CN1675547A - 采用磁性颗粒的具有内部自校正系统的流式测定 - Google Patents
采用磁性颗粒的具有内部自校正系统的流式测定 Download PDFInfo
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Abstract
本发明提供了一种用于检测试样中分析物的存在或量的基于膜的测定装置。该装置利用自校正的磁性结合测定形式(例如夹层测定,竞争性测定等等),包括能产生检测信号的检测探针(例如荧光非磁性颗粒)以及能产生校正信号的校正探针(例如荧光磁性颗粒)。试样中分析物的量与由校正信号强度值校正后的检测信号的强度值成比例(如正比或者反比)。已发现本发明的基于流控技术的装置能提供用于测定试样中分析物存在的精确、廉价、并且易于控制的方法。
Description
发明背景
在测定试样中存在和/或不存在分析物的试验中,通常使用多种分析方法和装置。例如,免疫测定法是利用免疫系统机制,即为了响应致病的或对生物体异质的抗原的存在而产生抗体。这些抗体和抗原,即免疫反应物,能够互相结合,从而引起高度特异性反应机制,可用于检测生物样品中特定抗原的存在或者浓度。
一些已知的免疫测定方法利用被可检测成分标记的免疫反应物以便在分析上可检测到分析物。例如,典型地是,“夹层式”测定法涉及混合试样与所述分析物的抗体。这些抗体是可移动的并联接着标记物或者探针,如染色乳胶珠,胶体金溶胶,或放射性同位素。再将该混合物与含有固定的分析物抗体带或区域的层析分离介质接触。层析分离介质通常呈类似于量尺的条带形式。当分析物和标记抗体的复合物到达层析分离介质上固定了抗体的区域时,就发生结合并且该结合的标记抗体滞留在该区域。这就指示了分析物的存在。该技术可用于获得定量或半定量的结果。Grubb等人的4168146号和Tom等人的4366241号美国专利中描述了这种夹层式测定法的例子。
另一种技术为“竞争式”测定法。在“竞争式”测定法中,典型地,标记物为标记的分析物或分析物类似物,其与样品中存在的任何非标记的分析物竞争性结合抗体。竞争性测定法被典型地用于检测诸如半抗原的分析物,每个半抗原为单价的并且只能够结合一个抗体分子。Deutsch等人的4235601号,Liotta的4442204号,以及Buechler等人的5208535号美国专利中描述了这种竞争性免疫测定装置的例子。
磁性结合测定法被广泛地用于从复杂样品中分离生物物质(例如,蛋白质、细胞、微生物),因为其易于通过磁场来操纵并且不需要专门的和昂贵的仪器。这样,磁性免疫测定法可提供快速而简单的技术来测定所述物质的存在与否。在这种测定方法中,使用了多种信号发生机制,包括颜色(吸收和反射),荧光,化学发光,放射性以及酶。
然而,常规的磁性免疫测定法每次用于获得分析物的定量信息时,通常需要对照样品以制成校正曲线。特别是在分析试样中生物物质的存在与否时,要同时测定多个对照样品,用于所述已知量的物质,从而在近似相同的条件下校正所述测定。遗憾地是,所述校正方法通常不是很方便、成本较高,对测试者来说比较麻烦。
因此,目前需要一种易于控制并且较为廉价的用于测定的准确校正系统。
发明概述
根据本发明的一个实施方式,揭示了一种用于检测试样中分析物的存在或者量的基于膜的装置(例如,基于测流膜的测定装置)。该装置包括与可产生检测信号的检测探针以及可产生校正信号的磁性校正探针流体连通的多孔膜。一般来说,检测探针和校正探针可以由能够产生可检测信号的任何物质构成。例如,一些实施方式中,这些探针选自于包括以下物质的组:生色基团、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、直接可见标记物、脂质体及其组合。例如,检测探针和校正探针可以为荧光化合物,如荧光颗粒。在一个特别的实施方式中,检测探针为荧光非磁性化合物,而校正探针为荧光磁性颗粒。如果需要的话,荧光磁性颗粒可以和特异性结合成分结合或者被阻断。
在一些实施方式中,该装置还包括一个或多个与该多孔膜流体连通的结合垫。如果需要,检测探针与校正探针被加在一个或多个所述结合垫上。该装置还可包括与所述多孔膜流体连通的加样垫。如果需要的话,将试样加在该加样垫上。另外,该装置还可包括与所述多孔膜流体连通的吸收垫以帮助试样的流动通过。
磁性装置设置在由该多孔膜界定的检测区附近。该磁性装置能够将检测探针和校正探针从施加到多孔膜上的溶液中分离出来。例如,在夹层测定形式的一个实施方式中,检测探针和校正探针与分析物形成复合物。当放置在检测区与磁性装置相作用时,这些分析物的复合物以及任何非复合形式的校正探针可从剩余试样中分离。
分离的检测和校正探针(复合形式的和/或非复合形式的)因此就能够指示试样中分析物的存在或者量。特别是,试样中分析物的量与检测区被分离出的检测探针(复合形式的和/或非复合形式的)所产生的检测信号强度成比例,所述检测信号经过检测区中分离的校正探针(复合形式的和/或非复合形式的)产生的校正信号强度值校正。例如,在一个实施方式中,试样中分析物的量与检测信号强度和校正信号强度的商成比例。
根据本发明的另一个实施方式,揭示了一种用于检测试样中分析物的存在或者量的方法。该方法包括:
i)提供基于膜的装置,所述装置包括:
a)与能够产生检测信号的检测探针以及能够产生校正信号的磁性校正探针流体连通的多孔膜,所述多孔膜界定了检测区域;以及
b)设置在邻近检测区处的磁性装置;
ii)将检测探针与校正探针与试样接触形成溶液;
iii)利用所述磁性装置在检测区从所述溶液中分离检测探针和校正探针;
iv)激发所述分离的检测探针(复合形式的和/或非复合形式的)以及所述分离的校正探针(复合形式的和/或非复合形式的),其中所述激发引起所述分离的检测探针发出检测信号,以及所述分离的校正探针发出校正信号;
v)在第一发射波长处测量所述检测信号的强度以及在第二发射波长处测量所述校正信号的强度,第二发射波长可以与第一发射波长相同或不同;以及
vi)比较所述检测信号和所述校正信号的强度,其中试样中分析物的量与经校正信号强度值校正的检测信号的强度值成比例。
分离的检测探针和校正探针可以被同时地或者分别地激发。同样,检测信号和校正信号的强度可以被同时地或者分别地测量。另外,在一个实施方式中,所述方法还包括为多个预定的分析物浓度对经校正信号强度校正的检测信号强度进行作图,从而得到校正曲线。
下面更详细地讨论了本发明的其它特征和方面。
附图简述
针对本领域的普通技术人员,说明书的以下部分参考以下附图对本发明进行全面而且有效的公开,其中包括最佳实施方式,所述附图包括:
图1是本发明的基于膜技术的装置的一个实施方式透视图;
图2是用于本发明的一种夹层测定形式实施方式的机制图解说明;
图3是用于本发明的另一种夹层测定形式实施方式的机制图解说明;
图4是用于本发明的一种竞争性测定形式实施方式的机制图解说明;
图5是用于本发明的另一种竞争性测定形式实施方式的机制图解说明;
图6是抗体与羧酸盐纳米颗粒共价结合的一个实施方式图解说明;
图7表示根据本发明一个实施方式中的校正探针(C)和检测探针(FP)的激发(EX)和发射(EM)光谱;
图8表示如实施方式1中所讨论的标准化荧光强度与促黄体生成激素(LH)量的关系曲线;
图9表示如实施方式2中所讨论的标准化荧光强度与促黄体生成激素(LH)量的关系曲线;以及
图10表示如实施方式4中所讨论的标准化荧光强度与C反应蛋白(CRP)量的关系曲线。
说明书和附图中重复使用的附图标记表示本发明的相同或类似特征或元件。
代表性实施方式详述
定义
