CN101166974A - 用于测定装置的流动控制技术 - Google Patents
用于测定装置的流动控制技术 Download PDFInfo
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- CN101166974A CN101166974A CNA2006800147349A CN200680014734A CN101166974A CN 101166974 A CN101166974 A CN 101166974A CN A2006800147349 A CNA2006800147349 A CN A2006800147349A CN 200680014734 A CN200680014734 A CN 200680014734A CN 101166974 A CN101166974 A CN 101166974A
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Abstract
本发明提供了一种用于控制在采用膜的测定装置中流体流动的方法。特别是通过向其施加溶剂处理剂在所述膜中形成一个或多个凹区。所述溶剂处理剂根据其对用于形成膜的材料的特定溶解能力来加以选择。例如,醇基溶剂,例如甲醇,可用作硝化纤维素膜的溶剂。在与溶剂处理剂接触后,形成了凹区,其可以起到与流动控制相关的各种不同功能。在一种特殊的实施方式中,所述凹区可用作在测定开始后能够向检测区输送可控体积的测试样品的计量通道。
Description
发明背景
通常希望控制流过测定装置的流体流速。例如,侧流(lateral flow)条带通常采用一种使测试样品在到达测试区之前流过的膜。大多数常规的侧流层析条带是针对容易大量获得的测试样品(例如尿液)而设计的。然而,当测试样品是血液时,采集大量的样品会给患者造成过多的疼痛。因此,所采用的一种技术是只将样品直接“点”到膜表面。之后,使用稀释剂冲洗该测试样品并将其携带至检测区。遗憾的是,样品转移所引起的变化以及样品向膜的扩散会导致在到达检测区之前其流动较大程度上不受控制和不均匀。这对于装置的精度具有不利的影响,因为整个检测区所捕获的分析物的量在测量时不恒定。
因此,当前需要一种简单而有效的技术来控制流体通过测定装置膜的流速。
发明简述
根据本发明的一种实施方式,公开了一种用于形成测定装置的方法。该方法包括向膜施加溶剂处理剂(solvent treatment)。该溶剂处理剂对于该膜具有足够的溶解能力,使得在膜中形成至少一个凹区。例如,在一种实施方式中,所述膜由硝化纤维素制成,溶剂处理剂包括丙酮,甲基乙基酮,甲基异丁基酮,乙酸乙酯,乙酸丁酯,乙酸甲氧基丙酯,乙二醇甲醚,乙二醇乙醚,以及乙二醇异丙醚,甲醇或乙醇。所述方法进一步包括在所述膜上形成检测区以帮助检测怀疑存在于测试样品中的分析物。在一种实施方式中,所述凹区为计量通道,该计量通道帮助向检测区提供可控的和恒定体积的测试样品。
根据本发明的另一种实施方式,公开了一种确定测试样品中分析物的存在的方法。该方法包括向膜施加溶剂处理剂,该溶剂处理剂对于该膜具有足够的溶解能力,使得在该膜中形成至少一个凹区。然后使计量通道与测试样品接触。
以下更详细地论述本发明的其它特征和方面。
附图简要说明
针对本领域的普通技术人员,本发明的全面和可实施的内容,包括其最佳方式,都参照附图在说明书的剩余部分进行了更加具体的阐述,其中:
图1是本发明的侧流测定装置的一种实施方式的透视图;
图2是图1所示的侧流测定装置的立体剖视图,其中在通道上架设有桥接元件;
图3是图2所示的侧流测定装置沿3-3线的横截面示意图;
图4是本发明的侧流测定装置的另一种实施方式的透视图,其中图4A示出设置在通道内的吸收性元件,图4B示出设置在吸收性元件和通道上方的桥接元件;
图5是根据本发明的另一种可以形成在膜中的通道实施方式顶视图;
图6是本发明的侧流测定装置的另一种实施方式的透视图。
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MB(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;脂笼蛋白(lipocalins);IgE抗体;细胞因子;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;弓形体病抗体,例如弓形体病IgG(Toxo-IgG)和弓形体病IgM(Toxo-IgM);睾酮;水杨酸盐;对乙酰氨基酚;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);流感病毒;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);脂蛋白,胆固醇,和甘油三酯;以及α-胎儿球蛋白(AFP)。滥用药物和受控物质包括但不限于安非他明;甲基安非他明;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、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;以及丙氧吩。其它可能的分析物在Everhart等人的U.S.6,436,651和Tom等人的U.S.4,366,241中有所记载。
本文所用术语“测试样品”通常是指被怀疑含有分析物的生物材料。测试样品可以来自任何生物源,例如生理流体,包括血液、组织液、唾液、眼晶状体液、脑脊髓液、汗液、尿液、乳液、腹水、粘液、鼻液、痰、滑液、腹膜液、阴道液、月经、羊膜液、精液等等。除了生理流体,也可以使用其它的液体样品,例如用于实施环境或食品测定的水、食品等。此外,怀疑含有分析物的固体材料也可用作测试样品。测试样品可以从生物源获得后直接使用,或者在预处理后使用以改良样品的特性。例如预处理可包括用血液制备血浆、稀释粘稠液等等。预处理方法还包括过滤、沉淀、稀释、蒸馏、混合、浓缩、干扰成分的灭活、以及添加试剂、溶菌等等。而且,有益的是,将固体测试样品改变成液态介质或者释放分析物。
详细说明
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神的情况下能够对本发明作出多种修改和变型。例如,作为一种实施方案的一部分而阐述或描述的特征可用在另一种实施方案上,从而产生又一种实施方案。因而,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方式的范围内。
概括而言,本发明涉及一种用于控制在采用膜的测定装置中流体流动的方法。特别是通过向膜施加溶剂处理剂在所述膜中形成一个或多个凹区。所述溶剂处理剂根据其对用于形成膜的材料的特定溶解能力来加以选择。例如,醇基溶剂,例如甲醇,可用作硝化纤维素膜的溶剂。在与溶剂处理剂接触后,形成了凹区,其可以起到与流动控制相关的各种不同功能。在一种特殊的实施方式中,所述凹区可用作在测定开始后能够向检测区输送可控体积的测试样品的计量通道。这种通道对于测试样品具有较小体积的实施方式特别有效,例如测试样品小于大约100微升,在一些实施方式中小于大约25微升,在一些实施方式中小于大约10微升。例如,用刺血针从患者的低疼痛部位(由于神经末梢比手指少),如前臂、大腿或其它可选择的血液测试位点获得全血血滴,通常体积在大约0.1到大约5微升。尽管其体积小,但本发明发明者们发现利用侧流检测技术仍然可以进行精确地分析所述血滴中分析物的存在。
