CN101322145B - 用于在生物流体样品内执行计数的设备和方法 - Google Patents
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Abstract
提供了用于对生物流体样品内的一种或多种特定成分进行计数的方法和设备。本方法的实施方式包括以下步骤:a)提供在第一平面构件与第二平面构件之间形成的腔室,所述第一平面构件是透明的,所述第一和第二平面构件以基本一致的高度相互分开;b)将所述生物流体样品引入到所述腔室中,其中所述腔室的高度的尺寸设置为使得所述样品在第一与第二构件之间延伸,并且相对于所述样品内的所述特定成分设置为使得在被引入到所述腔室中时所述特定成分不均匀地分布在所述样品内;c)检查所述腔室内的基本所有样品并对所有的至少一种特定成分进行计数;d)确定包含在所述腔室内的所述样品的体积;和e)确定每单位体积内所述至少一种特定成分的数量。
Description
申请人在此要求2005年10月19日提交的美国临时专利申请第60/728,058号和2005年10月25日提交的美国专利申请第11/257,757号的优先权,所述两个专利的公开内容在此以参考的方式并入。
技术领域
本发明大体上涉及用于分析生物流体的腔室,并且尤其涉及允许对生物流体内的颗粒物质进行计数的腔室。背景技术
全血计数(CBC)是对于全血的最频繁执行的测试组,并且包括许多单独的分析,例如白细胞计数(WBC)、红细胞计数(RBC)和血小板计数等等。所使用的方法在分析物集合的完整性、设备的复杂性和成本以及单次测试成本方面有变化。最不复杂的方法,例如在美国专利第4,156,570号中所描述的QBC方法的具有最便宜的资本费用并且执行简单,但通常具有较高的单次测试成本。QBC方法最适合操作者训练最少并且每天几乎不执行测试的重点照护检验的情形。在所述范围的另一端,医院或基准实验室所使用的大体积血液分析器能够具有大二十倍的资本成本,但是当在大量基础上使用时具有相对低的单次测试成本,这使得它们在这些设定的情形下更具成本效率。
对细胞进行计数的最简单且最古老的方法之一包括使用血细胞计数器。在血细胞计数器中,进行血液的精确稀释。随后将近似量的稀释物放置到具有足够高度的计数腔室中,当稀释的样品流入腔室时,该高度足以使稀释的样品保持与稀释的样品中发现的细胞同样的均匀性。也就是说,腔室一定不能因为样品流入和流过腔室而选择性地使任何细胞或其它成分浓缩或稀释。这是因为只对腔室已知区域中细胞的代表性部分进行计数。如果细胞的分布偏斜,则这样的计数将错误地反应整个样品的计数。
例如Abbot Cell-Dyn或Bayer Advia的较大的现代***基于流式细胞器(FC)的某些变量,其中将精确量的血液精确地稀释并在多个步骤中与试剂混合。流体阀给定了稀释的样品进入多个试验区中的路线。如同血细胞计数器一样,细胞在稀释剂内的分布必须保持相对均匀,使得稀释的样品的代表性部分的计数能够表示原始样品中的计数。该方法对仪器复杂性的要求达到了使得这些仪器的可靠性相对低的程度。实际上,采用这些较大的***,经常有需要基于每周的、或更经常的预防性维护或修理,这些维护或修理需要特殊训练的试验室技术人员或服务技师的技能,所有这些基本上都增加操作的成本。操作的另一隐形成本是使该***正常执行所需的清洗、清洁和校准程序。
在美国专利第6,723,290号、第6,866,823号、第6,869,570号和第6,929,953号中描述了中间的***,其中血液放置到单次使用的一次性物品中用于分析。这些专利描述了可靠的、成本低的、并且容易使用的方法和仪器,它们能够提供与上述流式细胞器***相同的分析数据范围。在该***中,将近似量的未稀释样品放置到一次性物品中,该一次性物品的特性允许样品内细胞的分布保持基本均匀。对给出的成像区域中的细胞进行计数,确定该区域的体积,然后计算每体积内的细胞计数。在该***中,如同血细胞计数器一样,只需要对添加到腔室的样品的一部分进行计数,因为细胞的分布基本均匀。但是该方法需要单次使用的一次性物品,这对于少量测试是有利的,但这并不特别地适用于大量测试使用。
有利的是具有一种***,其中在足够薄的腔室中能够对未稀释的全血样品中的成分计数以便能够从样品获得细胞计数和细胞形态,并且在该***中能够减轻不均匀的分布的影响。这种分析***将减小或消除样品的流体处置和精确测量或稀释,产生用于这种分析的简单得多且价格比较低廉的方法。发明内容
