CN1268905A - 有效生物电子装置的叠层组件 - Google Patents
有效生物电子装置的叠层组件 Download PDFInfo
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- CN1268905A CN1268905A CN97181305A CN97181305A CN1268905A CN 1268905 A CN1268905 A CN 1268905A CN 97181305 A CN97181305 A CN 97181305A CN 97181305 A CN97181305 A CN 97181305A CN 1268905 A CN1268905 A CN 1268905A
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Abstract
实行有效生物操作所用的装置及制造方法采用叠层结构(30,110)。在优选实施例中,第一平面样品支撑(50,72,104,122)包括至少一个样品通孔(56,74,90);平面电极(32,70,94,112,114)被置于邻近第一平面样品支撑(50,72,104,122)处,并有电极贯穿区(38,76);第二平面支撑(40,78,96,102,124)带有排气通孔(48,80,92,98);所述平面电极(32,70,94,112,114成叠层关系位于第一平面样品支撑(50,72,104,122)与第二平面支撑(40,78,96,102,124)之间。进一步的特征在于样品通孔(56,74,90)、电极通孔(38,76)和排气通孔(48,80,92,98)成重叠布置。最好是一些通孔、贯穿区和排气通孔或者是它们的全部为对准的。在另一实施例中,样品通孔的水平尺寸大于排气通孔的水平尺寸。在优选实施例中,样品支撑和平面支撑均由片状材料制成,最好由聚酰亚胺制成,其厚度实质上为1密尔到5密尔。电极最好选自贵金属,特别是金。各孔或者贯穿区最好都通过激光钻孔形成,最好还伴随以化学蚀刻。借助互相联系给出穿过多个支撑的导电通路,还有助于采用杂交电路,特别是小片挠曲电路。
Description
本发明涉及有效生物操作中所用的方法和装置。本发明尤其涉及包含有效电极的装置,所述电极特别适用于核酸的电泳迁移,及其杂交和分析。
本申请是1995年9月27日提交的申请序号为No.08/534,454,题为“有效可编程矩阵装置所用的设备及方法”的部分继续,而后者又是1994年9月9日提交的申请序号为No.08/304,657,目前已被授权,修订题目为“带多个电极的分子生物学诊断系统”的部分继续,还是1994年7月7日提交的申请序号为No.08/271,882,目前已被授权,修订题目为“电子精密控制分子生物学分析和诊断的方法”的部分继续,也是1993年11月1提交的申请序号为No.08/146,504,目前已被授权,修订题目为“分子生物学分析和诊断的有效可编程电子装置”的部分继续,以及1996年9月6日提交的申请序号为No.08/709,358,目前已被授权,题目为“有效生物学样品制备所用的装置和方法”的部分继续;在此,它们均被作为参考文献,即如这里所充分显示的那样。
分子生物学包括多种形式的核酸和蛋白分析技术。其中一些技术和方法构成临床诊断检测和实验的基础。这些技术包括核酸杂交分析、限制性酶分析、基因序列分析,以及核酸和蛋白的分离和纯化(例如参见J.Sambrook,E.F.Fritsch,和T.Maniatis,分子克隆:实验室手册22 Ed.,Colds pring Harbor LaboratoryPress,Cold Spring Harbor,纽约,1989)。
其中大多数方法都涉及对大量样品进行数目繁多的操作(例如,移液、离心、电泳)。它们通常很复杂且耗时,并需要很高的精度。一些技术因为缺乏灵敏性、专用性或重现性而限制了它们的应用。例如,这些问题限制了核酸杂交分析中的一些诊断应用。
有必要详细描述对遗传性或感染性疾病进行DNA杂交分析的全过程。概括地说,可将这种全过程分成若干步骤和若干子步骤(参见图1)。诊断遗传性疾病时,第一步需要获得样品(血样或组织样)。根据样品的种类,进行各种预处理。第二步涉及破碎或溶解细胞,以释放包含其它细胞成分的粗DNA材料。通常,需要几个子步骤除去细胞碎片,并进一步纯化粗DNA。在这一点上,存在几种进一步处理和分析的观点。一种观点认为将纯化的样品DNA变性,然后用染色斑、微珠、微平板等几种方法中的一种直接进行杂交分析。第二种观点称为“Southern斑点杂交”,采用限制性酶切断DNA,用凝胶电泳分离DNA片段,在薄膜滤器上点样,然后用特异性DNA探针序列与斑点杂交。该方法有效地降低了基因组DNA样品的复杂性,因此有助于改善杂交特异性和灵敏性。不利的是该程序耗时且繁复。第三种观点是采用聚合酶链反应(PCR)或其它扩增方法。相对于非目标序列,PCR法加大(增加)了目标DNA序列的数目。目标DNA的扩增有助于克服基因组DNA分析中,有关复杂性和灵敏性的问题。所有这些方法都是耗时,比较复杂,并且明显增加了诊断检测的成本。制备样品和DNA处理过程之后,进行真正的杂交反应。最后,对杂交实验进行检测和数据分析,得到分析结果。