膜可以由测试样品能够通过的任何材料制成。例如,膜可以由天然的、合成的、或者天然存在并被合成改性的材料形成,例如多糖(例如,纤维素材料,如纸和纤维素衍生物,像醋酸纤维素和硝化纤维素);聚醚砜;聚乙烯;尼龙;聚偏二氟乙烯(PVDF);聚酯;聚丙烯;硅石;无机材料,如去活氧化铝、硅藻土、MgSO4或其它均匀分散在多孔聚合物基质中的无机细碎材料,其中所述聚合物是例如聚氯乙烯、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)和合成的(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。特别希望用来形成所述膜的材料包括聚合物材料,例如硝化纤维素,聚醚砜,聚乙烯,尼龙,聚偏二氟乙烯,聚酯,和聚丙烯。应当理解,术语“硝化纤维素”是指纤维素的硝酸酯,其可以是单独的硝化纤维素,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。
膜的尺寸和形状通常可以有所不同,如本领域技术人员很容易理解的那样。例如,膜条带的长度可以是从大约10到大约100毫米,在一些实施方式中为大约20到大约80毫米,而在一些实施方式中,为大约40到大约60毫米。膜条带的宽度范围也可以是大约0.5到大约20毫米,在一些实施方式中,为大约1到大约15毫米,而在一些实施方式中,为大约2到大约10毫米。尽管不是必需的,但膜条带厚度可以足够小以允许基于透过的检测(transmission-based detection)。例如,所述膜条带的厚度可以小于大约500微米,在一些实施方式中,小于大约250微米,而在一些实施方式中,小于大约150微米。
如果需要的话,可通过刚性载体材料承载着所述膜。例如,载体可以设置成直接邻接膜,或者可以在膜和载体之间设置一个或更多中间层。无论怎样,载体通常都可由能够承载膜的任何材料构成。载体可以由可透光的材料构成,例如透明的或光散射的(例如半透明)材料。而且,通常希望载体是不透液的,这样液体流过膜时不会漏过载体。合适的载体材料的实例包括但不限于,玻璃;聚合物材料,例如聚苯乙烯,聚丙烯,聚酯(例如,Mylar薄膜),聚丁二烯,聚氯乙烯,聚酰胺,聚碳酸酯,环氧化物,甲基丙烯酸脂,和聚密胺(polymelamine)等等。为了向膜提供足够的结构化支撑,通常将载体选择成具有特定的最小厚度。同样,载体的厚度通常也不会大到反过来影响其光学属性。因而,例如,载体的厚度范围可在大约100到大约5000微米,在一些实施方式中,为大约150到大约2000微米,而在一些实施方式中,为大约250到大约1000微米。例如一种适合的膜条带,厚度大约为125微米,可以购自Millipore Corp.of Bedford,Massachusetts,名为“SHF 180UB25”。
正如本领域所公知,膜可以浇注在载体上,其中可以将得到的叠层冲切成预期的大小和形状。或者,所述膜可以仅利用诸如粘合剂之类的方式层压到载体上。在一些实施方式中,是将硝化纤维素或尼龙膜粘贴在Mylar薄膜上。粘合剂用于将所述膜粘结到Mylar薄膜上,例如压力敏感型粘合剂。据信这类层压结构能够从Millipore Corp.of Bedford,Massachusetts买到。还有其它合适的层压测定装置结构的实例记载于Durley,III等人美国专利US 5,075,077中,本文出于所有目的而引入它们的全文作为参考。
根据本发明,所述膜还限定至少一个在所述膜结构内凹陷的区。该凹区通过施加具有膜溶解能力的溶剂处理剂形成。该溶剂处理剂可含有一种或多种在特定条件下能够溶解成膜材料的溶剂。合适溶剂的一些实例包括二醇类,如丙二醇、丁二醇、三甘醇、己二醇、聚乙二醇、乙氧二甘醇、以及二丙二醇;二醇醚类,如乙二醇甲醚、乙二醇乙醚、以及乙二醇异丙醚;醚类,如二乙醚和四氢呋喃;醇类,如甲醇、乙醇、正丙醇、异丙醇、以及丁醇;甘油三酯类;酮类,如丙酮、甲基乙基酮、甲基异丁基酮;酯类,如乙酸乙酯、乙酸丁酯、乙酸甲氧基丙酯;酰胺类,如二甲基甲酰胺、二甲基乙酰胺、二甲基辛酸/癸酸脂肪酸酰胺以及N-烷基吡咯烷酮;腈类,例如乙腈、丙腈、丁腈和苄腈;亚砜类和砜类,例如二甲亚砜(DMSO)和环丁砜;等等。
当然,所选择的溶剂根据成膜所使用的材料而有所不同。例如,在一种特殊的实施方式中,所述膜由硝化纤维素形成。能够溶解硝化纤维素的溶剂(即活性溶剂)实例包括酮类,如丙酮、甲基乙基酮、甲基异丁基酮;酯类,如乙酸乙酯、乙酸丁酯、乙酸甲氧基丙酯;二醇醚类,如乙二醇甲醚、乙二醇乙醚、以及乙二醇异丙醚;醇类,如甲醇和乙醇。在一些实施方式中,可以采用只能够在特定条件下,例如在高温下或者在存在活性溶剂的情况下溶解硝化纤维素的潜溶剂。这种潜溶剂的实例可包括,例如,乙醇、异丙醇和丁醇。在一些情况下,可以采用活性溶剂和共溶剂(例如潜溶剂或其它活性溶剂)的混合物。这种共溶剂可协同提高所述活性溶剂的溶解能力,或者只是用来将低成本。当使用时,所述活性溶剂通常以大于大约50vol.%的量存在,在一些实施方式中大于大约60vol.%,在一些实施方法中为大约70vol.%到大约95vol.%。同样,所述共溶剂可以以小于大约50vol.%的量存在,在一些实施方式中小于大约40vol.%,在一些实施方式中为大约5vol.%到大约30vol.%。还有一些实施方式中,可以采用两种或多种潜溶剂的混合物。
溶剂的纯度也可以影响其溶解能力。也就是说,较高的溶剂纯度通常导致较高的溶解能力。因此,为了优化溶解能力,通常希望同样要优化溶剂的纯度。例如,在大多数实施方式中,本发明所采用的溶剂纯度大于大约95质量%,在一些实施方式中大于大约98质量%,在一些实施方式中大于大约99质量%。
可以利用任何公知的施加技术将所述溶剂处理剂施加到膜上。合适的施加技术包括例如,喷涂、印刷(例如喷墨、压印(pad)等)、移液、气刷、用分配泵计量等等。例如在一种特殊的实施方式中,利用通常用来在侧流条带上形成检测线的分配和可选择的干燥处理过程来施加所述溶剂处理剂。这种系统可包括将多孔膜片放在分配机上并使其穿过卷轴。这可以利用分批或连续处理的方式完成。当所述膜在下面通过时,所述分配机以直线方式释放精确体积的溶剂处理剂。然后所述片层通过干燥机并重新绕在轴上用以进一步加工。用于分批处理的一种这类试验室规模的分配泵系统可以购自Kinematic Automation,Inc.of TwainHarte,California,商标名为“MatrixTM 1600”。
所述溶剂处理剂也可以以有效形成预定尺寸和形状的凹区的任何量施加。最终所采用的量取决于各种因素,包括溶剂对所述膜材料的溶解能力,施加速度等等。例如,在一些实施方式中,所述溶剂处理剂的施加量在大约0.01到大约10微升每厘米膜宽度,在一些实施方式中,为大约0.1到大约10微升每厘米膜宽度,在一些实施方式中,为大约0.5到大约5微升每厘米膜宽度。
无论以何种方式形成,所述凹区通常都用作所述侧流装置的流动控制机制。例如,所述凹区可以阻断流体流过所述膜,直到测定开始之时,例如通过将所述膜设置成与另一膜呈流体连通的形式。或者,所述凹区仅用于减缓或控制流体通过所述膜的流动。例如,可以形成多个不连续的凹区(例如点)来降低膜结构的连续性。这样,迫使流过膜结构的流体沿着曲折的通道流动,这增加了流体到达检测区的时间。这样增加的流动时间具有许多好处,例如促进均匀混合并保证测试样品中的任何分析物都有足够的时间与期望的试剂反应。例如,测试样品到达检测区的时间可以为至少大约1分钟,在一些实施方式中为至少大约2分钟,在一些实施方式中为大约3到大约10分钟,在一些实施方式中为大约10到大约30分钟。
