结合实体相反的电荷(电势)被特异的结合实体系列地寻址。所有其它的微场所与特异结合实体保持相同的电荷。在结合实体不是多于某个微场所的粘附位点时，需要活化仅一个其它微场所以便影响电泳式转移到这特定的微场所上。特异结合实体被迅速地转移(几秒钟，或最好地短于1秒)通过溶液，并直接地浓缩在特定的微场所上在这儿并立即共价结合到特定的表面。在特定微场所上电子地浓缩反应物或分析物(70)的能力被表示在图7。所有其它微场所保持不受那个特异结合实体的影响。任何未反应的结合实体通过反向那个特定微场所的极性被移走，并被电泳到一个处理场所上。这种循环重复直至所有希望的微场所被它们特异结合实体所寻址。图8表示用特异性寡聚核苷酸结合实体(82、84、86)寻址特定微场所(81、83、85)的系列过程。
为寻址微场所的偶联过程简单地包括同时活化大量(特别的基团或线路)的微电极以便相同的特异结合实体被转移，浓缩，并与多于一个特定微场所起反应。
(3)装置的应用
一旦装置被特异结合实体自我寻址后，各种分子生物学类型的多步和多路反应和分析就能在装置上进行。本发明的装置能够电子地提供对多个重要反应参数的主动的或动态的控制。这种电子控制导致在反应速率，特异性，和灵敏性方面显著提高。在这些反应参数上的提高是由于装置电子地控制和影响下述事件的能力：(1)快速转移反应物或分析物到含有结合着特异结合实体的特定微场所上；(2)由于浓缩了与那个特定微场所上特异结合实体起反应的反应物或分析物而促进反应速率；和(3)从那个微场所上快速和选择地移走那些未反应的和非特异性结合的成份。这些优点被应用在一个新的被称为“电子严格性控制”的过程中。
本发明的自我可寻址装置能够快速地进行各种显微形式的多步和/或多路反应和过程；它包括，但不局限于：
—DNA和RNA杂交过程和分析以传统的方式，和新的改进的矩阵形式；
—分子生物学反应过程，例如，限制性酶反应和分析，连接反应，激酶反应，和扩增过程；
—抗体/抗原反应过程包括大或小的抗原和半抗原；
—诊断测定，例如，杂交分析，基因分析，指纹分析，和免疫诊断；
—生物分子偶联过程(即，共价和非共价标记核酸、酶、蛋白、或抗体用报告基团)；
—生物高分子合成过程，例如，寡聚核苷酸或肽的组合性合成；
—水溶性合成高分子的合成，例如，碳水化合物或线状聚丙烯酸酯；和
—大分子和纳米结构(纳米大小颗粒和结构)的合成和制造。
核酸杂交
核酸杂交被用作本发明的实例是因为它们带有最困难的多步和多路反应的特征。
权利要求的装置和方法允许核酸杂交以各种传统的和新的方式进行。装置电子地控制反应参数的能力极大地改进了核酸杂交分析，特别是装置提供电子严格性控制(ESC)的能力。
“核酸杂交”是表示发生在所有天然的合成形式的和衍生的核酸间的杂交，包括：脱氧核糖核酸(DNA)，核糖核酸(RNA)，聚核苷酸和寡聚核苷酸。
传统的杂交形式，如“斑点”杂交和“夹心”杂交，能用权利要求的装置以及大范围列阵或矩阵形式进行。
举例来说，一种用于DNA杂交分析的装置以如下的方式被设计、制造、和应用。微场所的列阵首先用微平版印刷技术制造。列阵上可寻址微场所的数量取决于最终的用途。装置以系列方式被一组特异的寡聚核苷酸快速地自我寻址。在这种情况下，特异的寡聚核苷酸是3′-末端醛基功能化的寡聚核苷酸在(6-mer到100-mer的范围)。醛基功能基团允许共价粘附到特定微场所粘附表面(见图4)。这特异的寡聚核苷酸类群能在传统的DNA合成仪上应用传统技术方便地合成。
合成每个特异寡聚核苷酸是从核糖核酸控制的多孔玻璃(CPG)载体上开始的。因此，3′-末端点合有一个核糖核苷酸，它在合成和纯化后通过过碘酸氧化容易地转变成一个末端二醛衍生物。含有醛基的寡聚核苷酸(40)将容易地与微场所表面的伯胺功能基团通过西佛碱反应过程反应。
装置用特异寡聚核苷酸的电子寻址在图8显示。第1个特定微场所(ML-1)(81)用它的特异序列寡聚核苷酸(SSO-1)(82)寻址是通过保持该特定微电极(ML-1)在一个正DC电势，而所有其它微电极被保持在一个负电势(图8(A))而完成的。在水缓冲液中醛基功能化的特异序列(SSO-1)被自由场电泳到ML-1处，在这儿它浓缩(＞106倍)和立即共价地结合到ML-1的表面(81)。所有其它微电极保持负的，并保留被保护或隔离，不与SSO-1序列(82)起反应。ML-1的电势然后反转成负(-)，以电泳任何未反应SSO-1到一个处理系统。该循环重复，SSO-2(84)→ML-2(83)，SSO-3(86)→ML-3(85)，SSO-n→ML-n直到所有期望的微场所用它们特异DNA序列所寻址(图8(D))。
另一种寻址装置的方法是从一个电子试剂提供装置上转移特异性结合实体例如特异性寡聚核苷酸。这种提供装置能装载大量结合实体或试剂并能被用作加样分析装置。结合实体将在两种装置间被电子地转移。这种步骤取消了在用结合实体寻址该装置过程中对物理操作，例如移液，的需求在装置与结合实体寻址过程中。
