CN101627308B - 微滴操作机构和运用磁性小珠的方法 - Google Patents
微滴操作机构和运用磁性小珠的方法 Download PDFInfo
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Abstract
一种提供与磁响应小珠接触并具有减少的物质量的微滴的方法。该方法主要包括以下步骤:(a)提供一包含以下部件的微滴操作机构(200):(i)包含有用来在一表面上进行微滴操作的电极(214)的基板(210);(ii)包含以下内容的初始微滴(218/222):(1)一个或多个磁响应小珠(220);(2)物质的初始量;和(3)初始体积;(b)将一个或多个磁响应小珠磁性固定在离开目标微滴分离区(224)一定距离的位置上;(c)执行一个或多个微滴操作,包含选定的微滴分离操作,用来得到包含以下内容的一组微滴:(i)包含所有上述一个或多个磁响应小珠并具有与初始浓度相比物质量下降的微滴(218);和(ii)缺少磁响应小珠的微滴(222)。
Description
授权信息
本发明得到美国国家卫生研究所授予的CA114993-01A2和DK066956-02,是在政府支持下完成的。美国政府对本发明拥有一定权利。
相关申请
本申请主张以下美国临时申请的优先权并将其全文纳入本申请:美国申请号60/900,653,2007年2月9日提出,其名称为“微滴操作期间固定磁响应小珠的方法”(Immobilization of magnetically-responsive beadsduring droplet operations);美国申请号60/980,772,2007年10月17日提出,其名称为“微滴中固定磁响应小珠的方法”(Immobilization ofmagnetically-responsive beads in droplets);美国申请号60/969,736,2007年9月4日提出,其名称为“微滴操作机构测定改进”(Droplet actuatorassay improvements),以及美国申请号60/980,762,2007年10月17日提出,其名称为“微滴操作机构测定改进”(Droplet actuator assayimprovements)。
技术领域
本发明总体上涉及微滴操作机构,特别是涉及用来进行基于微滴的试验方案的微滴操作机构,该试验方案需要利用含有小珠特别是磁响应小珠进行微滴操作。本发明还涉及上述微滴操作机构的制造方法和使用方法。
背景技术
本发明总体上涉及微滴操作机构,特别是涉及用来进行基于微滴的试验方案的微滴操作机构,该试验方案需要利用含有小珠特别是磁响应小珠进行微滴操作。本发明还涉及上述微滴操作机构的制造方法和使用方法。
微滴操作机构被广泛用于进行各种微滴操作。微滴操作机构通常包括一个基板,该基板上设有用来在其微滴科操作表面上进行微滴操作的电极,还可包括一第二基板,与上述微滴操作表面基本平行,形成一空隙,微滴操作在该空隙内进行。该空隙通常充满填充液,该填充液与将要在微滴操作机构上进行微滴操作的液体不相混容。
发明内容
在微滴操作机构的一些应用中,需要使用“小珠”进行各种测定。对于利用小珠的试验方案来说,这些小珠通常被用来在物质的混合物中约束一种或多种目标物质。例如,目标物质可以是测定物或杂质。有必需提供一种在微滴操作机构上对小珠进行洗涤的有效方法,以便在可能与小珠表面接触或暴露于小珠表面的含有小珠的微滴中减少一种或多种物质的数量。