提供一种用于对流体介质内的成分进行计数的方法和设备,其简单、精确并且成本相对低。该方法和设备尤其非常适于在抗凝血的全血样品内执行血细胞计数(即,WBC(白血球计数)、RBC(红血球计数)等)。在该方法中,将近似量的样品放置到高度非常小的腔室中,该腔室的高度通常小于20微米并且对于对血液进行计数,优选地为大约四个微米。在进入腔室时,样品内某些类型的成分的分布明显改变。在样品内对于某些成分在分布方面的改变可归因于样品内的所述成分相对于腔室高度的尺寸。如果将血液样品引入到腔室中,例如样品内的红血球将浓缩在腔室的周边而样品内的白血球将浓缩在腔室样品进口附近。红血球在样品内通常分散在距进口比白血球远的距离处,因为红血球较小并且通常具有高度可变的膜、并且能够适应紧凑的空间,而白血球较大并且与红血球相比相对地刚硬。尽管腔室相对薄的高度允许成分容易地可视化,但样品内成分的分布使得通常没有表示整个样品的样品局部区域。因此,没有表示整个样品的能够被计数以给出整个样品的精确计数的局部区域。在该方法中,与我们知道的所有其它计数法形成对比,检查添加到腔室的整个样品,并且计数要检查的特定类型的样品内的所有不均匀分布的细胞。一旦知道样品内的要检查的不均匀分布的细胞类型的总数,则能够通过用计数的细胞的数量除以包含在腔室内的体积来计算样品的该类型不均匀分布细胞的每单位体积的计数。小腔室内细胞分布的非均匀性的现象自从细胞计数以来是众所周知的,并因非常不合需要而总是被避免,因为几乎不可能手工对腔室内的所有成分手工计数以得到精确的总计数。另外,由这样的腔室使用的微小样品尺寸在这样的腔室内排除样品量的精确初始测量、或者无规律蔓延的样品的样品体积的随后计算。但是,随着近来允许作出这些计数并计算腔室样品的整个面积的精确且快速的数字成像***的出现,薄膜腔室现在能有利地用于获得血细胞或其它计数的简单且精确的方法。
在某些实施方式中,用于对生物流体样品内的一种或多种特定成分进行计数的本方法包括以下步骤:a)提供在第一平面构件与第二平面构件之间形成的腔室,所述第一平面构件是透明的,所述第一和第二平面构件以基本一致的高度相互分开;b)将生物流体样品引入到腔室中,其中所述腔室的高度设置为使得样品在第一与第二构件之间延伸到所述腔室的至少一部分,并且其中所述腔室高度相对于样品内的一种或多种特定成分的尺寸设置为使得所述一种或多种特定成分在引入到腔室中时不均匀地分布在样品内;c)检查腔室内的基本所有样品并对所有的至少一种特定成分进行计数;d)确定包含在腔室内的样品的体积;和e)确定每单位体积内至少一种特定成分的数量。
与我们知道的所有现有技术形成对比,本发明检查存在于限制在由两个相对平坦的基板限定的腔室中的薄膜中的整个生物流体样品(例如未稀释的全血),其中能够确定添加到腔室的样品的总体积。与所有只检查一部分样品的其它方法形成对比,对样品内所有的至少一种特定成分进行计数。术语“所有的至少一种特定成分”表示所述特定成分的所有特定类型。比如说,如果一种或多种特定成分包括成分A、B、和C,“至少一种特定成分”指的是成分A,则对“所有的至少一种特定成分”进行计数表示对样品内的所有成分A进行计数。
可使用由至少一个透明壁形成的任何腔室。能够通过例如微米加工、刻蚀、基板沉积的技术产生腔室。在共同未决的美国专利申请第09/885,193号和第09/366,881号中描述的技术是可接受的技术的示例,该计数使用隔离器元件层以实现腔室一致的厚度。
本方法需要基本精确地知道或可确定被引入腔室中的样品体积。术语“基本精确”限定为适于即将到来的测试的体积准确度。能够利用许多不同的技术执行样品的体积确定,包括但不限于:1)当利用可从例如Middlefield,CT的Zygo公司的来源获得的光学技术通过干涉成像首先淀积时计算样品体积;或者2)在薄膜形成(通过样品在腔室内扩展形成膜)之后通过测量样品膜的面积并用该面积乘以样品膜的平均高度来计算样品体积;或者3)利用或制造具有精确已知体积的腔室(即厚度和长度),其中添加的血液样品将流入腔室直到腔室不能包含更多的血液为止(即由于包含的血液的总量预先已知,所以能够用被计数的成分的总数除以已知的腔室体积以给出计数/体积)。