然而另一种寻址装置的方法是在特定的微场所进行组合的合成特异性寡聚核苷酸。组合的合成在下面部分中描述。
在装置被特异性DNA序列寻址后，列阵装置上的微场所保持作为独立的工作直流(DC)电极。这是可能的因为粘附到电极表面是以基础的微电极不被化学地或物理地绝缘的方式进行的。每个微电极仍然产生为了自由场电泳式转移其它带电DNA分子到和离开微场所表面需要的强直流电。DNA列阵装置对DNA杂交和任何其它随后反应的所有方面提供的完全电子控制。
电子地控制的杂交过程的一个实例表示在图9。在这种情况，每个可寻址的微场所具有一个特异性捕获序列(90)。含有目标DNA(92)的样品溶液被加到装置上。所有的微场所被活化并且样品DNA在微场所被浓缩(图9(B))。从稀溶液中来的目标DNA分子或在微场所高度浓缩，允许非常迅速地杂交到表面上特异性互补DNA序列上。反转微电极电势从微场所上排斥所有未杂交的DNA，而目标DNA保持已杂交状态(图9(C))。以同样的模式，报告探针在随后步骤中被杂交以便检测杂交复合物。
电子控制杂交过程通过提高整个杂交效率和通过从微场所区域移走非-特异DNA显著提高了目标DNA分子的随后检测。这是期望即10,000到100,000拷贝的目标序列在未扩增的基因组DNA中将是可识别的。这种类型的杂交反应能在数分钟内，最少的外界操作下进行。极度地漂洗不是必须的。
另一种DNA杂交测定的常见方式包括把目标DNA固定在表面，然后杂交特定探针到这些目标DNA上。这种方式能包括或相同的目标DNA在多个场所上，或不同的目标DNA在特定的场所上。图10表示这系列杂交方式的一种改进方式。在这种情况下微场所(101-107)被不同的捕获DNA分子所寻址。它们以系列方式被不同序列的特异性寡聚核苷酸(108，109)杂交。这微场所随后被偏压成正以便转移分子到它本身上而随后偏压成负以便转移分子到下一个微场所上。特异地杂交的DNA将保持在微场所上而不管电极的电势。序列特异性寡聚核苷酸能用一个合适的报告基团例如荧光团来标记。
权利要求的装置能够提供电子严格性控制。严格性控制对于杂交特异性是必须的，并且对于分辨点突变中一个碱基错配是特别重要的。图11显示电子严格控制如果被用于为一个碱基错配分析提高杂交特异性。电子严格控制也能被应用到多个碱基错配分析中。
准确配合的DNA杂交子(110)比错配DNA(112)杂交子稳定。通过偏压微场所成负(图11(B))和在一定时间内释放一固定量的电能，有可能变性或移走错配的DNA杂交子而保留准确配合的DNA杂交子(图11(C))。在进一步的改进中，权利要求的装置对每个发生在装置上的特定杂交反应提供独立的严格控制。用传统的或被动的列阵方式，不可能对发生在相同杂交溶液中的所有杂交过程获得最适严格性。然而，本发明的主动列阵装置能够对在不同微场所上的杂交反应提供不同的电子严格性，甚至这些杂交反应是发生在同批杂交溶液中。这一特性克服了传统矩阵杂交形式，杂交测序(SBH)形式，和其它多路分析的主要限制。
这种对杂交提供电子严格性控制的能力也提供了检测DNA杂交而不用报告基团标记的DNA探针的机制。它提供了一种方法来进行杂交过程本身更加直接的检测。一种荧光染料检测过程在图12显示并在实例4和6中描述。直接检测DNA杂交子通过应用DNA结合染料例如溴化乙锭能获得。染料结合到双链和单链DNA上但对前者有更大的亲和力。在图12(B)中，带正电荷的染料(122)被转移到负电地偏压的微场所上。染料与杂交的(120)和未杂交的(121)DNA序列两者结合(图12C)。通过偏压微场所成正和在固定时间内释放一定置的电能，结合到未杂交微场所上的染料分子被选择性地移走。应用的电能量对DNA杂交子无不利影响作用。
带有结合的染料分子的杂交DNA随后应用配套的或一体化的光学系统被荧光地检测。
下面重复由本发明的装置为核酸杂交反应和分析提供的重要的优越性：
(1)快速转移稀的目标DNA和/或探针DNA序列到杂交要发生的特定微场所上。这步在不多于几秒钟时间内发生。
(2)在杂交要发生的特定微场所上浓缩稀的目标DNA和/或探针DNA序列。这浓缩效应能超过一百万倍(＞106)。
(3)从已发生杂交的特定微场所上快速移走非-特异地结合的目标DNA序列。这步需时10到20秒。
(4)从已发生杂交的特定微场所上快速移走竞争的互补目标DNA序列。这步需时10到20秒。
(6)在数分钟内进行一次完全杂交过程的能力。
(7)进行一次带有最少外界操作或漂洗步骤的杂交过程的能力。
(8)应用电子严格性控制(ESC)移走部分杂交的DNA序列。
(9)进行在1000到100,000拷贝数范围内的未-扩增基因组目标DNA序列的杂交分析的能力。
(10)应用ESC提高单个碱基错配杂交(点突变)的分辨力。
(11)应用ESC在矩阵杂交中提供单个严格性控制。
(12)通过移走非-特异性背景成份提高杂交反应的检测。
(13)发展一种排除了应用共价标记的报告探针或目标DNA识别杂交反应需要的新程序。
装置的复制
