CN1348396A - 用于高效筛选的多通孔测试板 - Google Patents
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Abstract
一种保持待分析试样的方法及其装置,该装置包括一具有一对相对表面和众多通孔的测试板。每一个通孔从一个相对表面延伸到另一个相对表面。通孔分组排列,每组有至少两行和两列通孔。组分批排列,每批至少有两行和两列组。为了分析试样,将测试板的至少一个相对表面浸入待分析的溶液。部分溶液进入浸在溶液中的相对表面中的每一通孔的开口。在通孔充了溶液后,取出测试板,固定于一支撑面的上方。在每一个通孔中,表面张力保持着溶液。然后分析一个或多个通孔中的溶液并且找出其中一个通孔中的溶液供进一步研究。根据所确定的溶液在特定的通孔批和组中的位置对其位置作标记。
Description
技术领域
本发明总体上涉及到一种测试装置,具体地说,涉及一种用于高效筛选的多通孔测试板。有关申请
本申请是于1999年11月23日提出的申请号为09/471,852的在先美国专利申请的部分继续,该申请又是1999年3月19日提出的申请号为09/272,122的美国专利申请的继续,两者的全文在此引为参考。
背景技术
现有测试装置由具有一对相对表面和众多孔的测试板构成。孔从相对表面中的一面伸进,但不通到另一相对表面。孔用于保持待分析溶液的试样。
虽然这些装置可以使用,但存在一些问题。例如,这种测试装置中的孔很难装灌。需要用专门的输送系统,如大的定体积比分样系统,将溶液样品装入每个孔。这些专门的输送系统通常昂贵且难以操作。导致测试过程总费用的增加。
与这些现有测试装置相关的另一个问题与其结构有关。这些测试板的孔底部都是透明的,以便在测试期间光线可穿过试样。然而,测试板的其它部分需要用非透明材料制造。有这种结构特点的测试装置制作困难且价格昂贵。
与这些现有测试装置相关的又一个问题与操作者在测试装置中确定一特定孔的位置有关。一般,每个测试装置含有大量间隔相等的孔。因此,在众多孔中定位某一特定孔是困难的。
因此,需要一种改进的用于高效筛选的测试板。
发明内容
根据本发明的一个实施例,保持试样的方法包含若干步骤。首先,提供一具有一对相对表面和许多通孔的测试板。每个通孔从一个相对表面中延伸到另一个相对表面。然后,将测试板的相对表面的至少一面浸入待分析溶液,其中部分溶液进入浸在溶液中的相对表面上的每个通孔开口,而通孔中的气体从另一相对表面上的每个通孔开口排出。接着,将测试板从溶液中取出。表面张力作用将一些溶液保持在每个通孔中。最后,将测试板的相对表面置于一支撑面的上方并分析保持在至少一个通孔中的溶液。
根据本发明的另一个实施例,确定至少一个溶液试样位置的方法包含若干步骤。首先,提供一具有一对相对表面和许多通孔的测试板。测试板中每一个通孔从一个相对表面延伸到另一个相对表面。测试板上的通孔分组排列。每组有至少两行和两列通孔。一旦有了测试板,就把溶液装入通孔中并进行分析。根据分析,确定至少一个通孔中的溶液作进一步分析。根据所确定的通孔所在的组对其位置作标记。
根据本发明的另一个实施例,筛选试样的方法包含几步骤。首先,为筛选准备试样溶液。其次,提供一具有一对相对表面和许多通孔的测试板。在测试板中,每个通孔从一个相对表面延伸到另一相对表面。然后,将测试板的至少一个相对表面浸入溶液。部分溶液进入测试板的浸在溶液中的相对表面中的每个通孔开口。溶液进入通孔后,将测试板从溶液中取出,通孔中靠表面张力保持了至少部分溶液。然后,对一个或多个通孔中的溶液进行分析。
根据本发明的另一个实施例,保持含有待分析细胞的溶液样本的装置包括一个有一对相对表面和许多通孔的测试板。每个通孔从测试板一个相对表面上的开口延伸到另一相对表面上的开口,并且开口的大小能保持住许多细胞。测试板的至少一个相对表面上的有通孔的部分凹下,使得测试板中的开口相对于该相对表面向内有一定距离。
根据本发明的另一个实施例,保持分析试样的装置还包括一个有一对相对表面和许多通孔的测试板。每一个通孔从一个相对表面延伸到另一个相对表面。测试板上的通孔排列成若干组,每组有至少两行和两列通孔。
本发明保持分析试样的方法和装置有许多优点。例如,本发明简化了测试过程。通过简单的把测试板的一面浸入或淹没在溶液里,就能将被分析的溶液试样装入测试板。因此,本发明不需使用单独的输送系统将溶液装入测试板上的孔中。
本发明也简化了测试装置的结构。测试装置只需将其一个相对表面用另外的定距件隔开,或通过机器加工造成凹入部分,然后在该凹入部分穿过测试板钻很多通孔。与现有测试装置不同,本发明不需任何特别加工技术来使孔底部透明,因为通孔整个穿过测试板。