在一种特殊的实施方式中,所述凹区起着计量通道的功能,其用于向检测区提供可控和恒定体积的测试样品以用于分析。因此,下面将更加详细地介绍其中凹区起着侧流测定装置的计量通道的各种本发明的实施方式。然而应当明白,以下的说明仅是举例,本发明显然还可以设计出其它的实施方式。
例如参见图1-3,示出了一种侧流测定装置20的实施方式,其包括层压到载体21上的膜23。该装置20还可以包含位于所述膜23的末端27旁边或附近的吸收垫(未示出)。所述吸收垫通常接收已经迁移通过整个膜23的流体。正如本领域内所公知,吸收垫可以帮助促进毛细作用和流体流过膜23。
如图所示,膜23还限定了凹区或计量通道35。尽管该实施方式中只示出了一个计量通道35,但应当明白根据本发明也可以采用多个凹区。所述计量通道35通常可具有任何预期的横截面形状,例如矩形、圆形、正方形、三角形、梯形、V字形、U字形、六边形、八边形、不规则形状等等。例如,在所示实施方式中,计量通道35呈矩形。此外,计量通道35可以是直线形、锥形、曲线形、蛇形、迷宫状或者具有任何其它希望的构型。
同样,所述计量通道35的尺寸还可以根据其预期的功能而有所不同。例如,当用作计量通道时,计量通道35的尺寸可以是使得能够迅速通过被动毛细作用流动来吸收测试样品。当流体与通道壁的粘附力大于液体分子之间的内聚力时通常发生毛细流动。特别地,毛细压力与通道的横截面尺寸成反比,而与液体的表面张力成正比,并乘以流体与形成通道的材料的接触角的余弦。因此,为了促进毛细流动,计量通道35在膜23的纵向“L”上的长度可小于大约20毫米,在一些实施方式中为大约0.001到大约10毫米,在一些实施方式中为大约0.01到大约4毫米。当然,该长度也可以作为宽度的函数改变。
计量通道35的尺寸规定了将输送到检测区31的测试样品的最终体积。更具体来说,在施加到其上之后测试样品将很快填满计量通道35的空体积,任何过量样品将从装置20除掉。为了帮助将可控体积的测试样品输送到检测区31,计量通道35的高度或深度可以改变以容纳所需体积的样品。例如,计量通道35的深度可以是从大约0.1微米到大约800微米,在一些实施方式中为从大约20微米到大约400微米,在一些实施方式中为从大约80微米到大约200微米。所述计量通道35还可以具有与膜23相同或基本上相同的宽度(在“W”方向上)。通过这种方式,测定开始后测试样品将更均匀地流过膜23的整个宽度。从而所述测试样品将最终以更均匀的方式到达测试区31,从而提供更加准确的结果。例如在一些实施方式中,计量通道35的宽度为大约0.5到大约20毫米,在一些实施方式中为大约1到大约15毫米,在一些实施方式中为大约2到大约10毫米。当然,计量通道35的宽度、深度、和/或长度也可以作为尺寸的函数加以改变。在这种情况下,所指出的宽度、深度或长度是平均尺寸。
当计量通道35的表面张力接近或超过水的表面张力(即72mN/m)时,其通过毛细作用吸收水性样品(例如血液)的能力提高。因此如果需要的话,可以用一种或多种润湿剂处理计量通道35以提高表面张力。本发明中可采用的一种润湿剂是亲水性润湿剂,例如非离子表面活性剂。合适的非离子表面活性剂的实例包括乙氧基化烷基酚类,乙氧基化和丙氧基化脂肪醇类,氧化乙烯-氧化丙烯嵌段共聚物,乙氧基化的(C8-C18)脂肪酸酯类,氧化乙烯与长链胺类或酰胺类的缩合产物,氧化乙烯与醇类的缩合产物,炔二醇类,及它们的混合物。各种合适的非离子表面活性剂的特别实例包括但不限于甲基gluceth-10,PEG-20甲基葡萄糖二硬脂酸酯,PEG-20甲基葡萄糖倍半硬脂酸酯,C11-15烷醇聚醚-20(pareth-20),鲸蜡醇聚醚-8(ceteth-8),鲸蜡醇聚醚-12(ceteth-12),dodoxynol-1 2,laureth-1 5,PEG-20蓖麻油,聚山梨酯20,硬脂醇聚醚-20,聚氧乙烯-10十六烷基醚,聚氧乙烯-10十八烷基醚,聚氧乙烯-20十六烷基醚,聚氧乙烯-10油基醚,聚氧乙烯-20油基醚,乙氧基化壬基苯酚,乙氧基化辛基苯酚,乙氧基化十二烷基苯酚,或者乙氧基化(C6-C22)脂肪醇,包括3到20个氧化乙烯部分,聚氧乙烯-20异十六烷基醚,聚氧乙烯-23甘油月桂酸酯,聚氧乙烯-20甘油硬脂酸酯,PPG-10甲基葡萄糖醚,PPG-20甲基葡萄糖醚,聚氧乙烯-20山梨聚糖单酯,聚氧乙烯-80蓖麻油,聚氧乙烯-15十三烷基醚,聚氧乙烯-6十三烷基醚,laureth-2,laureth-3,laureth-4,PEG-3蓖麻油,PEG600二油酸酯,PEG400二油酸酯,以及它们的混合物。市场上可买到的非离子表面活性剂可包括SURFYNOL系列的炔二醇表面活性剂,购自Air Products andChemicals of Allentown,Pennsylvania;TWEEN系列的聚氧乙烯表面活性剂,购自Fisher Scientific of Pittsburgh,Pennsylvania;以及TRITON系列的聚氧乙烯表面活性剂(例如TRITONX-100,聚氧乙烯-10异辛基环己基醚),购自Sigma-Aldrich Chemical Co.of St.Louis,Missouri。
除了表面活性剂之外,还有其它合适的润湿剂,其中包括当用水或者用水或醇基电解液润湿时比干燥时显著更光滑的水溶性或水溶胀性聚合物。这种亲水性聚合物的实例包括,例如藻酸钠、钾和钙,羧甲基纤维素,琼脂,明胶,聚乙烯醇,骨胶原,果胶,几丁质,壳聚糖,聚(α-氨基酸),聚酯,聚-1-己内酯,聚乙烯吡咯烷酮,聚氧化乙烯,聚乙烯醇,聚醚,多糖,亲水性聚氨酯,聚羟基丙烯酸酯,聚甲基丙烯酸酯,葡聚糖,黄原胶,羟丙基纤维素,甲基纤维素,以及N-乙烯基吡咯烷酮、N-乙烯基内酰胺(N-vinyllactam)、N-乙烯基丁内酰胺、N-己内酰胺、其它具有极性支链基团的乙烯基化合物、具有亲水性酯化基团的丙烯酸酯和甲基丙烯酸酯、羟基丙烯酸酯、丙烯酸以及它们的组合的均聚物和共聚物。
本发明的溶剂施加技术可具有额外的好处,即,其无需单独的处理,例如用疏水性材料处理,就能赋予计量通道35的壁以屏障性质。例如,参见图3,示出了计量通道35的一种实施方式的横截面,其根据本发明已经进行了溶剂处理。尽管该实施方式的膜23包含孔60,但之前位于计量通道35的壁39附近的任何孔在该通道微加工之后要么被破坏,要么在尺寸上大大减小。同样,计量通道35具有由载体21限定的底表面41,其通常由疏水性材料制成。通过这种方式,基本上抑制了测试样品流动通过壁39和流到膜23下方。或者,所述计量通道35可以不延伸到载体21,这样膜23形成了通道的底表面。在这种情况下,溶剂处理剂也可以破坏之前位于该底表面附近的任何孔。
如果需要的话,使用者可以将测试样品直接施加到计量通道35中,或者测试样品可以从该测定装置20的其它一些位置提供给计量通道35,例如从样品垫,滤血器等等。在一种实施方式中,使用者可以仅向计量通道35施加一滴全血(例如来自刺血针、手指或其它可代替部位如前臂的血滴)。该测定装置20有时可以构造成有助于将测试样品施加到计量通道35的形式。例如,参见图6,示出了测试装置20的一种实施方式,其包括计量通道35,膜23和载体21。在该特殊的实施方式中,膜23和载体21的一些部分被去除,这样在通道35处形成尖端24。例如,该尖端24可以提供按压使用者皮肤的位点,从而将血液转移到计量通道35。
