CN1720455A - 基于膜的测定装置中钩效应的减小 - Google Patents
基于膜的测定装置中钩效应的减小 Download PDFInfo
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Abstract
本发明提供了一种用于检测测试样品中分析物的存在或数量的基于膜的测定装置。该装置采用其上具有多个微孔颗粒的层析区。层析区能够以简单、有效和相对廉价的方式有效减小“钩效应”。尤其是,多个微孔颗粒使得较大尺寸的分析物/探针复合物在未复合的分析物之前到达检测区。由于基本上抑制了未复合的分析物与复合物竞争检测区中的结合位点,因此可限制“假阴性”的发生,甚至在分析物浓度较高的时候。
Description
发明背景
多种不同的分析方法和设备普遍用于流通测定中,用于确定测试样品中可能存在的分析物的存在和/或浓度。例如,免疫测定法利用免疫系统机制,其中抗体是响应作为有机体的病原或外源的抗原的存在而产生的。这些抗体和抗原即免疫反应物能够彼此结合,借此产生能够用来确定生物样品中特定抗原的存在或浓度的高度特异性反应机制。
有几种公知的免疫测定法,这些方法利用由可检测的成分标记的免疫反应物,从而能够对分析物进行分析检测。例如,“夹心型”测定法一般涉及使测试样品与可检测的探针(例如染色乳胶或放射性同位素)混合,这些探针与分析物的特异性结合部分缀合。缀合探针(conjugated probes)与分析物形成复合物。这些复合物然后到达固定抗体区,在此处抗体与分析物之间发生结合,从而形成三元的“夹心复合物”。夹心复合物位于用于检测分析物的区域。此技术用来获得定量或半定量结果。这些夹心型测定的一些实例在
Grubb等人的U.S.4,168,146和
Tom等人的U.S.4,366,241中有所描述。
然而,许多传统的“夹心型”测定形式在暴露到较高的分析物浓度时都遇到明显不准确的问题。具体地说,当分析物以高浓度存在时,测定样品中的大部分分析物不与缀合探针形成复合物。这样,未复合的分析物在到达检测区之后,就与复合的分析物竞争结合位点。由于未复合的分析物没有用探针标记,因此不能检测到。据此,如果相当大量的结合位点都被未复合的分析物所占据,那么测定就可表现出“假阴性”。该问题被普遍称作“钩效应(hook effect)”
已经提出多种用于减小免疫测定中的“钩效应”的技术。例如,Neumann等人的U.S.6,184,042中描述了一种用于减小夹心测定中的钩效应的技术。该技术涉及在带有至少两种能够结合分析物的受体的固相存在下培养分析物。第一受体是选自抗体、抗体片段及其混合物的结合分子的低聚体。第二受体结合或能够结合到固相上。可溶性低聚抗体的使用据说能够减小“钩效应”。
然而,对以简单、有效和相对廉价的方式来减小“钩效应”的改进技术,仍然存在需求。
发明概述
按照本发明的一个实施方案,公开了一种用于检测测试样品中分析物的存在或数量的流通测定装置。这种流通测定装置包括与能够产生检测信号的缀合检测探针相通的多孔膜。此多孔膜限定出层析区,在层析区内固定有多个微孔颗粒。这些微孔颗粒能够在相互之间限定出多个空间,这些空间的平均尺寸大于微孔的平均尺寸。在一些实施方案中,微孔的平均尺寸比空间的平均尺寸至少小约100%,而在一些实施方案中,至少小约150%,在一些实施方案中,至少小约250%。微孔颗粒可选自聚苯乙烯、聚丙烯酰胺、聚丙烯腈;硅珠、以及这些物质的组合,并且其表面对于分析物可以是化学惰性的。
多孔膜还限定出位于层析区上游的检测区。捕获试剂固定在检测区内,该试剂被构造成能够结合到缀合检测探针上。在检测区内,缀合检测探针能够产生检测信号,其中由所述检测信号来确定测试样品内分析物的量。
按照本发明的另一个实施方案,公开了一种用于检测测试样品中分析物的存在或含量的流通夹心测定装置。这种测定装置包括与能够产生检测信号的缀合检测探针相通的多孔膜。缀合检测探针被构造成在与测试样品中的分析物接触时能够与其结合,从而形成分析物/探针复合物和未复合的分析物。多孔膜限定出层析区,在层析区内固定有众多微孔颗粒。这些微孔颗粒被构造成使未复合的分析物以比分析物/探针复合物慢的速率流过层析区。多孔膜还包括位于层析区下游的检测区。捕获试剂固定在检测区内,所述捕获试剂被构造成能够结合到分析物/探针复合物上,从而复合物在检测区内产生检测信号,其中由检测信号来确定测试样品内分析物的量。