本发明也使操作者很容易地识别装有需进一步分析的试样的特定通孔。本发明不是在测试板上等距设置通孔,而是把通孔分组排列,以至少两行和两列通孔为一组,又把组分批排列,以至少两组或更多组为一批。组之间间隔比组内通孔之间间隔大些,批之间间隔比组之间间隔更大些。因此,操作者很容易根据通孔在测试板上所处的批、组、行和列识别特定的通孔。
附图说明
图1是本发明的一个实施例的多通孔测试板的俯视图;
图2是图1中所示的多通孔测试板沿线2-2取得的横截面图;
图3是如本发明在一对蒸发板之间的另一个多通孔测试板的立体分解图;
图4是本发明的另一个实施例的有多通孔测试板的测试装置的方框图;
图5是本发明的另一个实施例的多通孔测试板的俯视图;
图6是图5中所示的多通孔测试板沿线6-6取得的横截面图;
图7是本发明的又一个实施例的多通孔测试板的俯视图;
图8是本发明的一个实施例的测试板组件的俯视图;
图9是图8所示组件的部分剖开的透视图。
具体实施方式
本发明的一个实施例的测试装置10示于图1。测试装置10包括具有一对相对表面14和16(表面16示于图2)和许多通孔18的测试板12。通孔18位于测试板12每一面的凹入部分20和22中。通孔18分组24排列,每组至少有两行和两列通孔18,并且分批26排列,每批两个或多个孔18组。测试装置10具有很多优点,包括简化了把溶液样本S装进测试装置10的通孔18的过程,简化了测试装置10的结构,并使操作者很容易地识别装有试样的特定通孔18。
参照图1和图2,测试装置10包括测试板12,在此具体实施例中测试板12是由非透明材料如铝和聚丙烯制成,也可使用其它材料,如泰氟隆、聚苯乙烯、不锈钢、聚乙烯,或任何金属或塑料。当使用非光学方法进行分析时,如分析沾在薄膜上的物质时,也可用透明材料,如玻璃或透明塑料制成测试板12。
测试板12包括一对相对表面14和16。在此具体实施例中,相对表面14和16除了在凹入部分20和22以外大体上是平的,但面14和16相互间也可以是其它关系。每一个相对表面14和16都有一凹入部分20和22,它们是在测试板12上机械加工成的,但也可使用其它技术制成凹入部分20和22,如通过模压或增加间隙。当将测试板12的相对表面14和16中的任一表面置于支撑面28上时,凹入部分20或22连同其中的众多通孔18与支撑面28之间空出间隙。如果通孔18的开口30和32与支撑面28接触,则通孔18中的溶液将从通孔18流出。在此具体实施例中,在每个相对表面14和16上由凹入部分20或22形成了环绕测试板12的外围的脊34。虽然测试板12中形成的凹入部分20或22使得通孔18与支撑面28之间空出了间隙,但用其它类型的支撑结构也能使通孔18与支撑面28之间空出间隙,如附于测试板12上的支架可把测试板12和通孔18支撑在支撑面28之上。
见图5和6,是本发明实施例的另一个测试装置50。测试装置50与图1和2中的测试装置10相同,不同的是测试装置50没有一对凹入部分。相反,该装置有一凹入部分52和一凸出部分54。当把测试板51放在支撑面上时,凹入部分52必须面对支撑面以使通孔与支撑面间空出间隙。虽然所示为测试装置50的一个例子,但测试板51的相对表面可是其它结构。例如,凸出部分54可以与测试板51的上表面齐平。
参照图1到3,测试板12还包括一可选手柄36和在测试板12的一边容纳手柄36一端的开口38,但也可采用其它方法将手柄36与测试板12连接,如用螺栓连接手柄36。手柄36从测试板12的边缘伸出,用于在装灌和测试期间操纵测试板12。
在测试板12中有许多通孔18。通孔18从一个相对表面14的凹入部分20中的开口30延伸到另一相对表面16的凹入部分22中的开口32。在此具体实施例中,通孔18大体上为圆柱形,但通孔18也可以为其它形状,如横截面为六边形的形状或圆锥型。在此具体实施例中,每一个通孔18的直径约为1毫米并可装约5.5微升的溶液S和细胞C,但直径、容量和每个通孔18装的细胞C的数量根据需要可以不同。如图4所示,溶液S连同其中的细胞C由表面张力保持在通孔18中。具体来说,可能需要根据被分析的溶液S和该溶液的表面张力特性来改变通孔18的大小。例如,本领域普通技术人员知道,缓冲液与含盐培养基相比可能有不同的表面张力特性。必须有足够的表面张力才能在通孔18中保持溶液S的试样。
本发明的优点之一是测试板12容易制造。在有相对表面的板上可钻有适量的通孔。该板可有一个或多个凹入部分20、22,通孔可穿过板12的凹入部分。因为通孔18是穿通的,故在通孔18中不需有透明的底。在测试期间,照射进通孔18的光线将穿过通孔。而对于现有技术中的孔,测试装置也需要是非透明的,但因孔不穿通测试装置,故孔底部需要用透明材料制成,以便使光穿过试样进行光学分析。现有测试装置的制作是困难的和昂贵的。