本发明一方面提供在微滴应用中使用磁响应小珠的微滴操作中有效固 定磁响应小珠的方法。这方面的例子包括那些要求执行小珠洗涤试验方案的测定,例如焦磷酸测序(Pyrosequencing)和免疫测定方面的应用。在一实例中,本发明提供在微滴分离操作期间采用磁力固定磁响应小珠的技术方案。本发明的技术方案在微滴操作机构内洗涤磁响应小珠的试验方案方面十分有用。本发明的技术方案还具有能够避免磁响应小珠不适当的凝集和聚集的优点。在微滴分享操作中,这些技术方案能够固定微滴内几乎所有的磁响应小珠。本发明的技术方案可确保在微滴洗涤操作期间固定和保持几乎所有的磁响应小珠。洗涤过程结束后,本发明的技术方案确保液体内几乎所有的磁性小珠重新悬置,几乎不存在凝集或聚集。
本发明另一方面提供改进的微滴操作机构和相关的进行基于微滴的改进的测定操作的方法。本发明的一些实施方案提供降低微滴操作机构内磁场交叠的机制。本发明的另一些实施方案提供减少小珠和微滴操作机构内其他物质的机制。本发明再一些实施方案中提供改进微滴操作机构内微滴检测操作的机制。
定义
本申请文件中使用的术语具有如下含义。
“启动”(Activate)是指一个或多个电极结构改变其一个或多个电极中的电气状态从而导致一个微滴操作的动作。
“小珠”(Bead),对于微滴操作机构上的小珠而言,是指任何能够在微滴操作机构上或附近的微滴相互作用的小珠或颗粒。小珠可以具有很多形状,例如球形、大体上球形、卵形、圆盘形、立方形和其他三维开关。例如,小珠能够在微滴操作机构上被搬运到微滴内部,或是针对微滴操作机构进行设置,使微滴操作机构上的微滴能够与微滴接触,不论在微滴操作机构之上和/或之外。小珠可以使用很多种材料制造,包括,例如,树脂和聚合物。小珠可以具有任何适宜的尺寸,包括,例如,微米级小珠、微米级颗粒粒、纳米级小珠、纳米级颗粒。在一些情况下,小珠具有磁响应特性,在另一些情况下,小珠不特别具有磁响应特性。对于磁响应小珠,磁响应材料即可以是小珠的全部构成材料,也可以是小珠构成成分之一。小珠的其余成分可以包括:聚合材料、覆层、能够附着测定试剂的另一半成分等。适合的磁响应小珠见2005年11月24日公开的美国专利公开号2005-0260686号,其名称为“最好使用磁性颗粒为固相的复合流测定”(Multiplex flow assays preferably with magnetic particle sa ssolidphase),由于该申请对磁响应材料和小珠方面的教示,本申请纳入其全部公开内容作为参考。小珠可包括一个或多个附着于其上的生物细胞种群。在一些情况下,上述生成细胞为纯种群。在另一些情况下,上述生物细胞包括不同的细胞种群,即,互相作用的细胞种群。
“微滴”(Droplet)是指微滴操作机构上的一团液体。例如,一个微滴可以完全被填充液包覆或被填充液和微滴操作机构的一个或多个表面束缚。微滴的形状可以是多种多样的,通常包括(但不限于)圆盘形、条形、截断的球形、椭圆形、球形、扁球形、半球形、卵形、柱形,以及进行微 滴操作时形成的各种形状,例如融合或分离时形成的开关,或是这些形状与微滴操作机构的一个或多个表面接触后形成的形状。
“微滴操作”(Droplet operation)是指任何在微滴操作机构上对微滴进行操作。例如,微滴操作可包括:将一个微滴加载到微滴操作机构上;由源微滴分配出一个或多个微滴;将一个微滴分离、分开或划分为两个或更多的微滴;在任意方向上将一个微滴由某一位置搬运到另一位置;将两个或两个以上微滴融合或结合成一个微滴;将微滴稀释;将微滴混合;搅动微滴;将微滴变形;使一个微滴保持在一位置上;培育(incubating)微滴;加热微滴;蒸发微滴;冷却微滴;去除微滴;将微滴搬运至微滴操作机构之外;本申请中描述的其他微滴操作;以及/或上述操作的任意组合。用语“融合”、“溶合”、“结合”或类似的说法被用来描述由两个或更多微滴产生一个微滴这一过程。