这里使用的术语“分析物”通常涉及待检测的物质。例如,分析物可包括抗原物质、半抗原、抗体及其组合。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(包括出于治疗目的以及出于违禁目的而服用的)、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施方式包括铁蛋白,肌酐激酶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,奎尼丁,促黄体生成激素(LH),促卵泡激素(FSH),雌二醇,孕酮,IgE抗体,维生素B2微球蛋白,糖化血红蛋白(Gly.Hb),皮质醇,毛地黄毒苷,N-普鲁卡因乙酰胺(NAPA),普鲁卡因胺,风疹抗体如风疹IgG和风疹IgM,弓形体抗体如弓形虫IgG(Toxo-IgG)和弓形虫IgM(Toxo-IgM),睾丸激素,水杨酸盐,醋氨酚,B型肝炎病毒表面抗原(HBsAg),B型肝炎核心抗原的抗体,如B型肝炎核心抗原IgG和IgM抗体(抗HBC),人类免疫缺陷病毒1和2(HIV1和HIV2),人类T细胞白血病病毒1和2(HTLV),B型肝炎e抗原(HBeAg),B型肝炎e抗原抗体(抗HBe),促甲状腺激素(TSH),甲状腺素(T4),总三碘甲状腺原氨酸(总T3),游离三碘甲状腺原氨酸(游离T3),癌胚抗原(CEA)以及甲胎蛋白(AFP)。滥用药物以及受控制的物质包括但不限于,安非他明,脱氧麻黄碱,巴比妥酸盐,如阿米妥、司可巴比妥、戊巴比妥、苯巴比妥、以及巴比妥,苯化重氮,如利眠宁和安定,大麻的化学成分,如印度大麻制剂和大麻叶和花制剂,可卡因,芬太尼,LSD,安眠酮,鸦片剂,如海洛因、吗啡、可待因、二氢吗啡酮、二氢可待因酮、美沙酮、羟可酮、氧吗啡酮和鸦片,苯环己哌啶,以及丙氧吩。Tom等人的第4366241号美国专利中记载了其它可能的分析物。
这里使用的术语“试样”通常涉及被怀疑含有所述分析物的材料。试样可以从提供源中一获得就直接使用或者经由预处理步骤以改善样品的性质。试样可以获得自任何生物来源,例如生理性液体,包括血液、唾液、接目镜液体、脑脊髓液、汗液、尿液、乳汁、腹水、raucous、滑液、腹膜液、羊水或其类似物。试样在使用前可经过预处理,例如从血液中制备血浆,稀释粘液,或类似处理。处理方法包括过滤、蒸馏、浓缩、灭活干扰组分,以及加入试剂。除了生理性体液之外,也可使用其它液体样品,例如用于环境和食品生产测定的水、食物产品及其类似物。此外,被怀疑含有所述分析物的固体材料也可用作试样。在一些例子中,最好对固体试样进行修饰以便形成液体介质或者释放出分析物。
发明详述
现在将详细参考说明本发明的多个实施方式,它们的一个或多个实例列在了下面。每个提供的实例用于解释发明,而不是对发明的限定。实际上,对本领域技术人员来说,在不偏离本发明范围和实质的情况下很明显可以做出各种修改和变化。例如,图示或者描述说明的作为一个实施方式部分的特征,可以被用于另一个实施方式中从而得到另外一个实施方式。因此,如本发明所附的权利要求及其等价物的范围中包括这类修改和变化。
本发明主要致力于一种用于检测试样中分析物的存在或量的基于膜的测定。装置利用自校正的磁性结合测定法(例如夹层测定,竞争性测定等等),包括能产生检测信号的检测探针(例如荧光非磁性颗粒)以及能产生校正信号的校正探针(例如荧光磁性颗粒)。试样中分析物的量与经校正信号强度值校正的检测信号的强度值成比例(例如正比或者反比)。已发现该自校正系统能提供用于测定试样中分析物存在的精确、廉价、并且易于控制的方法。
例如,参见图1-2,现在将更为详细地说明根据本发明制成的基于测流膜的装置20的一个实施方式。如图所示,装置20包括可选择性地由刚性材料21支持的多孔膜23。一般来说,多孔膜23可以由试样能够通过的多种材料中的任何一种构成。例如,构成多孔膜23的材料可包括但不限于,天然的、合成的或者经合成修饰的自然产生的材料,例如多糖(如纤维素材料如纸,以及纤维素衍生物如醋酸纤维素和硝酸纤维素);硅石;无机材料如惰性氧化铝、硅藻土、MgSO4、或其它均匀分散在多孔聚合物基质中的无机细小物质,其中聚合物如氯乙烯、氯乙烯-丙烯共聚物、和氯乙烯-醋酸乙烯共聚物;织物,天然形成的(如棉花)与合成的(如尼龙或人造丝);多孔胶,如硅胶、琼脂糖、葡聚糖和凝胶;聚合膜,如聚丙烯酰胺,等等。在一个特别的实施方式中,多孔膜23由硝酸纤维素和/或聚砜膜材料构成。应当明白,术语“硝酸纤维素”涉及纤维素的硝酸酯,其可以是单独的硝酸纤维素,或者与硝酸和其它酸如1至7个碳原子的脂肪族羧酸的混合酯。
装置20还可以包含吸收垫28。该吸收垫28通常接收移动通过整个多孔膜23的液体。如本领域所知,该吸收垫28可有助于促进毛细作用以及流体流过该膜23。
开始检测试样中的分析物时,使用者可直接将试样加到多孔膜23的一部分,然后通过该部分移动到一个或多个检测和校正区域(描述见下)。或者,试样可先加到与该多孔膜23流体连通的加样垫上(未示出)。可用于构成加样垫的合适物质包括但不限于,硝酸纤维素、纤维素、多孔聚乙烯垫、以及玻璃纤维滤纸。如果需要,该加样垫还可以含有一个或多个检测预处理试剂,所述试剂扩散性或非扩散性地附着在加样垫上。
在所示的实施方式中,试样从加样垫(未示出)移动到与该加样垫一端流体连通的结合垫22。结合垫22是由试样能够通过的材料构成的。例如,在一个实施方式中,结合垫22由玻璃纤维构成。尽管只给出了一个结合垫22,应当明白其它的结合垫也可以用于本发明。
可将多种检测探针41加到该结合垫22上,用以帮助检测试样中分析物的存在与否。这些探针41被包含在结合垫22上时,当分析物从加样垫流经结合垫22时,所述探针可与分析物结合。一旦与分析物结合,探针41将随后用于鉴别分析物的存在或者不存在。检测探针41既可用于装置20的检测又可用于其校正。然而在可替代的实施方式中,也可在结合垫22上施加单独的校正探针43,用来与检测探针41结合以有助于同时进行校正和检测,从而消除常规测定校正体系通常造成的不准确性。然而应当明白的是,检测探针41和/或校正探针43可以同时地或者分别地施加在装置20的任何部位上,而不需要加在结合垫22上。而且,还应当明白的是,检测探针41和/或校正探针43可以加到相同或不同的结合垫上。
通常能够产生可见的或者利用仪器可检测到的信号的任何物质可被用作检测探针41和/或校正探针43。有多种适合的物质包括生色基团,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,直接可见标记物,包括胶体金属(如金)和非金属颗粒、染色颗粒、酶或底物、或者有机聚合物乳胶颗粒,脂质体或其它含有信号发生物质的囊泡,等等。例如,Litman等人的第4275149号美国专利中披露了一些适合作为探针的酶,在此出于各种目的对其进行全文引用作为参考。酶/底物体系的一个例子为碱性磷酸酶和底物硝基蓝四唑-5-溴-4-氯-3-吲哚磷酸,或者其衍生物或类似物,或者底物4-甲基伞形酮(methylumbelliferyl)-磷酸盐。Jou等人的第5670381号和Tarcha等人的第5252459号美国专利中还披露了其它合适的探针,在此出于各种目的对其进行全文引用作为参考。
在一些实施方式中,检测探针41和/或校正探针43包括产生可检测信号的荧光化合物。所述荧光化合物可为分子、聚合物、树枝状大分子、颗粒及类似物。例如,一些适合的荧光分子的例子包括但不限于,荧光素、铕螯合物、藻胆蛋白、罗丹明以及其衍生物和类似物。另外,还有一些商业上用的适合的荧光颗粒的例子,包括Molecular Probes公司出售的商品名为“FluoSphere”(Red580/605)和“TransfluoSphere2”(543/620)以及“Texas Red”的荧光羧基微球和同为Molecular Probes公司出售的5-和6-羧基四甲基罗丹明。