除了用特异性结合实体分别地寻址单个装置以外，也可能生产一种主装置，它能拷贝特异的结合实体到其它装置上。这代表了生产装置的另一种方法。复制装置的过程显示在图13。一个带有已用特异性结合序列寻址的微场所的主装置与各个互补DNA序列(130)杂交。这些互补序列被活化并因此能够共价结合到微场所粘附层上。
一个未寻址的含有粘附层的姐妹装置(132)与已杂交的主装置配合(图13(B))。主装置的微场所被偏压成负而姐妹装置的微场所被偏压成正。DNA杂交子被变性并转移到姐妹装置上，在这儿活化了的DNA序列共价地结合到微场所上(图13(C))。这过程能以并联地或串联地实施，取决于装置的几何形状以便微场所间的交叉干扰达最低。这些杂交子能通过应用足够的负电势或使用一种带正电的离液剂或变性剂被变性。
识别系统
在荧光结合反应的情况下，能够使用一种落射荧光类型的显微镜检测系统来分析结合反应。系统的灵敏度取决于配套的图像识别元件(CCD，ICCD，微通道片)或光子计数PMT系统。另一种方法是直接地与装置以夹心方式配套一种灵敏的CCD识别器或离子雪崩光电二极管(APD)识别器。再另一种方法是在装置中组合进光电子或微电子检测系统。
组合的生物高分子合成
本发明的装置也能够进行生物高分子例如寡聚核苷酸和肽的组合的合成。这种过程允许自我引导的合成发生而无需任何外界引导或影响。这种组合的合成允许非常大量的序列在一个装置上合成。组合的合成的基本概念包括应用装置在可寻址的微场所上运输，浓缩和反应各种单体，结合试剂，或封闭试剂。这概念利用装置保护一些场所不受附近试剂的影响的能力。对这概念也重要的是在这些化学合成过程中选择性步骤的识别，其中一种或多种反应物具有一个净正电或负电，或为这些过程构建合适的试剂。
组合的寡聚核苷酸合成的一种方法显示在图14。这种方法从一套选择性的可寻址微场所(140)开始，该微场所表面已用封闭的伯胺(X-NH-)基团(142)衍生过。这过程的起始步骤包括应用一种带电的去封闭试剂(144)使电极选择性地去封闭。在这种情况下，这试剂能携带一个正(+)电荷。这过程是通过应用对那些正被去封闭的电极加上一个负电势，而对那些保持被保护状态的电极加上一个正电势(图14(B))而进行的。应用正和负电势到选择的电极上引起带电试剂在那些正被去封闭的微场所上浓缩，并从其它电极表面排除试剂。
在第二步，化学结合上第1个碱基，在这儿是胞嘧啶，到去封闭的微场所上是通过简单地暴露该系统于磷酰胺试剂(X-C)而进行的。这(C)核苷酸结合到去封闭的微场所表面，而不结合到任何封闭的电极表面(图14(C)和(D))。在这点上正常的磷酰胺化学进行着直到下步去封闭步骤。
在第二个去封闭步骤(图14(D))，那些将结合下个碱基的电极点被赋于负电，而那些仍保持被保护状态的被赋于正电。现在该系统暴露将结合的下个碱基中，在这儿是(X-A)(148)，并获得选择的结合到去封闭的微场所上(图14(E)和(F))。这结合和去封闭过程反复进行，直到所有不同的DNA序列在每个可寻址的微场所表面被合成。
上述的实例代表一种合成核酸的可能方法。另一种方法包括完全水溶DNA合成。在这种情况下，带电的水溶结合试剂，例如1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺(EDCA)，被用于与水溶性核苷酸衍生物一起进行寡聚核苷酸合成。这种方法将比现有的基于有机溶剂的方法具有重要的优越性，现有的方法需要极度地封闭碱基的组成部分。水溶性合成将是花费少的并消除了使用那些在现今基于有机溶剂过程中使用的多个有毒物质。第三种方法包括应用带电的单体。
在DNA合成外，相似的过程能发展用于肽合成，和其它复杂高分子的合成。在本说明书中仔细考虑的实例代表这技术的起始点，并是基于DNA或肽合成的有机溶剂合成过程。
在如下实例中的缓冲液、溶液，和培养液的配方描述在J.Sambrook，E.F.Fritsch and F.Maniatis，分子克隆：实验手册，2nd.，Cold Spring Harbor Laboratory Press，ColdSpring Harbor，New York，1989。
实施例1： 寡聚体试剂
合成的DNA探针应用传统的磷酰胺化学在Applied Biosystems自动DNA合成仪上合成。寡聚体被设计成含有5′氨基或3′核糖核苷末端。5′端功能活化的实现通过应用ABI氨基连接臂2试剂而3′端功能活化则通过启动从一个RNA  CPG载体上的合成开始。3′核糖核苷酸末端能通过能与伯胺基团反应生成席佛碱的过碘酸氧化方法转化成一个二醛基末端。反应条件如下：水中溶解20-30 O.D.的寡聚体使终浓度达1 O.D./μl。加入1体积的0.1M醋酸钠，pH 5.2和1体积0.45M过碘酸钠(用新鲜水配制)。在周围温度下在黑暗中保持搅拌并反应至少2小时。加样反应混合物到0.1M磷酸钠pH 7.4缓冲液平衡的Sephadex G-10柱上(巴氏德移液管，0.6×5.5cm)。收集200μl级分，点样2μl水溶液在薄层层析(孔C)上并收集紫外(UV)吸收级分。