通常,把样品制备和处理步骤从其它杂交、检测和分析的主要步骤中分离出来,独立操作。实际上,常把包括样品制备和DNA处理的几个子步骤作为独立于其它子步骤的不连续操作单独进行。更详细地研究这些子步骤时,可以通过多种方法得到样品,例如,获得全血样、组织或其它生物液体样品。样品为血样时,处理样品以除去血红细胞,保留所需的白细胞。这一过程通常采用密度梯度离心来实现。然后对白细胞进行细胞破碎或溶解,以释放DNA;最好采用声学法、冷冻/干燥法、或添加胞溶试剂的方法。然后用离心步骤从细胞碎片中分离粗DNA。杂交前,使双链DNA变性成为单链型。双链DNA的变性通常包括加热(>Tm)、改变盐浓度、加碱(NaOH)或加变性剂(脲、氯仿等)。操作者建议用电化学方法将DNA变性为单链型。理论陈述如下:在电极表面,电子转移给DNA,这有效地削弱了双链结构,导致链分离。一般地参见公开于1992年3月18日的Stanley的英国专利申请UK.2,247,889,“DNA的电势变性”。
核酸杂交分析通常涉及用大量探针DNA从相对地说为大量的非目标核酸复合物中检测极少量特异性目标核酸(DNA或RNA)。样品制备过程中降低DNA复杂性的子步骤可以用于检测低复制数(即10,000到100,000)的目标核酸。通过多聚酶链反应(PCR)扩增目标核酸序列,在一定程度上克服了DNA复杂性。(参见M.A.Innis等,PCR方案:方法和应用指南。Academic Press,1990)。而且,扩增会导致产生大量目标核酸序列,以改善随后的探针直接杂交步骤,扩增过程冗长并且繁杂,该程序相对于其它子步骤一般必须独立进行。因此进行扩增步骤需要较复杂和相对较大的设备。
真正的杂交反应是全过程最为重要的步骤和中心步骤。杂交步骤包括将制备好的DNA样品与特异性报告探针接触,在一系列优选条件下与目标DNA序列杂交。可以用任一种方法进行杂交。例如,在多种滤膜和固体支撑模块上进行多样品核酸杂交分析(参见G.A.Beltz等的酶学方法,Vol.100,Part B,R.Wu,L.Grossman,K.Moldave,Eds.Aca demic Press,纽约,19章,266-308页,1985年)。一种方法称为“斑点印渍”杂交,涉及目标DNA非共价附着于滤膜,随后用放射性同位素标记的探针杂交。“斑点印渍”杂交得以广泛应用,并形成若干成型方法(参见M.L.M.Anderson和B.D.Young,核酸杂交——实践研究,B.D.Hames和S.J.Higgins,Eds.,IRL Press,华盛顿特区,73-111页,1985年)。基因突变的多重分析(D.Nanibhushan和D.Rabin,EPA 0228075,1987年7月8日)、重叠克隆的检测以及基因组图谱的构建等方法已经成熟(G.A.Evans,美国专利号US.5,219,726,1993年6月15日)。
在微型多重装置或矩阵装置上(例如DNA芯片)进行多样品核酸杂交分析的新技术已经成型(参见M.Barinaga,253科学,1489页,1991年;W.Bains,10,生物/工程,757-758页,1992年)。这些方法通常涉及将特异性DNA序列附着于固体支撑物的非常小的特异性区域,例如DNA芯片的微孔。这些杂交方法是传统“斑点印渍”和“三明治”杂交系统的微量形式。
微量杂交可以用于“杂交测序”(SBH)(参见M.Barinaga,253,科学,1489页,1991年;W.Bains,10,生物/工程,757-758页,1992年)。SBH可以应用所有可能的n-核苷酸低聚物(n-mers)鉴定未知DNA样品中的n-mers,随后用算法分析校准,以确定DNA序列(R.D rmanac等,4,基因组,114,1989年;Strezoska等,88,美国国家科学进展10089,1992年;R.Drmanac和R.B.Crkven jakov,美国专利US.5,202,231,1993年4月13日)。
进行SBH有两种方法。第一种方法为:将所有可能的n-mers排列在支撑体上,然后用目标序列杂交。第二种方法为:将目标序列附着于支撑体,然后用所有可能的n-mers作为探针分析。这两种方式都存在与多重杂交有关的探针直接杂交和附加困难等基本问题。
Southern的英国专利申请GB8810400,1988;E.M.Southern等,13,基因组1008,1992,建议用第一种方式进行DNA分析和测序。Southern通过PCR扩增基因组DNA,鉴定了一种已知的单点突变。Southern同时描述了在固体支撑体上排列低聚核苷酸用于SBH的方法。然而,Southern没有说明如何对每种低聚核苷酸获得最佳排列的精确条件。