当测试样品是全血时,计量通道35可以用红细胞凝集剂(即凝集素)处理以帮助将红细胞从血清中分离。这种凝集剂可以单独施加或者包含用于形成计量通道35的在溶剂处理剂内。例如,在一种实施方式中,计量通道35的壁39和/或表面41上可以施加包含在溶剂处理剂内的凝集剂。在施加之后,将处理剂干燥以去除任何溶剂并留下凝集剂的干燥残余物。通过这种方式,检测区31只对血清或血浆进行分析,这可以提高对小体积测试样品的半定量或定量检测。凝集素可以是外源凝集素,例如伴刀豆球蛋白A或者番茄(Lycopersicon esculentum),或者特异性结合红细胞的抗体,例如多克隆兔抗人红细胞抗体制剂。凝集素通常以足以凝集测试样品大多数红细胞的量施加。还可以施加其它的试剂以选择性地结合或阻碍某些其它生物样品成分的移动。例如,可以用使红细胞从血浆中分离的试剂处理计量通道35,使得可以分析血浆成分,例如分析物(如C反应蛋白(C-reactive protein))。或者,可以施加通过其生物、化学或物理性质选择性地分离生物样品成分的试剂。可以用减少血液样品成分的非特异性结合或非特异性吸附的其它试剂来处理计量通道35。例如,可以用蛋白质,例如白蛋白(如牛血清白蛋白)来处理计量通道35。
为了启动测试样品从计量通道35流到测试区31,可以采用多种技术。例如,参见图2,示出了一种桥接元件51,其放置在计量通道35的上方使其与膜23流体连通。更具体来说,该桥接元件51具有在更靠近检测区31的位置接触膜23并与膜23流体连通的第一端53,以及同样与膜23接触并流体连通的相对第二端55。桥接元件51提供一种毛细“提升”作用,其将来自计量通道35的小体积测试样品拉起。一旦被所述桥接元件51所吸收,测试样品就能够流过膜23到达检测区31以进行分析。桥接元件51可以由测试样品能够流动通过的任何材料制成。例如,桥接元件51可以由上述用于形成膜23的任何上述膜基材料制成。可以使用的一些具体材料包括但不限于尼龙、硝化纤维素、纤维素、多孔聚乙烯垫、以及玻璃纤维滤纸。
当血液是测试样品时,桥接元件51也可以起到血液分离过滤器的作用。血液分离过滤器选择性地滞留全血样品中包含的细胞成分(例如红细胞)并将血液样品的剩余成分(例如血浆或血清)输送到检测区。该血液分离过滤器可以由任何适当的材料制成,例如能够从流体过滤细胞(如血细胞)的疏水性材料。可以采用各种包装或筛分深度(sievingdepth)的过滤器,例如玻璃纤维,用红细胞捕获剂处理后的纤维素或玻璃过滤器,玻璃纤维过滤器,合成纤维过滤器或包含任何上述材料组合的复合材料。例如,玻璃纤维过滤器可以从Whatman plc of Kent,UnitedKingdom;Millepore Corp.of Beillerica,Massachusettes;以及Pall Corp.of Ann Arbor,Michigan购买到。这种玻璃纤维过滤器可具有范围在大约0.05到大约9微米的纤维直径和大约50到大约150g/m2的密度。合适的血液分离过滤器的其它实例记载于Allen等人的美国专利U.S.5,416,000,以及Shull等人的的美国专利申请公开No.2004/0126833和Zhou的2003/0032196中,本文出于所有的目的而引入其全文作为参考。如果需要的话,血液分离过滤器可以用例如如上所述的一种或多种剂(例如凝集素)进行处理。
参见图4,示出了侧流测定装置20的另一种实施方式。如图4A中所示,吸收性元件70设置在形成于膜23中的计量通道35内。尽管不是必需的,但该吸收性元件70有助于启动测试样品从计量通道35流到桥接元件51(图4B)。例如,当需要进行测定时,将吸收性元件70放到计量通道35中并吸收测试样品。如图4B中所示,然后将桥接元件51放置成接触吸收性元件70并与吸收性元件70流体连通。通过这种方式,测试样品可以简单地从吸收性元件70流到桥接元件51。
应当明白的是,所述通道无需形成于检测区所在的膜上。例如,所述通道可以形成于第一膜上,其之后放置成与第二膜流体连通以进行测定。例如,参见图5,示出了这种分离膜83的一种实施方式,其含有以上述方式形成的通道85。为了启动测定,采用桥接元件81,其具有接触膜83并与膜83流体连通的第一端91和相对的第二端95。该相对的第二端95可设置成与侧流测定装置(未示出)的膜流体连通,例如毗邻样品垫、缀合垫等等,以启动测试样品从通道85流到检测区(未示出)。
无论采用何种特定的机制来将计量通道35设置成与膜23流体连通,通常都要用稀释剂(或洗涤剂)来帮助将测试样品输送到检测区31。所述稀释剂通常施加到计量通道35的上游,使其可以启动向检测区31方向的流动。例如,在施加之后,稀释剂可流过所述膜23,直到到达桥接元件51的第一端53(图1-2)。然后所述稀释剂流过桥接元件51,在这里其与来自计量通道35的测试样品混合并帮助携带测试样品流到桥接元件51的第二端55。最后,稀释剂/测试样品混合物从所述第二端55流到检测区31以进行分析。所述稀释剂可以是粘度足够小以使流体能够通过毛细作用移动并且支持分析物与任何结合剂之间的反应(例如不会干扰抗体/抗原相互作用)的任何材料。在一种实施方式中,所述稀释剂含有水、缓冲剂;盐(例如NaCl);蛋白质稳定剂(例如BSA、酪蛋白、海藻糖或血清);和/或清洁剂(例如非离子表面活性剂)。代表性缓冲剂包括,例如磷酸盐缓冲剂(PBS)(例如pH 7.2),2-(N-吗啉代)乙烷磺酸(MES)(例如pH 5.3),HEPES缓冲剂,TBS缓冲剂等等。
仅用于举例说明目的,现在将更详细地描述一种利用图1-3所示的测定装置进行免疫测定的实施方式。免疫测定采用免疫系统机制,其中响应有机体病原性或外源性抗原的存在而产生抗体。这些抗体和抗原,即免疫反应物能够彼此结合,由此引起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。为了启动免疫测定,首先将测试样品(例如全血)施加到计量通道35,例如用刺血针、针头、滴管、移液管、毛细装置等等。一但计量通道35中包含了预期量的测试样品,就将桥接元件51放在计量通道35上方并将稀释剂施加到装置20。桥接元件51和稀释剂的施加可以同时或顺次进行,并可以通过手动或自动操作实施。稀释剂的施加部位可根据需要改变。例如,在一些实施方式中,稀释剂施加到与膜23流体连通的其它膜上,如样品垫(未示出)或缀合垫(未示出)。所述样品垫和缀合垫可以由流体能够通过的任何材料制成,例如玻璃纤维。而且,如果需要的话,计量通道35可以以上述方式形成于样品垫和/或缀合垫中。
为了帮助检测测试样品中的分析物,可以向样品垫和/或缀合垫预先施加某种物质,或者将其预先与稀释剂或测试样品混合,该物质视觉可见或者可通过仪器检测到。通常能够产生在视觉上或通过仪器设备可检测的信号的任何物质都可用作检测探针。合适的可检测物质可包括,例如发光化合物(例如荧光的、磷光的等等);放射性化合物;可见化合物(例如有色染料或金属物质,如金);脂质体或其它含有信号生成物质的囊泡(vesicles);酶和/或底物等等。其它合适的可检测物质记载于Jou等人的U.S.5,670,381和Tarcha等人的U.S.5,252,459中,本文出于所有目的而引入它们的全文作为参考。如果可检测物质是有色的,则理想的电磁辐射是互补波长的光。例如,蓝色的检测探针强烈地吸收红光。