不论所采用的使探针具有信号生成能力的技术,人们通常希望探针41和/或校正探针43为磁感应探针。一般来说,如果一种材料受施加的磁场影响,例如,被吸引或排斥或者具有可检测的磁化率或感应度,就被认为是具有“磁感应性”或者“磁性”。例如,一些可用于向探针提供磁性能的合适的磁感应性材料的例子包括但不限于,顺磁性材料、超顺磁性材料、铁磁性材料、亚铁磁性材料以及变磁性材料。特别的例子有,金属如铁、镍、钴、铬、锰等,镧系元素如钕、铒等,合金如铝、镍、钴、铜等的磁性合金,氧化物如氧化铁(Fe3O4)、氧化亚铁(Fe2O3)、氧化铬(CrO2)、氧化钴(CoO)、氧化镍(NiO2)、氧化锰(Mn2O3)等,复合材料如铁素体等,以及固溶体如氧化铁磁铁矿等。
在一些实施方式中,检测探针41和/或校正探针43是荧光的并且具有磁性。荧光磁性探针在本领域中一般来说是已知的并且通常包括磁感应成分和荧光成分。例如在一些实施方式中,将一个或多个荧光染料应用于磁性颗粒上以形成探针,而在其它的实施方式中,将荧光染料应用于与磁性颗粒偶联的非磁性颗粒上。一些适合的荧光染料的例子包括但不限于,单甲川染料、三甲川染料、五甲川染料、喹啉染料、方酸基染料等等。嘧啶类的单甲川染料典型地能发出蓝色或绿色的荧光,而喹啉类典型地能发出绿色或黄绿色荧光。三甲川染料基本上漂移至红光波长,而五甲川染料漂移的更多,常呈现红外荧光辐射。这种荧光染料的特例包括单不限于酞菁、2,3-萘肽菁、方酸菁(squaraine)以及克酮酸衍生物。其它合适的荧光磁性颗粒记载在Luotola等人的第4731337号、Chandler等人的第6268222号美国专利中。在此出于各种目的对其进行全文引用作为参考。
当检测探针41和/或校正探针43是如上所述的颗粒时,一般来说根据诸如所选颗粒的类型、膜上孔大小以及膜组分之类的因素,颗粒的平均直径可随需要而变化。例如在一些实施方式中,颗粒探针的平均直径范围可以从大约0.01微米到大约1000微米,一些实施方式中从大约0.01微米到大约100微米,而在一些实施方式中从大约0.01微米到大约10微米。在一个特别的实施方式中,颗粒探针具有的平均直径从大约1至大约2微米。一般来说,颗粒基本上为球形,但是在本发明中也适合使用其它的形状,包括但不限于,盘状、杆状、棒状、不规则形状等等。本领域技术人员来应明白,颗粒的组成、形状、尺寸和/或密度可以有很大范围的变化。
检测探针41和/或校正探针43能够与分析物结合(共价或非共价地)或者物理吸附。然而通常需要以一些方式对探针进行修饰,以便其更易于与分析物结合。在这种情况下,检测探针41和/或校正探针43可用某些特异性结合组分90a和/或90b(参见图2)进行修饰,所述特异性结合组分连接其上形成探针配合物。
特异性结合组分一般来说涉及特异性的结合对组分,即两个不同的分子,其中一个分子与第二个分子化学和/或物理结合。例如,免疫反应性特异性结合组分包括抗原、半抗原、寡核苷酸配基、抗体及其复合物,包括通过重组DNA方法或者肽合成法而制成的。抗体可以是单克隆或者多克隆抗体,重组蛋白或其混合物或片段,以及抗体和其它特异性结合组分的混合物。这类抗体的制备方法以及其作为特异性结合组分的适用性的详细内容对本领域技术人员来说是已知的。
其它常规的特异性结合对包括但不限于,生物素与抗生物素蛋白,碳水化合物与凝集素,互补核苷酸序列(包括DNA杂交试验中用来检测目标核酸序列的探针和捕获核酸序列),互补肽序列包括那些通过重组方法获得的序列,效应物与受体分子,激素与激素结合蛋白,辅酶与酶,酶抑制剂与酶等等。此外,特异性结合对还可包括原特异性结合组分的类似物组分。例如,分析物的衍生物或者片段,即分析物类似物,只要其具有至少一个与分析物相同的抗原表位。
通常利用各种已知技术中的任何一种就能使特异性结合组分90a和/或90b联接至探针41和/或43上。例如,利用羧基、氨基、醛基、溴化乙酰基、碘化乙酰基、硫醇基、环氧基以及其它反应性或联接官能团,以及自由基残基和自由基正离子可以实现特异性结合组分90a和/或90b与探针41和/或43的共价联接,通过其能够完成蛋白质的偶联反应。也可以引入表面官能团作为功能化的共聚单体,这是因为微粒的表面可以含有较高浓度的极性基团。而且,尽管微粒探针通常在合成后进行功能化,但在诸如聚(苯硫酚)这类的情况下,微粒能够与蛋白质直接共价联接而不需要进一步修饰。例如图6,其表示了本发明一个实施方式中共价结合探针的过程。如图所示,结合过程的第一步为利用碳化二亚胺在探针表面上活化羧基。第二步,活化的羧酸基团与抗体的氨基反应形成酰胺键。所述活化作用和/或抗体偶联可在缓冲液中进行,例如磷酸盐缓冲液(PBS)(如pH值7.2)或2-(N-吗啉)乙基磺酸(MES)(如pH值5.3)。如图所示,得到的探针可以被乙醇胺所阻断,从而形成探针复合物。除了共价联接,其它联接技术如吸附作用也可用于本发明。
参见图1-2,首先将含有分析物的试样加到加样垫上。接着该试样从加样垫移动到结合垫22上,在此分析物与检测探针41和/或校正探针43混合。根据所选的探针类型,分析物可与检测探针41和/或校正探针43结合形成复合物49(参见图2)。例如,在一个实施方式中,含有分析物的试样与(1)和第一结合组分90a结合的荧光非磁性颗粒41以及(2)和第二结合组分90b结合的荧光磁性颗粒43混合。在该实施方式中,分析物与荧光非磁性颗粒41和荧光磁性颗粒43形成夹层复合物49。另外,由于结合垫22与多孔膜23流体连通,该复合物49可从结合垫22移动到多孔膜23上的检测区31中。
在检测区31,接着将复合物49与任何未结合的复合荧光磁性颗粒43通过磁性装置60捕获,并采用常规技术从剩余样品中分离。例如,可用磁场发生器产生磁场引起磁感应性探针的感应。合适的磁场发生器包括但不限于,永磁体和电磁体。典型的磁分离过程包括在液体介质中将样品与磁性颗粒混合通过亲和反应结合分析物,再通过施加磁场将未结合的磁性颗粒与分析物复合物从样品介质中分离。如果不是全部的磁性颗粒,则大多数磁性颗粒会及时沉淀下来,除了那些胶体颗粒。因而,可以搅拌该液体介质从而使颗粒悬浮足够长的时间以便发生生物亲和性结合反应。已知的搅拌方法例子包括晃动、涡流、摇动、旋转或类似操作于部分填充的容器。一些商业上使用的合适的磁性分离装置包括纽约成功湖的Dynal公司生产的Dynal MPC系列分离器,其中在容器的外部设置永磁体,所述容器用于容纳测试介质,该装置仅仅用于分离。单独对测试介质中的磁性颗粒进行混合从而进行亲和结合反应。此外,其它用于捕获磁性颗粒的方法在Liberti等人的5200084号,Tuunanen等人的5647994号,Wang等人的5795470号,以及Siddiqi的6033574号美国专利中有所记载,在此出于各种目的对其全文引用作为参考。
一旦被捕获,复合的和未复合的荧光磁性颗粒43以及复合物49的荧光信号可以用常规的技术测得。例如,在一个实施方式中,颗粒43和复合物49可被相同的外部源所激发。在该实施方式中,该外部源提供激发波长的辐射,从而引起颗粒43发光,其波长与复合物49发出的波长不同。这就可以分别测得复合物49与颗粒41的存在。或者,也可以使用分别的外部源来分别测量颗粒43与复合物49。
一般来说,荧光是特定荧光组分的三步过程形成的结果。第一步中,外部源诸如白炽灯或激光提供能量并被荧光化合物所吸收,形成激发电子单重态。第二步中,激发态存在有限的时间,在此期间荧光化合物经历了构象变化并与其分子环境发生多种可能的交互作用。在此期间,激发态能量部分消耗,形成松弛态,产生荧光发射。第三步是荧光发射阶段,其中能量被释放,荧光化合物回到其基态。发射的能量低于其激发能量(光或者激光)因而波长较长。这种能量或者波长的改变或者区别使得发射能量可被检测得到并且可与激发能量相区别。