本发明公开了一种用于检测测试样品中分析物的存在或数量的方法。该方法包括:
i)提供一种流通测定装置,该装置包括与能够产生检测信号的缀合检测探针相通的多孔膜,此多孔膜限定出层析区和位于层析区下游的检测区,在层析区内固定有多个微孔颗粒,其中捕获试剂固定在检测区内;
ii)使含有分析物的测试样品与缀合检测探针接触,从而形成分析物/探针复合物和未复合的分析物;以及
iii)使分析物/探针复合物和未复合的分析物到达层析区,然后到达检测区,其中分析物/探针复合物在未复合的分析物之前到达检测区。
下面更详细地论述本发明的其它特征和方面。
附图简述
本发明的全面和可实施的公开内容,包括其最佳方式,针对本领域的普通技术人员,都参照附图在说明书的剩余部分得到更加具体的阐述,其中:
图1是本发明的流通测定装置的一个实施方案的透视图;
图2图示出将抗体共价缀合到羧基化纳米颗粒上的一个实施方案;
图3是本发明的流通测定装置的一个实施方案的示意图,是在未复合的分析物穿过层析区之前示出的;
图4是图3的实施方案的示意图,是在未复合的分析物穿过层析区之后示出的;
图5是图1所示层析区的分解图。
附图标记在本说明书和附图中的重复使用意味着其代表本发明的相同或类似特征或部件。
代表性实施方案详述
定义
正如本文所用的,术语“分析物”通常是指待检测的物质。例如,分析物可包括抗原性物质、半抗原、抗体以及这些物质的组合。分析物包括但不限于毒素、有机化合物、蛋白质、肽、微生物、氨基酸、核酸、激素、类固醇、维生素、药物(包括那些为了治疗目的而施用的药物和那些为了违法目的而施用的药物)、药物中间体或副产物、细菌、病毒颗粒以及任何上述物质的代谢物或抗体。一些分析物的具体实例包括铁蛋白;肌酸激酶MIB(CK-MB);地高辛;苯妥英;苯巴比妥;卡马西平;万古霉素;庆大霉素;茶碱;丙戊酸;奎尼定;促黄体生成激素(LH);促卵泡激素(FSH);雌二醇、黄体酮;C-反应蛋白;lipocalins;IgE抗体;维生素B2微球蛋白;糖化血红蛋白(Gly、Hb);氢化可的松;毛地黄毒苷;N-乙酰普鲁卡因酰胺(NAPA);普鲁卡因酰胺;风疹抗体,例如风疹-IgG和风疹IgM;毒胞质抗体,例如毒胞质IgG(Toxo-IgG)和毒胞质IgM(Toxo-IgM);睾酮;水杨酸盐;乙酰氨基苯酚;乙肝病毒表面抗原(HBsAg);乙肝核心抗原的抗体,例如抗-乙肝核心抗原IgG和IgM(抗-HBC);人免疫缺陷病毒1和2(HIV1和2);人T-细胞白血病病毒1和2(HTLV);乙肝e抗原(HBeAg);乙肝e抗原的抗体(抗-HBe);促甲状腺素(TSH);甲状腺素(T4);全三碘甲状腺原氨酸(全T3);游离三碘甲状腺原氨酸(游离T3);癌胚抗原(CEA);以及α-胎儿蛋白(AFP)。滥用和受控物质的药物包括但不限于麻黄碱;脱氧麻黄碱;巴比妥酸盐,例如异戊巴比妥、司可巴比妥、戊巴比妥、苯巴比妥和巴比妥;苯二氮杂类,例如利眠宁和安定;大麻素类,例如印度大麻和大麻;可卡因;芬太尼;LSD;安眠酮;鸦片制剂,例如海洛因、吗啡、可待因、盐酸二氢吗啡酮、氢可酮、美沙酮、氧可酮、氧吗啡酮和鸦片;苯环利定;和丙氧吩。其它潜在的分析物在
Everhart等人的U.S.6,436,651和
Tom等人的U.S.4,366,241中有所描述。
本文所用术语“测试样品”通常是指被怀疑含有分析物的材料。测试样品可从源体获得后直接使用,或者进行预处理以改善样品的特性。测试样品可来自任何生物源,例如生理流体,包括血液、间质液、唾液、眼晶状体液、脑脊髓液、汗液、尿液、乳液、腹水、raucous、滑液、腹膜液、阴道液、羊膜液等。测试样品在使用前可预处理,例如用血液制备血浆、稀释粘稠液等。处理方法包括过滤、沉淀、稀释、蒸馏、浓缩、干扰成分的灭活、以及试剂的加入。除了生理流体之外,还可以使用其它液态样品,例如用于环境或食品生产性能测定的水、食品等。此外,被怀疑含有分析物的固体材料也可用作测试样品。在一些情况下,有益的是,改善固体测试样品以形成液态介质或释放分析物。
详细描述
现在详细参照本发明的多个不同实施方案,其中的一个或多个实例在以下列出。每个实例都是为了解释本发明,而对本发明没有限定作用。事实上,对于本领域技术人员显而易见的是,在不脱离本发明的范围或精髓的情况下能够对本发明作出多种修改和变型。例如,作为实施方案的一部分而阐述或描述的特征可用在另一个实施方案上,从而产生又一个实施方案。于是,本发明意在覆盖这样的修改和变型,即它们在所附的权利要求书及其等同物的范围内。