参照图1,测试板12有约2000个通孔18,这些通孔从一个相对表面14延伸到另一个相对表面16,但通孔18的数量也可根据需要而改变。在此具体实施例中,为有助于操作者识别特定通孔18,把通孔18分成组和批排列。每组24有至少两行和两列通孔18,每批26有至少两行和两列组24。在此具体实施例中,每组24有5行5列通孔18,在此例中,有八十个组24,每组有二十五个通孔18,但这些数据可根据需要而改变。在此例中,一组内的通孔18的行间和列间间隔为1.5毫米,此距离可以改变,每一组24中通孔18的行间和列间间隔可以根据需要而不同。在此具体实施例中,组24的每批包含两行和10列组24,在此例中,共有四批26,每批含有二十组24通孔18,所述数据也可根据需要而改变。在此例中,一批26中的组24之间的间隔约2.0毫米,批26之间间隔约2.5毫米,这些距离可根据需要而改变。
通过将通孔18按批26和组24排列,使操作者很容易在测试板12中识别出特定通孔18并取出特定试样。通孔18的批26帮助操作者识别通孔18所处大概区域,然后组24帮助操作者缩小通孔18所处位置的范围。通孔18在每组24中的行和列指出通孔18的精确位置。批26、组24、行和列之间的间隔不同,使操作者在视觉上很容易识别特定通孔18。如果所有通孔18的间隔相同,则识别特定通孔18就很困难,并且操作者很容易错过他/她应找的位置,从错误的通孔18中选出试样。
在测试装置10和50中,通孔18分组24和批26排列以帮助操作者,但也可按其它方式排列通孔18。例如,当测试装置是被机器人而不是人使用时,通孔18也可等距隔开,如图7的测试装置60的实施例所示。除了通孔18是等距隔开外,测试装置60与所述测试装置10和50相同
如图3所示,测试装置10也可有一对可选蒸发板40和42。蒸发板40和42分别安装在测试装置10的一个相对表面14和16上。通过螺栓、夹具或其它机械装置把蒸发板40和42固定到测试板12上。当在凹入部分20和22之上把蒸发板40和42固定到测试板12上时,测试板12的相对表面14和16中的凹入部分20和22仍在通孔18的开口30和32与蒸发板40和42之间空出间隙。蒸发板40和42帮助保存测试板12的通孔18中的溶液S试样,防止其蒸发和受污染。
可以不使用测试板12的凹入部分,而提供包括测试板和蒸发板的组件,在测试板和蒸发板之间提供定距件,把通孔的开口与蒸发板隔开。除了测试板和蒸发板之间的定距件,或代替之,可在蒸发板上制作凹入部分。测试板中的凹入部分、蒸发板中的凹入部分或定距件之任意组合均可用于在通孔的开口和蒸发板之间造成间隙。
根据本发明的一个实施例,提供可叠起堆放的测试板,在测试板中间可有或没有蒸发板。可叠放的测试板可有凹入部分,或可在可叠放的测试板之间使用有凹入部分的蒸发板。测试板中的凹入部分、蒸发板中的凹入部分或定距件之任意组合均可用于提供堆叠的测试板,其中每个测试板与相邻测试板的表面、与蒸发板隔开一定距离,或与两者都隔开一定距离。
下面参照图1到4所示的测试装置10,讨论本发明的一个应用实例。在此具体实例中,用紫外线辐射、化学诱变、或其它诱变技术诱变细胞C。培养细胞C供分离之用。培养了细胞C后,将其在含有荧光基质(fluorgenic substrate)或显色基质(chromogenicsubstrate)的培养基中稀释为每10微升一个细胞C。对此例来说,具有细胞C的培养基称为溶液S。因此,细胞C在通孔18中随机分布,许多通孔18可含有一个或多个细胞C。
虽然公布了准备溶液S和细胞C的例子,但如本领域普通技术人员容易理解的那样,可以使用其它方法和技术准备用于测试装置10的试样。
接下来,提供一具有一对相对表面14和16及许多通孔18的测试板12,每一通孔从一个相对表面14延伸到另一相对表面16。测试板的至少一个相对表面14浸入准备好的溶液S中。溶液S进入测试板12的每一通孔18的开口30和32,而通孔18中的气体通过通孔18的另一端的开口30和32排出。或者,可用溶液S淹没测试板12,以便溶液S从顶部开口30进入每一通孔18。
本发明的优点之一是溶液S易于装入每一通孔18。如上所述,在相对较短的时间内,可将溶液S试样装入测试板12中的所有通孔18,而不用任何类型的专用溶液输送系统。现有带孔的测试装置需要专用的溶液输送系统,如大型定体积比分样设备,才能把溶液装入每个孔中。这些专用溶液输送系统使用困难且价格昂贵。
溶液S被吸入通孔18后,把测试板12从溶液S中取出。表面张力将溶液保持在每个通孔18中。在此具体实施例中,如图4所示,每个通孔18有约1毫米的直径,可保持约5.5微升溶液S和细胞C。每个通孔18的直径和容量可按具体应用的需要和要求而改变。在所述操作中,手柄36用于控制测试板12的位置。
把测试板12从溶液S中取出后,测试板12可置于支撑面28上。因为通孔18位于测试板12的凹入部分22中,通孔18的开口32与支撑面28之间隔开一定间隙,以便由表面张力保持的溶液S保留在通孔18中。一对蒸发板40和42可装在测试板12的相对表面14和16上以防止测试板12中的溶液S的试样蒸发或被污染。