一般来说,荧光检测利用波长过滤从激发光子中分离发射光子,以及利用检测器记录发射光子并产生可记录的输出,所述输出通常是电信号或者摄影图像。通常有四种类型的公知检测器:荧光分光光度计与微板读数器,荧光显微镜,荧光扫描仪以及流式细胞仪。本发明使用的一种适合的荧光检测器为新泽西Edison的SPEX工业公司销售的FluoroLog III荧光分光光度计。
尽管不需要,但特别理想的检测和校正探针对的选择标准包括:(1)吸收光谱或者或荧光光谱没有或者很少有光谱重叠,这样才能分别地测量发射强度;(2)当相互接近时检测和校正探针之间没有显著的荧光能量传递,这样它们能够独立地发光;以及(3)相对较长的发射波长(例如大于约600nm),这样生物液体的自身荧光对该荧光测量中的影响很小。例如图7表示了激发光谱具有很少重叠的校正探针和检测探针的例子,这样它们能够分别地被激发。
另外如果需要,已知的“时间分辨荧光检测”技术也可用于本发明。时间分辨荧光检测的设计是利用一定荧光材料,如铕((III))和铽((III))的镧系螯合物的荧光特性,减少来自于发射源或者散射过程(激发辐射的散射引起)的背景信号。当在较短波长处激发螯合物后,这些螯合物显示出强烈的红色飘移、窄带、长寿命的发射。典型地是,由于生色基团在分子中离镧系元素位置很近,该螯合物具有强烈的紫外吸收带。在生色基团吸收了光之后,激发能量可从该激发的生色基团传递到镧系元素。接着该镧系元素具有了荧光发射特性。采用脉冲式激发和按时选通的检测,以及窄带发射滤波器,可以仅仅对来自镧系元素螯合物的荧光进行特定检测,而排除样品中存在的其它物质的发射光,这些发射光通常寿命较短或者是具有较小波长的发射。测量荧光的其它时间分辨技术在Davidson的5585276号和Hemmila等人的5637509号美国专利中有所记载,在此出于各种目的对其进行全文引用作为参考。
不考虑测量荧光的技术,通过比较捕获的荧光非磁性颗粒41与捕获的荧光磁性颗粒43的荧光信号可以确定分析物的绝对量。可对捕获的荧光非磁性颗粒41的荧光强度Is与捕获的荧光磁性颗粒43的荧光强度Ic进行比较。捕获的荧光磁性颗粒43的总量为预定和已知的,因而可以作校正目的使用。例如,在一个实施方式中,分析物的量与Is和Ic的比率成正比。根据检测区31的强度范围,可以确定分析物大致的浓度范围。结果,校正和样品测试可在大致相同的条件下同时操作,这样就提供了可靠的定量或半定量的结果,灵敏度也有所提高。
如果需要,可以在已知的分析物浓度范围内对Is与Ic的比率和分析物浓度进行作图从而得到校正曲线。为了测得未知试样中分析物的量,根据该校正曲线可将该信号比转换成分析物浓度。值得注意的是,对于任意给定样品,复合的和未复合的荧光磁性颗粒的捕获效率通常是相同的。因此,并不认为捕获效率的改变会显著干扰样品与样品之间的结果,这是因为用荧光强度比率(即Is/Ic)代替了绝对的荧光。还应注意的是,也可以就Is与Ic之间的其它数学关系对分析物浓度进行作图从而得到校正曲线。例如,在一个实施方式中,可以就Is/(Is与Ic)的值对分析物浓度进行作图从而得到校正曲线。
根据本发明也可设计其它各种实施方式。例如,参见图3,上述的和图1所示的装置20也可变为夹层测定的另一种形式。例如在一个实施方式中,先将含有分析物的试样与(1)结合了第一结合组分190a的荧光非磁性颗粒141a,(2)荧光磁性颗粒143,以及(3)结合了第二结合组分190b的荧光磁性颗粒141b混合。在该特别实施方式中,荧光磁性颗粒143可被诸如β-酪蛋白的阻断剂阻断,以防止与分析物的非特异性结合,从而使这些颗粒143仅仅用作校正探针。此外,第一特异性结合组分190a和第二特异性结合组分190b可以为分析物类似物。
术语“阻断剂”意思是连接到探针表面使之“阻断”或防止非分析物质与该表面结合的试剂。阻断剂可包括但不限于,β-酪蛋白,白蛋白如牛血清白蛋白,pluronic或其他表面活性剂、聚乙二醇、聚乙烯醇,或者上述化合物的硫衍生物,以及其它本领域普通技术人员公知的阻断材料。
参见图3,分析物与复合的荧光非磁性颗粒141a和复合的非荧光磁性颗粒141b形成夹层复合物149。由于结合垫22与多孔膜23流体连通,因此复合物149可以从结合垫22移动到多孔膜23上的检测区31。在检测区31,接着复合物149以及任何未结合的颗粒143和/或141b被磁性装置60所捕获并从剩余样品中分离。如上所述,通过比较捕获的荧光非磁性颗粒141a的荧光强度Is与捕获的荧光磁性颗粒143的荧光强度Ic,可以确定分析物的绝对量。特别是捕获的荧光磁性颗粒143的总量是预定和已知的,因而可以作校正目的使用。因此,在该实施方式中分析物的量与Is和Ic的比例成正比。
另外,参见图4,上述的和图1所示的装置20也可变为竞争性测定形式。例如在一个实施方式中,先将含有分析物的试样与(1)结合了第一结合组分290a的荧光非磁性颗粒241,以及(2)结合了第二结合组分290b的荧光磁性颗粒243混合。在该特别实施方式中,第一结合组分290a可与分析物相同,而第二结合组分290b可以为分析物类似物。
混合之后,分析物与复合的荧光非磁性颗粒241竞争复合的荧光磁性颗粒243,这样形成了分析物与荧光磁性颗粒243的复合物249a以及荧光磁性颗粒243与荧光非磁性颗粒241的复合物249b。由于结合垫22与多孔膜23流体连通,复合物249a和249b可从结合垫22移动到多孔膜23上的检测区31。在检测区31,接着复合物249a和249b以及任何未结合的颗粒243被磁性装置60所捕获并从剩余样品中分离。如上所述,通过比较捕获的荧光非磁性颗粒241的荧光强度Is与捕获的、复合或未复合的荧光磁性颗粒243的荧光强度Ic,可以确定分析物的绝对量。特别是捕获的荧光磁性颗粒243的总量是预定和已知的,因而可以作校正目的使用。因此,在该实施方式中分析物的量与Is和Ic的比例成反比。
参见图5,上述的和图1所示的装置20也可变为另一种竞争性测定形式。例如在一个实施方式中,先将含有分析物的试样与(1)结合了第一结合组分390a的荧光非磁性颗粒341a,(2)荧光磁性颗粒343,以及(3)结合了第二结合组分390b的非荧光磁性颗粒341b混合。在该特别实施方式中,第一结合组分390a可与分析物相同,而第二结合组分390b可以为分析物类似物。此外,荧光磁性颗粒343可被诸如β-酪蛋白的阻断剂阻断,以防止与分析物的非特异性结合,从而这些颗粒只用作校正探针。
混合之后,分析物与复合的荧光非磁性颗粒341a竞争复合的非荧光磁性颗粒341b,这样形成了分析物与非荧光磁性颗粒341b的复合物349a以及非荧光磁性颗粒341b与荧光非磁性颗粒341a的复合物349b。由于结合垫22与多孔膜23流体连通,复合物349a和349b可从结合垫22移动到多孔膜23上的检测区31。在检测区31,接着复合物349a和349b以及任何未复合的颗粒343和/或341b被磁性装置60所捕获并从剩余样品中分离。如上所述,通过比较捕获的荧光非磁性颗粒341a的荧光强度Is与捕获的荧光磁性颗粒343的荧光强度Ic,可以确定分析物的绝对量。特别是捕获的荧光磁性颗粒343的总量是预定和已知的,因而可以作校正目的使用。因此,在该实施方式中分析物的量与Is和Ic的比率成反比。
尽管上面描述了该装置构造的多种实施方式,但应当明白的是,一般来说本发明的装置可以具有任何想要的构造,而不需要包括所有的上述元件。此外,装置20还可使用不同的测定形式。例如,可以形成如图4所示和上面所描述的竞争性测定,除了颗粒241是荧光磁性颗粒而颗粒243是荧光非磁性颗粒。同样,可以形成如图5所示和上面所描述的竞争性测定,除了颗粒341a是非荧光磁性颗粒而颗粒341b是荧光非磁性颗粒。其它多种装置构造和/或测定形式在Lambotte等人的5395754号,Jou等人的5670381号以及Malick等人的6194220号美国专利中有所记载,在此出于各种目的对其全文引用作为参考。