总体上,本发明涉及一种用于检测测试样品中分析物的存在或数量的基于膜的测定装置。该装置采用层析区,多个微孔颗粒位于层析区上。层析区能够以简单、有效和相对廉价的方式有效减小“钩效应”。尤其是,众多微孔颗粒允许大尺寸的分析物/探针复合物在未复合的分析物之前到达检测区。由于基本上抑制了未复合的分析物与复合物在检测区竞争结合位点,因此可以限制“假阴性”的发生,甚至在分析物的浓度较高的情况下。
例如,参照图1,现在更详细地描述按照本发明形成的流通测定装置20的一个实施方案。如图所示,装置20包含任选由刚性材料21支撑着的多孔膜23。通常,多孔膜23可以由测试样品能够通过的任何材料制成。例如,用来形成多孔膜23的材料可包括但不限于天然材料、合成材料、或者天然存在的被合成改性的材料,例如多糖(诸如纸和纤维素衍生物之类的纤维素材料,例如醋酸纤维素和硝基纤维素);聚醚砜;尼龙膜;硅石;均匀分散在多孔聚合物基质中的无机材料,例如去活氧化铝、硅藻土、MgSO4或其它无机精细材料,其中聚合物为例如氯乙烯、氯乙烯-丙烯共聚物和氯乙烯-醋酸乙烯酯共聚物;布,包括天然存在的(例如棉花)及合成的(例如尼龙或人造纤维);多孔凝胶,例如硅胶、琼脂糖、右旋糖苷和明胶;聚合物膜,例如聚丙烯酰胺等等。在一个特定实施方案中,多孔膜23是由硝基纤维素和/或聚酯砜材料形成的。应该理解,术语“硝基纤维素”是指纤维素的硝酸酯,其可以是单独的硝基纤维素,或者是硝酸与其它酸(例如具有1-7个碳原子的脂肪族羧酸)的混合酯。
装置20还可以包含芯吸(wicking)垫28。芯吸垫28通常接收已经通过整个多孔膜23迁移的流体。正如本领域内所公知的,芯吸垫28有助于促进毛细作用和通过膜23的流体流动。
为了在测试样品内启动分析物的检测,使用者可直接将测试样品加入到一部分多孔膜23上,然后样品可通过膜23移动。或者是,测试样品可以先加到与多孔膜23以流体相通的取样垫(未示出)上。可用来形成取样垫的一些适宜材料包括但不限于硝基纤维素、纤维素、多孔聚乙烯垫和玻璃纤维滤纸。如果需要的话,取样垫还可含有扩散地或非扩散地附着到其上的一种或多种测定预处理试剂。
在图示的实施方案中,测试样品从取样垫(未示出)移动到以与取样垫一端相通的方式放置的缀合垫22上。缀合垫22由测试样品能够通过的材料形成。例如,在一个实施方案中,缀合垫22由玻璃纤维形成。虽然仅仅示出一个缀合垫22,但是应该理解,其它缀合垫也可用于本发明。
为了易于准确检测测试样品内分析物的存在或缺乏,将探针施加在装置20的多个不同部位。如以下更详细描述的,探针可用于分析物的检测和校正。通常能够产生可目视检测或通过仪器设备检测的信号的任何物质都可以用作探针。各种合适的物质包括发色团;催化剂;荧光化合物;化学发光化合物;磷光化合物;放射性化合物;直接目视标记物,包括胶状金属(例如金)和非金属颗粒、染料颗粒、酶或底物、或有机聚合物胶乳颗粒;脂质体或含有信号生成物的其它囊泡等等。例如,适合用作探针的一些酶公开在Litman等人的U.S.4,275,149中,该文献在此作为参考全部引入本文。酶/底物系统的一个实例是酶碱性磷酸酶和底物硝基蓝四唑-5-溴-4-氯-3-吲哚基磷酸盐、或者这些物质的衍生物或类似物、或者底物4-甲基伞形基(umbelliferyl)-磷酸盐。其它合适的探针在Jou等人的U.S.5,670,381和Tarcha等人的U.S.5,252,459中有所描述,这些文献在此作为参考全部引入本文。
在一些实施方案中,探针可含有产生可检测信号的荧光化合物。荧光化合物可以是荧光分子、聚合物、树枝状物质、颗粒等等。合适荧光分子的一些实例例如包括但不限于荧光素、铕螯合物、藻胆蛋白质、若丹明以及这些物质的衍生物和类似物。可目视检测的有色化合物也能够用作探针,借此在无需其它信号生成试剂的情况下,提供了样品中分析物的存在或浓度的直接有色读数。