在此具体例子中,然后可选择在约摄氏37度的受控温度和约70%的湿度下培养测试板12,温度和湿度可根据具体应用而改变。在培养期间,细胞繁殖并产生有价值的蛋白质(细胞可产生可能有价值的酶、抗体或代谢物)。通过对水解作用所释放的荧光团或显色团(fluorgenic or chromogenic groups)的测量,分析蛋白质如酶的水解基质的能力。
虽然公布了处理测试板12中溶液S的试样的一个例子,但也可使用本领域普通技术人员所知的其它处理和分析试样的方法和技术。
接下来,在此具体例子中,使用有光源44和检测器46的图像分析器检测在通孔18中有细胞C的溶液S的试样(如图4所示)。光线从光源44向测试板12中的通孔18的开口30发射并穿过测试板12的通孔18中的溶液S。检测器46位于测试板12的另一侧,检测从通孔18中的溶液S穿过的光线。根据所检测的发射光的变化,用本领域普通技术人员所知的方法可以确定有关溶液S的特定试样的特性信息。在此具体例子中,图像分析器能够确定哪个通孔18的溶液S含有最高浓度的被转化基质,因而含有最多的酶。在此情况下,目的是提取产生最多数量酶的细胞C。以同样的方法,可以确定产生最多有价值的蛋白质或化学产物的细胞C。
虽然公布了使用光学方法分析测试板12中溶液S的试样的一个例子,也可使用其它的如非光学的方法和技术分析试样。例如,含有细胞C的溶液S的试样的测试板可被吸到(be blotled onto)一层膜上,用于进行Western污渍分析(Western blot analysis),或者,将有细胞C的试样S吸到含有物质的基质上,由此可凭视觉观测基质的改变。因此,当使用非光学方法分析测试板12中的溶液试样时,测试板12可由透明材料制造。
接下来,在此具体例子中,操作者提取溶液S的含有最高浓度的转化基质的试样。根据每个确定的孔18位于哪一批26、哪一组24及组24内的哪行哪列,可识别和找到含有最高浓度的转化基质的溶液S的通孔18。本发明的优点之一是通孔分组24和批26排列,使操作者易于识别测试板12上的特定通孔18。取出需要的试样后,操作者就以本领域普通技术人员熟知的方法对那些试样做进一步分析。
虽然公布了提取测试板12中的一个或多个溶液S试样的一个例子,但也可使用其它方法和技术提取试样。例如,如果使用机器人查找和提取特定试样,可使用不同的,例如如图7所示的测试装置60。机器人不需要将通孔18分组24和批26排列,尽管这样排列可能有助于机器人识别和取出需要的试样。
根据本发明的一些实施例,测试板是以组件或基底的形式。例如,该测试板可由一些单个元件组成,由这些元件组成的组件有相对的表面和很多从一面延伸到另一面的通孔。本发明的用这种组件构成的测试板的例子是如图8和9所示的由毛细管束制成的测试板。
如图8和9所示,一块板、基底或组件70由被箍带74绑在一起的毛细管束72构成。此实施例的组件的通孔是纵向延伸且穿过每个毛细管中心的孔。箍带74可有相对表面76和78,每面大体上是平的并大体上互相平行。箍带可由金属、塑料、玻璃、橡胶、混炼胶、或任何其它适当材料制成。每个毛细管72有第一末端80和第二末端82。毛细管的第一末端80构成基底或组件70的一个相对表面84,毛细管72的第二末端82构成基底或组件70的一个相对表面86。
如图8和9所示,组成基底或组件70的毛细管束72中的每个毛细管在其第一末端80和其第二末端82之间的长度至少是毛细管平均直径的2倍。最好,每个毛细管的长度大于其平均直径的4倍,最好大于平均直径许多倍数。每个毛细管可以是例如微毛细管或空心光纤。
毛细管的形状可以是空心圆柱体或具有其它圆形的、椭圆形的、或多边形的横截面。每个毛细管的平均直径范围最好是从约0.001毫米到约1毫米,每个毛细管的长度范围最好是从约1毫米到约1厘米。毛细管的大小最好是使每个毛细管的容积能保持约0.0001微升到约10微升的液体试样,例如约5.5微升。毛细管的直径、长度和容积可根据需要和要求而改变。根据本发明的一些实施例,不是必须用一箍带把毛细管绑成一束,因为毛细管可被熔合、焊接、粘接或保持为一束。
图8和9中的实施例的毛细管数量最好是从约100到1000以上,例如,从约500到约1500。最好,毛细管成行排列,行又成列排列。在图8和图9的实施例中毛细管束72为圆形截面,箍带74是环形,但其它形状的管束和箍带也属本发明的范围。例如,毛细管可排为长方形或方形阵列并被箍带围绕,箍带最好也是矩形或方形。对长方形或方形阵列的毛细管,容易识别其列和行,简化对阵列中单个毛细管的识别。