另外,尽管上面描述了多种实施方式,特别地涉及将荧光用作校正和检测机制,但其它已知的检测机制也同样可应用于本发明。例如,在一些实施方式中,检测和/或校正探针可为化学发光或者磷光化合物。例如化学发光探针可以通过使用本领域已知的适当的反应物激发。根据本发明还可以设计出其它的实施方式和构造。
发明者已发现本发明的基于膜的测定装置可用于控制磁性探针并建立分析物的分离和检测。特别是将磁性分离和检测技术(例如荧光)结合在一完整系统中。而且,该系统是自校正形式的从而消除了使用常规的外部校正技术时对对照校正样品的需要。在一个实施方式中,通过使用荧光磁性探针实现自校正。荧光磁性探针以及荧光非磁性探针发出的荧光可以在同一样品中分别被检测到。因为磁性颗粒的数量是预定的,当确定被捕获的荧光非磁性探针的量并随后确定分析物的量时,系统进行自校正。另外,由于校正和检测探针的荧光是在同样条件下同时测量的,可以避免诸如温度和仪器不稳定性等许多变化可能造成的干扰,从而提高检测可靠性和稳定性。
参考以下实施例,可以更好地理解本发明。
实施例1
证明了利用如图3所示的夹层测定法可检测分析物存在的能力。首先将下列组分加入6个Eppendorf管中:
(1)25微升共价结合的非荧光磁性颗粒(PBS缓冲液中3毫克每毫升);
(2)15微升共价结合的荧光非磁性颗粒(PBS缓冲液中2毫克每毫升);
(3)10微升用β-酪蛋白(PBS缓冲液中3毫克每毫升)阻断的荧光磁性颗粒;以及
(4)促黄体生成激素(LH)分析物,范围从0,10微升(1微克每毫升),20微升(1微克每毫升),40微升(1微克每毫升),40微升(2微克每毫升),到80微升(2微克每毫升)。
向每个Eppendorf管加入适量的PBS缓冲液至最终体积为150微升。在室温下孵化并轻轻摇动该试样10分钟。再通过Dynal公司的磁性分离器将磁性颗粒分离。弃去每个管的上清液再将磁性颗粒重新悬浮于1.5毫升的PBS中。每次荧光测量使用300微升该荧光磁性颗粒悬浮液。用N.J.Edison SPEX工业公司的“Fluorolog III荧光分光光度计”采用直角模式测量样品的荧光。对于荧光磁性颗粒,采用470纳米的激发波长和560纳米的发射波长,对于荧光非磁性颗粒,采用570纳米的激发波长和605纳米的发射波长。积分时间为0.2秒。
图8显示了作为每个样品中LH量的函数的标准化和校正后的荧光强度。将测量的样品的荧光强度除以对照样品的荧光强度得到标准化强度。对照样品为不含分析物的样品。
实施例1中所用的颗粒形成如下:
非荧光磁性颗粒
通过磁分离器将125微升10%的经羧基修饰的顺磁性颗粒(0.35微米,Estapor超顺磁性微球,来自Bang’s Laboratories公司)用1.5毫升碳酸盐缓冲液洗涤一次,PBS洗涤两次。再将洗涤后的颗粒重新悬浮于0.6毫升的PBS和15毫克的碳化二亚胺(来自Polysciences公司)中。在振荡器上使该混合物在室温下(RT)反应30分钟。再将活化的颗粒用硼酸盐缓冲液洗涤两次。将该活化的颗粒再次重悬浮于1.2毫升的硼酸盐缓冲液中。之后,将30微升LHβ-单克隆抗体(9.8mg/ml,购自Fitzgerald国际工业公司)加入该活化的颗粒中。室温下让反应混合物在振荡器上反应过夜。然后收集该活化的颗粒并在1毫升0.1摩的乙醇胺中孵化并轻摇15分钟。再将该颗粒用PBS洗涤两次并在4℃下储存于含有0.1摩PBS,0.15摩NaCl,1%β-酪蛋白,5%甘油以及0.1%NaN3的缓冲液中。
荧光非磁性颗粒
根据上述步骤将“荧光非磁性”颗粒共价结合,但是所述结合组分是LHα-单克隆抗体(9.8毫克每毫升,购自于Fitzgerald国际工业公司),而不是LHβ-单克隆抗体。所用的该颗粒是购自于Molecular Probes公司的FluoSpheres羧基修饰微球。该颗粒尺寸为0.5微米,在580纳米波长激发下发出红色荧光,并且其发射波长为605纳米。
荧光磁性颗粒
在Eppendorf管中加入100微升2.76%荧光超顺磁性颗粒的固体(购自于宾西法尼亚沃灵顿的Polysciences公司)悬浮液和1毫升硼酸盐缓冲液(0.1摩,pH=8.5)。这些颗粒平均直径在1至2微米之间,并且确信为含铁微球,其具有可以被动吸附的聚乙烯表面以及与蛋白质反应的官能团。通过购自于Dynal公司的磁性分离器分离该颗粒,并重悬于200微升的0.1摩硼酸盐缓冲液中,该缓冲液中含有10毫克每毫升的β-酪蛋白。悬浮液孵化30分钟并轻轻混匀。上述步骤重复两次。所述分离的颗粒重悬于200微升PBS中并且4℃储存。
促黄体生成激素(LH)
“促黄体生成激素(LH)”购自于Fitzgerald国际工业公司。
实施例2
证明了利用如图2所示的夹层测定法可检测分析物存在的能力。首先将下列组分加入6个Eppendorf管中:
(1)5微升共价结合的荧光非磁性颗粒(PBS缓冲液中2毫克每毫升);
(2)15微升物理吸附的结合荧光磁性颗粒(PBS缓冲液中3毫克每毫升);以及
(3)促黄体生成激素(LH)分析物范围从0,5,10微升到20,40,100微升(2微克每毫升)。
向每个Eppendorf管加入适量的PBS缓冲液至最终体积为150微升。室温下孵化并轻轻摇动该试样25分钟。再通过Dynal公司的磁性分离器将磁性颗粒分离。弃去每个管的上清液再将磁性颗粒重新悬浮于1.5毫升的PBS中。每次荧光测量使用300微升该荧光磁性颗粒悬浮液。用N.J.Edison SPEX工业公司的“Fluorolog III荧光分光光度计”采用直角模式测量样品的荧光。对于荧光磁性颗粒,采用470纳米的激发波长和560纳米的发射波长,对于荧光非磁性颗粒,采用570纳米的激发波长和605纳米的发射波长。积分时间为0.2至1秒。
图9显示了作为每个样品中LH量的函数的标准化和经校正的荧光强度。
实施例2中所用的颗粒形成如下:
荧光非磁性颗粒
“荧光非磁性”颗粒的形成如实施例1中所述。
荧光磁性颗粒
将2.76毫克荧光超顺磁性颗粒(2.5%固体水悬浮液)购自于宾西法尼亚沃灵顿的Polysciences公司。将该颗粒用硼酸盐缓冲液洗涤三次,并通过购自于Dynal公司的磁分离器分离该颗粒。将洗涤后的颗粒重悬于200微升硼酸盐缓冲液,并加入82微克β-促黄体生成激素(β-LH)单克隆抗体(1毫克每毫升,购自于Fitzgerald国际工业公司)。将该混合物在室温下轻轻混匀过夜。再通过磁分离器收集该颗粒,并在200微升β-酪蛋白(硼酸盐缓冲液中10毫克每毫升)中孵化30分钟并轻轻混匀以阻断非特异性的结合位点。被阻断的颗粒用PBS洗涤两次并储存在0.1摩的PBS中。
促黄体生成激素(LH)
“促黄体生成激素(LH)”购自于Fitzgerald国际工业公司。
实施例3
自校正的磁性结合测定法与非校正性的磁性结合测定法比较。
没有自校正
首先将下列组分加入5个Eppendorf管中(表I中第2-6号管):
(1)15微升共价结合的非荧光磁性颗粒(0.1摩PBS缓冲液中3毫克每毫升);
(2)15微升共价结合的荧光非磁性颗粒(PBS缓冲液中2毫克每毫升);
(3)20微升促黄体生成激素(LH)分析物(1微克每毫升);以及
(4)20微升PBS。
对照Eppendorf管中仅含有20微升PBS(表I中第1号管)。
室温下孵化并轻轻摇动该样品20分钟。再通过Dynal公司的磁分离器将磁性颗粒分离。弃去每个管的上清液再将磁性颗粒重新悬浮于1.5毫升的PBS中。每次荧光测量使用300微升该荧光磁性颗粒悬浮液。用N.J.Edison SPEX工业公司的“Fluorolog III荧光分光光度计”采用直角模式测量样品的荧光。在不同天,采用570纳米的激发波长和605纳米的发射波长,测量荧光。
表I列出了每天测得的相对荧光数据。