探针,诸如如上所述的探针,可单独使用或与微粒(有时称作“珠”或“微珠”)结合使用。例如,可使用天然存在的微粒,例如晶核、支原体、质粒、质体、哺乳动物细胞(例如红细胞血影)、单细胞微生物(例如细菌)、多糖(例如琼脂糖)等等。此外,还可采用合成微粒。例如,在一个实施方案中,采用用荧光染料或有色染料标记的胶乳微粒。虽然任何胶乳微粒都可用于本发明,但是胶乳微粒一般是由以下物质形成的:聚苯乙烯、丁二烯苯乙烯、苯乙烯-丙烯酸-乙烯基三元共聚物、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、苯乙烯-马来酐共聚物、聚醋酸乙烯酯、聚乙烯基吡啶、聚二乙烯基苯、聚对苯二甲酸丁二酯、丙烯腈、氯乙烯-丙烯酸酯等,或者这些物质的酐、羧基、氨基、羟基或酰肼衍生物。其它合适的微粒在Jou等人的U.S.5,670,381和Tarcha等人的U.S.5,252,459中有所描述,这些文献在此作为参考全部引入本文。一些商业上可购得的合适荧光颗粒的实例包括商品名为“FluoSphere”(Red580/605)和“TransfluoSphere”(543/620)、由Molecular Probes,Inc.出售的荧光羧基化微球,以及也是由Molecular Probes,Inc.出售的“Texas Red”和5-及6-羧基四甲基若丹明。商业上可购得的合适有色胶乳微粒的实例包括由Bang’s Laboratory,Inc.出售的羧基化胶乳珠。
在一些情况下,需要用一些方式来给探针改性,以便使探针能够更容易地结合到分析物上。在这样的情况下,探针用某些粘附到其上的特异性结合部分来改性,以形成缀合探针。特异性结合部分通常是指特异性结合对,即两个不同的分子,其中一个分子化学和/或物理结合到第二个分子上的一员。例如,免疫反应特异性结合部分可包括抗原、半抗原、适体(aptamers)、抗体和这些物质的复合物,包括那些通过DNA重组方法或肽合成而形成的物质。抗体可以是单克隆或多克隆抗体、重组蛋白质或其混合物或片段,以及抗体和其它特异性结合部分的混合物。这些抗体的制备细节和它们用作特异性结合部分的适宜性是本领域技术人员所公知的。其它常用的特异性结合对包括但不限于生物素和亲和素、糖类和凝集素、互补核苷酸序列(包括用于DNA杂交测定中的探针和捕获核酸序列,用于检测靶核酸序列)、互补肽序列(包括用重组方法形成的那些互补肽序列)、效应子和受体分子、激素和激素结合蛋白、酶辅因子和酶、酶抑制剂和酶等。此外,特异性结合对可包括作为原始特异性结合部分类似物的部分。例如,可使用分析物的衍生物或片段,即分析物-类似物,只要它具有至少一个与分析物共同的表位即可。
特异性结合部分一般可利用任何各种公知技术附着到探针上。例如,特异性结合部分对探针(例如微粒)的共价附着,可利用羧基、氨基、醛基、溴乙酰基、碘乙酰基、巯基、环氧基和其它反应性或连接性官能团以及残余的游离基和游离基阳离子来实现,通过这些基团可完成蛋白偶合反应。还可包括作为官能化共聚单体的表面官能团,因为微粒的表面可含有较高表面浓度的极性基团。此外,虽然微粒探针经常在合成之后官能化,在某些情况下例如为聚(苯硫酚),但是微粒能够与蛋白质直接共价连接,而无需进一步改性。例如,参照图2,该图表示出用于共价缀合探针的本发明的一个实施方案。如图所示,缀合的第一个步骤是,用碳二亚胺活化探针表面上的羧基。在第二个步骤中,活化的羧酸基团与抗体的氨基反应,从而形成酰胺键。活化和/或抗体偶合可发生在缓冲液中,例如磷酸盐缓冲的盐水(PBS)(例如pH为7.2)或2-(N-吗啉代)乙磺酸(MES)(例如pH为5.3)。如图所示,所获得的探针然后可例如用乙醇胺封闭,从而形成探针缀合物。除了共价键合之外,其它附着技术,例如物理吸附,也可用于本发明。
如上所示,测试样品中的一些分析物可以不用所需的方式复合到缀合探针上,尤其是当分析物以高浓度存在于测试样品中时。该未复合的分析物随后与复合的分析物在检测区31竞争捕获试剂(如下所述),借此对测定装置20的准确度具有不利影响。为了抵消该影响,多孔膜23包含层析区35,众多微孔颗粒50分布在层析区上。如图3-5所示,微孔颗粒50的存在允许层析区35作为“凝胶渗透”柱,较大的分子以比较小分子快的速率通过层析区35。具体地说,如图5所示,尺寸大于微孔颗粒50的微孔51的分子不能通过,由此被迫流过颗粒50之间的空间52,即通过膜23的孔(如方向箭头L2所示)。由于颗粒50的微孔51在颗粒结构内形成“曲折路径”(即具有复杂形状的路径),因此分子通过微孔51比通过颗粒50之间的空间52花费的时间要长。据此,当通过层析区35时,较大尺寸的分子首先出去。中间尺寸的分子根据其尺寸不同程度地渗透过微孔颗粒50。最后,非常小的分子流过颗粒50的微孔51(如方向箭头L1所示),并最终由此排出色谱区35。一般来说,分析物/探针复合物的尺寸大于未复合的分析物的尺寸。因此,复合物能够在未复合的分析物到达检测区31之前到达检测区31并与其上含有的捕获试剂结合。以这种方式,复合的与未复合的分析物之间的竞争得到抑制。