对于本发明来说,读取或者细胞计数仪器在功能上可类似于共同未决的美国专利申请第09/981,581号和第10/023,405号中所示。
根据以下提供的本发明的详细描述并且如附图所示,本发明的这些及其它目的、特征和优点将变得明显。附图说明
通过参考以下附图进一步阐明本发明的原理。
图1是根据本发明的教示具有由公知且相对均匀的空间分开的两个透明表面的腔室的示意图。
图2是大量血液已被引入腔室之后图1的腔室示意图的横截面。
图3是示出腔室的概略顶部平面图,以便示出充满的和未充满的腔室。
图4是腔室的中央区域的放大图解视图。
图5是腔室的周围区域的放大图解视图。具体实施方式
参考图1至5,用于分析生物流体的本设备包括一个或多个腔室2,所述腔室2由以下文中称为腔室高度16的距离相互分开的第一平面构件和第二平面构件限定。第一平面构件和第二平面构件中的至少一个平面构件足够透明,使得可对设置在腔室2内的生物流体样品成像。为了便于描述本发明,所述平面构件在下文中称为“顶”平面构件4和“底”平面构件3。顶平面构件4在下文中还被描述成透明的。在替代的实施方式中,不是顶平面构件4、或者除顶平面构件4以外,底平面构件3可以是透明的。
平面构件3、4能够由具有不同或相同特征的各种材料形成。与本申请属于共同所有者并且在此以参考的方式完整并入的序号为PCT/2005/011602的专利协作条约专利申请披露了可接受的平面构件3、4的实例。作为另一示例,顶平面构件4可由聚对苯二甲酸乙二醇酯(PET)条带形成,该聚对苯二甲酸乙二醇酯条带分别具有大约25μ和一英寸的厚度和宽度。底平面构件3能够类似地由相似宽度的PET条带形成,且具有大约128μ的厚度。其中平面构件3、4为柔性的本发明的实施方式允许腔室2卷绕在卷轴上。
尽管实践本发明不需要侧壁,但在某些实施方式中,腔室2还由一个或多个侧壁7进一步限定。在优选的实施方式中,侧壁7由在顶平面构件4与底平面构件3之间延伸的粘结材料(bonding material)构成。可定位侧壁7以产生不同的腔室构造。例如,在某些实施方式中,可涂覆粘结材料,使得一个或多个侧壁7延伸基本横跨平面构件3、4的宽度。在其它的实施方式中,侧壁7可形成为基本或完全包围腔室2的形状。例如图3所示的实施方式示出由粘结材料形成的椭圆形侧壁7的包围。侧壁7可由不同于粘结材料的材料制成。
对于使用粘结材料的侧壁7的实施方式,粘结材料可由任何的各种不同材料构成,所述材料附着于平面构件3、4,或者与平面构件3、4相互作用,以便足以产生适于保持腔室2内样品的密封。在优选的实施方式中,粘结材料是具有将平面构件3、4相互附连的粘附特征的材料。包括光固化(light-curing)粘合剂的粘结材料尤其有用,所述光固化粘合剂的许多示例可容易地得到。
在某些实施方式中,本发明包括设置在腔室内的一个或多个隔离器元件5。可接受的隔离器元件5的实例在共同未决的专利申请第09/885,193号和第09/366,881号以及PCT专利申请PCT/2005/011602号中披露,所述三个专利申请在此以参考的方式完整地并入。可接受的隔离器元件5的示例是由聚苯乙烯制成的、具有公知并且精确受控的直径的球形珠状物。其中在平面构件3、4由基本刚性的材料形成的实施方式中,取决于腔室的实际构造,可以不需要隔离器元件5。
在某些实施方式中,顶平面构件4包括一个或多个入口8和通风孔隙10。入口8对于生物样品提供通往腔室的通路。通风孔隙10提供一个通道,当生物样品被引入腔室2时空气可通过该通道溢出。在至少一部分腔室2打开(例如,腔室2的侧壁未形成完整的包围)的实施方式中,可省略入口8和通风孔隙10。
为了说明本发明设备的效用,提供用于使用该设备的方法的以下例子。但是,本发明的方法和设备不局限于这些特定的例子。
参考图2,示出通过填充孔8已添加未稀释的抗凝血的全血样品6的腔室2。在某些应用中,不需要样品6填充整个腔室2。在顶平面构件4和底平面构件3中的一个或两个都相对柔性的这些实施方式中,优选的是腔室2不是完全充满的,而是留有小的未充满区域9。未充满区域9在这样的腔室2的实施方式中是有利的,因为来自未充满区域的毛细力在腔室2的平面构件3、4上施加强的向下的力,该力对保持腔室2的高度16的一致是有益的。
