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CN1202929A - 用于主动可编程矩阵器件的设备和方法 - Google Patents

用于主动可编程矩阵器件的设备和方法 Download PDF

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Publication number
CN1202929A
CN1202929A CN96198521A CN96198521A CN1202929A CN 1202929 A CN1202929 A CN 1202929A CN 96198521 A CN96198521 A CN 96198521A CN 96198521 A CN96198521 A CN 96198521A CN 1202929 A CN1202929 A CN 1202929A
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Prior art keywords
hybridization
reaction
biological
detection
dna
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CN96198521A
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Inventor
M·J·赫勒尔
J·P·奥坎内尔
R·D·钧科沙
R·G·索斯诺斯基
T·R·雅克森
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NANOGEN CO Ltd
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NANOGEN CO Ltd
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Publication of CN1202929A publication Critical patent/CN1202929A/zh
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Abstract

进行分子生物学诊断、分析和多步多路切换反应的一个系统,该系统为了主动进行微观受控反应,应用了一个可自寻址自汇编的微电子系统。最好是一个流体系统使样品流经生物芯片的一个活性区域,从而提高诊断检测效率。该流体系统最好包括一个有窗口的流动室。生物芯片电极的脉冲式激活最好与该流体系统一起使用,从而对生物样品中的物质进行更完全地取样。改进型检测系统利用一个位于一个光导(诸如一种液体光导)中最好同轴取向的激发纤维(诸如一种光纤)。按照此方法,小几何平面系统可以进行荧光成像,产生了一个高度自动化的DNA诊断系统。为了分析及诊断目的,对在电子变性过程中的荧光信号波动进行了详细的说明和分析。综合这种荧光波动信息和其它信息,从而产生了一个改进的分析方法。DNA指纹法用来将在测试位点上将给定长度的DNA片段和捕获序列杂交,然后测定影响杂交(诸如去杂交)所需的逆转偏置电平,并测定DNA片段的长度。

Description

用于主动可编程矩阵器件的设备和方法
发明范围
本发明涉及以多种形式进行多步分子生物学类型诊断分析的装置和系统。更具体地说，分子生物学类型分析包括各种核酸杂交反应和相关的生物高聚物合成。此外，可以进行抗体/抗原反应和其它临床诊断。相关申请信息
本申请是题目为“分子生物学自动诊断系统(AUTOMATEDMOLECULAR BIOLOGICAL DIAGNOSTIC SYSTEM)”申请(1994年9月9日提出申请，申请序号为No.08/304,657)的部分继续申请；后者是题目为“用于分子生物学分析和诊断的可自寻址自汇编的微电子系统”(SELF-ADDRESSABLE SELF-ASSEMBLING MICROELECTRICSYSTEMS AND DEVICES FOR MOLECULAR BIOLOGICALANALYSIS AND DIAGNOSTICS)(1994年7月7日提出申请，申请序号为No.08/271,882)的部分继续申请；后者是“用于分子生物学分析和诊断的主动可编程电子装置(ACTIVE PROGRAMMABLEELECTRONIC DEVICES FOR MOLECULAR BIOLOGICALANALYSIS AND DIAGNOSTICS)”申请(1993年11月1日提出申请，序号为No.07/146,504)的部分继续申请。
发明背景
分子生物学包括种类繁多的核酸和蛋白质分析技术。其中的许多技术和方法形成了临床诊断分析和检测的基础。这些技术包括核酸杂交分析、限制性内切酶分析、基因序列分析和核酸及蛋白质的分离与纯化(参见例如J.Sambrook，E.F.Fristch，和T.Maniatis，分子克隆：实验手册，第二版，冷泉港实验室出版社，纽约，冷泉港，1989年(Molecular Cloning：A Laboratory Manual，2 Ed，Cold Spring HarborLaboratory Press，Cold Spring Harbor，New York，1989)。
其中大多数技术涉及对大批样品进行多种操作(例如取液、离心、电泳)。它们通常复杂且费时，且一般要求高精确度。许多技术由于缺乏敏感性、特异性、或重现性使其应用受到限制。例如，这些问题限制了核酸杂交分析的许多诊断性应用。
对遗传病或传染病进行DNA杂交分析的全过程非常复杂。一般来说，该全过程可分为多个步骤和子步骤(参见图1)。就遗传病的诊断而言，第一步包括获取样品(血液或组织)。根据样品的类型，进行各种预处理。第二步包括破碎或裂解细胞，然后它们释放出粗品DNA和其它细胞组分。一般还需要进行几个子步骤以去除细胞碎片和进一步纯化粗品DNA；至此，进一步的处理和分析有几种选择：一种选择包括使纯化DNA样品变性并以多种方法中的一种方法进行直接杂交分析(斑点印迹法、微珠法、微量滴定板法等)。第二种选择称作Southern印迹杂交法，包括用限制性内切酶切割DNA，在电泳凝胶上分离DNA片段，再将DNA片段印迹到膜滤器上，然后将该印迹物与特性的DNA探针序列进行杂交。此方法有效地降低了基因组DNA样品的复杂性，并因此有助于提高杂交的特异性和敏感性。不幸的是，该方法冗长且费力。第三种选择是进行聚合酶链反应(PCR)或其它扩增方法。PCR方法扩增(增加)靶DNA序列的数目。靶DNA的扩增有助于解决与基因组DNA分析中的复杂性和敏感性有关的问题。所有这些方法均费时，相对复杂，且显著地增加诊断检测的成本。在样品制备和DNA处理步骤之后，才进行真正的杂交反应。最后，进行检测和数据分析，将杂交事件转化为分析结果。
样品制备和处理的步骤是独立进行的，与杂交、检测和分析的另一主要步骤分开。实际上，包括样品制备和DNA处理的步骤通常作为一个独立于其它子步骤的独立操作而进行。关于这些操作的详细介绍如下，通过多种方法获取样品，例如全血、组织或其它生物流体样品。关于血液，加工样品以去除红细胞，保留所要的具核细胞(白细胞)。该方法一般是采用密度梯度离心进行的。然后进行细胞破碎或细胞裂解，采用的技术最好是超声处理、冻融或加入裂解试剂。通过离心步骤分离粗制DNA和细胞碎片。杂交前使双链DNA变性成单链形式。双链DNA变性的技术包括加热(＞Tm)、改变盐浓度、加入碱(NaOH)或变性剂(尿素、甲酰胺等)。研究人员建议在电化学池中使DNA变性成为单链形式。该理论是：在电极界面上电子转移到DNA上，它有效地削弱DNA双链结构并导致DNA双链分离。一般参见1992年3月18日公布的Stanley“利用电势的DNA变性(DNA Denaturation by anElectric Potential)”的英国专利申请2,247,889。