色谱区35一般提供一个明显不同的区域(例如,线、点等),尽管本发明肯定包含多个区域。例如,在图示的实施方案中,采用一条线。当采用这条线的时候,线宽通常是可变的。例如,在一些实施方案中,分析物流动方向L上的线宽为,从施加分析物的部位(例如缀合垫22)到检测区31所测总距离的约10%-约100%,并且在一些实施方案中,为约10%-约50%。而且,这条线可位于基本上垂直于测试样品通过装置20的流动的方向上。同样地,在一些实施方案中,这条线可位于基本上平行于测试样品通过装置20的流动的方向上。
用于给定测定中的合适微孔颗粒50的选择标准包括各种因素,例如感兴趣的分析物的性质、测试条件、所采用的探针性质等。一般,期望微孔颗粒50具有相对均匀的孔和粒径分布以及良好的机械和化学稳定性。此外,一般还期望,微孔颗粒50的表面对测定装置20的其它组件保持化学惰性。例如,微孔颗粒50的表面相对于分析物通常是化学惰性的。可用于本发明的微孔颗粒50的一些实例包括但不限于合成的聚合颗粒,例如聚苯乙烯(例如高度交联的聚苯乙烯)、聚丙烯酰胺、聚丙烯腈;硅珠等。一些适宜的合成微孔颗粒50的具体实例在诸如
Stoy的U.S.4,110,529;
Ley等人的U.S.4,940,734;和
Gooke等人的U.S.5,314,923中有所描述,这些文献在此作为参考全部并入本文。在探针也是微孔颗粒的实施方案中,应该理解,层杆区35的微孔颗粒50可以与探针相同。
微孔颗粒50的平均直径通常可按需要来改变。例如,在一些实施方案中,颗粒50的平均直径可为约0.1-约1000微米,在一些实施方案中,为约0.1-约100微米,在一些实施方案中,为约1-约10微米。一般,颗粒50基本上是球形的(即珠),尽管包括但不限于板、棒、条、不规则形状等的其它形状也适用于本发明。正如本领域技术人员所领会的,颗粒50的成分、形状、尺寸和/或密度可广泛变化。
一般来说,颗粒50的微孔51的平均尺寸(即直径)小于由多孔膜23的孔52形成的颗粒50之间的空间。具体地说,微孔51的平均尺寸一般比上述空间的平均尺寸至少小约100%,在一些实施方案中,至少小约150%,在一些实施方案中,至少小约250%。例如,在一些实施方案中,微孔51具有小于约100纳米的平均尺寸,在一些实施方案中,为约5-约100纳米,在一些实施方案中,为约10-约60纳米。作为对照,多孔膜23的孔52一般具有大于约200纳米的平均尺寸,在一些实施方案中,为约200-约5000纳米,在一些实施方案中,为约200-约2500纳米。
测定装置20还可包含检测区31,在检测区31上固定有能够结合到缀合探针上的捕获试剂。例如,在一些实施方案中,捕获试剂可以是生物捕获试剂。这些生物捕获试剂在本领域内是公知的,并且可包括但不限于抗原、半抗原、抗体、蛋白A或G、亲和素、链霉亲和素、二级抗体、以及这些物质的复合物。在许多情况下,期望这些生物捕获试剂能够与探针上存在的特异性结合部分(例如抗体)结合。此外,还期望用各种非生物材料作为捕获试剂。例如,在一些实施方案中,捕获试剂可包括聚电解质。聚电解质可具有净的正或负电荷,以及通常为中性的净电荷。例如,具有净正电荷的聚电解质的一些合适实例包括但不限于聚赖氨酸(在商业上从Sigma-Aldrich Chemical Co.,Inc.of St.Louis,MO购得)、聚乙烯亚胺;环氧氯丙烷官能化的聚胺和/或聚酰胺型胺类,例如聚(二甲基胺-共-环氧氯丙烷);聚二烯丙基二甲基-氯化铵;阳离子纤维素衍生物,例如用季铵盐水溶性单体接枝的纤维素共聚物或纤维素衍生物等等。在一个特定实施方案中,可采用作为含有季铵盐水溶性单体的纤维素衍生物的CelQuatSC-230M或H-100(从National Starch&Chemical,Inc.购得)。此外,具有净负电荷的聚电解质的一些适宜实例包括但不限于聚丙烯酸,例如聚(乙烯-共-甲基丙烯酸,钠盐)等等。还应该理解,其它聚电解质也可使用,例如两亲聚电解质(即具有极性和非极性部分)。例如,合适的两亲聚电解质的一些实例包括但不限于聚(苯乙烯基-b-N-甲基2-乙烯基碘化吡啶鎓)和聚(苯乙烯基-b-丙烯酸),它们可从Polymer Scource,Inc.of Dorval,Canada购得。