在一些实施方案中,可检测物质可以是能产生光学可检测信号的发光化合物。例如,合适的荧光分子可包括但不限于,荧光素、铕螯合物、藻胆蛋白、罗丹明,以及其衍生物和类似物。其它合适的荧光化合物有半导体纳米晶体,通常称作“量子点”。例如,所述纳米晶体可包含通式为CdX的核心,其中X为Se、Te、和S等等。纳米晶体还可以由通式为YZ的包被壳所钝化,其中Y是Cd或者Zn,Z是S或Se。其它合适的半导体纳米晶体实例还可以记载于Barbera-Guillem等人的U.S.6,261,779和Dapprich的U.S.6,585,939中,本文出于所有目的而引入它们的全文作为参考。
此外,合适的磷光化合物可包括一种或多种金属的金属配合物,例如钌、锇、铼、铱、铑、铂、铟、钯、钼、锝、铜、铁、铬、钨、锌等等。尤其优选的是钌、铼、锇、铂和钯。金属配合物可包含一个或多个有助于该配合物在含水或非含水环境中溶解的配体。例如,配体的一些合适实例包括但不限于,吡啶、吡嗪、异烟酰胺、咪唑、联吡啶、三联吡啶、菲咯啉;联吡啶并吩嗪;卟啉、卟吩以及其衍生物。所述配体可以例如,由烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、羧酸根、甲醛(carboxaldehyde)、酰胺、氰基、氨基、羟基、亚氨基、羟基羰基、氨基羰基、脒、胍、酰脲基、含硫基团、含磷基团、N-羟基-琥珀酰亚胺的羧酸酯所取代。
卟啉和卟吩金属配合物具有用亚甲桥偶联在一起的吡咯基,从而与金属螯合的内部孔洞形成环状结构。这些分子中的许多在室温下在合适溶剂(例如水)中以及无氧环境下表现出强烈的磷光性质。能够表现出磷光性质的一些合适卟啉配合物包括但不限于,铂(II)粪卟啉-I和III,钯(II)粪卟啉,钌粪卟啉,锌(II)-粪卟啉-I,及其衍生物等等。类似地,能够表现出磷光性质的一些合适卟吩配合物包括但不限于,四-meso-氟苯基卟吩铂(II)和四-meso-氟苯基卟吩钯(II)。还有其它合适的卟啉和/或卟吩配合物记载于Schmidt等人的U.S.4,614,723;Hendrix的U.S.5,464,741;Soini的U.S.5,518,883;Ewart等人的U.S.5,922,537;Sagner等人的U.S.6,004,530;以及Ponomarev等人的U.S.6,582,930中,本文出于所有目的而引入它们的全文作为参考。
还可以利用联吡啶金属配合物作为磷光化合物。合适的联吡啶配合物的一些实例包括但不限于,二[(4,4’-甲氧基)-2,2’-联吡啶]2-[3-(4-甲基-2,2’-联吡啶-4-基)丙基]-1,3-二氧戊环钌(II);二(2,2’联吡啶)[4-(丁-1-醛)4’-甲基-2,2’-联吡啶]钌(II);二(2,2’联吡啶)[4-(4’-甲基-2,2’-联吡啶-4’-基)-丁酸]钌(II);三(2,2’联吡啶)钌(II);(2,2’-联吡啶)[二-二(1,2-二苯基膦基)亚乙基]2-[3-(4-甲基-2,2’-联吡啶-4’-基)丙基]-1,3-二氧戊环锇(II);二(2,2’-联吡啶)[4-(4’-甲基-2,2’-联吡啶)-丁胺]钌(II);二(2,2’联吡啶)[1-溴-4(4’-甲基-2,2’-联吡啶-4-基)-丁烷]钌(II);二(2,2’-联吡啶)马来酰亚氨基己酸;4-甲基-2,2’-联吡啶-4’-丁酰胺钌(II)等等。可表现出磷光性质的其它合适的金属配合物还记载于Richter等人的U.S.6,613,583;Massey等人的U.S.6,468,741;Meade等人的U.S.6,444,423;Massey等人的U.S.6,362,011;Bard等人的U.S.5,731,147;以及Massey等人的U.S.5,591,581中,本文出于所有目的而引入它们的全文作为参考。
在一些情况下,发光化合物可能具有较长的发光寿命和较大的“斯托克司频移”。术语“斯托克司频移”通常定义为,发光辐射的谱线或波段移向比激发线或波段更长的发射波长。较大的斯托克司频移使得发光化合物的激发波长保持远离其发射波长,并且由于激发和发射波长之间的较大差异使得较容易从发射信号中去除反射的激发辐射,因而是人们所希望的。而且,大斯托克司频移还使得来自样品中的发光分子和/或蛋白质或胶体的光散射的干扰降到最低,这些蛋白质或者胶体存在于一些体液(例如血液)中。此外,大斯托克司频移还使得对用来消除背景干扰的昂贵、高精度滤光片的需要最小化。例如,在一些实施方案中,发光化合物具有大于大约50纳米的斯托克司频移,在一些实施方案中大于大约100纳米,而在一些实施方案中为大约100到大约350纳米。
例如,具有大斯托克司频移的示例性荧光化合物包括钐(Sm(III))、镝(Dy(III))、铕(Eu(III))和铽(Tb(III))的镧系螯合物。在螯合物以相当短的波长激发之后所述螯合物可表现出强烈的红移、窄带、长寿命发光。通常,由于发色团位于分子中的镧系元素附近,所以螯合物具有强烈的紫外发射波带。由发色团激发之后,激发能量可以从激发的发色团传递到镧系元素上。之后是该镧系元素的荧光发射特性。例如,与荧光素仅为大约28纳米相比,铕螯合物的斯托克司频移在大约250到大约350纳米。同样,与其它荧光标记的大约1到大约100纳秒的寿命相比,铕螯合物的荧光寿命很长,其寿命大约为100到大约1000微秒。此外,这些螯合物具有窄发射波谱,通常在大约50%的发射处带宽小于大约10纳米。一种合适的铕螯合物是N-(对异硫氰酸根合苄基)二亚乙基三胺四乙酸-Eu+3。
此外,本发明中还可以使用在水溶液或悬液中惰性、稳定并且具有固有荧光的镧系元素螯合物,从而无需胶束形成试剂,它们通常用来保护在水溶液或悬液中具有有限溶解度并存在猝灭问题的螯合物。这种螯合物的一个实例是4-[2-(4-异硫氰酸根合苯基)乙炔基]-2,6-二([N,N-二(羧甲基)氨基]甲基)吡啶[参见:Lovgren,T.等;Clin.Chem.42,1196-1201(1996)]。一些镧系元素螯合物还表现出特别高的信噪比。例如,一种此螯合物是四配位基β-二酮化物-铕螯合物[参见:Yuan,J.和Matsumoto,K.;Anal.Chem.70,596-601(1998)]。除了上述荧光标记之外,适用于本发明的其它标记记载于Mullinax等人的U.S.6,030,840;Davidson的U.S.5,585,279;Singer等人的U.S.5,573,909;Wieder等的U.S.6,242,268;Hemmila等的U S.5,637,509,本文出于所有目的而引入它们的全文作为参考。
可检测物质,例如如上所述,可以单独使用或者与颗粒(有时称为“珠”或“微珠”)联合使用。例如,可以使用天然形成的颗粒,例如胞核、支原体、质粒、质体、哺乳动物细胞(例如红细胞影)、单细胞微生物(例如细菌)、多糖(例如琼脂糖)等等。此外,也可以利用合成颗粒。例如,在一种实施方案中,采用了标记有荧光或有色染料的乳胶微粒。尽管本发明中可以使用任何合成颗粒,但所述颗粒典型地是由以下物质构成:聚苯乙烯、丁二烯苯乙烯、苯乙烯丙烯酸-乙烯基三聚物、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、聚乙酸乙烯酯、聚乙烯基嘧啶、聚二乙烯苯、聚对苯二甲酸丁二醇酯、丙烯腈、氯乙烯-丙烯酸酯等等,或者其醛、羧基、氨基、羟基、或者酰肼衍生物。其它合适的颗粒记载于Jou等人的U.S.5,670,381,Tarcha等人的U.S.5,252,459和Bodzin等人的美国专利申请2003/139886中,本文出于所有目的而引入它们的全文作为参考。市场上可买到的合适荧光颗粒的实例包括Molecular Probes,Inc.出售的商品名为“FluoSphere”(Red 580/605)和“TransfluoSphere”(543/620)的荧光羧化微球,以及同样由Molecular Probes,Inc.出售的“Texas Red”,和5-、6-羧基四甲基罗丹明。此外,市场上可买到的合适的有色乳胶微粒实例包括Bang’s Laboratory,Inc.出售的羧化乳胶微珠。本发明中也可以采用金属颗粒(例如金颗粒)。