如下的寡聚体含有3′核糖核苷酸末端(U)：
ET12R       5′-GCT AGC CCC TGC TCA TGA GTC TCU
CP-1        5′-AAA AAA AAA AAA AAA AAA AAU
AT-A1       5′-CTA CGT GGA CCT GGA GAG GAA GGA
                GAC TGC CTG U
AT-A2       5′-GAG TTC AGC AAA TTT GGA GU
AT-A3       5′-CGT AGA ACT CCT CAT CTC CU
AT-A4       5′-GTC TCC TTC CTC TCC AGU
AT-A5       5′-GAT GAG CAG TTC TAC GTG GU
AT-A6       5′-CTG GAG AAG AAG GAG ACU
AT-A7       5′-TTC CAC AGA CTT AGA TTT GAC U
AT-A8       5′-TTC CGC AGA TTT AGA AGA TU
AT-A9       5′-TGT TTG CCT GTT CTC AGA CU
AT-A10      5′-CAT CGC TGT GAC AAA ACA TU
含有5′氨基的寡聚体通常地与荧光团，例如德克萨斯红(TR.ex，590nm，em.610nm)起反应。磺酰氯对伯胺基是非常活泼的以形成一个稳定的氨磺酰键。德克萨斯红-DNA结合物的形成如下：德克萨斯红磺酰氯(分子探针)溶解在二甲基甲酰胺(DMF)中到终浓度为50mg/ml(80mM)。寡聚体溶解在0.4M碳酸氢钠pH 9.0-9.1中，达终浓度1 O.D./μl(对21-mer是5.4mM)。在一个微试管中，10μl寡聚体和20μl德克萨斯红混合。在黑暗中让反应进行1小时。用氨水或羟胺终止反应，冻干样品并用PAGE纯化(Sambrooket al.，1989，Supra)。
如下的寡聚体含有5′氨基末端：ET21A      5′-Aminolink2-TGC GAGCTG CAG TCA GAC ATET10AL     5′-Aminolink2-GAG AGA CTC ATG AGC AGGET11AL     5′-Aminolink2-CCT GCT CAT GAG TCT CTCT2         5′-Aminolink2-TTT TTT TTT TTT TTT TTT TTRC-A1      5′-Aminolink2-CAG GCA GTC TCC TTC CTC TCCAGG TCC ACG TAGRC-A2      5′-Aminolink2-CTC CAA ATT TGC TGA ACT CRC-A3      5′-Aminolink2-GGA GAT GAG GAG TTC TAC GRC-A4      5′-Aminolink2-CTG GAG AGG AAG GAG ACRC-A5      5′-Aminolink2-CCA CGT AGA ACT GCT CAT CRC-A6      5′-Aminolink2-GTC TCC TTC TTC TCC AGRC-A7      5′-Aminolink2-GTC AAA TCT AAG TCT GTG GAARC-A8      5′-Aminolink2-ATC TTC TAA ATC TGC GGA ARC-A9      5′-Aminolink2-GTC TGA GAA CAG GCA AAC ARC-A10     5′-Aminolink2-ATG TTT TGT CAC AGC GAT G
实施例2： 在一种微加工的装置上的电子地可寻址微场所——聚赖氨
          酸方法
微电极从毛细管(0.2mm×5mm)制成。毛细管被充满合有0.1～1.0％聚赖氨酸的18-26％聚丙烯酰胺并让其聚合。多余的毛细管被做记号和移走以防止捕获在管子中的气泡并标准化管子长度。毛细管以这样一种方式安放以使它们共享一个共同的上缓冲液贮槽并有单独的低缓冲液贮槽。每个低缓冲液贮槽包含有一个铂线电极。
上槽中毛细管的顶表面被认为是可寻址的微场所，上和下槽充满0.1M磷酸钠pH 7.4缓冲液并用BioRad 500/1000电源在0.05mA恒流预电泳10分钟将2μl(0.1 O.D.)过碘酸氧化的ET12R移液入上贮槽同时电源接上在恒流下电泳2-5分钟。反转极性从而使测试毛细管被偏压面成负并电泳另一个2-5分钟。未结合的DNA被
吸掉上槽缓冲液并用缓冲液冲洗。拆除装置并安装一个新鲜的参考毛细管。重新充满贮槽并加入荧光标记的补体DNA，即，ET10AL-TR。在正电地偏压的测试微场所电泳地浓缩寡聚体，在0.05mA恒电流下达2-5分钟。反转极性并移走未结合的补体。移走测试毛细管并检查荧光。对非-特异性结合的负控制是按上述实施的只要用一个非互补性DNA序列ET21A-TR代替ET10AL-TR。