捕获试剂用作分析物/探针复合物的固定结合位点。具体地说,分析物,例如抗体、抗原等,一般具有两个结合位点。在到达检测区31之后,这些结合位点之一被缀合探针的特异性结合部分所占据。然而,分析物的游离结合位点能够结合到固定捕获试剂上。在结合到固定捕获试剂上之后,复合探针形成新的三元夹心复合物。
检测区31通常可具有任何数目的不同检测区,以便使用者能够更好地确定测试样品内特定分析物的浓度。每个区域可含有相同的捕获试剂,或者可含有用于捕获多种分析物的不同捕获试剂。例如,检测区31可包括两个或更多个不同的检测区(例如线、点等)。检测区可以线的形式位于基本上垂直于通过测定装置20的测试样品流的方向上。同样,在一些实施方案中,检测区可以线的形式位于基本上平行于通过测定装置20的测试样品流的方向上。
虽然检测区31可指示出分析物的存在,但是仅利用检测区31经常难以确定测试样品内分析物的相对浓度。于是,测定装置20还可包括校正区32。在该实施方案中,校正区32形成在多孔膜23上,并位于检测区31的下游。校正区32配有捕获试剂,该试剂能够结合穿过膜23的长度的任何剩余的未捕获探针。校正区32中所采用的捕获试剂可与检测区31中所用的捕获试剂相同或不同。而且,与检测区31类似,校正区32还可在任何方向上提供任何数目的不同校正区,以便使用者能够更好地确定测试样品内特定分析物的浓度。每个区域可含有相同的捕获试剂,或者可含有用于捕获不同探针的不同捕获试剂。
校正区可以用不同量的捕获试剂预先装载到多孔膜23上,以便在探针迁移后由每个校正区产生不同的信号强度。通过采用不同尺寸的校正区和/或通过改变每个校正区内的捕获试剂的浓度或体积,能够改变每个校正区内结合物的总量。如果需要的话,将过量的探针用于测定装置20,以便每个校正区达到其完全预定的信号强度电位。也就是说,沉积在校正区上的探针的量是预定的,因为校正区上采用的捕获试剂的量设定在预定的已知水平上。
总之,可按照本发明构建各种流通测定装置。关于这一点,现在更详细地描述本发明的多个不同的实施方案。然而,应该理解,下述实施方案仅仅是示范性的,本发明还包括其它实施方案。例如,参照图3-4,这些图表示出一个特定实施方案,其中探针41用于检测,探针43用于校正。在该实施方案中,检测探针41和校正探针43加入到缀合垫22上,并且在以与测试样品相通的方式放置时,由此能够流过装置20(如方向箭头L所指示的)。检测探针41与分析物A的特异性结合部分90缀合,因此,在探针41与分析物A接触之后就结合到其上,从而形成分析物/探针复合物49。
如图3所示,探针/分析物复合物49、任何游离的分析物A以及校正探针43从缀合垫22通过多孔膜23,直到到达层析区35为止,在层析区上有多个微孔颗粒50。较大的复合物49和校正探针43容易流过颗粒50之间的空间52,而较小的未复合的分析物A以较慢的速率流到颗粒50的微孔内。分析物/探针复合物49然后流过装置20,直到其到达检测区31为止,在检测区31,它们结合到捕获试剂91(例如抗体)上,形成夹心复合物53。而且,校正探针43流到校正区32并与捕获试剂(未示出)例如聚电解质结合。其后,如图4所示,未复合的分析物A穿过层析区35,到达检测区31。然而,由于复合物49已经结合到捕获试剂上,因此分析物A穿过检测区31和校正区32,直到其到达芯吸垫28为止。这样,在检测区31,能够由检测探针41的信号强度确定分析物的量。如果需要的话,此信号强度可以用校正区32中的校正探针43的信号强度来校正。信号强度可目视测定或借助于设备例如荧光读数器来测定。
虽然上面已经描述了装置结构的多个不同的实施方案,但是应该理解,本发明的装置一般可具有任何所需的结构,并且不必含有上述所有部件。各种其它装置结构和/或测定形式,例如在
Lambotte等人的U.S.5,395,754;
Jou等人的U.S.5,670,381;和
Malick等人的U.S.6,194,220中有所描述,这些文献在此作为参考全部并入本文。
本发明人已经发现,层析区在测定装置的多孔膜上的存在,能够以简单、有效和相对廉价的方式有效减小“钩效应”。尤其是,多个微孔颗粒位于层析区上,使得较大尺寸的分析物/探针复合物在任何未复合的分析物之前到达检测区。据此,未复合的分析物不与复合物竞争检测区上有用的结合位点。由于抑制了未复合的分析物占据检测区的大多数结合位点,因此可限制“假阴性”的发生,甚至在较高的分析物浓度时。