同时,Drmanac等,260科学1649-1652,1993,应用第二种方法对几种短DNA序列(116bp)进行测序。将目标DNA附着于薄膜支撑物(“斑点印渍”法)。随后用272标记的10-mer和11-mer低聚核苷酸对每种滤膜杂交。使用了较宽范围的条件实现对每种n-mer探针的特异性杂交。清洗时间从5分钟到整夜不等,温度从0℃到16℃不等。大多数探针需要在16℃条件下清洗3小时。使滤膜露置2到18小时,以便检测杂交信号。即使对单目标序列测序,减少低聚核苷酸探针,并使用最精确的条件,总假阳性杂交率仍为5%。
杂交检测和分析有各种方法。当检测和分析有赖于标记DNA探针的报告基团时,采用荧光分析、比色分析、或自动射线照相术进行分析。通过观察和测量激发的辐射,例如荧光辐射或颗粒发射,获得杂交信息。甚至当检测方法本身具有高度灵敏性时,检测杂交仍然很难,因为存在非特异性结合材料的背景。其他许多因素也降低了DNA杂交分析的灵敏性和选择性。
在传统的荧光检测系统中,使一种波长的激发能量传递到重点区,然后检测其他波长的能量。一般具有两毫米或更大重点区的大规模系统已经得以应用,其中全系统的质量没有因需要的光学元件的尺寸或将他们放置到光学上邻近重点区所致的能力限制。然而,对于小的几何体,例如低于2毫米的几何体,尤其是约500微米或更小尺寸的重点区,传统的荧光法证明不能够应用。通常激发光元件和发射光元件必须紧邻重点区。最好,聚焦的斑点尺寸相对地比较小,通常需要精密的光学设计。而且,因为通常期望检测区域最大化,为达到这些目的,光学元件的尺寸与它们距重点区的距离相比,变得更为重要,某些情况下,甚至抵消了获得的性能。
曾试图将某些处理步骤或子步骤进行组合。例如,曾提议用各种微电脑系统在支撑材料上制备阵列的DNA探针。例如,Beattie等,1992年圣地亚哥会议:基因识别,1992年11月,使用了一种微电脑系统,将含特异DNA序列的微滴,置于玻璃物质上各自独立的微型装配的样品池中。
通常,现有技术的处理过程非常费力耗时。例如,PCR扩增过程就很耗时,并增加了诊断费用。多步骤处理时,需要在一个步骤中或两个步骤之间有操作者参与操作,这并非很理想,因为增加了污染和操作失误的可能。另外,使用多种仪器或复杂的电脑系统进行样本处理时,考虑到需要的费用以及所需的物理空间,除非在最大型的实验室,否则,一般地说是难以进行的。
从上述讨论可以看出,已经进行了大量的努力,以提供多步骤、多重分子生物学反应的有效方法。然而,从上面陈述的原因看,这些技术仅仅是“零散”的,并且还很有限。各种这样的研究并不容易组合起来,形成可以进行完全DNA诊断分析的系统。尽管长期以来一直认为需要这样一种系统,仍没有提出满意的解决办法。
本发明公开了用于生物学诊断的有效电子装置中适用的组件和该组件的制造方法。在优选实施例中,一种多层的叠层装置至少包括第一平面样品支撑,该第一平面样品支撑带有通孔;邻近该第一平面样品支撑的平面电极,该电极有贯穿区;带有排气通孔的第二平面支撑;所述平面电极在第一平面样品支撑与第二平面支撑之间成叠层关系。进一步的特征在于所述样品通孔、电极贯穿区和排气通孔彼此重叠。在优选实施例中,各平面支撑部件可由薄片状材料制成,最好由比如DuPont(杜邦公司)的商标为KaptonTM的聚酰亚胺制成。平面支撑的首选厚度是在1-5密尔范围。应将样品支撑的材料选择成具有与有效生物装置的目标和目的相符的性质,例如表现出较低的DNA约束特性,有较低的固有荧光性,在酸性环境中相对地不活泼,以及是不导电的。
通过使用多层薄片可以形成堆叠结构或叠层结构。在一种具体实施例中,沿着朝向将要接纳生物材料之表面的方向将一层或多层附加层置于平面样品支撑的上方。类似地,可使多层结构或者叠层结构形成于第二平面支撑下方。所述各附加的叠层通常都将带有通孔,它们最好都将与所保有的通孔或贯穿区对准。有益的是可按多次配置的方式形成多层结构或叠层结构。在一种具体实施例中,可将电极配置在相对于所述叠层装置的样品一侧为不同深度处,以便做到电极与加于该装置的样品之间的位移距离不同。按照这种方式,这种不同的位移距离使各种功能——如关于同一装置实现减少复杂性并进行实验分析——得以最佳化。通过譬如采用在不同平面上的第一电极与第二电极之间配置插入平面支撑,可在不同的平面处形成各电极。
按照本发明的一个方面,第一平面样品支撑的通孔的水平尺寸不同于第二平面支撑的排气通孔的水平宽度。在一则实施例中,所述排气通孔的水平尺寸大于所述样品通孔的水平尺寸。最好在样品通孔中以及至少在部分排气通孔处带有渗透层。本实施例的潜在优点包括有利于平面电极处或其附近因与杂交反应不同范围的各种反应所生气体的排放,并且这种结构能够固定样品通孔、电极贯穿区内以及至少部分排气通孔处所配置的渗透层。另一个实施例中的样品通孔的水平尺寸大于排气通孔的水平尺寸。平面电极至少有一部分透过样品通孔而面向着外部。
按照本发明的另一方面,可使流体装置形成于所述叠层结构上,或形成于其内,或形成于邻近该叠层结构。例如可在所述叠层结构内带有一个泵,如磁力驱动的微型泵。以此方式,可泵入流体或使流体移过所述系统。