毛细管微场所的横截面用配有Hamamatsu ICCD照相图像系统的落射荧光显微镜观察。荧光结果表明补体ET10AL-TR杂交到结合实体/捕获序列上，并且即使当电势被改变成负时仍保持杂交状态。ET21A-TR非互补体当电势反转时不保留在测试毛细管上。
实施例3： 在一个工制造的装置上的电子地可寻址微场所——琥
          珀酰亚胺丙烯酸酯方法
本实施例描述共价地结合寡聚体的5′末端的另一种粘附化学。毛细管的制造同上述除了1％琥珀酰亚胺丙烯酸酯(分子探针)用于代替聚赖氨酸。毛细管新鲜制备因为琥珀酰亚胺酯与伯胺基起反应并是不稳定的，特别在高于pH 8.0时。毛细管按上述安放，并且贮槽充满0.1M磷酸钠pH 7.4缓冲液。在0.05mA预电泳毛细管10分钟。移液2μl含有5′氨基末端的ET10AL(0.1 O.D.)，进入上贮槽中然后电源接上电泳2-5分钟。反转极性以便测试毛细管被偏压成负并再电泳2-5分钟。未结合的DNA被排斥而共价结合的DNA保留下。
吸掉上槽缓冲液并用缓冲液冲洗。拆除参考毛细管并安装一个新鲜的参考毛细管。重新充满贮槽并加入荧光标记的补体寡聚体，ET11AL-TR和同上述一样电泳。对非特异结合的阴性对照同上述一样实施只要用一个非补体DNA序列ET21A-TR代替ET11AL-TR。
荧光结果表明补体ET11Al-TR杂交到捕获序列上并即使电势被改变成负时仍保持杂交状态。ET21A-TR非-补体当电势反转时不保留在工作毛细管上。
实施例4： 电子控制的荧光染料检测过程-PAGE
DNA染料例如溴化乙锭(EB)当结合入DNA时成为荧光的。当DNA是双链时比单链时荧光和结合亲和力更大。如同实施例1一样制备毛细管并同上述一样杂交。EB被加到溶液中(～0.05mM EB终浓度)测试毛细管被偏压成负因为EB是带正电的。毛细管在550nm激发和600nm发射时观察落射荧光。杂交的和未杂交的微场所表示红色荧光(从EB上)。
毛细管被重新安装并偏压成正以排斥EB。保持恒流在0.05mA达0.03伏特-小时。
     捕获              目标               正常的信号
     ET10AL            ET11AL(正)         ＞200
     ET10AL            ET21A(负)          1
在未杂交的微场所上的荧光减小而杂交的毛细管保持荧光。荧光信号用一台ICCD照相图像系统和特征峰荧光密度来测量。如果整个荧光信号区域被积分的话信噪比是＞＞1000倍。这表明了一种提高信噪比并从而提高测定的动力学范围的方法。
实施例5： 金属基质上的电子地可寻址场所
铝(Al)和金(Au)电线(0.25mm Aldrich)与溶于甲苯中的10％ 3-氨基丙基三乙氧基硅烷(APS)起反应。APS试剂容易地与金属表面氧化物和/或羟基基团起反应形成在氧化物和/或羟基基团与伯胺基团间的共价键。任何铝的预处理是不需要的。金线在5×SSC溶液中电解以便形成氧化层。另外地金属线能用高氯酸浴氧化。
APS反应的实施如下：金属线切成3英寸放入玻璃皿中。加入甲苯完全覆盖金属线并在加热板上加温到50～60℃。加入APS到终浓度10％。混合溶液并继续反应30分钟。用数倍体积甲苯冲洗3次，然后用数倍体积乙醇冲洗3次在50℃烘箱中干燥。经APS处理的金属线能与醛基反应形成席佛碱。结合实体ET12R同其它地方描述的一样用高碘酸氧化。电极被放入装有去空气水的槽中。电源加上0.05mA恒流保持3D秒。活化过的ET12R立即放入。接上电源，液体被吸出并加入新鲜水然后再次吸出。测试(偏压成正)和参考电极放入含有荧光标记的补体DNA，ET10-TR的杂交缓冲液(HB，5×SSC，0.1％SDS)中。2分钟以后用漂洗缓冲液(1×SSC，0.1％SDS)冲洗电极3次，每次1分钟并观察荧光(ex.590nm em.610nm)。
结果表明ET12R被特异地结合到处理过的金属表面上。测试电极是荧光的而参考电极无荧光。非-特异性DNA吸附到金属上是由在杂交缓冲液中的SDS所防止。因电解而粘附到金基质上和随后的APS处理是有效的。获得的信号是显著强于由未-氧化的金获得的信号。更加重要地，这实例表明金属表面能用一个结合实体化学地功能化和衍生并不与溶液成为绝缘状态。APS方法代表了形成DNA-金属结合物的多个现存化学方法中的一种。
实施例6： 电子地控制的荧光染料识别过程——金属线
DNA-铝电极基质如同实例5中描述的一样制备和杂交。杂交的和未杂交的DNA-Al电极用一个未衍生的Al线作为参考而制备。EB被加入到溶液中测试DNA电极被偏压成负来吸引染料。溶液被吸走并加入新鲜缓冲液。金属表面在显微镜下检查。