在第二实施方式中,图3示出相互邻近的一对腔室2′、2″。设置在左边的腔室2′示出部分地由侧壁包围7限定的未充满腔室。腔室2′的顶平面构件4包括入口8和一对通风孔隙10。生物流体样品6(例如,血液)已通过入口8被引入设置在右边的腔室2″。样品6从入口8蔓延以充满腔室的大部分,留有邻近通风孔隙10设置的小的空气空间9。因为腔室高度16与所述样品内的一种或多种特定成分(例如,白血球、红血球)的平均“厚度”(例如,直径)的相对值,所以成分在样品内的分布通常变得高度地不均匀。高度不均匀的分布与依赖成分的均匀分布来确保准确度的现有技术方法形成强烈对比。
通过示出入口附近的显微视野的图示,在图4中示出成分在腔室2内的不均匀分布的示意性示例。在该示例中,血浆11比红血球12更普遍。因为白血球的尺寸,所以白血球13也在该区域中集中。同样在该附图中见到隔离器颗粒5和血小板14。在该示例中,例如要计数的特定成分能够是白血球13或红血球12中的一个或多个。要计数的成分也能够是被标识成分的子集;例如,特定类型的白血球、或具有被选择性地染色以便可标识并且单独计数的表面表位(surface epitope)的白血球等。
相比之下,图5示意性地示出了显微视野,以描绘腔室2设置在腔室侧壁7附近的部分。在该视野中,大量红血球12邻近侧壁7并构成视野的大部分。
通过这些示例清楚的是利用只考虑一小部分样品的现有技术的方法实际上不可能有精确计数。本发明的方法和设备相比之下在要计数的成分不均匀分布的应用中能够提供精确计数。同时,能够获得与某些特定成分相关的特定信息(例如,白血球的泡孔形态)。为了利用本方法获得精确计数,利用数字摄像机成像全部样品,并且该图像接受对设置在腔室内的每个特定指标不均匀分散成分进行检测和计数的分析。取决于样品的面积,当对样品的整个区域进行成像时每次能够对图象帧执行该分析,或者一系列图像能够“缝合”在一起以形成同时分析的较大的图像。用于成像的合适的仪器和软件在美国专利第6,866,823号、第6,869,570号、和第6,929,953号中描述。于是相同的图像分析确定腔室内样品的实际体积。一旦完成计数并确定体积,则计算每单位体积的计数。
能够意识到的是通过向细胞特定的配位体添加萤光或其它标记并检查腔室以对具有束缚到细胞表面的配位体标记的细胞进行计数,本发明还能够执行流式细胞器的大部分功能。
尽管已关于本发明的详细实施方式示出和描述了本发明,但本领域的技术人员将理解的是在不偏离本发明的精神和范围的情况下,可作出本发明形式上和细节上的各种改变。
Claims (25)
1.一种用于对生物流体样品内的一种或多种特定成分进行计数的方法,包括以下步骤:
提供在第一平面构件与第二平面构件之间形成的腔室,其中,所述第一平面是透明的,所述第一和第二平面构件以一高度相互分开;
将所述生物流体样品引入到所述腔室中,其中所述腔室高度的尺寸设置为使得所述样品在第一与第二构件之间延伸到所述腔室的至少一部分,其中所述腔室高度相对于所述特定成分的尺寸设置为使得:在被引入到所述腔室中时所述特定成分在所述样品内不均匀地分布;
检查腔室内的基本所有样品并对所有的至少一种特定成分进行计数;
确定包含在所述腔室内的样品的体积;和
确定每单位体积内所述至少一种特定成分的数量。
2.如权利要求1所述的方法,其中所述生物流体样品是抗凝血的全血。
3.如权利要求2所述的方法,其中检查、确定体积和确定数量的所述步骤利用数字图像分析。
4.如权利要求3所述的方法,其中所述被计数的至少一种特定成分包括白细胞。
5.如权利要求4所述的方法,其中所述至少一种特定成分是具有被选择性地染色成可标识的并且单独计数的表面表位的白细胞的子集。
6.如权利要求1所述的方法,其中检查、确定体积和确定数量的所述步骤利用数字图像分析。
7.如权利要求1所述的方法,其中对不均匀分布在所述样品内的所有特定成分进行计数。
8.一种用于对生物流体样品内的一种或多种特定成分进行计数的方法,包括以下步骤:
提供在第一平面构件与第二平面构件之间形成的腔室,所述第一平面构件是透明的,所述第一和第二平面构件以一高度相互分开,所述腔室具有已知的体积;
将所述生物流体样品引入到腔室中,其中所述腔室的高度设置为使得所述样品在所述第一与第二构件之间延伸到所述腔室的基本整个范围,其中所述腔室高度相对于特定成分的尺寸设置为使得所述特定成分在被引入到所述腔室中时不均匀地分布在所述样品内;