核酸杂交分析一般包括在相对大量复杂的非靶核酸中用过量探针DNA检测非常少量的特异性靶核酸(DNA或RNA)。利用降低样品制备中DNA复杂性的子步骤有助于检测低拷贝数(即10,000-100,000)的靶核酸。通过应用聚合酶链反应(PCR)扩增靶核酸序列，在一定程度上解决了DNA复杂性(参见：M.A.Innis等，PCR操作步骤：方法和应用指南(PCR Protcols：A Guide to Methods and Applications)，科学出版社(Academic Press)，1990)。尽管扩增产生大量的靶核酸序列，有助于随后的直接探针杂交步骤，但是扩增涉及冗长且繁琐的步骤，它一般必须在相对于其它子步骤独立的基础上进行。事实上，需要复杂且相对大的装置进行扩增步骤。
真正的杂交反应代表整个过程中最重要和最中心的步骤。杂交步骤包括，在产生与靶DNA序列杂交的一组最佳条件下，将制备好的DNA样品与特异性报道探针混合接触。杂交可以以任意一种方法进行，例如在多种滤膜和固相支持体上进行多个样品的核酸杂交分析(参见G.A.Beltz等，酶学方法(Methods in Enzymology)，第100卷，B部分，R.Wu，L.Grossman，K.Moldave，Eds.科学出版社(Academic Press).纽约，第19章，第266-308页，1985)。一种方法称为“斑点印迹”杂交，包括将靶DNA非共价结合于滤膜上，随后使其与放射性同位素标记的探针杂交。“斑点印迹”杂交得到了广泛应用，并发展了许多改良法(参见M.L.M.Anderson和B.D.Young，核酸杂交-一种使用方法(Nucleic Acid Hybridization-A Practical Approach)，B.D.Hames和S.J.Higgins，Eds.IRL出版社，华盛顿，第4章，第73-111页，1985)。已发展了基因组突变的多种分析(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，美国专利号5,219,726，1993年6月15日)。
正在开发在微格式化多路切换或矩阵装置(例如DNA芯片)上进行多种样品核酸杂交分析的新技术(参见：M.Barinaga，253 Science，第1489页，1991；W.Bains，10 Bio/Technology，第757-758页，1992)。这些方法一般是使特异性DNA序列粘附于固相支持体的非常小的特异性区域上，如DNA芯片的微孔，这些杂交方法为传统“斑点印迹”和“夹层”杂交的微型化方法。
微格式化杂交法可以用于通过杂交测序(sequencing byhybridization)(SBH)(参见M.Barinaga，253 Science，第1489页，1991；W.Bains，10 Bio/Technology，第757-758页，1992)。SBH利用所有可能的n-核苷酸寡聚物n-mers)鉴定未知DNA样品中的n-mers，然后通过算法分析进行校正，产生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 Proc.Natl.Acad.Sci.USA 10089，1992；以及R.Dramanac和R.B.Crkvenjakov，美国专利#5,202,231，1993年4月13日)。
已有两种进行SBH的方法。第一种包括在一支持体上产生所有可能的n-mers，然后使其与靶序列杂交；第二种包括将靶DNA结合到支持体上，然后用所有可能的n-mers对其探测。以上两种方法均存在直接探针杂交的基本问题和另外与多样有关的困难。
Southern(英国专利申请GB 8810400，1988；E.M.Southern等，13Genomics 1008，1992)提出用第一种方法分析或测定DNA序列。Southern用PCR扩增的基因组DNA鉴定了一个已知单点突变。Southern还描述了一种在固相支持体上合成用于SBH的寡核苷酸阵列的方法。但是，Southern没有说明如何获得阵列上每一种寡核苷酸的最适严格条件。
同时，Drmanac等(260 Science 1649-1652，1993)应用第二种方法测定了几个短链(116 bp)DNA序列。将靶DNA结合到膜支持体(“斑点印迹”法)。每一滤膜再与272种标记的10-mer和11-mer寡核苷酸连续地杂交。应用较宽范围的严格条件获得每一n-mer探针的特异性杂交；洗涤时间由5分钟至过夜不等，温度为0℃-16℃。大多数探针在16℃下需要洗涤3小时。滤膜必须暴露2-18小时以便检测杂交信号。尽管是简单的靶序列，寡聚物探针数减少，且应用了可能的最严格的条件，但总的假阳性杂交率仍有5％。
有多种检测和分析杂交事件的方法。根据用来标记DNA探针的报道基团(荧光团、酶、放射性同位素等)，检测方法有灵光测定法、比色法或放射自显影。通过观察和测定放出的辐射，诸如荧光辐射或粒子的发射，获得杂交事件的信息。甚至当检测方法固有的敏感性很高时，杂交事件的检测仍很困难，因为存在非特异性结合物的本底。很多其它因素也降低DNA杂交分析的敏感性和选择性。
在传统的荧光检测系统中，将某一波长的激发能量传递到研究区域，并再发射并检测不同波长能量。人们已经生产出大型系统，它们一般拥有2毫米或更大的研究区域，其中整个系统的性质不会因为光学元件的大小要求或将光学元件置于光学上接近研究区域的能力而受到内在限制。但是对于小的几何结构，如小于2毫米，尤其是500微米左右或更小的研究区域，已证实传统的荧光计设计方法已不能满足需要。一般而言，必须将激发和发射光学元件置于研究区域附近。优选聚焦点比较小，但常要求更复杂的光学设计。而且，因为通常需要使检测区域最大化，因此为达到同光学元件与研究区域的距离有关这些目的所需的光学元件大小很重要，且在许多情况下要兼顾获得的性能。相应地，存在提高荧光检测系统的要求。
人们已试图将某些处理步骤或分步操作融合在一起。例如，已提出在支持体上制备DNA探针阵列的各种微型自动系统。Beattie等人在1992年圣地亚哥会议：遗传识别(The 1992 San Diego Conference：Genetic Recognition)(1992年11月)中采用一种微型自动系统将含有特异性DNA序列的微滴沉积在玻璃衬底上的各个微制造的样品孔内。
一般来讲，现有技术方法非常费事且耗时。例如，PCR扩增过程是非常耗时的并增加诊断检测的费用。无论在操作过程中还是在操作过程之间需要人为介入的多个步骤是不理想的，因为存在污染和操作者误差的可能性。而且，就经费和物理空间的需求而言，除非是大实验室，否则通常禁止使用多种仪器或复杂的自动机器系统进行单个过程。
从前面的讨论可见，为提供进行多步复合生物学反应的有效技术已作了大量尝试。但是，由于上述原因，这些技术方法是逐段且有限的。将这些不同方法融合在一起形成一个可以进行整个DNA诊断分析的系统是不容易的。尽管很久已来就认识到需要一个这样的系统，但是以前没有满意地解决这个问题。
发明概述
本发明涉及一种可自寻址自汇编的微电子装置和系统的设计、生产和使用，该系统可以微观的形式主动进行受控的多步加工和多路切换反应。这些反应包括(但不限于)大多数分子生物学方法，如核酸杂交、抗体/抗原反应和有关的临床诊断。此外，要求保护的装置和系统能够在给定装置的特定显微位置进行多步组合的生物高聚物合成，包括(但不限于)不同的寡核苷酸或肽的合成。
采用微型平版印刷和微型机械加工技术生产要求保护的装置和系统。该基本装置在其表面具有一个可寻址的显微位置矩阵；每一个显微位置能够电子控制并指导特异性结合物(如核酸、酶、抗体)转移并结合到该位置上。所有微观位置利用它们的特异性结合物进行寻址。该自寻址过程需要在流控技术或机械部件方面进行最小的外部干预。
该装置能够控制和主动进行许多分析和反应。通过自由场电泳可将分析物或反应物转移到任何的特定微观位置，在此使分析物或反应物有效地浓缩并与该微观位置上的特异性结合物反应。在杂交分析时，因为杂交反应物在特定显微位置浓缩，使特异性分析物或反应物检测的敏感性提高。通过逆转显微位置的极性可以去除未结合的分析物或反应物。因此，该装置也提高了反应特异性。用于核酸杂交或其它分析的基本装置又称作APEX器件，代表可寻址编程的电子矩阵(addressable programmable electronic matrix)。