按照本发明的又一方面,可利用小片弯曲电路技术,以便在与有效生物装置接触的操作过程中混成电子电路。另外可形成多级相互连接,比如可通过采用一层或多层之间的连接通路。按照本优选实施例,可使这些通路穿过第二平面支撑而不穿过适于接纳生物材料的最上面平面样品支撑露在装置的外面。
本发明的叠层电路结构及方法适于被用来形成有效生物装置。能能使综合地减少生物复杂性和诊断分析,以及具有反电极的装置形成于一个单一的装置中。
按照本发明的再一方面,可将多层的叠层化结构用于实现生物扩增过程,特别是聚合酶链反应(PCR)过程。可选择将一个或多个加热器集成于叠层结构中,或者使之邻近所述叠层结构,以帮助所述扩增过程。
因此,本发明的一个目的在于提供一种降低制造成本并实现小尺寸显微定位的有效生物装置。
本发明的另一目的在于提供一种从一个显微定位到另一显微定位以及从一个装置到另一装置具有高度均匀电极的装置。
本发明的又一目的在于提供一种减少气泡并减少熔蚀的有效生物装置。
本发明的再一目的在于提供一种改善气体排放、提高阻尼能力的有效生物装置。
图1A和1B表示有效可编程电子矩阵装置,图1A为其断面图,图1B为其透视图;
图2是包括沿面对样品取向之电极的多层结构的断面图;
图3是多层结构的断面图,该多层结构的排气通孔的水平尺寸比样品通孔的水平尺寸大;
图4是多层结构的断面图,该多层结构的排气通孔水平尺寸比样品通孔的水平尺寸大;
图5是多层结构的断面图,该多层结构的样品通孔的水平尺寸比排气通孔的水平尺寸大,所述样品通孔也比电极整个区域的水平尺寸大;
图6是多层结构的断面图,其中样品通孔的水平尺寸比电极整个区域的水平尺寸及排气通孔大;
图7是叠层化的多层结构断面图,该多层结构在离系统的样品表面不同距离处有第一电极和第二电极;
图8是叠层的多层结构断面图,该多层结构包括集成化的驱动装置,即一个泵;
图9是适于减少复杂性的电极图样及生物样品的平面图,图中带有包括回流电极;
图10是在同一平面内构图的电极以及在同一平面内围绕回流电极的3×3样品阵列所用样品支撑物的平面图。
图1A和1B示出本发明所用有效可编程电子矩阵杂交系统的简要说明。一般地说,基板10支撑以电子学方法可寻址之显微定位12的矩阵或阵列。为便于说明,图1A中的各显微定位被记为12A,12B,12C和12D。渗透层14位于每个电极12的上方。渗透层使较小的带电组织能够透过它,但限制较大带电组织,如DNA的迁移,以保持较大带电组织在试验的持续期间易于直接与各电极12接触。通过与电极12的接触,渗透层14降低了将会在DNA中出现的电化学分解作用,部分可能性是由于电泳作用所引致的过度pH值的缘故。它进一步还用于使各电极对DNA较强的非特定吸收最小化。连接区16位于渗透层14上面,它对目标物质提供特定的约束位置。连接区16被叠层为16A,16B,16C和16D,它们分别与电极12A-D的标记相对应。
使用时,槽18包括连接区16上方的空间,它包含为检测、分析或使用所需要的以及不需要的材料。使诸如荷电的DNA等荷电组织20被置于槽18内。按照本发明的一种情况,所述有效可编程矩阵系统包括使荷电物质20迁移到任何特定的显微定位12处的手段。启动时,显微定位12产生任意荷电的官能化特定约束组织20向着电极12的自由场电泳迁移。例如,如果使电极12A为正,电极12D为负,则电泳电力线22将在电极12A与12D之间穿行。电泳电力线22引起净带负电荷的荷电约束组织20向正电极12A迁移。具有净正电荷荷电物质20在电泳力作用下移向负的荷电电极12D。当净负荷电约束组织20实际已经与连接层16A接触,从而造成在电泳力作用下移动时,官能化的特定约束组织20成为以共价方式附于连接层16A上。
图2是本发明一种具体实施例叠层结构30的断面图。电极32最好具有普通片状或平面结构,至少电极32的中央部分是这样的。电极32有上表面34和下表面36。电极贯穿区38位于电极32内。本优选实施例中的电极贯穿区38是一个孔,也即电极32完全约束着电极贯穿区38。不过,并不需要使电极贯穿区38成为一个孔,只要能被电极32所约束或者部分被围绕即可,或者可将其从所述的孔后退设置成为圆环。
平面支撑40最好由片状材料制成。平面支撑40有上表面44和下表面46,此二表面通常是互相平行的。平面支撑40还包括一个至少由边缘42所部分限定的通孔48,它也被称为排气通孔,通孔48适于使气体容纳于其中,以便从叠层结构30排出,所述气体可能是来自比如在电极32处或其附近的电泳反应。
平面支撑50有下表面52和上表面54。再有,平面样品支撑最好为片状材料,其水平伸展明显地大于该样品支撑50的厚度,至少为10∶1倍。此平面样品支撑50有一样品通孔56,它最好是围绕其周界为连续的。
电极32被层叠于或者夹在平面样品支撑50与平面支撑40之间。理想的是使样品通孔56、电极贯穿区38和排气通孔48互相重叠,而且最好互相对准,基本上有同样的形状及水平宽度。所说水平宽度指的是沿图2中双头箭号方向,即所述片状平面内的尺寸。由平面样品支撑50的内缘62以及电极32的上表面64限定一个凹槽58。平面样品支撑50的内缘62最好在区域66处叠层,以便在电极32的上表面34与平面样品支撑50的下表面52之间形成较好的密封。