重新安装装置并加上正电电势达一定伏特小时。缓冲液被吸走，电极通过落射荧光被观察。这被反复直到在杂交的和未杂交的金属表面有一个显著的荧光区别。
     捕获               目标             正常的信号
     ET12R              ET10AL(正)       ＞140
     ET12R              无(负)           1
未杂交金属表面的荧光减小而杂交的金属表面保持荧光。荧光信号用一台ICCD照相图像系统和特征峰荧光密度来测量。如果整个荧光信号区域被积分则信噪比将是＞＞1000倍。本实施例表明一种增加信噪比和因此提高测量动力学范围的方法。相似的结果应用毛细管凝胶构型获得，指明电化学影响不极大地影响测量的实施。
实施例7： 主动地编程的电子矩阵(APEX)
          ——微机械加工制造
一个6个可寻址250μm毛细管场所的放射状列阵被微机械加工。该装置有一个共同的上槽和分离的下槽以便每个微场所的电势是单个可寻址的。一个唯一的寡聚体结合实体用在其它地方描述的方法定位于和结合到某个特异的毛细管微场所上。测试微场所有一个正电势而其它微场所有负电势以防止非-特异性相互作用。
列阵被漂洗然后与一个互补荧光标记的DNA探针杂交。列阵被漂洗以移走多余的探针然后在落射荧光显微镜下观察。只有特异地寻址的微场所将是荧光的。过程将用其它结合实体在其它场所重复并用一个标记了其它荧光成分的探针杂交来证明。
DNA序列被特异地置于事先确定的位置与其它场所只有可忽略的交叉干扰。这使得用几个到数百个唯一序列在事先确定的场所制造微矩阵成为可能。
实施例8： 主动的编程的电子矩阵(APEX)
          ——微平板印刷制造
一个8×8矩阵的50μm见方的铝电极垫在硅晶片(见图3)上被设计，制造和包装出来，带有一个开关盒(见装置制造部分详述)。进行数种材料和过程的改进同下述，以便提高芯片的选择性和有效性。
8a) 选择顶部复盖层
APS过程包含在整个芯片中。功能活化过程的选择性取决于芯片表面的反应性。为了减小功能活化和微场所周围区域随后DNA粘附，一种比SiO2或金属氧化物对APS低反应性的材料是需要的。光致抗蚀剂和氨化硅被试验。不同的顶部复盖层被加到二氧化硅芯片上。芯片用落射荧光检查并随后用APS处理接着共价粘附高碘酸氧化的多聚ARNA序列(Sigma，MW 100,000)。芯片用200nM用德克萨斯红标记的20-mer(T2-TR)溶液在杂交缓冲液中杂交，在37℃5分钟。芯片用WB漂洗3次并用1×SSC漂洗1次。芯片用荧光在590nm激发610nm处发射检查。
氮化硅被选中因为相对于二氧化硅它具有对APS更少的反应性并不象所试的光致抗蚀剂那样本身具有荧光。其它方法例如UV燃烧背景区域也是可能的。
8b) APEX物理的特性
完成的矩阵芯片应用一个配有B & L显微镜和CCD照相机的探针测试平台(微操作型号6000)视觉检查。芯片测试在测试垫和外围接触垫闻的连续性。这测试借助用连接在万用表上的操作探针头接触这些垫进行。连续性保证了垫已被蚀刻低到金属表面。这些垫随后检查在电解环境中的稳定性。金属线被调整以在正常干燥条件下操纵达1mA电流。然而，对潮湿环境的反应不知道。一滴(1～5μl)缓冲溶液(1×SSC)被移液到8×8矩阵上。表面张力保持液体在一处使得外围接触垫区域干燥。一个探针头接触接触垫而另一个探针头接触液体。电流增加到50nA以最高电压50V，使用HP6625A电源和HP3458A数字万用表。
开始的制造包括硅基质，一个二氧化硅绝缘层，铝沉积和模型，和一个氨化硅顶端层。这些芯片在潮湿环境中不非常稳定因为金属/氮接触面是天然物理的电解将破坏氮化层。这将导致垫电子地变短。进一步地，氮化硅和铝具有不同的膨胀系数以致于当电流加上时氮化层将断裂。这将导致溶液直接地接触金属，再次导致电解而进一步破坏氮化层。
第二制造步骤包括在铝金属和氮化硅层间的二氧化硅绝缘层。二氧化硅和铝具有更加兼容的物理特性并可形成一个较好的化学界面以提供更稳定和结实的芯片。
8c) DNA粘附
矩阵芯片用APS试剂按实例5中描述的方法功能化活化。芯片然后用高碘酸氧化的多聚A RNA处理(Sigma，平均分子量100,000)。芯片在WB中漂洗去除多余和未结合的RNA。这一过程用捕获序列复盖整个芯片并在暴露的金属表面比氮化物覆盖的区域有更高的密度。芯片与200nM T2-TR溶液在HB中杂交5分钟37℃。然后在周围温度下WB中洗3次和1×SSC中洗1次每次1分钟。芯片检查在590nm激发610nm发射的荧光。
开放的金属区域略有荧光并有垫的形状。低荧光密度和/或不规则边界表明这些垫没有完全地开放。额外的等离子体蚀刻时间是需要的。
8d) 电子控制的杂交
主动地杂交的实施借助应用实例8c中的芯片并偏压一个微场所成正。这是通过使用也能自动地偏压剩余的微场所成负的开关箱或通过使用一个外部溶液电极实现的。仅3微升水被放置在矩阵垫上。电流，～1-5nA，加上达数秒钟并加上0.1pmole T2-TR到溶液中。液体被移走芯片干燥并在德克萨斯红波长处检查荧光(ex.590nm，em.610nm)。