虽然已经就本发明的具体实施方案详细描述了本发明,但是本领域的技术人员应该理解,在领会上述内容之后,容易构思这些实施方案的替换形式、变型和等同物。因此,本发明的范围应该由所附的权利要求书及其等同物来确定。
Claims (33)
1、一种用于检测测试样品中分析物的存在或数量的流通测定装置,所述流通测定装置包括多孔膜,所述多孔膜与能够产生检测信号的缀合检测探针相通,所述多孔膜限定出:
层析区,在所述层析区内固定有多个微孔颗粒;以及
位于所述层析区下游的检测区,其中捕获试剂固定在所述检测区内,所述捕获试剂被构造成结合到所述缀合检测探针上,其中在所述检测区内,所述缀合检测探针能够产生检测信号,由所述检测信号来确定测试样品内分析物的量。
2、如权利要求1所述的流通测定装置,其中所述微孔颗粒在相互之间限定出多个空间,所述空间的平均尺寸大于所述颗粒的微孔的平均尺寸。
3、如权利要求1所述的流通测定装置,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约100%。
4、如权利要求1所述的流通测定装置,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约150%。
5、如权利要求1所述的流通测定装置,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约250%。
6、如权利要求1所述的流通测定装置,其中所述微孔的平均尺寸小于约100纳米。
7、如权利要求1所述的流通测定装置,其中所述微孔的平均尺寸为约10-约60纳米。
8、如权利要求1所述的流通测定装置,其中所述微孔颗粒选自聚苯乙烯、聚丙烯酰胺、聚丙烯腈、硅珠、以及这些物质的组合。
9、如权利要求1所述的流通测定装置,其中所述微孔颗粒的表面对于分析物是化学惰性的。
10、如权利要求1所述的流通测定装置,其中所述缀合检测探针包括选自以下的物质:发色团、催化剂、荧光化合物、化学发光化合物、磷光化合物、放射性化合物、直接目视标记物、脂质体、以及这些物质的组合。
11、如权利要求1所述的流通测定装置,其中所述多孔膜还包括能够产生校正信号的校正区,其中由所述校正信号校正的所述检测信号来确定测试样品内分析物的量。
12、如权利要求11所述的流通测定装置,其中所述多孔膜与校正探针相通,所述校正探针在存在于所述校正区内时产生所述校正信号。
13、如权利要求1所述的流通测定装置,其中所述装置是夹心型测定装置。
14、一种用于检测测试样品中分析物的存在或数量的流通夹心测定装置,所述测定装置包括多孔膜,所述多孔膜与能够产生检测信号的缀合检测探针相通,所述缀合检测探针被构造成在与测试样品中的分析物接触时能够与其结合,从而形成分析物/探针复合物和未复合的分析物,所述多孔膜限定出:
层析区,在所述层析区内固定有多个微孔颗粒,所述微孔颗粒被构造成使所述未复合的分析物以比所述分析物/探针复合物慢的速率流过所述层析区;以及
位于所述层析区下游的检测区,其中捕获试剂固定在所述检测区内,所述捕获试剂被构造成结合到所述分析物/探针复合物上,从而在所述检测区内,所述复合物产生检测信号,其中由所述检测信号来确定测试样品内分析物的量。
15、如权利要求14所述的流通夹心测定装置,其中所述微孔颗粒在相互之间限定出多个空间,所述空间的平均尺寸大于所述颗粒的微孔的平均尺寸。
16、如权利要求14所述的流通夹心测定装置,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约100%。
17、如权利要求14所述的流通夹心测定装置,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约150%。
18、如权利要求14所述的流通夹心测定装置,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约250%。
19、如权利要求14所述的流通夹心测定装置,其中所述微孔颗粒选自聚苯乙烯、聚丙烯酰胺、聚丙烯腈、硅珠、以及这些物质的组合。
20、如权利要求14所述的流通夹心测定装置,其中所述微孔颗粒的表面对于分析物是化学惰性的。
21、如权利要求14所述的流通夹心测定装置,其中所述多孔膜还包括能够产生校正信号的校正区,其中由所述校正信号校正的所述检测信号来确定测试样品内分析物的量。
22、如权利要求21所述的流通夹心测定装置,其中所述多孔膜与校正探针相通,所述校正探针在存在于所述校正区内时产生所述校正信号。