当使用时,颗粒的形状一般可以变化。例如,在一种特别的实施方案中,所述颗粒是球状的。然而,应当明白的是本发明也可以构思其它的形状,例如板状、棒状、盘状、条状、管状、不规则形状等等。此外,颗粒的大小也可以有所不同。例如,颗粒的平均尺寸(例如直径)范围可以在大约0.1纳米到大约100微米,在一些实施方案中,为大约1纳米到大约10微米,而在一些实施方案中,为大约10纳米到大约100纳米。
在一些情况下,可能希望以一些方式改变检测探针使其更容易与分析物结合。在这种情况下,检测探针可以通过粘附于其上的某种特异性结合成员改性以形成缀合探针(conjugated probes)。特异性结合成员通常是指特异性结合对的成员,所述特异性结合对即两个不同分子,其中一个分子化学和/或物理结合到第二个分子上。例如,免疫活性特异性结合成员可包括抗原、半抗原、适配体(aptamers)、抗体(第一或第二)、以及其复合物(complexes),包括通过重组DNA方法或肽合成法制成的那些。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断,以及抗体和其它特异性结合成员的混合物。这种抗体的制备细节以及其用作特异性结合成员的适用性是本领域技术人员公知的。其它常规的特异性结合对包括但不限于生物素和抗生物素蛋白(或其衍生物),生物素和抗生物素蛋白链菌素,碳水化合物和外源凝集素,互补核苷酸序列(包括在DNA杂交测定中用来检测靶核酸序列的探针和捕获核酸序列),互补肽序列包括通过重组方法所形成的那些,效应物和受体分子,激素和激素结合蛋白,辅酶(enzyme cofactors)和酶,酶抑制因子和酶等等。此外,特异性结合对可包括是原特异性结合成员的类似物的成员。例如,可以使用分析物的衍生物或片段(即“类似物”),只要其具有至少一个与分析物相同的抗原决定部位。
特异性结合成员通常可以利用任何各种公知的技术与检测探针相连。例如,利用羧基、氨基、醛基、溴乙酰基、碘乙酰基、硫醇基、环氧基和其它反应性或连接官能团,以及残余自由基和自由基阳离子,可以实现蛋白质的偶联反应,从而可以实现特异性结合成员与检测探针(例如,颗粒)的共价连接。表面官能团还可以作为官能化共聚单体被引入,因为所述检测探针表面可含有较高表面浓度的极性基团。此外,尽管所述探针通常在合成后进行官能化,例如用聚(苯硫酚)官能化,但所述探针也可以直接与蛋白共价连接而无需进一步改性。例如,在一种实施方案中,缀合的第一步是使用碳二亚胺活化探针表面的羧基。在第二步中,活化的羧酸基团与抗体的氨基反应形成酰胺键。所述活化和/或抗体偶联可以在缓冲液中进行,例如磷酸盐缓冲液(PBS)(例如,pH值7.2)或2-(N-吗啉代)乙烷磺酸(MES)(例如,pH值5.3)。然后得到的检测探针例如可以与乙醇胺接触,用以阻断任何残余的活性位点。总之,该过程形成了缀合的检测探针,其中抗体与所述探针共价连接。除了共价连接外,本发明中还可以采用其它的连接技术,例如物理吸附。
再次参见图1-2,稀释剂和任何任选的检测探针移动通过膜23,直到到达桥接元件51的第一端53。在通过该桥接元件51的第二端55之后,稀释剂和测试样品移动通过膜23,直到到达检测区31,其通常位于计量通道35的下游。本发明的发明者们发现,在到达检测区31后,测试样品的体积在检测区31的整个宽度上相对均匀。此外,由于该计量通道35,测试样品的体积也被预先确定在一个狭窄的的范围内。
在检测区31内,受体材料(receptive material)被固定,其能够与缀合的检测探针结合。所述受体材料可以选自与上述特异性结合成员相同的材料,包括,例如,抗原;半抗原;抗体结合蛋白,例如蛋白A,蛋白G,或蛋白A/G;中性抗生物素蛋白(neutravidin)(一种去糖基化(deglysolated)抗生物素蛋白衍生物),抗生物素蛋白(高度阳离子型66000道尔顿糖蛋白),抗生物素蛋白链菌素(52800道尔顿的非糖基化蛋白),或者captavidin(一种硝化的抗生物素蛋白衍生物);第一或第二抗体,及它们的衍生物或片段。在一个实施方式中,例如,受体材料是对测试样品中的抗原具有特异性的抗体。所述受体材料用作针对分析物和缀合检测探针之间形成的复合物的固定结合位点。尤其是,分析物例如抗体、抗原等,通常具有两个或多个结合位点(例如,抗原决定部位)。在到达检测区31后,这些结合位点之一被缀合探针的特异性结合成员所占据。然而,分析物的自由结合位点可以结合到固定的第一受体材料上。在与所述固定的受体材料结合后,所述复合探针便形成了新的三元夹心复合物。
除了检测区31,所述侧流装置20还可以限定出各种其它的区以提高检测准确度。例如,在一种涉及高分析物浓度的实施方式中,测定装置20可包含位于检测区31下游的指示区35,指示区35构造成提供所述分析物浓度是否达到测定饱和浓度(“钩状效应(hook effect)”区)的信息。该指示区35含有固定在所述膜23上的第二受体材料,并且此第二受体材料用作所述缀合检测探针的固定结合位点。为了在指示区35内实现期望的结合,通常希望所述第二受体材料能够区分与分析物复合在一起的那些检测探针和保持未复合状态那些检测探针。例如,在一种实施方式中,第二受体材料包括具有至少一个与分析物相同的抗原决定部位的分子,例如分析物分子,或其衍生物或片断(即类似物),使得其能够特异性地结合到未与分析物复合的抗体缀合物上。
或者,所述第二受体材料可以包括不是分析物分子或其类似物的生物材料,但其能够优先与未复合的缀合探针结合。在一种实施方式中,例如,第一受体材料可以是单克隆抗体,例如抗CRP IgG1。检测探针与不同于第一受体材料单克隆抗体的单克隆抗体如抗CRP IgG2缀合。在这种特殊的实施方式中,第二受体材料可以是第二抗体,例如羊抗人IgGF(ab’)2,其Fc片断已被吸附,因而只与IgG的Fab部分反应。因此,当不存在分析物时,第二抗体能够与抗CRP IgG2单克隆抗体的自由“Fab”结合域结合。然而,当测试样品中存在抗原时,其首先与抗CRP IgG2单克隆抗体的“Fab”结合域复合。所述抗原的存在使得“Fab”结合域之后不能与第二抗体结合。通过这种方式,指示区35内的第二抗体能够优先与未复合的检测探针结合。
尽管检测区31和可选择的指示区35可以提供准确的结果,但有时难以在实际测试条件下确定测试样品中分析物的相对浓度。因此,测定装置20还可以包括校正区32。在该实施方式中,校正区32形成于膜23上,并位于检测区31和可选择的指示区35的下游。然而可选择地,校正区32还可以位于所述检测区31和/或可选择的指示区35的上游。校正区32具有第三受体材料,其能够与通过膜23长度的任何校正探针结合。当使用时,校正探针可以含有与用于检测探针的可检测物质相同或不同的可检测物质。而且,所述校正探针还可以与例如如上所述的特异性结合成员缀合。例如在一种实施方式中,可以使用生物素化的(biotinylated)校正探针。一般来说,校正探针可以通过如下方式进行选择:使其在检测区31和指示区35不与第一或第二受体材料结合。校正区32的第三受体材料可以与检测区31或指示区35中使用的受体材料相同或不同。例如,在一种实施方式中,第三受体材料是生物受体材料,例如抗原,半抗原,抗体结合蛋白(例如蛋白A,蛋白G,或蛋白A/G),中性抗生物素蛋白,抗生物素蛋白,抗生物素蛋白链菌素,captavidin;第一或第二抗体,及它们的复合物。还希望采用各种非生物材料作为校正区32中的第三受体材料(例如聚电解质(polyelectrolytes)),例如Song等人的美国专利申请公开No.2003/0124739中所述,本文出于所有的目的而引入其全文作为参考。