在图8和9所示的实施例中,围绕毛细管束的箍带74在相对表面76和78之间的长度大于毛细管的相对两末端80和82之间的长度。因此,绑扎起来的组件可置于例如分析设备的表面上,而毛细管的末端不会接触该表面。此外,该组件可以堆叠而不会妨碍通孔中毛细管的保持力。
如同图1到7的测试板一样,示于图8和9中的组件可用初始液体试样装载或灌入以得到很多液体试样,每个试样含有一部分初始液体试样。或者,该组件可用多种初始液体试样装载,每个初始液体试样灌入至少一个通孔。在这里,“装载”和“灌入”意思是至少部分地装入,不一定要装满。例如,通过把组件或测试板浸入液体试样,或使组件或测试板的至少一个相对表面与液体试样接触,或使各通孔的内壁与一液体试样或各自的液体试样接触,从而对通孔装载或灌入。
液体试样与一相对表面之间的接触可通过淹没、浸入、滴管吸取、滴液、灌注等方式实现,或装填或至少部分填充众多毛细管或通孔,以便通过毛细作用将部分液体试样吸入各毛细管或通孔。当移走或中止液体试样与组件或测试板的接触后,组件或测试板的相对表面最好没有液体试样,以使各毛细管中所保持的部分试样互相隔离。
可使用自动装灌设备,而且若各个液体试样或液体试样部分只与通孔的内壁接触而不与组件的相对表面接触非常重要,则最好使用自动装灌设备。
根据本发明的实施例,提供一种高效筛选方法。该方法可筛选至少一个含待分析的目标成分或物质的液体试样。在这里,待分析的目标成分或物质可称为“被分析物”。被分析物可以是但不一定是生物试样。被分析物有可检测性,或在有标记化合物之类的物质的情况下或与之发生反应后产生可检测性。例如,被分析物自身可能表现出莹光特性。在液体试样被至少部分地装入众多通孔之后,通过确定哪些通孔含有存在莹光特性的试样,就可以检测出含有所述被分析物的那部分液体试样。
在另一个例子中,被分析物自身不具可检测性,但却依靠与标记化合物的反应而使标记化合物表现出可检测性。根据这样的实施例,在测试组件的通孔中预先或在后装入一种或多种标记化合物,使得在将液体试样装入众多通孔后,含有被分析物的那部分试样与标记化合物发生反应,从而使标记化合物表现出可检测性。在这种情况下,不是被分析物自身存在可检测性,而是由于被分析物的存在造成标记化合物的可检测性,直接检测到标记化合物,从而间接检测到被分析物。这样,本发明的方法就提供了一种从初始液体试样区分割和离析被分析物的途径。
根据所述高效筛选方法,部分液体试样装入有一对相对表面和许多通孔的测试组件,每个通孔从一个相对表面延伸到另一相对表面。最好,用至少部分液体试样至少部分地充填众多通孔,在各个通孔中表面张力保持相应的液体试样。可在各个通孔中,或在各个通孔系列中,装入多种液体试样。本方法涉及检测通孔中的哪些试样存在可检测性。
根据本发明的实施例,高效筛选组件最好有至少约100个通孔,更好地是有约1500个通孔,根据本发明的一些实施例,达到约1,000,000个通孔。与这些设备一起使用高效筛选方法,每天每组件可测试100,000,000个以上的试样或试样份数。
待筛选的被分析物可以是,例如生物细胞、生物细胞混合物、变异细胞、分泌物蛋白质(secretable protein)、酶、微生物、微生物混合物、污染物,或其组合。被分析物可以是一个或多个有机体的随机变异群体。如果被分析物是生物细胞混合物,它可以是与自然环境隔离的随机试样。可检测性可以是例如荧光性或吸附能力。在装灌高效组件之前,可用适当的稀释液稀释液体试样使得液体试样中被分析物的浓度为:当试样装入众多通孔时,在约四分之一到约二分之一数量的通孔中每个引入至少一个被分析物。
在某些情况下,即使有机物作为与其它有机物的混合物进入许多通孔,也有可能识别具有所需特性的有机物。在这种情况下,其它有机物的混合物如生物细胞混合物,在装灌之前可被稀释,使得每个通孔进入几个有机物或细胞。使用这种稀释技术可以检测到一个被分析物的存在。例如,可以从一群生物细胞及其变异细胞中检测出某个特定的变异体,尽管在每个通孔中存在的混合物中有很多细胞。于是,例如,如果一个试样含有1,000,000个细胞,而其中只有一个是称为“被分析物”的目标变异细胞,使用有10,000个通孔的测试板,试样可被稀释为当把1,000,000个细胞随试样装入通孔时,其中每个通孔含有约100个细胞。在被分析物的可检测特性即使在同一通孔中存在很多其它细胞也可检测的情况下,在一次检验中即可从99.99%的试样中分离出被分析物。
根据本发明所使用的测试板,包括图1到7的测试板和图8和9的组件,可由亲水材料或涂层、疏水材料或涂层或它们的组合组成,以便于将液体试样部分装入通孔。例如,组件的相对表面可由疏水材料制造或处理,使得液体试样在除了相对表面上与通孔开口紧密相接的地方以外受表面的排斥。按照这样的实施例,通过毛细作用将液体试样部分吸入通孔而不浸湿测试板的相对表面。因此,测试板在装入液体试样然后与液体试样分离后,在各通孔之间不存在流体的连通,对被隔离的试样部分的污染最小。按照本发明的一些实施例,通孔可有由亲水材料制成的、或涂上一层亲水材料的内壁,该亲水材料容易被含水试样或介质浸润。每个通孔的整个内壁可由亲水材料制成或处理,或只是部分内壁由亲水材料制成或处理。有亲水材料的通孔内壁和疏水材料的相对表面的测试板提供了极好的手段,可约束、隔离、或限制测试板的通孔内的液体试样的位置,同时保持相对表面的相邻表面区域大体上没有液体试样。