作为选择,可使一个或多个附加层叠层,或者换句话说添加于上述结构中。例如,可将附加的平面支撑层40a,40b和40c置于平面支撑40的下方。通孔40a′,40b′和40c′最好按与排气通孔48重叠的关系布置,而且最好是与之对准。类似地,可使一个或多个附加的样品支撑结构68位于,最好是叠置于平面样品支撑50上。再建议一个样品通孔70,其水平尺寸大于或等于样品通孔56的水平尺寸。
至少在所述凹槽58内设置一渗透层。作为选择,渗透层可以填满渗透区60,所述渗透区60最好终止在最上面的样品支撑68的上表面处,也可以将最上面的样品支撑68称作表层样品支撑,它给出一个露出于样品材料的表面。
所建议的有关结构的片性材料,如平面支撑40和平面样品支撑50是聚酰亚胺。聚酰亚胺片的一个来源是DuPont(杜邦)在KaptonTM商标下卖的,它的片形材料一般在1-5密尔这样薄的范围。一般说来,在有液体存在的情况下,这些材料要有较低的膨胀(最好小于10%,小于5%更好,而小于2%尤好),最好具有较低的固有荧光特性,这些材料在酸性环境(最好pH值为2,pH值为1更好)下实际上为惰性的,而且它们是电绝缘或不导电的。使用目前适用的比较薄的材料,如厚度为1密尔的片时,可以以1密尔宽的线和1密尔宽的间隙对其构图。
如图2所示,可将多个片叠层在一起,形成复合结构。在图2的示例性结构中,平面支撑40和平面样品支撑50的厚度为1密尔,平面支撑40a,40b和40c的厚度为5密尔,外部接触层68的厚度为2密尔。一般地说,在上面(即向着适于接纳样品的叠层结构30的侧面)使用多层样品支撑50、68,可以构成凹槽58。如图2所示,电极32在样品支撑68上表面之下约5-6密尔的凹槽底部(见图2中的相对箭号所示)。位于各个样品支撑层之间的粘结剂增大了所述凹槽的深度,典型的是每层粘结剂大约1密尔。如图2所示,整个叠层结构30的厚度约为25密尔(见图2中相对指向的箭号)。厚度超过200密尔,或者有如2密尔那样薄的叠层结构可以使用常规技术制作。
虽然聚酰亚胺是首选的材料,但其它材料满足要求的一种或多种包括: 聚甲基丙烯酸甲酯(PMMA)、聚四氟乙烯(PTEF-Teflon)、聚酯(Mylar)、聚苯乙烯、聚碳酸酯等材料。另外,为使所述多层或叠层结构30的特性最佳化,可将多层结构30的各层选自不同的材料。例如,可以建议最上面的样品支撑68的外露表面选择对生物材料有较低的附着力。可以选择支撑68具有固有的与生物材料较低的特定键联,或者可使样品支撑68的表面变成这种效果。可以选择一层或多层,特别是外部或接触样品支撑层68具有较高的反射率、较低的反射率(如全部用为黑材料或吸收材料),具有所需的结构特征(如对于键联目的和表面化学最佳特性的确定来说为较低的结构特征),或者具有疏水性特性或亲水性特性。最好各层样品支撑、样品支撑40和附加的样品支撑68都是无孔的。一般地说,建议叠层结构30是不渗透液体,如水的。
可建议将电极32制成于薄片,比如图2的聚酰亚胺薄片上,或与之成为一体。电极材料最好为贵金属,尤以金为好。一般地说,建议没有碱金属暴露于电极32中,碱金属将会有害地影响把生物材料,如DNA加给叠层结构30。如果存在生物材料,最好是考虑在材料中避开铜和铁,考虑有少量的铅和锡,或者至少应避免那些材料或它们的离子的暴露。电极30应当由一种通常为抗腐蚀的材料制成,并且为使泄漏电流最小或者避免泄漏电流,产生较少量的电泳,应使其结构是可与其它材料键联的,是可粘附于其它材料上的,并有较高的电化学电压,在这样的电压下,电极表面发射组分物质。其它可以想到的电极可由镍铬合金、铂、镍、不锈钢或氧化铟锡(ITO)制成,其中在采用光学检测时,特别是在孔口侧,使用ITO是方便的。本优选实施例中在采用聚酰亚胺时,首选的粘合剂是DuPont丙烯酸粘合剂或聚酯粘合剂。一般地说可以考虑所述粘合剂具有较低的挤出特性,以使在叠层过程中不会有过量的粘合剂比如在平面样品支撑50的内缘62处流出,免得有预先不可想到的过量粘合剂留在电极32的上表面64上。一般地说,粘合剂的厚度在1密尔量级。
图3是叠层结构30的断面图,其中电极70位于底侧上,也即在样品支撑72(或其它叠层支撑)上,面朝离开适于接纳样品的叠层结构30的一侧。样品通孔74和电极穿过区76最好具有相同的水平尺寸,并成重叠关系,最好成对准的关系。平面支撑78包括一排气通孔80,此排气通孔80与样品通孔74及电极贯穿区76也成重叠关系,最好成共轴对准的关系。平面电极70在样品支撑72与平面支撑78之间成叠层关系。
图3示出存在渗透层或可渗透聚合物82,为了图示更清晰,省略与图2共同的全部描述。另外,探针84在可渗透聚合物82的样品侧位于叠层结构30的样品一侧之上。