本发明的一个方面是，APEX器件采用一种流体系统，在所述流体系统中，样品在操作过程中流经APEX器件。在优选实施例中，流体系统包括一个流动室和一个废液密闭容器。样品通过入口进入流动室并流经APEX系统的活性区域。优选流动室具有特定的容积，优选范围为5-10微升。自动检测器件上的流动样品在稀释、浓缩和/或相对多样的DNA样品的杂交分析中提供重要的优势。例如，假如与同一样品室体积相比整个样品体积相对较大，那么样品的流动性可使整个样品获得更全面的分析。或者，当样品容积相对小和/或DNA浓度相对高，可以进行稀释以便使样品粘度降低。
关于本发明的另一方面，利用一个“系统”可以有顺序地进行另外的加工步骤或子步骤，这一系统是组件的一种集成布置。对每一组件进行合理设计和大小规格确定以进行特定功能。在本发明最全面的实施例中，一个系统可完成所有样品制备、杂交、检测和分析过程。以这种最完全的形式，首先制备样品，例如通过一个电子细胞分类器组件制备样品。一般而言，“电子的”更具体地是指组件将带电物质电泳转移进出的能力。而且通过一个粗制DNA分类器组件和一个限制性片段分类器组件可选地进行DNA的处理和降低DNA的复杂性。最后将最后处理的靶DNA转移到分析组件，以微观多路切换形式进行电子杂交分析。该分析组件装置也被叫作APEX或分析芯片，相关的检测和图像分析组件提供结果。
在该系统内，通过自由电场电泳、沟流、射流或其它技术，可以可选地在组件之间转移材料。电子试剂分配器组件可以可选地将试剂电泳转移到该系统的不同处理组件，可选地提供一个电极和吸引并保留带电废产物的带电基质材料，形成了一个带电废物处理系统。一个DNA片段电子贮存系统可以可选地用来为以后的杂交分析暂时保留其它DNA片段。
本发明的一个方面是通过从大多数不含所需靶DNA的DNA材料中分离含有所需靶序列的特异性DNA片段的多种处理，降低基因组DNA复杂性。粗制DNA可被转移并捕捉一个支持体上，然后用合适的限制性内切酶将结合的DNA切断。切割后，将DNA片段转移到进行特异DNA片段选择性杂交的一个组件上。通过进一步用限制性内切酶切割，可以使含有真正待分析靶序列的那些片断选择性地释放出来，并将其转移到该系统的分析组件(APEX芯片)。该步骤可以可选地重复应用于含有其它靶序列的其它片段。
该器件(或系统)的控制器提供该器件不同方面的各种控制。当应用一个含有可寻址微观位置的APEX器件或芯片时，该控制器可电控制各个微观位置，以便指导特异结合物转移和结合到该位置上。多步骤的多路切换反应可在完全准确的电子控制下进行，最好在一个基于微处理器的基本组件控制下进行。在该装置的微观位置上大大提高多步多路切换反应的速率、特异性和敏感性。用户通过诸如显示屏和输入键盘等的输入/输出装置接上该控制器。最好采用用户图形界面输入/输出装置连接到控制器，该控制器随后控制该系统的可寻址电子位置的电状态。具体地讲，控制器指导电源/波形发生器产生不同微观位置的电状态。电源/波形发生器与APEX器件或系统之间可选地使用一个接口，该接口最好包括通过一个多功能输入/输出装置连接受到控制器控制的一排继电器。继电器最好用来通过控制连接的极性、连接与否以及供给单个位置电位或电流供应大小，将电源/波形发生器与APEX器件连接。控制器最好控制杂交系统照明光源。检测器、图像处理和数据分析系统可选地与APEX器件通过光连接耦合。在推荐实施例中，荧光显微镜接收和放大来自该装置不同微观位置上发生的杂交反应的图像。荧光辐射通过滤光片，由一组电荷耦合器件阵列或微通道板检测器进行测定。再进行图像的贮存和分析。结果最好在监视器上显示给用户。
在本发明的一个方面，利用一个在小几何平面系统中检测荧光的改进装置。在推荐实施方案中，在研究区域与该检测器之间配置的光导路径内配置一种光传输件，诸如一个光纤。在最佳实施方案中，在液体光导中同轴布置一个光纤。一个激发光源(诸如激光)通过光学镜片提供辐射，使得激发纤维将激发辐射传送至研究区域。激发纤维最好同轴配置在返回光导路径内，至少在与研究区域相邻的邻近端。返回路径最好包括液体光导，后者最好包括光学镜片，以接收研究区域的发射，并且将该发射通过该光导转移至该检测器。
在本发明的另一方面，形成的杂交系统在含有控制电子电路的衬底上具有许多微观位置。具体地说，提供开关电路以分别对微观位置寻址。通过相对于待进行样品接触的背面制成电连接。另外，在微观位置下面配置一个光路(诸如波导管)，以允许从背面进入该微观位置。必要时，光学激发可以通过波导管导向该微观位置。可以通过背面的波导管检测发出的辐射。在本发明的再一方面中，在该系统上，特别是杂交矩阵区上，配置一个样品容纳系统。在推荐实施方案中，调整该矩阵杂交区(包括样品容纳组件)，以脱离提供电子控制和检测器元件的其余器件。
在本发明的另一方面，描述了形成矩阵杂交系统的改进方法。在一个方法中，用绝缘层(诸如厚的氧化物)形成一个衬底，诸如硅。诸如通过沉积金属(例如铝或金)，然后诸如通过常规的光刻技术形成图案，形成导电的微观位置。形成绝缘涂层，诸如通过PFCVD形成的TEOS。在TEOS层上可选地形成氮化物钝化涂层。通过氮化物和玻璃形成微观位置的开孔。诸如钛钨之类物质的胶粘改进材料可以用来连接金属层，以促进与该氧化物和/或玻璃的粘附。在再一改进中，可以通过钻蚀该衬底支承的氧化物层上配置的氮化物层，在电极顶部形成阱。
可以进行各个微观位置的电子控制，以便控制电压或电流。设定一个方面时，可以监视另一方面。例如，当设定电压时，可以监视电流。电压和/或电流可以以直流方式施加，或随时间变化。例如最好使用脉冲电流或DC偏置。该脉冲系统最好与流控系统，特别是流动室设计的流控系统一起使用。通过协调脉冲序列和流速，可以更有效地询问整个样品体积的样品。另外，甚至对于非流动情况，诸如没有脉冲的非靶材料(例如DNA)的量相对高时，可能淹没活化测试位点。脉冲技术一般在较高的离子强度下产生较高的靶迁移率，减低探针的烧光作用，提高杂交效率，提高点突变鉴别和增强DNA指纹法。
在本发明的再一方面中，已经惊奇地发现，DNA杂种电子变性器件获得的荧光信号在与该杂交有关的电子电平和功率电平上或其附近波动。具体地说，该荧光信号的波动在荧光标记探针从粘附于APEX垫上的捕捉序列去杂交之前产生荧光强度的升高或波尖。该荧光波尖的功率大小、振幅和斜率提供诊断的分析工具。该荧光波动与其它测量方法的组合也表示杂交匹配/错配状态，诸如电子熔化(在电子间隔控制期间降低50％荧光)的考虑可以组合提供一个更有效、更可靠的杂交匹配/错配分析。
本发明又一方面是提供用一种微型电子装置改进的DNA指纹分析系统。这样一种装置用于鉴别大约100-3000个碱基对大小的靶。将具有给定长度的荧光标记片段结合到一显微位置的捕获探针上。对该显微位置施加反向电位，其大小足以测定该捕获探针与该标记片段的结合量。一般通过在升高的电源下施加一个反向电位，以便使该位点的靶去杂交，在电流电平较低时长度较长的DNA被选择性地去杂交。因此，去杂交电流电平与DNA大小有关。
因此，本发明的目的之一是提供一个用于生物材料样品制备、处理、杂交、检测和分析的系统装置。
本发明又一目的是提供一个在一个集成系统内将多个步骤或子步骤合并的系统。
本发明又一目的是提供一个自动DNA诊断系统。
本发明再一目的是提供一个改进的荧光检测系统，对小几何平面检测尤其有用。
本发明的另一目的提供流体系统(如一个流动室)和一个自动检测仪的集成的一次性组合物。
本发明的另一目的是提供一个能够用常规技术高效和低成本地生产的系统。
本发明的又一目的是提供一个改进DNA指纹法及分析系统，该系统可以电子鉴别不同长度的DNA片段。
附图的简要说明
图1显示样品制备、杂交、检测和数据分析的步骤及子步骤的顺序。
图2A和2B显示主动可编程矩阵系统的剖视图(图2A)和透视图(图2B)。
图3显示金属掩膜层上的主动可编程矩阵系统结构。
图4显示主动可编程矩阵系统的详细平面图。
图5是单个微观位置和电子连接的透视图。
图6是包括流动室和AEPX装置的流体系统的剖视图。
图7是PCMCIA板上的包括流动室、废液密闭系统和诊断系统的流体系统的平面图。