表I:荧光检测
管 | 第1号 | 第2号 | 第3号 | 第4号 | 第5号 | 第6号 | 标准偏差% |
第1天 | 13 | 254 | 215 | 263 | 285 | 291 | 11 |
第2天 | 12 | 235 | 207 | 300 | 263 | 299 | 15 |
第3天 | 12 | 183 | 176 | 213 | 270 | 266 | 20 |
第4天 | 18 | 265 | 226 | 275 | 282 | 293 | 10 |
第5天 | 9 | 207 | 193 | 246 | 236 | 244 | 10 |
第6天 | 14 | 227 | 202 | 252 | 262 | 274 | 12 |
标准偏差% | 23 | 13 | 8 | 11 | 6 | 7 |
具有自校正
首先将下列组分加入5个Eppendorf管中(表II中第9-13号管):
(1)15微升共价结合的非荧光磁性颗粒(0.1摩PBS缓冲液中3毫克每毫升);
(2)15微升共价结合的荧光非磁性颗粒(PBS缓冲液中2毫克每毫升);
(3)20微升被β-酪蛋白(PBS缓冲液中3毫克每毫升)阻断的荧光磁性颗粒;以及
(4)20微升促黄体生成激素(LH)分析物(1微克每毫升);以及
(5)20微升PBS。
对照Eppendorf管中仅含有20微升PBS(表II中第8号管)。
室温下孵化并轻轻摇动该样品20分钟。再通过Dynal公司的磁性分离器将磁性颗粒分离。弃去每个管的上清液再将磁性颗粒重新悬浮于1.5毫升的PBS中。每次荧光测量使用300微升该荧光磁性颗粒悬浮液用“Fluorolog III荧光分光光度计”采用直角模式测量样品的荧光。在不同天,对于荧光磁性颗粒采用470纳米的激发波长和560纳米的发射波长,对于荧光非磁性颗粒采用570纳米的激发波长和605纳米的发射波长。
表II列出了每天测得的相对荧光数据。
表II:荧光检测
管 | 第1号 | 第2号 | 第3号 | 第4号 | 第5号 | 第6号 | 标准偏差% |
第1天 | 31/32 | 352/47 | 344/43 | 300/41 | 318/44 | 369/39 | 12 |
第2天 | 31/42 | 324/42 | 329/41 | 323/46 | 338/47 | 418/43 | 14 |
第3天 | 28/39 | 307/40 | 333/42 | 282/42 | 288/40 | 425/46 | 12 |
第4天 | 30/41 | 267/36 | 292/36 | 271/41 | 281/38 | 356/43 | 8.8 |
第5天 | 21/29 | 252/33 | 292/34 | 258/38 | 275/36 | 328/37 | 10 |
第6天 | 21/25 | 237/33 | 307/38 | 265/40 | 288/35 | 358/39 | 12 |
标准偏差% | 13 | 3 | 3 | 4 | 5 | 6 |
从两种体系的每组样品比较可以看出,甚至在小心控制的条件下,自校正系统的标准偏差(Std.Dev%)比没用自校正时的标准偏差小得多。由于自校正系统很少受测量条件影响,所以可预计,当没有对条件进行小心控制时,自校正系统的标准偏差仍将比没有自校正的标准偏差更小。
实施例3中使用的颗粒形成如下:
非荧光磁性颗粒
“非荧光磁性”颗粒的形成如上面实施例1中所述。
荧光非磁性颗粒
“荧光非磁性”颗粒的形成如上面实施例1中所述。
荧光磁性颗粒
“荧光磁性颗粒”的形成如上面实施例2中所述。
促黄体生成激素(LH)
“促黄体生成激素(LH)”购自于Fitzgerald国际工业公司。
实施例4
证明了利用如图3所示的夹层测定法可检测分析物存在的能力。首先将下列组分加入6个Eppendorf管中:
(1)30微升共价结合的非荧光磁性颗粒(PBS缓冲液中2毫克每毫升);
(2)20微升共价结合的荧光非磁性颗粒(PBS缓冲液中2毫克每毫升);
(3)15微升用β-酪蛋白(PBS缓冲液中1毫克每毫升)阻断的荧光磁性颗粒;以及
(4)C反应蛋白(CRP)分析物范围从0,5,10,20,50到100微升(PBS中0.2微克每毫升)。
室温下孵化并轻轻摇动该试样20分钟。再通过Dynal公司的磁性分离器将磁性颗粒分离。弃去每个管的上清液再将磁性颗粒重新悬浮于1.5毫升的PBS中。每次荧光测量使用300微升该荧光磁性颗粒悬浮液。用N.J.Edison SPEX工业公司的“Fluorolog III荧光分光光度计”采用直角模式测量样品的荧光。对于荧光磁性颗粒,采用将470纳米的激发波长和560纳米的发射波长,对于荧光非磁性颗粒采用570纳米的激发波长和605纳米的发射波长。积分时间为0.2至1秒。图10显示了作为每个样品中CRP剂量的函数的标准化荧光强度。
实施例4中所用的颗粒形成如下:
非荧光磁性颗粒
通过磁分离器将125微升10%的经羧基修饰的顺磁性颗粒(0.35微米,Estapor超顺磁性微球,来自Bang’s Laboratories公司)用1.5ml碳酸盐缓冲液洗涤一次,磷酸盐缓冲液(PBS)洗涤两次。再将洗涤后的颗粒重新悬浮于0.6毫升的PBS和15毫克的碳化二亚胺(来自Polysciences公司)中。在振荡器上使该混合物在室温下(RT)反应30分钟。再将活化的颗粒用硼酸盐缓冲液洗涤两次。将该活化的颗粒再次重悬浮于1.2ml的硼酸盐缓冲液中。之后,将30微升抗C反应蛋白(anti-CRP1)单克隆抗体(Mab A5804,2mg/ml,购自Biospacific公司)加入该活化的颗粒中。室温下让反应混合物在振荡器上反应过夜。然后收集该活化的颗粒并在1毫升0.1摩的乙醇胺中孵化轻摇15分钟。再将该颗粒用PBS洗涤两次并在4℃下储存于含有0.1摩PBS,0.15摩NaCl,1%β-酪蛋白,5%甘油以及0.1%NaN3的缓冲液中。
荧光非磁性颗粒
根据上述步骤将“荧光非磁性”颗粒共价结合,除了该结合组分是用抗C反应蛋白(抗-CRP2)单克隆抗体(2mg/ml,购自Biospacific公司)代替抗-CRP1。所用的该颗粒是购自于Molecular Probes公司的FluoSpheres羧基修饰微球。该颗粒尺寸为0.5微米,在580纳米波长激发下发出红色荧光,并且其发射波长为605纳米。
荧光磁性颗粒
100微升2.76%荧光超顺磁性颗粒固体(购自于宾西法尼亚沃灵顿的Polysciences公司)的悬浮液。这些颗粒平均直径在1至2微米之间并且确信为含铁微球,其具有可以被动吸附的聚乙烯表面以及与蛋白质反应的官能团。再向Eppendorf管中的颗粒加入1毫升硼酸盐缓冲液(0.1摩,pH=8.5)。通过购自于Dynal公司的磁分离器分离该颗粒,并将颗粒重悬于0.1M硼酸盐缓冲液中的200微升10mg/mlβ-酪蛋白溶液中。悬浮液保温30分钟并轻轻混匀。上述步骤重复两次。所述分离的颗粒重悬于200微升PBS中并且4℃储存。
C反应蛋白(CRP)
所述“C反应蛋白(CRP)购自于BioPacific公司。
实施例5
证明了构成基于膜技术的测定的能力。首先,将由硝酸纤维素制成的Millipore SX多孔膜样品压覆于长约30厘米的相应的支持片上。膜的一端连接纤维素吸收垫(Millipore公司)。膜的另一端压覆两个玻璃纤维垫(样品垫和结合垫)。该结合垫和吸收垫与膜直接接触,而样品垫与结合垫直接接触。
再用2%的聚乙二醇山梨醇单月桂酸酯(Sigma-Aldirich的名为“Tween20”的非离子表面活性剂)处理每个样品的样品垫,并在37℃下干燥1小时。用非荧光磁性颗粒、荧光非磁性颗粒、荧光磁性颗粒、Tween20以及蔗糖浸泡该结合垫,再在37℃下干燥1小时。“非荧光磁性颗粒”、“荧光非磁性颗粒”以及“荧光磁性颗粒”的形成如上面实施例1中所述。