根据本发明的一些实施例,为便于毛细作用,最理想是在一相对表面上紧邻每个通孔的开口处提供亲水材料,而相对表面的其它区域仍然或设置为疏水材料或非亲水材料。测试板的任一相对表面或两相对表面可由所述的疏水材料、亲水材料或两种材料制成或处理,但如果是靠浸润技术装载通孔,与液体试样接触的相对表面除了紧邻通孔开口、最好是环绕通孔开口的区域外,最好都用疏水材料处理或制作。
可用本发明的组件和其它测试板进行的典型的高效筛选方法包括吸收率转录分析(absorbance transcription assays)、荧光转录分析(fluorescent transcription assays)、荧光分泌酶分析(fluorescent secreted enzyme assays)、微生物筛选分析(microorganism screening assays)。能受益于本发明的测试板和方法的这些和其它合适的分析记载于:Arndt等,A rapid geneticscreening system for identifying gene-specific suppressionconstructs for use in human ce1ls(“用于人体细胞的鉴别基因特异性抑制构造的快速遗传筛选系统”),Nucleic Acids Res.(《核酸研究》),28(6):E15(2000);Rolls等,A visual screen of aGFP-fusion library identifies a new type of nuclear envelopemembrane protein(“用GFP-fusion库的可视筛选来鉴别一种新型核膜膜蛋白”),J.Cell Biol(《细胞生物学杂志》),146(1):29-44(1999);Sieweke,Detection of transcriptionfactor partners with a yeast one hybrid screen(“用酵母一代杂交筛选来检测转录因子偶对”),Methods Mol.Biol.(《分子生物学方法》),130:59-77(2000);和WO 97/37036,所有这些在此全文引作参考。
在已经叙述了本发明的基本概念之后,对于本领域的技术人员来说更清楚的是,所述详细描述只是举例,而不是限制性的。虽然没有在此明确阐述,但对于本领域的技术人员来说,可以进行各种更改、改进和变更。这些受本发明启发的更改、改进和变更在本发明的要旨和范围之内。从而,本发明仅受限于以下的权利要求及其等效方案。
Claims (57)
1.一种保持溶液的方法,方法包括:
提供一具有一对相对表面和许多通孔的测试板,每个通孔从一个相对表面延伸到另一个相对表面;
将测试板的至少一个相对表面浸入溶液,其中部分溶液进入浸在溶液中的相对表面中的每一通孔的开口;和
从溶液中取出测试板,其中,在每一个通孔中,由表面张力保持着一些溶液;和
将测试板的相对表面置于一支撑面的上方。
2.如权利要求1所说的方法,其中每一个通孔的大小能容纳由表面张力所保持的那部分溶液里的很多细胞。
3.如权利要求1所说的方法,其中测试板里的通孔分组排列,每组有至少两行和两列通孔。
4.如权利要求3所说的方法还包括根据通孔所在的组识别至少一个通孔的位置。
5.如权利要求4所说的方法还包括确定被识别的通孔在组中的行和列。
6.如权利要求3所说的方法,其中测试板上的通孔的组分为批排列,每批有至少两行和两列组。
7.如权利要求6所说的方法还包括根据通孔所在的批确定其位置。
8.确定至少一个溶液试样位置的方法,该方法包括:
提供一具有一对相对表面和许多通孔的测试板,每一个通孔从一个相对表面延伸到另一个相对表面,其中通孔分组排列,每组有至少两行和两列通孔,溶液存于至少若干通孔中;
识别至少一个通孔中的溶液;
根据通孔所在的组定位被识别的通孔。
9.如权利要求8所说的方法还包括为所识别的通孔确定在组中的行和列。
10.如权利要求8所说的方法,其中测试板上通孔的组分批排列,每一批有至少两行和两列通孔组。
11.如权利要求10所说的方法还包括根据通孔所在的批确定其位置。
12.保持含有待分析细胞的溶液样品的板,该板包括:
具有一对相对表面的平台;和
平台中的很多通孔,每一个通孔从平台中一个相对表面上的开口延伸到另一个相对表面的开口,每个通孔的大小能容纳很多细胞;