图4表示叠层结构30的断面图,此结构在平面支撑78的厚度方面与图3不同。其实图3中的平面支撑78比较厚,最少至少是2倍于,较好的是3倍于,最好大体上为5倍于样品支撑72那样厚,图4的结构具有实质上等于样品支撑72及平面支撑78A的厚度。
与样品通孔74的容积相比,图3和图4的每一种叠层结构都包含容积比较大的排气通孔80。排气通孔80相对于样品通孔74容积的测量尺寸最好被选择为便于减少气体起泡,并排放气体。例如,取用2对1的容积比,4对1更好,而最好是6对1的比率。在图3和图4的实施例中,较大的排气通孔80容积用于使可渗透聚合物或渗透层82稳定于叠层结构30内。如果可渗透聚合物或渗透层82胀起地与液体接触,则这一特点就尤其是有利的。另外,与不具有如此容积比例的结构相比,图3和图4的结构具有较大的阻尼能力。在图3和图4的结构中,可选择由较厚、较硬的非片状材料制成平面支撑78、78A。例如可将叠层结构30附加于其它的结构,如由丙烯酸、塑料、金属等形成的模塑的气流槽或其它结构。
图5和图6表示的实施例中,叠层结构30具有样品通孔90,它宽于排气通孔92的水平宽度。图5中的电极94位于平面支撑96上,此平面支撑96具有与电极贯穿区100相同水平尺寸的排气通孔98。图5中排气通孔92的水平尺寸比平面支撑96内的排气通孔98及电极贯穿区100的水平尺寸大。图6采用平面支撑102,它较厚于平面样品支撑104,比如2倍厚于平面样品支撑104。
图7是叠层结构110的断面图,其中第一层电极112和第二层电极114离开该结构适于容纳样品的外表面116的距离不同。在图7所示实施例中插入的平面支撑层118用作第一层电极112与第二层电极114之间的补偿结构。所插入的平面支撑层118包括插入通孔120。最左侧的插入通孔120位于叠层结构110的样品一侧上面,而在右手侧上面的插入通孔120是作为排气通孔而配置的。平面样品支撑122位于邻近所插入的平面支撑层118处并夹在第一层电极112中。第二平面支撑层124位于邻近所插入的平面支撑层118处,它们之间插有第二层电极114。如前面各图所示,探针126被配置于渗透层128上面或在其中,所述渗透层128至少充入样品通孔区130,并在图7的左手侧的插入通孔120上面。
图8是包含微型化结构142的叠层结构140的断面图,所述微型化结构142位于叠层结构140之上,或在其中,或者邻近叠层结构140。图8表示一流体泵144,它包括以配合关系所表示的齿轮传动装置146。该齿轮传动装置146以始终互相作用的旋转力为基础而转动,所述旋转力如加给被置于齿轮传动装置146内的磁铁之振荡磁场所提供的力。流体入口148和流体出口150给出一个与流体泵144相联系的流体通道。相邻层152和水平层154为齿轮传动装置146提供容器。流体入口148和流体出口150由支撑156与外层158形成的孔隙或者间隙所限定。虽然图8这示出流体泵144,但也可采样与本发明的目标和目的一致的其它微型化结构142。例如,其它微型化结构142可包括微型化机械、其它直线电机装置、阀门、致动机构,或者其它微型流体部件。参见比如Dewa,Andy等人的“CIGA制作的自环管式齿轮泵的设计和实现(Design and Implementation of CIGA FabricatedSelf-Ringing In-Line Gear Pumps)”,Solid State Sensor andActuator Workshop,Hilton Heid,S.C.,6月2-6,1996年。
图9表示关于一个包括减少复杂性和/或样品处理区160、回流电极区162和试验区164的装置的电极或金属化图样的平面图。迹线166被表示成离开所述各区160、162、164,用于使外部与本装置或其它电子器件连接。减少复杂性和/或样品处理区160包括迹线166,这些迹线带有圆形电极168,而圆形电极168具有电极贯穿区170。回流电极162由迹线166所连接。试验区164的迹线166终结于展开之电极区172,并有电极贯穿区174。
图10表示被回流电极围绕的诊断试样位置的3×3阵列平面图。(被虚线所围绕的)阵列180表示呈圆形形式并有电极贯穿区184的基本迹线182。平面样品支撑位于电极迹线132上方,并由平面样品支撑内缘186来表示。反电极188的直径大于所述试样位置,最好至少为2∶1;3∶1更好。圆形电极190的内缘终结于电极贯穿区192内。可以选择电极内缘终结于离开支撑的通孔区,成为环形形式,以致离开金属与通孔间支撑的环形间隙。迹线194使圆形电极区182、190连到电子装置或电子连接器(未示出)。按挠曲工艺选择电路可有利于电子元件定位于叠层结构30上。
最好采用能够高产率、低成本制作高质量器件的方法制成所述叠层结构。可以通过任何与本发明的目的和目标相符的公知方法制成各种孔,如排气通孔、样品通孔和电极贯穿区。例如,微型钻孔可以形成有如3-8密尔那样小的孔,而激光钻成的孔可以是像4密尔那样小,或者光刻制图所得的孔可以成为基本上是1密尔。一般地说,采样现有技术,最薄的片能够形成最小直径的孔。可以选用化学蚀刻从孔处除去碎屑。这种技术特别有利于激光钻孔之后,以便减少或者除去此前剥落的材料。在把各电极成图于所述支撑上并且加工各层之后,叠层结构或复合结构即被粘附在一起。通常希望只有很少或者没有粘合剂的挤出物,以免露出的电极区域不均匀。按照一种具体的实施方式,先制成较大的孔,然后再通过激光打孔钻出较小的孔。另外,可以先制成带排气通孔及各个孔的各支撑,然后再于放置粘合剂之前通过比如光学对准使之对准。