图8是包括电子细胞分类器矩阵、DNA选择器、限制性片段选择器和杂交矩阵的系统平面图。
图9是控制系统的方框说明图。
图10显示不同电压和电流状态的用户指示。
图11是用于小型几何结构系统的荧光检测系统的剖视图。
图12A是20-mer寡聚物双链(100％AT)的随外加功率(微瓦特)变化的相对荧光强度曲线图。
图12B是19-mer寡聚物双链(53％GC)的相对荧光强度对外加功率(微瓦特)的曲线图。
图13A是20-mer寡聚物双链(100％AT)的相对荧光强度对外加功率(微瓦特)的曲线图。
图13B是19-mer寡聚物双链(53％ GC)相相对荧光强度对外加功率(微瓦特)的曲线图。
图14A显示含有捕获探针、靶DNA和报道探针的错配测试位点的剖视图。
图14B是靶DNA和具有相关荧光团的报道探针的剖视图。
图14C是一荧光反应图，该图显示相对荧光强度与随脉冲序列时间变化的曲线图。
图15A是含有捕获探针、靶DNA和具有嵌入荧光团的报道探针的匹配测试位点的剖视图。
图15B是靶DNA和具有嵌入荧光团的报道探针的剖视图。
图15C是相对荧光强度随脉冲序列时间变化的曲线图。
图16A-D是用于DNA指纹法和分析的精密电控制装置的多个测试位点的剖视图。
本发明的详细说明
图2A和图2B简要说明了本发明的主动可编程电子矩阵杂交系统。一般来讲，衬底10支持一个电子可寻址微观位置12的矩阵或阵列。为了便于说明，将图2A的不同微观位置分别标为12A，12B，12C和12D。渗透层14位于各个电极12上面。渗透层允许相对小的带电物质通过它转移，但是阻止大的带电物质如DNA与电极12直接接触。渗透层14避免了DNA由于直接与电极12接触而发生电化学降解，而且起到避免DNA与电极发生强的非特异性吸附的作用。粘附区16配置在渗透层14之上，为靶物质提供特异性结合位点。与电极12A-D相对地将粘附区16分别标为16A、16B、16C和16D。
在操作中，储液器18包括粘附区16上面的空间，储存器中含有需要及不需要检测、分析或使用的物质。将带电物质20(如带电DNA)置于储液器18中。本发明方面之一是，该主动可编程矩阵系统包括了将带电物质20转移到任一特定微观位置12的方法。当活化时，一个微观位置12产生将任一带电功能化特异性结合物20移向电极12的自由场电泳转移，例如，假如使电极12A为阳极，而电极12D为阴极，那么电泳力线22将在电极12A与12D之间通过，电泳力线22引起带净负电荷的带电结合物20向阳极12A转移。带净正电荷的带电物质20在电泳力作用下移向带负电的电极12D。在电泳力作用下，已功能化的带净负电荷的结合物20由于其本身的移动与粘附层16A接触，功能化的特异性结合物20共价结合于粘附层16A。
电泳转移的发生，是因为在该系统内施加的电压足以产生电解和离子转移。诸如通过电解质溶液中的离子运动，产生电泳迁移，电流流经该系统。这样，通过离子电流和传统电子组件(如电极和控制电路)完成的其余电路形成一个完整的电路。例如对于含有常规物质(如氯化钠、磷酸钠、缓冲液及离子物质)的电解质溶液，诱导电解和离子移动的电压大于或等于大约1.2伏特。
可以对不发生反应的粘附层(诸如16B和16C)进行保护，例如使其相应的电极12B和12C为阴极。这产生源自粘附区16B的电泳力线(为了简便仅讨论16B，16C的结果与16B类似)。电泳力线24驱动带负电结合物20从粘附区16B移向粘附区16A。这样，此时在需要与带电分子20不发生反应的粘附区16周围形成“力场”保护。
该系统一个非常有利的结果是，在信号粘附层16的相邻区域中可以高度浓缩带电结合物20。如透视图2B所见，如果一个微观位置26A带正电，而其余微观位置带负电，那么电泳力线将使带净负电结合物20移向微观位置26A。图2A显示了微观位置26A的粘附层16、渗透层14和下面的相关电极12的组合。这样，可以得到使分析物或反应物在该器件的任一特定微观位置浓缩和进行反应的方法。在特异性结合物20粘附到粘附层16之后，下面的微电极可以以直流(DC)方式起作用。在保持的电荷与分析物或反应物分子相反的任一微观位置上，这一独特特性允许游离于溶液中相对稀的带电分析物或反应物分子先后或同时转移、浓缩及发生反应。在选定的微观位置26上浓缩低浓度的分析物或反应物分子的能力，大大加块这些微观位置26上的反应速度。
在所需反应完成后，可以逆转电极的电位，由此产生与先前吸引力方向相反的电泳力。这样，可从微观位置26去除非特异性分析物或未反应物分子。特异性分析物或反应产物可以从任一显微位置释放出，并转移至其它位置以进行进一步分析；或贮存到其它可寻址位置；或者完全从该系统移出。通过逆转电场去除或去浓缩物质，由于导致非特异结合的去除而增强该系统的分辨力。通过控制现在排斥粘附层16上非特异性结合物的电泳力的大小，可以获得严格的电子控制。升高电极12的电位，以便使产生的电场大小足以部分地去除杂交DNA序列，因此可以鉴定单个错配杂交，可以鉴定点突变。
在不同粘附层16上可同时或连续进行操作。例如，参考图2A，利用所示电位，可以首先在粘附层16A产生反应。电极12A的电位可以逆转，即为阴极，而相邻的电极12B可以变成阳极。照此，发生一系列反应。没有特异性结合于粘附层16A的物质被电泳力转移到粘附层16B。这样，在然后经受正电泳力的特定粘附层上利用其浓缩方面功能提供高度浓缩。然后浓缩物质被移至邻近或其它粘附层16。或者，在有一个源自电极12，通过粘附层16进入储液器18的电泳力场的意义上，可以使许多粘附层16去保护。通过使多个粘附层16去保护，进行多种反应。每一位点26实际起着独立的生物“测试管”的作用，因为由一给定粘附层16寻址的特殊环境不同于其它粘附层16周围的环境。
图3显示主动可编程电子矩阵系统的金属掩膜层的平面图。大量的单个电极30最好形成阵列，例如形成8×8的单个电极30矩阵。可以可选地提供另外的控制焊盘或转储焊盘(dump pads)32，有助于产生所需电泳场。电极30和焊盘32与接触焊盘34连接。所示的68个接触焊盘相应于64个电极30及4个焊盘32。引线36分别将电极30和焊盘32连接接触焊盘34。如图所示，使用扇出图案允许从电极30和焊盘32的相对聚焦区连接到掩膜边界36。
图4是图3掩膜的详细分解平面图。产生的金属化系统本质上类似于掩蔽图案。所示电极30大致形成方形结构。引线36将电极30与接触焊盘34连接起来(图3)，引线36的推荐线宽是1-20微米。
图5显示单个电极50的透视图。电极50直接与引线52相连，渗透层54配置在引线50之上，粘附层56配置于渗透层54之上。
用微石版印刷术生产的器件的渗透层厚度可以为1nm-1000μm，最好是500nm-100μm。渗透层应该覆盖整个电极表面，渗透层可以由任何适合的物质构成，如聚合物、膜、多孔金属氧化物(即氧化铝)、陶瓷、溶胶-凝胶、多层式复合材料、粘土和受控多孔性玻璃。
图6是流体系统和APEX类检测系统的剖视图。图7是印刷电路板上图6流体系统在其较大的内含物环境中的平面图。参考数字在可能的程度上用于说明。生物芯片60(最好是前述APEX型芯片)与一种流体系统结合在一起。在推荐实施例中，该流体系统包括一个流动室62，流动室62邻近并配置于生物芯片60之上，最好与生物芯片60紧密接触。流动室62最好有一窗口64，允许光线通向生物基片60。流动室窗口66在边缘处与流动室62接触。流动室窗口可以是石英或部分根据其透射和非荧光性质选择的合适物质。选用的流动室窗口66的折射率最好与样品溶液的折射率匹配。通过流动室62提供入口68和出口70，样品室74由流动室62、流动室窗口66和生物芯片60一起限定。在推荐实施例中，样品室74的体积为5-10微升左右。输入管76最好与入口68相连。输入管76可选地与诸如通过一个阴Luer圆锥形系统形成的流体接口78相连。输出管80最好与出口70相接。该流体系统组件最好由惰性物质构成，例如四氟乙烯或其它医用级塑料。流动室62和相关组件可用任何已知技术(例如模塑或机械加工)形成。