其中,至少一个相对表面的有通孔的部分凹下,以便平台中的开口与相对表面之间空出间隔。
13.如权利要求12所说的板,另一相对表面的有通孔的部分凹下。
14.如权利要求12所说的板,另一相对表面的有通孔的部分凸出。
15.如权利要求12所说的板,其中每一个通孔的大小能容纳由表面张力保持的部分溶液中的许多细胞。
16.如权利要求9所说的板,其中通孔在基底上分组排列,每组有至少两行和两列通孔。
17.如权利要求16所说的板,其中组成批排列,每批有至少两行和两列组。
18.如权利要求17所说的板,其中批之间的第一距离不同于组之间的第二距离、不同于每一行中通孔之间的第三距离、不同于每一列中通孔之间的第四距离。
19.如权利要求18所说的板,其中第三和第四距离大体上相同。
20.一种保持待分析试样的装置包括:
一具有一对相对表面的板;和
板上的许多通孔,每一个通孔从一个相对表面延伸到另一个相对表面;
其中通孔在板上分组排列,每组有至少两行和两列通孔。
21.如权利要求20所说的装置,其中组成批排列,每批有至少两行和两列组。
22.如权利要求21所说的装置,其中批之间的第一距离不同于组之间的第二距离,不同于每一行中通孔之间的第三距离,不同于每一列中通孔之间的第四距离。
23.如权利要求22所说的装置,其中第三和第四距离大体上相同。
24.如权利要求20所说的装置,至少一个相对表面的有通孔的部分凹下,以便测试板中的开口与相对表面之间空出间隔。
25.如权利要求20所说的装置,其中每一个通孔的大小能容纳悬浮在溶液中的许多细胞。
26.如权利要求25所说的装置,其中每一个通孔保持的溶液大约在0.1微升到10微升之间。
27.如权利要求20所说的装置还包括一个连接到测试板上的手柄。
28.一种分析溶液的方法,该方法包括:
为筛选准备试样溶液;
提供具有一对相对表面和许多通孔的测试板,每一个通孔从一个相对表面延伸到另一个相对表面;
将测试板的至少一个相对表面浸入溶液,其中部分溶液进入浸在溶液中的相对表面中的每一通孔的开口;
从溶液中取出测试板,其中,在每一个通孔中,表面张力保持着一些溶液;和
分析一个或多个通孔中的溶液。
29.如权利要求28所说的方法,其中分析步骤是对一个或多个通孔中的溶液进行光学分析。
30.如权利要求28所说的方法,其中分析步骤是对一个或多个通孔中的溶液进行非光学分析。
31.如权利要求1所说的方法还包括分析保持在至少一个通孔中的溶液。
32.提供很多液体试样的方法,该方法包括:
提供一具有一对相对表面和许多通孔的测试组件,每一个所述通孔从一个相对表面延伸到另一个相对表面;和
用各液体试样至少部分填充所述众多通孔,其中在各相应系列的通孔中,表面张力保持着相应的溶液试样。
33.权利要求32的方法,其中所说至少部分填充包括将组件的至少一个相对表面与至少一种液体试样接触,使得部分该至少一种液体试样部分地装入相应系列的所述通孔。
34.权利要求33的方法,还包括,在所述接触之后,使组件的相对表面与所述液体试样分开,使相对表面上大体上没有所述液体试样,从而使得保持在各通孔中的所述试样互相隔离。
35.权利要求32的方法,其中所述接触包括把至少一个所述相对表面浸入所述至少一种液体试样。
36.权利要求32的方法,其中所述组件包括众多长度大体上一样的并且大体上互相平行的毛细管,其中每个毛细管有第一末端和第二末端,毛细管的所述第一末端构成一个所述相对表面,而毛细管的所述第二末端构成另一个所述相对表面。
37.权利要求36的方法,其中所述众多毛细管被保持装置扎在一起,该保持装置是一个有相距第一距离的相对表面的箍带,其中该箍带的相对表面位于大体上互相平行的相应平面上,所述组件的相对表面各位于相应平面上并且大体上平行于所述箍带的各平面,所述箍带的相对表面之间的距离大于所述组件的相对表面之间的距离。
38.权利要求32的方法,其中通孔分组排列,每组有至少两行通孔。
39.识别测试组件中液体试样位置的方法,该方法包括:
提供具有一对相对表面和众多通孔的测试组件,每一个所述通孔从一个所述相对表面延伸到另一个所述相对表面,其中通孔分组排列,每组有至少两行和至少两列通孔,其中,部分液体试样位于至少一些通孔中;
识别至少一个通孔中的溶液;和
根据通孔所在的组定位被识别的通孔。
40.保持待分析液体试样的组件,该组件包括:
具有一对相对表面的基底;和
基底中的众多通孔,每个通孔从基底的一个相对表面上的开口延伸到另一相对表面上的开口,所述通孔的大小靠毛细作用提供足够的表面张力来保持各自的液体试样。
41.权利要求40的组件,其中每个所述通孔有一个在相对表面之间延伸的长度和一个垂直于相对表面的平均直径,其中所述长度比所述平均直径至少大两倍。
42.权利要求41的组件,其中所述长度比所述平均直径大许多倍。