当使用时,聚电解质可具有净正电荷或负电荷,以及通常成中性的净电荷。例如,具有净正电荷的聚电解质的一些合适实例包括但是不限于,聚赖氨酸(可从Sigma-Aldrich Chemical Co.,Inc of St.Louis,Missouri买到),聚乙烯亚胺;环氧氯丙烷-官能化多胺和/或多酰氨基胺(polyamidoamines),例如聚(二甲胺-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,例如接枝有季铵水溶性单体的纤维素共聚物或纤维素衍生物;等等。在特定的实施方式中,可以使用CelQuatSC-230M或H-100(可从National Starch&Chemical,Inc.得到),其是含有季铵水溶性单体的纤维素衍生物。此外,具有净负电荷的聚电解质的一些合适实例包括但是不限于,聚丙烯酸类,例如聚(乙烯-共-甲基丙烯酸,钠盐)等等。应该明白的是,也可以使用其它的聚电解质,例如两性聚电解质(即具有极性和非极性部分)。例如,合适的两性聚电解质的一些实例包括但是不限于,聚(苯乙烯基-b-N-甲基2-乙烯基吡啶碘化物)和聚(苯乙烯基-b-丙烯酸),两者都可以从PolymerSource,Inc of Dorval,Canada获得。
尽管通常可以使用任何聚电解质,但针对特殊应用选择的聚电解质根据检测探针、校正探针、膜等的性质可以有所不同。特别地,聚电解质的分布的电荷使其能够结合具有相反电荷的物质。因此,例如,具有净正电荷的聚电解质通常良好的具备结合带负电探针的能力,而具有净负电荷的聚电解质通常良好的具备结合带正电探针的能力。因此,在这种情况下,这些分之间的离子相互作用使得所需要的结合作用发生在校正区32内。然而,尽管离子相互作用主要用于在校正区32内实现期望的结合,但聚电解质也可以与具有相似电荷的探针结合。
由于聚电解质设计成与探针结合,故通常希望该聚电解质基本上不扩散地固定在所述膜23的表面上。否则,该探针将不易被使用者检测到。因此,所述聚电解质可以以这种方式应用到膜23上:使其基本上不扩散到膜23的基质中。特别地,所述聚电基质通常与膜23表面上存在的官能团形成离子和/或共价键,从而使其保持固定在上面。尽管不是必需的,但所希望在聚电解质和膜23之间形成共价键以更加持久地将聚电解质固定在上面。例如,在一种实施方式中,首先将用于形成聚电解质的单体形成溶液,然后直接施加到膜23上。可以采用各种溶剂(例如有机溶剂、水等等)来制备该溶液。一经施加后,就采用加热、电子束辐射、自由基聚合等方式引发单体的聚合反应。在一些情况下,随着单体的聚合,它们与膜23的某些官能团形成共价键,从而将所得到的聚电解质固定于其上。例如,在一种实施方式中,乙撑亚胺单体可以与一些膜(例如硝化纤维素)表面上存在的羧基形成共价键。
在另一种实施方式中,聚电解质可以在施加到膜23之前形成。如果需要的话,可以利用有机溶剂、水等等首先将聚电解质形成为溶液。之后,将聚电解质溶液直接施加到膜23上然后干燥。干燥之后,所述聚电解质可以与该膜23表面上存在的某些具有与电解质相反的电荷的官能团形成离子键。例如,在一个实施方式中,带正电的聚乙烯亚胺可以与一些膜(例如硝化纤维素)表面上存在的带负电羧基形成离子键。
此外,所述聚电解质还可以利用各种公知的技术交联到所述膜23上。例如,在一些实施方式中,可以使用表氯醇官能化的多胺和/或多酰氨基胺作为可交联的带正电聚电解质。这些材料的实例在Keim的美国专利US.3,700,623,Keim的U.S.3,772,076以及Keim的U.S.4,537,657中有所记载,本文出于所有的目的引入它们的全文作为参考,并且据说它们由Hercules,Inc.,Wilmington,Del.出售,商标名为KymeneTM。例如,KymeneTM450和2064是表氯醇官能化的多胺和/或多酰氨基胺化合物,其含有可以与一些类型的膜(例如硝化纤维素)上存在的羧基形成共价键并且当固化时可与膜的聚合物主链交联的环氧化物环和季铵基团。在一些实施方式中,交联温度范围可以在大约50℃到大约120℃,交联时间范围可以是从大约10到大约600秒。
尽管上面已经描述了多种用于非扩散地将聚电解质固定在膜23上的技术,但应当明白的是,本发明中也可以采用任何其它的用于非扩散地固定聚电解质化合物的技术。实际上,上述方法仅用于举例说明可以用于本发明的技术。例如,在一些实施方式中,可以向聚电解质溶液中加入一些可以基本上抑制这种聚电解质扩散到膜23的基质中的成分。
检测区31,指示区35和校正区32可以分别具有任意数量的不同检测区域,使得使用者可以更好地确定测试样品中一种或多种分析物的浓度。每个区域可以包含相同的受体材料,或者可以包含不同的受体材料。例如,所述区可以包括两个或多个不同的区域(如线、点等)。所述区域可以设置成方向基本上垂直于测试样品流动通过测定装置20的方向的线条形式。类似地,在一些实施方式中,所述区域可以设置成方向基本上平行于测试样品流动通过测定装置20的方向的线条形式。
在一些情况下,膜23还可以限定对照区(未示出),其向使用者提供测定正确实施的信号。例如,对照区(未示出)可以含有固定的受体材料,该受体材料通常能够与探针或与固定在探针上的受体材料形成化学和/或物理键。这些受体材料的一些实例包括但不限于抗原、半抗原、抗体、蛋白A或蛋白G、抗生物素蛋白、抗生物素蛋白链菌素、第二抗体及它们的复合物。此外,还希望利用各种非生物材料作为对照区受体材料。例如,在一些实施方式中,对照区受体材料还可以包括例如如上所述的聚电解质,其可以结合未捕获的探针。由于对照区的受体材料仅特异于探针,故无论分析物是否存在都会形成信号。对照区可以位于沿膜23上的任何位置,但优选位于检测区31和指示区35的下游。
根据本发明可以获得定性、半定量和定量的结果。例如,当需要半定量或定量检测分析物时,检测区31、指示区35、和/或校正区32处产生的任何信号强度可以用光学读取装置测量。该光学读取装置的实际配置和结构通常可以有所不同,本领域技术人员应很容易理解这点。例如,可以利用的光学检测技术包括但不限于,发光(例如荧光、磷光等),吸光度(例如荧光的或非荧光的),衍射等等。例如,在Kaylor等人的公开号为2003/0119202的美国专利申请公开中描述了一种适合的反射分光光度计,本文出于所有目的而引入该公开全文作为参考。在另一种实施方式中,可以使用反射模式分光光度计来检测荧光信号的强度。例如,在Song等人的公开号为2004/0043502的美国专利申请公开中描述了适合的分光荧光光度计和相关的检测技术,本文出于所有目的而引入该公开全文作为参考。同样地,透射模式检测系统也可以用于信号强度检测。