不难理解,当上述用语用于两个或两个以上微滴时,可用来表示任何能够导致两个或更多微滴结合成为一个微滴时所进行的多个微滴操作的组合。例如,“将微滴A与微滴B融合”这一操作可通过搬运微滴A使这与静止状态的微滴B接触、搬运微滴B使这与静止状态的微滴A接触、或是搬运微滴B和A使两者互相接触等方式实现。用语“分离”、“分开”或“划分”不是用来暗示得到的微滴的尺寸方面具有某种特定的结果(即,得到的微滴的尺寸可相同,也可以不相同),也不是用来暗示得到的微滴数量是特定的(得到的微滴的数量可以是2、3、4、5或更多)。用语“混合”是指使微滴内的一种或多种成份更为均匀的微滴操作。微滴的“加载”操作的例子包括微量渗析加载、压力辅助加载、机器手加载、被动加载和移液管加载。
磁响应小珠的“固定”是指微滴被限制在微滴操作机构上的微滴或填充液中的某位置上。例如,在一实施方案中,被固定的小珠被限位,使微滴的分离操作能够进行,得到一个包含所有小珠的微滴和一个不包含小珠的微滴。
“磁响应”(Magnetically responsive)是指对磁场的响应。“磁响应小珠”(Magnetically responsive beads)中包含磁响应材料,或是该小珠完全由磁响应材料构成。磁响应材料的一些例子包括:顺磁材料、铁磁材料、铁氧体磁材料、变磁材料。适宜的顺磁材料包括:铁、镍、钴,以及金属氧化物,例如Fe3O4、BaFe12O19、CoO、NiO、Mn2O3、Cr2O3、CoMnP。
“洗涤”一词在针对洗涤一磁响应小珠时指从与该磁响应小珠接触的微滴中降低与该磁响应小珠接触或暴露于该磁响应小珠的一种或多种物质的数量和/或浓度。这种物质量和/或浓度的降低可以是部分的、大体上完全的、或是完全的。该物质的包含范围很广,例如用于进一步分析的目标物质以及不需要的物质,例如样品的部分成分、污染物和/或多余的试剂。在一些实施例中,洗涤操作从一与磁响应小珠接触的初始微滴开始,该微滴中包含具有初始量和初始浓度的物质。可利用各种微滴操作进行洗涤操作。洗涤操作可产生一包含有磁响应小珠的微滴,而该微滴具有的物质总量和/或浓度小于该物质的初始量和/或浓度。本说明书中其他部分描述了其他实施例,还有一些实施例也由于本说明书的公开而变得清楚。
术语“上部”和“下部”在说明书全文中指微滴操作机构的上基板和下基板,这仅仅是为了方便起见,因为微滴操作机构的功能与其空间位置无关。
当本说明书提及某一特定成分,例如一个层、区域或基板被放置于或形成于另一成分“之上”时,该成分可以是直接位于另一成分之上,或者,也可以存在中介成分(例如,一层或多层覆层、层、中间层、电极或触点)。还应理解用语“放置于”和“形成于”可互换使用,用来描述某一特定成分如何相对于另一成分定位。因此,用语“放置于”和“形成于”不是对材料移动、放置或制造的特定方法的限定。
当处于任意形态的液体(例如:移动或静止的微滴或连续体)被描述为位于一电极、阵列、矩阵或表面“处”或位于其“之上”、“上方”时,该液体可直接与该电极/阵列/矩阵/表面接触,或与插于该液体和该电极/阵列/矩阵/表面之间的一个或多个层或薄膜接触。
附图说明
当描述一微滴“位于”或“加载于”一微滴操作机构之上时,应将其理解为:该微滴在微滴操作机构上处于一种便于该微滴操作机构对该微滴执行一个或多个微滴操作的位置,该微滴在微滴操作机构上处于一种便于检测该微滴的属性或来自该微滴的信号,并且/或者该微滴已经在微滴操作机构上接受某种微滴操作。
图1A和图1B是在微滴分离操作第一和第二阶段使用中的微滴操作机构局部的第一和第二俯视图。
图2A和2B是微滴操作机构中包含有离开分离区的磁铁的部分的侧视图和俯视图。
图3是微滴操作机构中包含有两块位于微滴之上和之下的磁铁部分的侧视图。