43.权利要求40的组件,还包括由表面张力保持在至少一系列所述通孔中的生物液体试样。
44.权利要求40的组件,其中该组件有一束长度大体上一样的并且大体上互相平行的毛细管。
45.分析一个或多个液体试样的方法,该方法包括:
提供一具有一对相对表面和众多通孔的测试组件,每一个通孔从一个相对表面延伸到另一个相对表面;和
用相应的液体试样至少部分装入众多所述通孔,其中,在各系列通孔中,靠表面张力保持相应的液体试样;和
分析至少一个所述通孔中的至少一个所述液体试样。
46.权利要求45的方法,其中所说至少部分装入包括将组件的至少一个相对表面与至少一种液体试样接触,使得部分所述至少一种液体试样至少部分地装入相应系列的所述通孔。
47.权利要求45的方法,其中该方法包括分离试样中的被分析物。
48.权利要求45的方法,其中众多所述液体试样各个含有生物细胞混合物,并且至少一个所述液体试样含有至少一个被分析物细胞。
49.权利要求48的方法,其中该方法包括从不含有被分析物细胞的液体试样中,分离出所述至少一个含有至少一个所述被分析物细胞的液体试样。
50.一高效筛选方法包括:
提供至少一个含有直接或间接产生可检测性的被分析物的液体试样;
提供一具有一对相对表面和众多通孔的测试组件,每个通孔从一个相对表面延伸到另一个相对表面;
用至少部分所述至少一种液体试样至少部分地装入众多所述通孔,其中,在相应系列的众多通孔中,表面张力保持着相应的部分液体试样;和
检测出所述众多通孔的哪一个含有包括所述被分析物的液体试样。
51.权利要求50的方法,其中所述组件有至少100个所述通孔。
52.权利要求50的方法,其中所述被分析物是生物细胞。
53.权利要求50的方法,其中所述被检测性是荧光或吸附特性。
54.权利要求50的方法,其中所述被分析物至少是变异细胞、分泌物蛋白质、酶、微生物之一。
55.权利要求50的方法,还包括,在至少部分填充所述众多通孔之前,稀释所述至少一种液体试样,使其中所述被分析物的浓度为:当所述至少一种试样被至少部分地装入所述众多通孔时,在约二分之一到约四分之一的所述众多通孔中含有至少一个所述被分析物。
56.权利要求50的方法,其中所述至少一种液体试样由生物细胞混合物组成,所述被分析物由所述细胞混合物中的至少一种细胞组成。
57.权利要求56的方法,还包括,在至少部分填充所述众多通孔之前,稀释所述至少一种试样,使所述混合物的生物细胞的浓度为:当所述至少一种试样被至少部分地装入所述众多通孔时,至少一系列所述通孔含有所述混合物的一系列微生物细胞,其中,在至少一个所述通孔中含有至少一个所述被分析物细胞。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104837559A (zh) * | 2012-10-09 | 2015-08-12 | Jn迈德西斯私人有限公司 | 用于样本分离的改进的装置和方法 |
CN114235738A (zh) * | 2021-12-16 | 2022-03-25 | 中国标准化研究院 | 太赫兹光谱检测用样品池、评估抗体效价的方法及应用 |
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US6436632B2 (en) | 2002-08-20 |
AU756982B2 (en) | 2003-01-30 |
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US20020192716A1 (en) | 2002-12-19 |
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WO2000056456A1 (en) | 2000-09-28 |
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US10195579B2 (en) | 2019-02-05 |
ATE526580T1 (de) | 2011-10-15 |
US6306578B1 (en) | 2001-10-23 |
NZ513390A (en) | 2003-01-31 |
EP1165235A1 (en) | 2002-01-02 |
US20060183171A1 (en) | 2006-08-17 |
AU3758300A (en) | 2000-10-09 |
CA2367912A1 (en) | 2000-09-28 |
US7666360B2 (en) | 2010-02-23 |
US20160089649A1 (en) | 2016-03-31 |
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