输出管80最好提供从流动室60至储液器82的连通路径。在推荐实施例中，储液器82的最小体积为1.2ml左右。如图所示，形成一般的非膨胀性废液管样的储液器82。在该实施中，废液储存管82充满了从流动室62流经输出管80的流体。在另一实施例中，储液器82可以是可膨胀结构，诸如一个可膨胀的聚酯薄膜袋。储液器82可以可选地在真空下操作，由此提供额外的力，使样品流入储液器82。这样的真空结构可以通过诸如真空容器(vacutainer)制成。
生物芯片60最好用胶粘剂86固定在印刷电路板84之上，诸如FR4线路板。胶粘剂86可以是用于表面安装技术中的任何类型的常规胶粘剂，根据需要胶粘剂可以是传导性或非传导性的。例如，胶粘剂86可以是导热的环氧树脂。引线88从生物芯片60连接到印制引线90。可以采用常规技术，例如球焊或应用0.001英寸AlSi或金线进行楔焊。采用常规技术在印刷电路板上形成印制引线90。如图7所示，印刷电路板是按PCMCIA方式形成的，使得68个位置的电接点92提供印制引线90与连接于电接点92的电子装置之间的接口。可采用常规方式。
引线88最好埋嵌或封装于一种保护性材料中，诸如非传导性的抗紫外线环氧树脂。该保护性材料最好提供引线88以电绝缘性，提供引线88的防湿层并提供整个器件强度的机械支持。印制电路极及其上面形成的结构的整体刚性由任选框架96产生。
关于图6和图7结构组成的推荐模式，生物芯片60最好通过胶粘剂86粘附于印刷电路板84上，下一步是引线88从生物芯片60连接到印制引线90。然后引线88封装于保护性材料94中，从胶粘剂88向外配置的生物芯片60的中心区保持空隙。在APEX装置中该空隙区约7.5mm2，然后流动室62与生物芯片60直接相连。在推荐实施例中，流动室62可以由与所述目的和材料相容的任一材料构成，诸如医用级塑料。生物芯片60可以诸如由硅构成。然后流动室62可以通过胶粘剂粘附于生物芯片60的硅上面，此胶粘剂一般相对较薄。将流动室62固定于生物芯片60上与将引线88封装于保护性材料94中的顺序可以调换，即在加保护性材料之前可以将流动室62或其它组件固定到生物芯片60上。
最好将生物芯片60置于图7结构的旋转回转中心。在某些实施例中，生物芯片60包括一个渗透层或配置于生物芯片60表面上的其它层。这些材料通常旋涂于生物芯片60表面上。通过将生物芯片60置于旋转由上，除了流动室窗口66外以及可选地除其它组件(例如框架96、输入管76、流体接口78、输出管80和储存器82)之外，图7整个结构均可以旋转，以便将材料加到生物芯片60表面上。因为转速通常可以较大，例如对于某些聚合物为10,000rpm，因此将生物芯片60置于旋转中心可使旋转涂更容易。通过在诸如渗透层和捕获序列等结构上形成旋转，可以形成图7所示类型的一般结构，根据需要放入用于分析的合适聚合物和捕获序列。此外，在所有其它结构基本上形成后，通过在生物芯片60上形成相关分析层，允许在加入生物敏感性物质(如渗透层和附着序列)之前，对已生产好的器件进行预清洗。
图8显示自动样品制备和制备材料杂交的完整系统100。将样品102(诸如血液或其它生物材料)加入系统100。一般提供一个加样口104。当样品102上面有生物容器结构时，不通过加样口104进入就不能将样品102直接放入系统100，此时一般需要用加样口104。可以可选地将保护层(诸如玻璃或透明塑料)置于系统100外。
在系统100中，用电子细胞分类器矩阵组件108、DNA选择器组件110和限制性片段选择器组件112一起共同完成样品的制备。根据预定的用途，可以进一步说明选择器组件112，例如限制性片段选择器112从人类基因组DNA或背景DNA中分离细菌或病毒核酸。电子细胞分类器矩阵组件108由下面的电极、渗透层和粘附层组成。这些有效地形成了附着细胞的位置矩阵。各个位置的面积和整个矩阵面积一般大于分析仪器组件的面积。因此，适当调节电子细胞分类器矩阵，以适应不同样品及不同样品大小的细胞数的变化。粘附层一般可以是细胞选择性的，或者对不同类型细胞为单一选择性的。多组位置可选地制成对一种类型细胞的选择性，通过将特异性抗体或细胞粘附因子结合到粘附层上，赋予细胞选择性。矩阵108通过自由场电泳操作。
粗制DNA选择器110和选择器112起着结合电子细胞分类器矩阵108输出的粗制DNA的作用，且允许从结合材料上选择性地切割所需DNA。术语“粗制”仅用于指DNA分离或DNA复杂性降低中的非最后阶段。DNA结合于一个区域中的选择器，该区被认为不含有所需DNA材料。然后诸如应用限制性内切酶将所需DNA材料从结合材料上切下。在分析传染病时，设计选择器112从人基团组或其它背景DNA中分离细菌或病毒核酸。用物理方法将切断的非结合材料从粗制DNA选择器110转移到选择器112。最好用电泳转移方法取出切断的材料。通过将切断的材料结合到一选择器上，用一种限制性内切酶作用于该物质，以便切割含有所需DNA的非结合部分，可以重复该过程。
例如，人类DNA含有约100,000个基因，总DNA中的大部分组成不含所需DNA信息的重复序列。可以通过利用含重复序列的这些非信息部分将该DNA结合到选择器上。可以从被认为含有所需待分析DNA的非结合DNA切开结合DNA。然后用使该材料结合到选择器的特异性更强的DNA序列重复该过程。
然后将选择器112的输出物供应APEX芯片114。按图2A和2B所述方法进行矩阵114的操作。
可以提供电子试剂分配器系统116，以将试剂输入系统100。如果试剂是带电的，最好通过电泳力转移试剂。系统100可选地包括电子废物处理系统118。废物处理系统118吸引带电废物颗粒并通过将带电物保留在其表面而进行处理。系统100的另一可选组件是DNA片段贮藏系统120。该片段贮藏系统起暂时保存DNA片段的作用，以用于进一步的分析。
系统100可以可选地提供辅助电极122。辅助电极122可以有助于整个系统100的材料的电泳移动。沿长轴选择性激活辅助电极122，可以加速或抑制物质的移动。
除加样孔104外，可以可选地包括系统100以外的其它进出口，例如流体进出口124用来为系统100加入额外的流体。此外，所示电连接126配置于系统100周围，用来提供诸如与驱动板/计算机接口138的电接触(图9)。
系统100可能包括了部分或所有上述功能。例如，通过DNA选择器110和限制性片段选择器112进行的复杂性降低形式的样品制备组合可与分析矩阵114联合在一起。然而，根据需要可将任何或所有上述功能组合在一起。
图9显示包括控制器130的整个系统的方框图。通过供给该电极可控电压或用通过该电极的受控电流使APEX器件中下面的电极激活。当独立控制APEX器件每一个电极的电位或电流时，实现全部功能。这由APEX控制器系统完成。
控制器计算机130与用户输入/装置(诸如显示器132和输入装置134)相连。显示器132可以是任何形式的常规显示器，诸如监视器或计算机荧光屏。输入134可以是任何常规的用户输入装置，诸如键盘、鼠标或触摸屏装置。控制器计算机130与电源和波形发生器136连接。控制器130设定电源和波形发生器136，以提供输出到接口138的电流或电压。在推荐实施例中，电压或波形发生器136能够提供精确调节的电压和电流源。控制器计算机80通过多功能输入/输出板140提供给接口138控制信号。接口138提供一个与PAEX系统142接触点的简化连接。
该接口最好包括继电器，后者允许电压和波形发生器136之间与APEX系统142的特定电极选择性地连接。在一个实施例中，接口138包括多个继电器，后者将电压和波形发生器与APEX系统142电极连接。这些连接允许选择或不选择电压和波形发生器136之间通向APEX系统142电极的一个路径。此外，另一继电器允许选择供给APEX系统142电极的电压极性。如果诸如从多个输出电压136可获得多个源电平，那么待连接APEX系统142电极的特定电平的设定可以独立于其它电极的电平。
因此，如结合图2A所述，通过将某些电极(例如12B和12C)设为阴极，但电位低于电极12D，使粘附区16B和16C受局部力场的保护。
接口138可以用来选择APEX系统142中各个电极所需的电压。或者，通过使用分压器可以得到这样一种不同的电压布置。