23、一种用于检测测试样品中分析物的存在或数量的方法,所述方法包括:
i)提供一种流通测定装置,所述装置包括多孔膜,所述多孔膜与能够产生检测信号的缀合检测探针相通,所述多孔膜限定出层析区和位于所述层析区下游的检测区,在所述层析区内固定有多个微孔颗粒,其中捕获试剂固定在所述检测区内;
ii)使含有分析物的测试样品与所述缀合检测探针接触,从而形成分析物/探针复合物和未复合的分析物;以及
iii)使所述分析物/探针复合物和所述未复合的分析物到达所述层析区,然后到达检测区,其中所述分析物/探针复合物在所述未复合的分析物之前到达所述检测区。
24、如权利要求23所述的方法,其中所述微孔颗粒在相互之间限定出多个空间,所述空间的平均尺寸大于所述颗粒的微孔的平均尺寸。
25、如权利要求23所述的方法,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约100%。
26、如权利要求23所述的方法,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约150%。
27、如权利要求23所述的方法,其中所述微孔的平均尺寸比所述空间的平均尺寸至少小约100%。
28、如权利要求23所述的方法,其中所述微孔颗粒选自聚苯乙烯、聚丙烯酰胺、聚丙烯腈、硅珠、以及这些物质的组合。
29、如权利要求23所述的方法,其中所述微孔颗粒的表面对于分析物是化学惰性的。
30、如权利要求23所述的方法,其中还包括测定所述检测区内产生的检测信号的强度。
31、如权利要求23所述的方法,其中所述多孔膜还包括能够产生校正信号的校正区,其中由所述校正信号校正的所述检测信号来确定测试样品内分析物的量。
32、如权利要求31所述的方法,其中所述多孔膜与校正探针相通,所述校正探针在存在于所述校正区内时产生所述校正信号。
33、如权利要求32所述的方法,其中还包括通过针对多个预定的分析物浓度绘制由校正信号的强度校正的检测信号的强度来产生校正曲线。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106153924A (zh) * | 2015-03-23 | 2016-11-23 | 中国科学院宁波材料技术与工程研究所 | 试剂盒、检测系统,其制备方法及应用 |
CN106153924B (zh) * | 2015-03-23 | 2017-10-27 | 中国科学院宁波材料技术与工程研究所 | 试剂盒、检测系统,其制备方法及应用 |
CN112534039A (zh) * | 2018-08-06 | 2021-03-19 | 贝克顿·迪金森公司 | 带有分离膜的侧向流动免疫测定设备 |
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US20080014659A1 (en) | 2008-01-17 |
US7662643B2 (en) | 2010-02-16 |
ES2312837T3 (es) | 2009-03-01 |
US20040121480A1 (en) | 2004-06-24 |
CA2508774A1 (en) | 2004-07-22 |
ATE408833T1 (de) | 2008-10-15 |
EP1573326B1 (en) | 2008-09-17 |
WO2004061454A1 (en) | 2004-07-22 |
DE60323672D1 (de) | 2008-10-30 |
CA2508774C (en) | 2011-07-05 |
KR20050085270A (ko) | 2005-08-29 |
TW200424524A (en) | 2004-11-16 |
EP1573326A1 (en) | 2005-09-14 |
KR101072756B1 (ko) | 2011-10-11 |
US7247500B2 (en) | 2007-07-24 |
CN100476437C (zh) | 2009-04-08 |
MXPA05005951A (es) | 2005-08-18 |
AU2003290552A1 (en) | 2004-07-29 |
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