虽然为了清楚和理解之目的已通过图示及举例对前述发明作了一些详细的描述,但很容易理解,对于那些熟悉本发明领域的普通技术人员而言,可以进行某些不脱离所附各权利要求之精髓和范围的改变及变型。
Claims (42)
1.一种实行有效生物操作的装置,包括:
至少带有一个样品通孔的第一平面样品支撑;
邻近所述第一样品支撑的平面电极,它有电极贯穿区;
带有排气通孔的第二平面支撑;
其特征在于,所述平面电极在所述第一样品支撑与第二平面支撑之间呈叠层关系,并且样品通孔、电极通孔和排气通孔成重叠布置。
2.如权利要求1所述的实行有效生物操作的装置,其中平面样品支撑为聚酰亚胺的。
3.如权利要求1所述的实行有效生物操作的装置,其中平面样品支撑选自一组聚甲基丙烯酸甲酯(PMMA)、聚四氟乙烯、聚酯薄膜树脂、聚苯乙烯和聚碳酸酯。
4.如权利要求1所述的实行有效生物操作的装置,其中平面样品支撑的厚度实质上为从1密尔到5密尔。
5.如权利要求1所述的实行有效生物操作的装置,其中所述电极为金的。
6.如权利要求5所述的实行有效生物操作的装置,其中所述金为IIIA类金。
7.如权利要求1所述的实行有效生物操作的装置,其中所述电极为镍铬合金的。
8.如权利要求1所述的实行有效生物操作的装置,其中所述电极为不锈钢的。
9.如权利要求1所述的实行有效生物操作的装置,其中所述电极为铂的。
10.如权利要求1所述的实行有效生物操作的装置,其中所述电极为贵金属的。
11.如权利要求1所述的实行有效生物操作的装置,其中所述电极为镍的。
12.如权利要求1所述的实行有效生物操作的装置,其中所述电极为氧化铟锡电极。
13.如权利要求1所述的装置,其中所述排气通孔的水平尺寸比样品通孔的水平尺寸大。
14.如权利要求13所述的实行有效生物操作的装置,其中所述排气通孔的水平宽度至少为样品通孔的水平宽度的两倍。
15.如权利要求14所述的实行有效生物操作的装置,其中所述排气通孔的水平宽度至少为样品通孔的水平宽度的三倍。
16.如权利要求13所述的装置,其中还包括位于样品通孔、电极贯穿区和至少部分排气通孔内的渗透层。
17.如权利要求1所述的实行有效生物操作的装置,其中所述样品通孔的水平宽度大于排气通孔的水平宽度。
18.如权利要求1所述的实行有效生物操作的装置,其中还包括外部样品支撑。
19.如权利要求1或18所述的实行有效生物操作的装置,其中还包括位于邻近第二平面支撑的平面支撑。
20.如权利要求1或18所述的实行有效生物操作的装置,其中所述样品支撑具有较低的反射率。
21.如权利要求1或18所述的实行有效生物操作的装置,其中所述样品支撑具有较低的荧光性。
22.如权利要求1或18所述的实行有效生物操作的装置,其中所述样品支撑具有疏水性。
23.如权利要求1或18所述的实行有效生物操作的装置,其中所述样品支撑具有亲水性。
24.如权利要求1所述的装置,其中还包括杂交电路。
25.如权利要求24所述的实行有效生物操作的装置,其中杂交电路采用小片挠曲电路。
26.如权利要求1所述的实行有效生物操作的装置,其中利用激光钻孔形成所述电极贯穿区。
27.如权利要求1所述的实行有效生物操作的装置,其中所述电极贯穿区经受化学蚀刻。
28.如权利要求1所述的实行有效生物操作的装置,其中所述平面电极包括迹线部分。
29.一种实行有效生物操作的叠层装置,包括:
至少带有一个样品通孔的第一平面样品支撑,该第一样品通孔具有第一水平尺寸;
邻近所述第一平面样品支撑的平面电极,它有电极贯穿区;
带有排气通孔的第二平面支撑,该排气通孔具有一种水平尺寸;
其特征在于,所述平面电极在所述第一平面样品支撑与第二平面支撑之间呈叠层关系,并且样品通孔、电极通孔和排气通孔成重叠布置,而且所述样品通孔的水平尺寸与所述排气通孔的水平尺寸不同。
30.如权利要求29所述的实行有效生物操作的叠层装置,其中所述样品通孔的水平尺寸比排气通孔的水平尺寸大。
31.如权利要求30所述的叠层装置,其中将所述平面电极安置成朝向适于接纳样品的渗透层。
32.如权利要求29所述的实行有效生物操作的叠层装置,其中所述样品通孔的水平尺寸小于排气通孔的水平尺寸。
33.如权利要求32所述的实行有效生物操作的叠层装置,其中还包括位于样品通孔、电极贯穿区和至少部分排气通孔内的渗透层,从而给出一个部分在所述电极之下部分并在所述排气区内的渗透层。
34.一种在样品上实行有效生物操作的多层装置,所述装置适于在该装置的样品表面接纳样品,它包括:
至少带有一个样品通孔的第一平面样品支撑;
邻近所述第一平面样品支撑的第一平面电极,它有电极贯穿区,该第一平面电极位于离开所述样品表面第一距离处;