在推荐实施例中，控制器计算机130是Macitosh Quada 950。应用National Instrument Corporation LabVIEW软件为用户提供软件界面，以设计与APEX相连装置的程序及收集和处理检测数据。NationalInstrument NuBus板提供Quadra 950型计算机130与电源装置136的硬件接口，电源装置产生源电压和电流，并测定实际电流和电压值以及检测结果。
用户通过LabVIEW软件形成的虚似仪器控制检测过程。对于用户可能进行的操作控制和控制APEX进行检测的某些检测结果，虚拟仪表可以为用户友好地提供图示。用户通过Quadra 950型计算130的键盘和鼠标(集中在输入装置134)与虚拟仪表联系。虚拟仪表为National Instrument NB-MIO-16XL多功能输入/输出装置提供软件界面；以及为连接到Quadra 950计算机的NuBus数据总线的NationalInstrument DMA 2800板提供软件界面。
多功能I/O板能够为外部装置提供数字信号和/或模拟信号，通过虚拟仪表实现用户指定的程序序列。在虚拟仪表控制下，MIO板能够将连接到APEX的装置产生的信号数字化并存储在Quadra 950中。DMA 2800提供一种能力，绕过Quadra 950 CPU，迅速存储MIO板通过存储器直接存取获得的数据。对于遵守IEEE 488通讯和数据传送标准的外部装置(这包括大多数现代化仪器)的控制，DMA 2800也提供一个GPIB(IEEE 488)接口。
在控制器的推荐实施例中，两个外部装置用于产生通向APEX的电压或电流。作为一个准确调节电压或电流的电源，Keithley 236源/测量单位(SMU 236)电源装置提供足够的稳定性和适应性。SMU 236或者施加电压并测量产生的电流，或者提供电流源并检测产生的电压。在GPIB控制下通过DMA 2800板，由虚拟仪表对该装置进行编程，以控制电流或电压电平和时间依赖性；并测量及存储供给APEX的实际电压和电流。
通过接口138中的继电器阵列，将源电流或电压施加到APEX上。对APEX每一电极不连接、接正极或负极，继电器提供独立的切换。推荐实施例也提供一个以上的源/测量电源，为不同电极提供不同电平的正和负电压或电流。具有9个16通道、底盘连接中的3类继电器模块的National Instrument SCXI底盘，总共可提供144个继电器。每一个电极使用两个继电器，提供与正极或负极电源连接或不连接的电源。在推荐实施例中，一束电缆通过一个Cerprobe探头卡将这些继电器与PAEX器件连在一起，Cerprobe探头卡提供探针与APEX器件连接焊盘的机械接触。
对于DNA杂交检测荧光激活，控制器计算机130可选地控制用于激发荧光的照明光源。在推荐实施例中，光源144是一种激光，输出合适波长的辐射，激活APEX系统142中的荧光标记物。
APEX系统142的输出经过观测通路146到达检测器148。观测通路可以是诸如通过光纤的物理连接，或可以诸如通过一台显微镜的光路。在观测通路中可以采用滤光器降低非APEX系统142荧光标记物发射光谱波长的检测器照度。此外，需要降低检测器148激光照明光源144激发波长下的照度时，可应用陷波滤波器。检测器148可以可选地诸如通过应用冷却型CCD摄像机，形成APEX系统142的图像。除了形成光学图像之外，或者作为形成光学图象的替代方法，应用传统方法(诸如光电二极管或光电倍增管)检测APEX系统142的标记物射出的荧光辐射。检测器148的输出提供给数据处理/分析系统150。该系统监控APEX系统142中检测探测物的电平。一个专门的系统可以可选地用于分析系统150。
在推荐实施例中，一个数字转换帧捕获板与Quadra 950 NuBus连接，以提供对视频摄像机(诸如用于推荐实施例中的Optronics冷却型彩色CCD摄像机)记录图像存储的捕获。CCD摄像机通过带有合适滤光器的显微镜观测APEX，以目测APEX上的荧光。
其它系统可以实现控制器的所有上述功能，但是可以使用加入印刷电路板中的常规装置和常规软件，以控制具有类似用户友好介面的用于对该装置编程的板。这些其它系统也可以将继电器阵列的转换元件加入到主动可编程矩阵系统下面的半导体装置。
渗透层(即图2的层14)可以由以下材料构成，但不限于以下材料，例如膜、金属氧化物(例如氧化铝)、碳链聚合物、碳-硅链聚合物、碳-磷链聚合物、碳-氮链聚合物、硅链聚合物、聚合物合金、多层式聚合物复合材料、相互渗透聚合物材料、陶瓷、控多孔玻璃，溶胶-凝胶形成的材料、气凝胶形成的材料、水凝胶形成的材料、多孔石墨、粘土或沸石。
渗透层将结合物与电极表面分开。已经采用微平版印刷术和微机械加工技术制造微观位置。渗透层位于一个阱中(参见例如图2A)，或渗透层可以无凹进，只是涂上一层覆盖电极的渗透层。任何一种布置均可通过渗透层的旋涂完成。微观位置表面的化学改性和微观位置上面的聚合物层的化学改性产生特殊化的表面功能结合位点。
网型渗透层涉及形成网状结构的聚合物分子的自由排列，网状结构的平均孔径大小取决于交联程度。我们已经证明用含有丙烯酰胺作为单体的几种可聚合制剂制成了网型渗透层。我们已采用三乙二醇二丙烯酸酯、四乙二醇二丙烯酸酯和N，N’-亚甲基-双丙烯酰胺作为交联剂。将分子量为330千道尔顿和25千道尔的多聚1-赖氨酸混合为丙烯酰胺/共聚物制剂，以提供将特殊化功能结合到渗透层表面的工具。将该混合物浇注到微观位置表面上，然后用紫外光进行光致聚合。某些情况下加入AuCl4作为光致引发剂。由水和非水溶剂，如甲醇、四氢呋喃、乙腈、丙酮和这些溶剂的混合物熔炼聚合物制剂。
DNA捕获探针可以通过Schiff碱反应连接到渗透层表面，Schiff碱反应是连接到DNA捕获探针上的一个氧化核糖核苷与多聚1-赖氨酸的伯胺之间发生的反应。这提供了将特异性功能共价结合到渗透层表面的证据。
将一个氧化DNA探针通过电泳转移到一个表面微观位置。该捕获探针用荧光标记进行标记，这证明通过电泳寻找微观位置的能力。
将粘附的具有荧光标记的氧化捕获探针通过电泳移向一微观位置上的渗透层表面。可用机械方法将渗透层从微观位置去除。没有观察到荧光标记的捕获探针存在的证据。这证明渗透层保护DNA不与电极表面接触的能力。
在水解产生的泡出现之前，在没有用渗透层修饰的金质微观位置达到的最大直流电流密度为8毫安/cm2；在水解产生的泡出现之前，用丙烯酰胺基渗透层修饰的金质微观位置上述到的最大直流电流密度为40毫安/cm2。这证明在水解形成泡之前，渗透层提高最大电流强度的能力。
由一层或多层聚电解质形成离聚物夹心渗透层。这些聚电解质层可以具有相同电荷或不同电荷，或可以是带电嵌合结构。
两层离聚物夹层的构成是，底层为过氟化磺酸聚电解质(Nafion)，上层为多聚1-赖氨酸。将Nafion底层浇注在微观位置上并让其干燥，然后将该底层暴露于1％(重量)的多聚1-赖氨酸水溶液。阳离子的赖氨酸基聚合物强烈地吸附在阴离子的Nafion底层上。通过Schiff碱反应，多聚1-赖氨酸层允许氧化DNA捕获探针结合到渗透层表面。Nafion底层是阴离子的，可以选择渗透阴离子，如DNA。
图10显示图形用户界面的实例。窗口160为显示器的全貌，提供识别信息162。在直角坐标系统中鉴定主动可编程矩阵系统的不同焊盘。显示器164的每一显示为电参数，诸如焊盘的电流或电压。框164A是一个焊盘(3，4)随时间变化的电流。其中电流随时间变化，且在应用过程中改变方向。框164B显示在所示时间过程中没有外加电流的焊盘(3，5)。框164C显示焊盘(4，4)随时间变化的电流；其中相对于框164A中报道的焊盘(3，4)的时间，焊盘(4，4)电流延迟了。框164D显示焊盘(4，5)随时间变化没有外加电流。框164E显示焊盘(1，1)，电压为一恒定的负直流电压值。框164F显示焊盘(3，4)随时间变化的电压，为一更大的负直流电压值。在所有情况下，框中的虚线为编程电流或电压，实线为测量的电流或电压。
除了上述本发明的推荐实施例和替代方法外，还有几个可能的替代方法。例如，只要同时施加DC偏置电压或电流，就可以及时调节引起离子迁移的电场。使用叠加在DC偏置电压或电流上的AC信号，可产生三个效应：1)使非特异结合DNA形成的背景最小化，2)提供一种电子严格控制方法，可变的控制是交流电流或电压的频率，3)提供使DNA空间校准的方法。