检查腔室内的基本所有所述样品并对所有的至少一种所述特定成分进行计数;和
确定每单位体积内所述至少一种特定成分的数量。
9.如权利要求8所述的方法,其中所述生物流体样品是抗凝血的全血。
10.如权利要求9所述的方法,其中检查、确定体积和确定数量的所述步骤利用数字图像分析。
11.如权利要求10所述的方法,其中所述被计数的特定成分包括白细胞。
12.如权利要求11所述的方法,其中所述特定成分是具有被选择性地染色成可标识并且单独计数的表面表位的白细胞的子集。
13.如权利要求8所述的方法,其中检查、确定体积和确定数量的所述步骤利用数字图像分析。
14.一种用于对生物流体样品内的一种或多种特定成分进行计数的设备,包括:
透明的第一平面构件;和
第二平面构件;
其中所述第一平面构件和第二平面构件以一高度相互分开,并且所述高度相对于所述样品内的所述特定成分设置为使得在被引入到所述腔室中时所述特定成分不均匀地分布在所述样品内。
15.如权利要求14所述的设备,还包括在所述第一平面构件与第二平面构件之间延伸的一个或多个侧壁。
16.如权利要求15所述的设备,还包括设置在所述第一平面构件中的入口。
17.如权利要求16所述的设备,还包括一个或多个通风孔隙。
18.如权利要求15所述的设备,其中所述一个或多个侧壁包括粘结材料。
19.如权利要求18所述的设备,其中所述侧壁形成为基本或完全包围腔室区域的形状。
20.如权利要求19所述的设备,还包括设置在所述第一平面构件中的入口。
21.如权利要求20所述的设备,还包括一个或多个通风孔隙。
22.如权利要求15所述的设备,其中所述一个或多个侧壁基本由粘结材料构成。
23.如权利要求22所述的设备,其中所述侧壁形成为基本或完全包围腔室区域的形状。
24.如权利要求23所述的设备,还包括设置在所述第一平面构件中的入口。
25.如权利要求24所述的设备,还包括一个或多个通风孔隙。
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CN1632576A (zh) * | 2005-01-04 | 2005-06-29 | 济南市中心医院 | 流式细胞仪专用溶血素及其制备方法与应用 |
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AU2006304717A8 (en) | 2008-07-03 |
US20100273244A1 (en) | 2010-10-28 |
US20170299497A1 (en) | 2017-10-19 |
WO2007047908A3 (en) | 2007-06-14 |
AU2006304717B2 (en) | 2010-05-27 |
EP1949310A4 (en) | 2011-11-23 |
JP4977711B2 (ja) | 2012-07-18 |
ES2716944T3 (es) | 2019-06-18 |
US9696252B2 (en) | 2017-07-04 |
US8158434B2 (en) | 2012-04-17 |
CA2626271A1 (en) | 2007-04-26 |
CA2626271C (en) | 2011-07-12 |
EP1949310B1 (en) | 2019-02-27 |
HK1123873A1 (en) | 2009-06-26 |
EP1949310A2 (en) | 2008-07-30 |
US20070087442A1 (en) | 2007-04-19 |
JP2009512859A (ja) | 2009-03-26 |
JP2012098302A (ja) | 2012-05-24 |
WO2007047908A2 (en) | 2007-04-26 |
US7731901B2 (en) | 2010-06-08 |
US20100272345A1 (en) | 2010-10-28 |
CN101322145A (zh) | 2008-12-10 |
AU2006304717A1 (en) | 2007-04-26 |
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