仅仅正电地偏压的微场所是荧光的。这能重复数次以便选择性地杂交其它微场所。此外，在某微场所荧光的DNA借助偏压原始场所成负而目的场所成正能被转移置于另一个微场所上。
8e) 电子控制的寻址和装置制造
矩阵被功能化活化用APS如同上述。结合实体CP-1用高碘酸氧化方法活化。矩阵中4个微场所偏压成正而剩余的微场所被偏压成负。2μl水被置于矩阵上并加上电流。加上结合实体，CP-1，并允许在指定的场所浓缩。移走液体，芯片用水简单冲洗并将2μl水置于芯片上。再次，加上电流达数秒钟并加入0.1皮摩尔T2-TR。在短时间后液体被移走整个芯片在WB中漂洗3次。干燥芯片检查荧光。
结果指明正电地偏压的微场所是荧光的。本实施例示范了用特异结合实体选择性寻址微场所，定位和共价结合序列到微场所上，以及互补目标序列特异性杂交到衍生的微场所上。
8f) 基因的模式APEX芯片
带有3′核糖核苷末端的DNA结合实体被合成它对HLA基因dQa的多态性是特异的。这结合实体用上述的高碘酸氧化法来活化。反向补体也合成带有5′氨基末端并与荧光团结合，例如德克萨斯红，若丹明或Bodipy染料，如同在其它处描述的。微场所用伯胺基通过APS处理被功能性活化，如同其它处描述的。数μl溶液置于矩阵上而留下接触垫干燥。通过偏压该微场所成正某特异微场所被寻址，加入高碘酸氧化过的DNA寡聚体，约0.1皮摩尔，并转移定位共价地结合到那个场所上。极性被反转未结合的结合实体分子被移走。对另一个结合实体在另一个寻址的微场所重复该过程直到所有特殊的结合实体被结合到芯片上。芯片然后杂交到单个荧光标记的补体序列上以便确定结合反应的特异性以及立刻整个地显现所有被寻址的微场所。在相同的已被变性移走互补寡聚体(10分钟90℃在0.05％SDS中)的芯片上，寻址的微场所与未标记的反向补体或基因组DNA杂交。通过别处描述的荧光染料检测测定法而识别。
结果将表明微场所是特异地被独特的结合实体寻址。对负电偏压的微场所的非特异的结合可忽略不计。装置和配合的结合实体化学在变性条件下是稳定的，因此使得寻址的和制造的装置能重复使用。变性杂交子的其它方法是增加电流和/或增加加上电流的时间。
实施例9： 电子的严格性控制
装置影响电子严格性控制的能力是用Ras癌基因模式系统来示范的。一个单碱基对错配反向地影响解链温度(Tm)，双螺旋稳定性的一种指标。传统的区别错配和完全配合的方法(即严格性控制)取决于温度和盐的条件。严格性也受到电泳的电势的影响。下面列出的寡聚体能被配对而形成具0～2个错配的杂交子。寡聚体结合实体被结合到微场所上并杂交，如同其它处描述的一样。微场所的极性然后反转，杂交子接受恒电流达一定时间，或确定的功率水平以便变性错配对而不影响完全配合。
Ras-G    5′-GGT GGT GGG C GC CG G CGG TGT GGG CAA GAU-3′
Ras-1            3′-CC G CG GC C GCC ACA C-Aminolink2-5′
Ras-2            3′-CC G CG GC A GCC ACA C-Aminolink2-5′
Ras-3            3′-CC G TG GC A GCC ACA C-Aminolink2-5′
Ras-T    5′-GGT GGT GGG C GC CG T CGG TGT GGG CAA GAU-3′
微电极是从毛细管制造的如同其它处描述。结合实体Ras-G经高碘酸氧化并共价地结合到已寻址的微场所上。Ras-G微场所随后与完全配合的Ras-1-TR杂交，与一个碱基对错配(G-A)的Ras-2-TR或二个碱基对错配(G-A或G-T)的Ras-3-TR杂交。微场所荧光检查以便证实互补序列是杂交的和杂交到何种程度。毛细管被重新安装并加上恒电流达到控制的时间直到错配杂交子被移走而不显著影响完全地配合的杂交子。
结果将指明严格性能受到电泳的电势的影响。该实施例示范了每个微场所能具有单个的严格性控制，因此克服了对于被限制于单个共同的严格性水平的大范围的并联过程技术的一个主要障碍。

Claims (14)

1.一种用于电子控制含有对某个结合场所特异结合实体和非特异结合实体的溶液中带电结合实体的相互作用的方法，它包括下列步骤：
放置该溶液接触含有第1基础电极的和一个覆盖的渗透层的第1结合场所，和含有第2基础电极的和一个覆盖的渗透层的第2结合场所；
放置所述第1结合场所在相对于所述第2结合场所的一个吸引势，在所述第1场所浓缩结合实体。
2.一种用于电子控制含有对第1和第2结合场所特异结合和非特异结合DNA序列的溶液中DNA杂交的方法，它包括下列步骤：
放置该溶液接触第1、第2和第3场所；
放置所述第1和第2结合场所在一个正电势而所述第3场所在一个负电势，在所述第1和第2场所浓缩DNA；