有许多杂交DNA荧光检测法的替代方法。大多数替代技术也涉及捕获探针或靶探针或报道DNA探针的修饰，探针上的报道基团产生可检测信号。其中几个基于纯物理检测的技术不需要报道基团。这些替代技术分类如下：(1)线性光学方法，包括荧光法、时间调节荧光法、荧光猝灭调节法、极性选择性荧光法、吸收法、镜面反射法、折光率变化法、椭圆测量术、表面等离子体激元共振检测法、化学荧光法、斑纹干涉测量术和磁-光Kerr效应；(2)非线性光学法，包括次谐波振荡、三次谐波振荡、参数综合法、光频外差探测法、相位共轭弧立子阻尼法和光学Kerr效应法；(3)基于热效应的方法，包括差动扫描量热法、多频差动扫描量热法和差动热量分析法；(4)基于质量变化的方法，包括晶体微量天平、悬臂微量天平、表面声波和表面Love波；(5)电化学法，包括电流分析法，库仑分析法、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，和(6)应用标记基团的放射性检测法。
图11是改进型检测系统的截面图。样品170包含一个研究区域172，研究区域172可能包括样品170上的多个区域。常规用于荧光系统中的任何不同的激发源174和检测器176可以与本发明一起采用。
最好通过激发纤维178完成将能量从激发源174输送到研究区域172。激发光纤178最好是光纤光导。激发纤维178有一输入端180和输出端182。输出端182可用一种本领域技术人员已知的方式形成，以便提供来自激发源174能量的聚焦投射。可选的纤维发射系统光学镜片184接收激发源174的输出，再将辐射提供给激发纤维178的输入端180。
研究区域172发射的辐射(由研究区域172与检测器176之间的虚线表示)经过光导186。光导186最好包括一个液体光导部分188。液体光导188周围有一个外壳190，外壳起着装存液体光导188的作用。近侧透镜192位于外壳190内的光导186部分，朝向研究部位172。远侧端194位于外壳190内的光导186末端，朝向检测器176。
在推荐实施例中，激发纤维178同轴线形成于光导186中。激发纤维178的输出端182最好通过孔196配置于近端镜片192中。接此方式，激发源174的辐射可以通过激发纤维178，供应到研究区域172，而不经过近端透镜192的光学元件。或者，激发纤维178的输出端182可以位于液体光导188中，这样激发源174的辐射在供给研究区域172之前通过远侧透镜194的光学元件。应用激发纤维178(诸如光纤)允许激发源174和样品170之间一定程度的机械去耦合。例如，激发源174和检测器176安装在原位，在样品170上方移动光导186和激发纤维178。激发纤维178最好包含沿着光导186旋转轴配置的轴区198。激发纤维178轴区198的光路和光导186的同心轴向排列使检测器176对准。液体光导188最好使来自研究区域172的能量更完全地转移到检测器176。另一方面，虽然液体光导188更完全地覆盖来自近侧透镜192的输出，但在光导186中也可采用纤维束。
已经以新方式用前述APEX器件产生一个方法，使该器件的分析或诊断能力提高。令人惊奇地发现，在DNA杂种的电子变性过程中荧光信号波动。该方法在DNA杂交和单碱基错配的分析中具有特殊用途。具体地讲，在已知为严格控制的电子变性过程中，刚好在荧光标记探针与连接到APEX芯片垫的捕获序列去杂交前，观测到荧光强度的升高或尖峰。
图12A和12B显示在APEX芯片上进行的电子变性实验的结果，APEX芯片上有25个直径为80微米的测试微观位置，电极为铂电极。为此，用1微米厚的抗生物素蛋白/琼脂糖渗透层覆盖该芯片，该实验应用两个5’-标记bodipy德克萨斯红(Texas Red)(Ex 590nm，EM 630nm)靶探针。图12A的探针是一个含100％AT的20 mer(5’-BYTR-AAATTTTAATA TATAAT-3’)，其解链温度(Tm)是33℃。图12B的探针是一含53％GC的19 mer(5’-BYTR-CCACGTAGAACTGCTCATC-3’)，其解链温度(Tm)为54℃。(解链温度或Tm指完成50％去杂交的温度)。合适的生物素标记的互补捕获序列结合到几个测试焊盘(同一芯片上)上的抗生物素蛋白/琼脂糖渗透层上。捕获探针的密度为每一焊盘～108个探针。在50mM磷酸钠(pH7.0)、500mM NaCl中浓度为～1.0μM的荧光标记靶探针首先与5580芯片上的结合探针杂交。然后用20mM NaPO4(pH7.0)彻底冲洗该芯片。
通过使测试焊盘偏置为负值并在90秒时间内将测试焊盘的功率从～10-1微瓦(μW)增至～2×102微瓦(μW)，进行电子变性。每个靶探针测试三个焊盘。绘制荧光强度随增加功率变化的相对变化图。使一个探针与其互补序列去杂交所需要的电泳力或功率一般与其DNA双螺旋的结合能或Tm(解链温度)有关。在以上实验中，使具有53％GC的19-mer探针(Tm为54℃)去杂交所需的总功率(μW)高于具有100％AT的20-mer探针(Tm为33℃)去杂交所需的总功率，即对于去杂交完成50％的等效电子解链点(Em)，53％GC探针的Em高于100％AT探针的Em。对于荧光波动(图12A和12B，圆圈区域)，也观察到具有53％GC的10-mer探针也明显不同于具有100％AT的探针。
图13A和13B显示在APEX芯片进行的变性实验结果，该APEX芯片上有25个测试显微位置，每一测试显微位置有一20微米深的阱，阱底是铂电极。芯片上的肼结构充满抗生物素蛋白/琼脂糖复合材料，形成20微米深的渗透层。在深阱实验中所用的荧光靶探针、捕获探针和方案与产生图12A和12B信息的器件操作中所用的相同。与第一个实验一样，含53％GC的19-mer(Tm为54℃)探针去杂交所需总功率高于具有100％AT的20-mer探针(Tm为33℃)，100％AT探针的斜率也比53％GC探针的斜率小很多。在深阱实验中，具有53％GC的19-mer探针的荧光波动/尖峰非常明显。
荧光波动现象与去杂交过程中的序列特异性密切相关。对于包括单个碱基错配分析在内的很多方面的杂交分析，荧光尖峰的功率电平值(μW)、波幅和斜率都是有用的。荧光波动(Fp)值，即与荧光波动相关的那些数值(例如开始反应值、峰高和斜率)与电子解链(Em)值(即荧光半高值)一起，为杂交匹配/错配分析提供的可靠性加和肯定性显著增加。通过结合两个或更多的分析检测，可进行更有效、更准确的测定。
在以上实验中，靶探针在5’末端位置标记上Bodipy德克萨斯红荧光团。虽然Bodipy TR不是对环境特别敏感的荧光团，但是它在电子变性过程仍然显示明显的效应。使用对环境敏感性变高的荧光团，在其荧光特性中获得更大的荧光波动。
敏感性荧光标记位置最好靠近初始变性位置。与在靶或探针的末端进行标记相反，通过将荧光标记靠近变性位点，可以增加特异性并使效应加强。如图14A和15A所示，一个嵌入荧光团200可以位于报道探针202和靶DNA 204之间。图14A显示一状态，因为错配碱基206，报道探针202与靶DNA 204错配。图14A和15A每个图中，捕获探针208的作用是捕获靶DNA 204，焊盘210提供电泳作用。插入型荧光标记可以是例如溴化乙锭或吖啶、或任何与该器件目的和作用一致的已知荧光标记物。
图14B和15B显示通过焊盘210在荧光波动上给予一个电脉冲后，报道探针202、靶DNA 204和错配碱基位点206的状态。由插入环境变为非插入环境导致标记物荧光信号强度的主要变化。
此外，使用荧光团标记指导的错配位置不需要杂交体在该过程中完全变性。如图14C和15C所示，分析过程最好是应用引起错配杂交位点相对于匹配杂交位点部分变性和部分复性的合适的脉冲式“Fp”功率。该方法产生错配杂种位点上观察到的波动的荧光信号，而匹配杂种位点的荧光信号则没有变化。图14C和15C显示随改变的外加功率变化的相对荧光强度。该方法为单碱基错配分析提供了一个特异性和分辨率高的方法。该方法的优点还包括：(1)该方法可用较传统杂交方法的那些探针更长的探针(＞20-mer)，(2)通过放置荧光标记，探针特异性更高(尤其是对单碱基错配)，和(3)因为该方法不需要杂交体结构完全变性，每一样品可重复进行分析，从而可以诸如通过标准求均数的方法等，获得更高的统计显著性数据。