每个样品的中间部分下面放一个磁条形成检测区。此后,将40微升PBS缓冲液加到第一样品的加样垫上,40微升促黄体生成激素(LH)(0.5微克/毫升)加到第二样品的加样垫上,以及40微升LH(5微克/毫升)加到第三样品的加样垫上。30分钟后,用“Fluorolog III荧光分光光度计”采用正面模式并相对样品成30°角测量在检测区捕获的荧光磁性颗粒和荧光非磁性颗粒。对于荧光磁性颗粒,采用470纳米的激发波长和560纳米的发射波长,对于荧光非磁性颗粒,采用560纳米的激发波长和605纳米的发射波长。
上述三种样品的荧光检测信号分别计为187000,217000和271000。上述三种样品的荧光校正信号分别计为99000,103000,81000。
尽管已经根据特定实施方式对本发明进行了详细描述实施方式,但应当认识到,本领域技术人员根据对前文的理解,可以容易地设计出这些实施方式的替换物、变形物以及等价物。因此,本发明的保护范围应当为以下权利要求及其等同物的范围。
Claims (41)
1.一种用于检测试样中分析物的存在或者量的基于膜的测定装置,所述装置包括:
与可产生检测信号的检测探针和可产生校正信号的磁性校正探针流体连通的多孔膜,所述多孔膜界定了检测区;以及
设置在邻近所述检测区处的磁性装置,其中所述磁性装置能够将所述检测探针和所述校正探针从施加到所述多孔膜上的试样中分离出来,其中所述试样中分析物的量与在所述检测区由所述分离的检测探针产生的检测信号强度成比例,所述检测信号经所述检测区中由所述分离的校正探针产生的校正信号强度校正。
2.如权利要求1所述的装置,还包括一个或多个与所述多孔膜流体连通的结合垫,所述检测探针和所述校正探针施加于所述一个或多个结合垫。
3.如权利要求1所述的装置,其中所述多孔膜与施加样品的加样垫流体连通。
4.如权利要求1所述的装置,还包括与所述多孔膜流体连通的吸收垫,以有助于试样流过。
5.如权利要求1所述的装置,其中所述检测探针和所述校正探针为荧光化合物、化学发光化合物、磷光化合物或其组合。
6.如权利要求1所述的装置,其中所述检测探针为荧光非磁性化合物。
7.如权利要求1所述的装置,其中所述校正探针为荧光磁性颗粒。
8.如权利要求1所述的装置,其中所述检测探针能够与分析物结合。
9.如权利要求1所述的装置,还包括非荧光磁性颗粒。
10.如权利要求9所述的装置,其中所述非荧光磁性颗粒能够与分析物结合。
11.如权利要求1所述的装置,其中所述分离的检测探针包括由所述检测探针形成的复合物。
12.如权利要求1所述的装置,其中所述分离的校正探针包括由所述校正探针形成的复合物。
13.如权利要求1所述的装置,其中所述试样中分析物的量与在所述检测区由所述分离的检测探针产生的检测信号强度和在所述检测区由所述分离的校正探针产生的校正信号强度的商成比例。
14.一种用于检测试样中分析物的存在或者量的基于测流膜的测定装置,所述装置包括:
与可产生检测信号的检测探针、可产生校正信号的荧光磁性校正探针、以及可选择性的非荧光磁性颗粒流体连通的多孔膜,所述多孔膜界定了检测区;以及
设置在邻近所述检测区处的磁性装置,其中所述磁性装置能够将所述检测探针和所述校正探针从施加到所述多孔膜上的试样中分离出来,其中所述试样中分析物的量与在所述检测区由所述分离的检测探针产生的检测信号强度成比例,所述检测信号经所述检测区中由所述分离的校正探针产生的校正信号强度校正。
15.如权利要求14所述的装置,还包括一个或多个与所述多孔膜流体连通的结合垫,所述检测探针和所述校正探针施加于所述一个或多个结合垫。
16.如权利要求14所述的装置,其中所述多孔膜与施加样品的加样垫流体连通。
17.如权利要求14所述的装置,还包括与所述多孔膜流体连通的吸收垫,以有助于试样流过。
18.如权利要求14所述的装置,其中所述检测探针为荧光非磁性复合物。
19.如权利要求14所述的装置,其中所述分离的检测探针包括由所述检测探针形成的复合物。
20.如权利要求14所述的装置,其中所述分离的校正探针包括由所述校正探针形成的复合物。
21.如权利要求14所述的装置,其中所述试样中分析物的量与在所述检测区由所述分离检测探针产生的检测信号强度和在所述检测区由所述分离校正探针产生的校正信号强度的商成比例。
22.一种用于检测试样中分析物的存在或者量的方法,所述方法包括:
i)提供基于膜的装置,所述装置包括:
a)与能够产生检测信号的检测探针以及能够产生校正信号的磁性校正探针流体连通的多孔膜,所述多孔膜界定了检测区域;以及
b)设置在邻近所述检测区处的磁性装置;
ii)将所述检测探针和所述校正探针与所述试样接触形成溶液;
iii)利用所述磁性装置在所述检测区从所述溶液中分离所述检测探针和所述校正探针;
iv)激发所述分离的检测探针以及所述分离的校正探针,其中所述激发引起所述分离的检测探针发出所述检测信号,以及所述分离的校正探针发出所述校正信号;
v)在第一发射波长处测量所述检测信号的强度以及在第二发射波长处测量所述校正信号的强度,所述第二发射波长可以与第一发射波长相同或不同;以及
vi)比较所述检测信号和所述校正信号的强度,其中所述试样中分析物的量与经所述校正信号强度值校正的所述检测信号的强度值成比例。
23.如权利要求22所述的方法,其中所述基于膜的装置还包括一个或多个与所述多孔膜流体连通的结合垫,所述检测探针和所述校正探针应用于所述一个或多个结合垫。
24.如权利要求22所述的方法,其中所述多孔膜与施加样品的加样垫流体连通。
25.如权利要求22所述的方法,还包括与所述多孔膜流体连通的吸收垫,以有助于试样流过。
26.如权利要求22所述的方法,其中所述检测探针是非磁性的。
27.如权利要求22所述的方法,所述分离的检测探针包括由所述检测探针形成的复合物。
28.如权利要求27所述的方法,其中所述复合物是与分析物形成的。
29.如权利要求22所述的方法,所述分离的校正探针包括由所述校正探针形成的复合物。
30.如权利要求28所述的方法,其中所述复合物是与分析物形成的。
31.如权利要求22所述的方法,其中所述第一发射波长与所述第二发射波长不同。
32.如权利要求22所述的方法,所述方法还包括为多个预定分析物浓度就经所述校正信号强度值校正的所述检测信号强度值进行作图,从而得到校正曲线。
33.如权利要求22所述的方法,其中所述分离的检测探针与所述分离的校正探针同时被激发。
34.如权利要求22所述的方法,其中所述分离的检测探针与所述分离的校正探针分别被激发。
35.如权利要求22所述的方法,其中同时测量所述检测信号和所述校正信号的强度。
36.如权利要求22所述的方法,其中分别测量所述检测信号和所述校正信号的强度。
37.如权利要求22所述的方法,其中所述检测和校正探针是化学发光的。
38.如权利要求22所述的方法,其中所述检测和校正探针是磷光的。
39.如权利要求22所述的方法,其中所述检测和校正探针是荧光的。
40.如权利要求38所述的方法,其中使用荧光读数器测量所述检测信号和所述校正信号强度。
41.如权利要求39所述的方法,其中所述荧光读数器利用时间分辨荧光分光光度计测量所述检测和所述校正信号。
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US7943395B2 (en) | 2003-11-21 | 2011-05-17 | Kimberly-Clark Worldwide, Inc. | Extension of the dynamic detection range of assay devices |