放置所述第1和第2特异性结合场所在一个负电势而所述第3场所在一个正电势；和
放置所述第1和第2结合场所在相对于所述第3场所的负电势，其中所述负电势或电流足以从所述第1和第2场所上移走非特异地结合的DNA，而不足以移走特异地结合的DNA序列。
3.一种用于电子控制含有对第1结合场所和随后第2特异结合场所特异和非特异DNA序列的溶液中DNA杂交的方法，它包括下列步骤：
放置该溶液接触所述第1、第2和第3场所；
放置所述第1结合场所在一个正电势而所述第2结合场所在一个负电势，在所述第1场所上浓缩DNA；
放置所述第1结合场所在一个负电势而所述第2结合场所在一个正电势，在所述第2场所浓缩DNA；和
放置所述第1和第2结合场所在相对于所述第3结合场所的负电势，其中所述负电势或电流足以从所述第1和第2场所上移走非特异地结合的DNA而不足以移走特异地结合的DNA。
4.权利要求3的杂交方法，其中所述负电势或电流是逐渐地增加或减少的。
5.权利要求2或3的方法，其中复合的特异和非特异DNA序列被应用于一个结合场所的列阵上。
6.权利要求1的用于电子控制相互作用的方法，它包括下列步骤：
放置所述第1结合场所于一个相对于第2结合场所的排斥势，
其中所述排斥势足以从所述第1结合场所上移走非特异地结合的结合实体，而不足以移走特异地结合的结合实体。
7.权利要求1的方法，进一步包括将特异性结合实体附着在第一结合场所的渗透层上。
8.权利要求1的方法，进一步包括将在第一结合场所上浓缩的结合实体与结合到渗透层的互补的特异性结合实体相互作用。
9.权利要求8的方法，进一步包括反转第一结合场所的电势，其数量足以从所述第1结合场所上移走非特异地结合的结合实体，而不足以移走特异地结合的结合实体。
10.权利要求1的方法，其中的特异性结合实体包括一种能通过共价键与其它分子特异性亲和结合的生物分子。
11.权利要求1的方法，其中的特异性结合实体包括一种能通过非共价键与其它分子特异性亲和结合的生物分子。
12.权利要求1的方法，其中的特异性结合实体包括一种能通过共价键与其它分子特异性亲和结合的合成分子。
13.权利要求1的方法，其中的特异性结合实体包括一种能通过非共价键与其它分子特异性亲和结合的合成分子。
14.权利要求1的方法，其中的特异的结合实体选自：脱氧核糖核酸(DNA)、核糖核酸(RNA)，合成的寡聚核苷酸、抗体、蛋白质、肽、凝集素、修饰的多糖，合成的复合大分子，具功能的纳米结构，合成高分子，修饰/封闭的核苷酸/核苷，修饰/封闭的氨基酸、荧光团、生色团、配体、螯合物和半抗原。
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FI961843A0 (fi) 1996-04-30
EP0727045A1 (en) 1996-08-21
EP0727045B1 (en) 2001-12-19
FI961843A (fi) 1996-06-20
ATE211259T1 (de) 2002-01-15
EP1120156A2 (en) 2001-08-01
EP0727045A4 (en) 1998-04-22
CN1141078A (zh) 1997-01-22
US5929208A (en) 1999-07-27
AU8125794A (en) 1995-05-23
CA2175483C (en) 2004-11-30
CA2175483A1 (en) 1995-05-11
EP1120156A3 (en) 2001-10-24
DE69429535D1 (de) 2002-01-31
EP1120469A3 (en) 2001-10-24
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EP1120155A3 (en) 2001-10-24
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AU692800B2 (en) 1998-06-18
US5605662A (en) 1997-02-25
DK0727045T3 (da) 2002-04-15
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PT727045E (pt) 2002-06-28
BR9407952A (pt) 1996-11-26
EP1120155A2 (en) 2001-08-01
CN1920055A (zh) 2007-02-28
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WO1995012808A1 (en) 1995-05-11
EP1120469A2 (en) 2001-08-01
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