此处公开的精密电子装置最好可以用于DNA指纹法和分析。通过测定引起不同长度的片段与捕获探针序列去杂交必需的不同电子力，电子可寻址阵列可以测定DNA片段大小。如图16A-D所示，显示的三个测试位点210记为测试位点A、B和C。在实际器件中，测试位点数可能远远高于此数字，为了说明其原理和技术显示了3个测定位点。采用上述技术将捕获探针212连接在测试位点210上。给定(虽然可能是未知的)的第一长度片段214在测试位点C 210上与捕获探针210杂交。假设长度与片段214不同的第二片段216在测试位点B 210与捕获探针212杂交。同样，假设长度与片段214、216不同的第三片段218杂交到测试位点A 210上的捕获探针212上。
然后，测试位点210在升高的电流电平下受到逆转电位作用。监测测试部210的荧光信号。随着逆转电位的升高，诸如通过观察图12A，图12B，13A和13B所示的峰，或者通过完全去杂交，检测去杂交的指标。在推荐的实施例中，212检测片段214，216和218与捕获探针的完全去杂交。因为不同长度的片段214、216和218的长度不同，它们将带有不同的净电荷量。因此，随着测试位点210电位的升高，那些具有较多净电荷的片段214、216和218受力更大，相应地，会在较低电位下脱离测试位点210。图16B显示一状态，其中测试位点C 210已达到或超过引起片段214与捕获探针212去杂交的逆转电位。下一步，如图16C所示，当测试位210的逆转电位达到使片段216受的力足以迫使与捕获序列212去杂交的电平时，片段216与测试位点B 210分离。最后，当逆转电位进一步升高时，最短片段218与测试位点A 210的捕获序列212分离。这样，确定使不同大小片段与每一测试位点分离所需的电位或电流，该电位或电流与片段大小有关。
虽然为了达到清楚和容易理解的目的，通过图解和举例已经相当详细地描述了上述发明，根据本发明所讲授的技术，本领域普通技术人员易于看出，不脱离该发明所附权利要求书的精神或范围，可以进行某些变化或修改。

Claims (48)

1.一种器件，用于增强检测样品和生物芯片的活性区域之间的生物学反应，该器件包括：
具有一个活性区域的生物芯片，以及
用来使该样品流经该生物芯片活性区域的流体系统。
2.权利要求1的增强检测生物学反应的器件，其中该流体系统直接与该生物芯片接触。
3.权利要求1的增强检测生物学反应的器件，其中该流体系统包括一个流动室。
4.权利要求3的增强检测生物学反应的器件，其中该流动室实际上环绕该生物芯片的活性区域。
5.权利要求4的增强检测生物学反应的器件，其中该流动室还包括一个窗口，用来允许从该生物芯片的活性区域辐射到该器件的外部。
6.权利要求5的增进检测生物学反应的器件，其中该窗口为一个端口窗口。
7.权利要求3的增进检测生物学反应的器件，其中该流动室具有特定的体积。
8.权利要求7的增进检测生物学反应的器件，其中该流动室的体积实际上为5-10微升。
9.权利要求3的增进检测生物学反应的器件，其中该流动室还包括一个入口和一个出口。
10.权利要求9的增进检测生物学反应的器件，还包括一个与出口连接的储液器。
11.权利要求10的增进检测生物学反应的器件，其中储液器包含一个废液管。
12.权利要求10的增进检测生物学反应的器件，其中储液器包括一个膨胀结构。
13.权利要求1的增进检测生物学反应的器件，其中该生物芯片位于一个电路板上。
14.权利要求13的增进检测生物学反应的器件，其中该电路板是一种PCMCIA板。
15.权利要求13的增进检测生物学反应的器件，还包括连接生物芯片与电路板的电线。
16.权利要求15的增进检测生物学反应的器件，其中该电路板是一种印刷电路板。
17.权利要求15的增进检测生物学反应的器件，其中这些引线埋置于一种保护性材料之中。
18.权利要求17的增进检测生物学反应的器件，其中该保护性材料包括抗紫外线的环氧树脂。
19.增进检测含有待测物质的样品与生物芯片之间生物学反应的方法，该生物芯片含有一个活性区域，此方法包括以下步骤：
使样品流到生物芯片的活性区域，
为了检测样品中的物质活化该生物芯片，
该物质流入一个储液器。
20.权利要求19的增进检测生物学反应的方法。还包括在生物芯片上检测样品物质存在的步骤。
21.权利要求20的增进检测生物学反应的方法，其中该检测步骤包括光学检测。
22.权利要求21的增进检测生物学反应的方法，其中该光学检测包括荧光检测。
23.一种光学检测系统，用来使辐射传递到样品研究区域，和使研究区域的辐射传递到检测器；包括：
一个有入口端和出口端的激发纤维，
一个适于在样品研究区域和检测器之间配置的光导，
该激发纤维包括一个轴向区域，该轴向区域包括激发纤维的出口端，其中轴向区域中的激发纤维实际上与光导的轴平行。
24.权利要求23的光学检测系统，其中该激发纤维是一种光纤。
25.权利要求23的光学检测系统，其中该光导包括一个液体光导。
26.权利要求23的光学检测系统，还包括一激发源，适于将辐射提供到激发纤维的入口端。
27.权利要求26的光学检测系统，其中该激发源是一种激光。
28.权利要求23的光学检测系统，还包括一个纤维发射系统镜片，适于接收激发源的辐射，然后将其传入激发纤维的入口端。
29.权利要求23的光学检测系统，其中该激发纤维的轴向区域与光导同轴。
30.权利要求23的光学检测系统，其中该光导结构还包括光学元件。
31.权利要求30的光学检测系统，其中该光学元件至少包括一个透镜。
32.权利要求31的光学检测系统，其中该光学元件包括一个近端透镜，适于接收来自研究区域的辐射。
33.权利要求32的光学检测系统，其中该近端透镜包括一个小孔，通过该孔配置激发纤维的出口端。
34.样品与探针的杂交分析方法，该分析应用了一种严格电子控制装置；包括以下步骤：
在该严格电子控制装置上，在杂交状态下为该样品与探针提供荧光标记，形成荧光标记杂交产物，
监测杂交产物的荧光，
使杂交产物受到不同电泳力作用，以及
分析该荧光信号。
35.权利要求344杂交分析方法，其中分析该荧光的荧光波动值。
36.权利要求35的杂交分析方法，其中测定该荧光波动值的开始反应值。
37.权利要求35的杂交分析方法，其中测定该荧光波动值的高度。
38.权利要求35的杂交分析方法，其中测定该荧光波动值的斜率。
39.权利要求34的杂交分析方法，其中分析该波动的功率电平。
40.权利要求34的杂交分析方法，还包括以下步骤：
进行样品与探针杂交的第二种检测，
将第一种分析获得的信息合并到第二种测定结果中，提供一个杂交指标，第一种分析包括使杂交产物受到不同电泳力的作用。
41.权利要求40的杂交分析方法，其中该第二种杂交检测包括测定电子解链点。
42.权利要求34的杂交分析方法，其中该荧光标记紧邻起始变性部位。
43.权利要求42的杂交分析方法，其中该荧光标记插入位置紧邻单个碱基错配位点。
44.权利要求43的杂交分析方法，其中该荧光标记物是溴化乙锭。
45.权利要求43的杂交分析方法，其中该荧光标记物是吖啶。
46.权利要求34的杂交分析方法，其中该电泳力小于进行该样品与探针去杂交所需的电泳力。
47.权利要求34的杂交分析方法，其中该杂交产物受到波动型电泳力作用。
48.在一种电子自寻址阵列上进行DNA指纹法的方法，该阵列的每一测试位点上都有捕获探针，在这些测试位点上荧光标记物与杂交物质连接在一起；此方法包括以下步骤：
在第一个测试位点上第一长度DNA片段与捕获探针杂交，
在第二个测试位点上第二长度DNA片段与捕获探针杂交，
当该电子自寻址阵列位点的电位逆转时，观测一个或多个测试位点的荧光信号，以及
检测在一电位下达到去杂交的那些位点。
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US5849486A (en) 1998-12-15
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