第二平面电极,它有电极贯穿区,该第二平面电极位于离开样品表面比第一平面电极离开样品表面大的距离处;
一个插入的平面支撑层用来支撑所述第二平面电极。
35.如权利要求34所述的实行有效生物操作的多层装置,其中所述第一平面电极和第二平面电极被置于邻近所述插入平面支撑的相对的表面处。
36.一种实行流体操作的多层叠层装置,其中包括:
外部支撑层;
按与所述外部支撑层成叠层关系设置的相邻层;
按与所述相邻层成叠层关系设置的第二支撑层;
包含于所述叠层装置中的微型化结构。
37.如权利要求36所述的实行流体操作的装置,其中所述微型化结构是流体泵。
38.如权利要求37所述的实行流体操作的装置,其中所述流体泵是以磁方式驱动的泵。
39.如权利要求38所述的实行流体操作的装置,其中所述以磁方式驱动的泵是一个配合的齿轮传动泵。
40.如权利要求37所述的实行流体操作的装置,其中还包括对所述流体泵的流体输入口。
41.如权利要求40所述的实行流体操作的装置,其中所述流体输入口由所述外部支撑与相邻层之间的间隙限定。
42.如权利要求40所述的装置,其中还包括对所述流体泵的流体输出口。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/753,962 | 1996-12-04 | ||
US08/753,962 US6287517B1 (en) | 1993-11-01 | 1996-12-04 | Laminated assembly for active bioelectronic devices |
Publications (1)
Publication Number | Publication Date |
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CN1268905A true CN1268905A (zh) | 2000-10-04 |
Family
ID=25032892
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN97181305A Pending CN1268905A (zh) | 1996-12-04 | 1997-11-26 | 有效生物电子装置的叠层组件 |
Country Status (9)
Country | Link |
---|---|
US (2) | US6287517B1 (zh) |
EP (1) | EP0961652A1 (zh) |
JP (1) | JP2002501611A (zh) |
KR (1) | KR20000057400A (zh) |
CN (1) | CN1268905A (zh) |
AU (1) | AU733523B2 (zh) |
BR (1) | BR9713991A (zh) |
CA (1) | CA2274047A1 (zh) |
WO (1) | WO1998024544A1 (zh) |
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CN103443624A (zh) * | 2007-03-26 | 2013-12-11 | 纳米系统公司 | 形成受控单分子层的方法和装置 |
CN101960300A (zh) * | 2008-05-28 | 2011-01-26 | 松下电器产业株式会社 | 使用电化学测定装置检测或者定量目标物质的方法、电化学测定装置以及电化学测定用电极板 |
CN101960300B (zh) * | 2008-05-28 | 2013-05-29 | 松下电器产业株式会社 | 使用电化学测定装置检测或者定量目标物质的方法、电化学测定装置以及电化学测定用电极板 |
Also Published As
Publication number | Publication date |
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CA2274047A1 (en) | 1998-06-11 |
WO1998024544A1 (en) | 1998-06-11 |
AU5367198A (en) | 1998-06-29 |
KR20000057400A (ko) | 2000-09-15 |
JP2002501611A (ja) | 2002-01-15 |
US6287517B1 (en) | 2001-09-11 |
US6423271B1 (en) | 2002-07-23 |
AU733523B2 (en) | 2001-05-17 |
BR9713991A (pt) | 2000-02-08 |
EP0961652A1 (en) | 1999-12-08 |
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