尽管上面描述了多种装置构造的实施方式,但应当明白,本发明的装置通常可以具有任何需要的构造,并且无需包含所有的上述元件。例如,在Lambotte等人的U.S.5,395,754;Jou等人的U.S.5,670,381;Malick等人的U.S.6,194,220中描述了各种其它的装置构造,本文出于所有目的而引入它们的全文作为参考。
利用本发明的测定装置,还可以使用各种测定形式来测试分析物的存在与否。例如,“夹心”形式一般涉及使测试样品与检测探针混合,这些探针与分析物的特异性结合成员(例如抗体)缀合,从而在分析物与缀合探针之间形成复合物。然后使这些复合物与固定在检测区内的受体材料(例如抗体)相接触。分析物/探针缀合复合物与固定的受体材料之间发生结合,从而定位能够检测以指示分析物存在的“夹心”复合物。这项技术可用于获得定量或半定量的结果。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,这里出于所有的目的而引入它们的全文作为参考。在竞争性测定中,标记的探针通常是和与分析物相同或类似的分子缀合。因此,标记的探针与目标分析物竞争可用的受体材料。竞争性测定法通常用于检测诸如半抗原之类的分析物,每个半抗原是单价的并且仅能够结合一个抗体分子。竞争性免疫测定装置的实例在Deutsch等人的U.S.4,235,601、Liotta的U.S.4,442,204和Buechler等人的U.S.5,208,535中有所记载,这里出于所有的目的而引入它们的全文作为参考。在Lambotte等人的U.S.5,395,754;Jou等人的U.S.5,670,381以及Malick等人的U.S.6,194,220中还描述了各种其它的装置构造和/或测定形式,本文出于所有目的而引入它们的全文作为参考。
参考下面的实施例可以更好地理解本发明。
实施例
证实了通过溶剂处理剂形成通道的可能性。将长度大约30厘米的硝化纤维素膜(HF 120,购自Millipore,Inc.)层压到载体卡片上。将纤维素纤维芯吸垫(Millipore Co.)连接到所述膜的一端。之后,利用“Kinematic 1600”试剂分配模块(Kinematic Automation,Inc.of TwainHarte,California)通过将纯的甲醇在硝化纤维素上以12微升每秒(1μl/cm分配速率,12cm/s的床速)的速率制成条带,形成计量通道。所得到的计量通道深度大约为0.18毫米,长度大约为2毫米。然后利用“Kinematic 2360”切割机(Kinematic Automation,Inc.of Twain Harte,California)将卡片切成4毫米宽的条带,从而得到4毫米宽的半侧流浸渍条(“半条带”)。
尽管已经就本发明的具体实施方式详细描述了本发明,但本领域技术人员应该理解,在领会上述内容之后,很容易构思这些实施方式的替换形式、变型方式和等同方式。因此,本发明的范围应当由所附权利要求书及其等同方式来确定。
Claims (20)
1.一种用于确定测试样品中分析物的存在的方法,该方法包括:
向膜施加溶剂处理剂,所述溶剂处理剂对该膜具有足够的溶解能力,使得在膜中形成至少一个凹区;以及
之后,使该凹区与测试样品接触。
2.权利要求1的方法,进一步包括向所述膜提供稀释剂以有利于所述测试样品的流动。
3.权利要求1或2的方法,其中所述测试样品是全血。
4.权利要求3的方法,进一步包括从全血中分离血浆、血清或上述二者以进行分析。
5.前述任何一项权利要求的方法,其中所述测试样品的体积为大约0.5到大约25微升,优选从大约1到大约10微升。
6.前述任何一项权利要求的方法,其中所述测试样品从所述凹区流到检测区。
7.一种用于形成测定装置的方法,该方法包括:
向膜施加溶剂处理剂,所述溶剂处理剂对该膜具有足够的溶解能力,使得在膜中形成至少一个凹区;以及
在所述膜上形成检测区以帮助检测怀疑存在于测试样品中的分析物。
8.权利要求6或7的方法,其中所述膜限定出所述检测区,并且所述检测区位于所述凹区的下游。
9.权利要求6到8中任何一项的方法,其中在所述检测区之内受体材料固定在所述膜上,所述受体材料能够结合检测探针或其缀合物。
10.权利要求6到9中任何一项的方法,进一步包括将与检测区流体连通的桥接元件放在所述凹区之上。
11.前述任何一项权利要求的方法,其中所述溶剂处理剂包括活性溶剂。
12.权利要求11的方法,其中所述溶剂处理剂进一步包括共溶剂,该共溶剂选自活性溶剂和潜溶剂。
13.权利要求11或12的方法,其中所述活性溶剂以大于约50vol.%的量存在于所述处理剂组合物中。
14.前述任何一项权利要求的方法,其中所述溶剂处理剂包括二醇,二醇醚,醚,醇,甘油三酯,酮,酯,酰胺,腈,亚砜或砜。
15.权利要求14的方法,其中所述溶剂处理剂包括丙酮,甲基乙基酮,甲基异丁基酮,乙酸乙酯,乙酸丁酯,乙酸甲氧基丙酯,乙二醇甲醚,乙二醇乙醚,以及乙二醇异丙醚,甲醇或乙醇。
16.前述任何一项权利要求的方法,其中所述膜由选自以下的聚合物材料制成:硝化纤维素,聚醚砜,聚乙烯,尼龙,聚偏二氟乙烯,聚酯,和聚丙烯。
17.前述任何一项权利要求的方法,其中所述溶剂处理剂的施加量为大约0.01到大约10微升每厘米膜宽度,优选为大约0.5到大约5微升每厘米膜宽度。
18.前述任何一项权利要求的方法,其中在所述膜中形成多个不连续的凹区。
19.前述任何一项权利要求的方法,其中所述凹区的宽度与所述膜的宽度相同或基本上相同。
20.前述任何一项权利要求的方法,其中所述溶剂处理剂进一步包括润湿剂,凝集剂或其组合。
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- 2006-03-27 CN CN2006800147349A patent/CN101166974B/zh not_active Expired - Fee Related
- 2006-03-27 KR KR1020077024665A patent/KR20080015784A/ko not_active Application Discontinuation
- 2006-03-27 MX MX2007013523A patent/MX2007013523A/es unknown
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Publication number | Publication date |
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KR20080015784A (ko) | 2008-02-20 |
US20060246597A1 (en) | 2006-11-02 |
CN101166974B (zh) | 2013-05-15 |
WO2006118707A2 (en) | 2006-11-09 |
US8124421B2 (en) | 2012-02-28 |
US20110097734A1 (en) | 2011-04-28 |
MX2007013523A (es) | 2008-01-11 |
WO2006118707A3 (en) | 2007-04-05 |
EP1875235A2 (en) | 2008-01-09 |
US7858384B2 (en) | 2010-12-28 |
JP2008539426A (ja) | 2008-11-13 |
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