US20050136550A1 (en) | 2003-12-19 | 2005-06-23 | Kimberly-Clark Worldwide, Inc. | Flow control of electrochemical-based assay devices |
US7943089B2 (en) | 2003-12-19 | 2011-05-17 | Kimberly-Clark Worldwide, Inc. | Laminated assay devices |
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US20050191704A1 (en) | 2004-03-01 | 2005-09-01 | Kimberly-Clark Worldwide, Inc. | Assay devices utilizing chemichromic dyes |
US20050244953A1 (en) | 2004-04-30 | 2005-11-03 | Kimberly-Clark Worldwide, Inc. | Techniques for controlling the optical properties of assay devices |
-
2002
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- 2002-11-01 US US10/286,342 patent/US7632653B2/en active Active
-
2003
- 2003-07-10 KR KR1020117014422A patent/KR20110089194A/ko not_active Application Discontinuation
- 2003-07-10 WO PCT/US2003/021522 patent/WO2004021005A1/en not_active Application Discontinuation
- 2003-07-10 DE DE60332539T patent/DE60332539D1/de not_active Expired - Lifetime
- 2003-07-10 CA CA2495209A patent/CA2495209C/en not_active Expired - Lifetime
- 2003-07-10 MX MXPA05001681A patent/MXPA05001681A/es active IP Right Grant
- 2003-07-10 KR KR1020057002264A patent/KR101032172B1/ko active IP Right Grant
- 2003-07-10 EP EP03791570A patent/EP1532450B1/en not_active Expired - Lifetime
- 2003-07-10 AT AT03791569T patent/ATE467835T1/de not_active IP Right Cessation
- 2003-07-10 AU AU2003247957A patent/AU2003247957A1/en not_active Abandoned
- 2003-07-10 CN CNB038193930A patent/CN100365417C/zh not_active Expired - Lifetime
- 2003-07-30 TW TW092120776A patent/TW200424521A/zh unknown
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CN101375166B (zh) * | 2006-01-25 | 2013-07-10 | 皇家飞利浦电子股份有限公司 | 用于分析流体的装置 |
CN101603962B (zh) * | 2008-06-10 | 2013-09-11 | 熊慧 | 一种免疫纳米磁珠诊断试剂盒 |
US10010272B2 (en) | 2010-05-27 | 2018-07-03 | Profusa, Inc. | Tissue-integrating electronic apparatus |
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CN105120750A (zh) * | 2013-03-14 | 2015-12-02 | 普罗菲尤萨股份有限公司 | 用于校正光学信号的方法和装置 |
US10045722B2 (en) | 2013-03-14 | 2018-08-14 | Profusa, Inc. | Method and device for correcting optical signals |
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CN107677806A (zh) * | 2017-10-24 | 2018-02-09 | 天津大学 | 基于磁富集的荧光定量高灵敏可视化联检免疫层析试纸条的制备和检测方法 |
CN107677806B (zh) * | 2017-10-24 | 2019-08-20 | 天津大学 | 基于磁富集的荧光定量高灵敏可视化联检免疫层析试纸条的制备和检测方法 |
CN108982872B (zh) * | 2018-07-25 | 2022-04-05 | 苏州丰泰医疗用品贸易有限公司 | 一种基于微球和荧光标记的快速检测抗原或抗体方法 |
CN108982872A (zh) * | 2018-07-25 | 2018-12-11 | 苏州丰泰医疗用品贸易有限公司 | 一种基于微球和荧光标记的快速检测抗原或抗体方法 |
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MXPA05001681A (es) | 2005-04-19 |
US7632653B2 (en) | 2009-12-15 |
CA2495209A1 (en) | 2004-03-11 |
US20080096288A1 (en) | 2008-04-24 |
US7670786B2 (en) | 2010-03-02 |
TW200424521A (en) | 2004-11-16 |
EP1532450B1 (en) | 2012-09-05 |
US7285424B2 (en) | 2007-10-23 |
ATE467835T1 (de) | 2010-05-15 |
US20040043502A1 (en) | 2004-03-04 |
WO2004021005A1 (en) | 2004-03-11 |
AU2003247957A1 (en) | 2004-03-19 |
KR101032172B1 (ko) | 2011-05-02 |
EP1532450A1 (en) | 2005-05-25 |
KR20050062529A (ko) | 2005-06-23 |
KR20110089194A (ko) | 2011-08-04 |
US20040043511A1 (en) | 2004-03-04 |
CN100365417C (zh) | 2008-01-30 |
DE60332539D1 (de) | 2010-06-24 |
CA2495209C (en) | 2011-10-25 |
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