图4A和4B是微滴操作机构中包含有四块环绕微滴的磁铁的部分的侧视图。
图5A和5B分别是处于微滴分离操作第一和第二阶段的微滴操作机构的第一和第二局部俯视图
图6是包含有用来降低磁场交叉的磁屏障的微滴操作机构的侧视图。
图7是包含有用来降低磁场交叉而磁极相向排列的磁铁的微滴操作机构的俯视图。
图8是按图7的方式排列的磁场图。
图9是用来减少微滴检测区域遗留物的微滴操作机构的局部俯视图。
图10A和10B是设置为减少遗留物的微滴操作机构的局部俯视图。
图11A、11B、11C是设置为提高微滴检测敏感度的微滴操作机构的侧视图。
图12是设置为提高微滴检测敏感度的微滴操作机构的俯视图。
图13是设置为提高微滴检测敏感度的微滴操作机构的侧视图。
图14A和14B是模块化微滴操作机构组件的俯视图,为磁铁组件在微滴操作机构的朝向设置提供了通用组件。
图15是模块化微滴操作机构组件的侧视图,是另一个为磁铁组件在微滴操作机构的朝向设置提供了通用组件的非限定性的例子。
具体实施方式
本发明涉及用来固定磁响应小珠的微滴操作机构以及这种微滴操作机构的制造和使用方法。例如,该微滴操作机构可用来固定微滴操作机构上微滴中的小珠,从而有助于执行需要将小珠固定的试验方案,例如小珠洗涤试验方案。本发明还提供用来减少或消除微滴操作机构中微滴物质遗留物的技术,以及在微滴操作机构进行信号检测的最优化技术。
1微滴分离期间的微滴损失
图1A和1B分别是使用中的微滴操作机构100在微滴分离操作中的第一和第二阶段的俯视图。微滴操作机构100采用了一种不适合于利用所示特定技术在不损失磁响应小珠的情况下有效分离微滴的设置方案。微滴操作机构100包括第一基板110和第二基板(图中未示),二者之间存在一缝隙,该缝隙起到液体流道的作用。第一基板110包含一组微滴操作电极112,用来在鼻涕虫形状的微滴114上进行微滴操作,该微滴114悬浮于填充液中并包含磁响应小珠116。可在距微滴操作电极112足够近的位置上布置一块磁铁118,以便对磁响应小珠116起到一定程度的固定作用。
图1A和1B展示了当微滴操作机构100内存在由磁铁118产生的磁场的情况下的分离操作。磁铁118的放置不适于在分离操作后微滴114上被选作用来保持小珠的中部区域(例如,离开微滴边缘之外的区域)内所有磁响应小珠的定位。因此,一定数量的磁响应小珠116在微滴分离操作中连通了分离区域120,如图1A所示,并且导致了小珠的损失,如图1B所示。图1B显示了包含一定原始量磁响应小珠116的第一微滴122和包含一定剩余量磁响应小珠116的第二微滴124。换句话说,分离操作的最终结果是损失了磁响应小珠116。本发明人发现造成小珠损失的决定性因素在于磁响应小珠116没有全部被适当地吸引、固定并保持在微滴114内的中部区域和/或距离分离区域120足够远的地方。
2.为防止/降低小珠损失对磁铁进行的配置
结合图2、3、4、5A描述了本发明提供的改进的具有各种磁性设置的微滴操作机构,在这些微滴操作机构中将磁铁进行布置,以便于有效分离包含小珠的微滴和洗涤磁响应小珠。这些附图展示了磁铁配置结合微滴操作机构使微滴分离不产生或只产生很少的小珠损失,并且对于有效地洗涤磁响应小珠也非常有用。可将一块或多块磁铁布置于微滴操作机构上的微 滴附近,使磁响应小珠受到适当的吸引并在微滴内固定,最好是位于离开在分离操作期间形成的颈部区域一段距离的中部区域。采用这种方式,微滴分离操作完成时,所有或几乎所有的磁响应小珠都被保留在一个微滴之内。类似地,可在鼻涕虫状微滴内进行分离操作,其与固定的小珠离开一定距离,其已足以减少或消除小珠损失。如下文将结合实例说明的那样,一个或多个磁铁将相对于微滴操作机构设置于包含有磁响应小珠的微滴之上、之下和/或旁边,以及为实现这一目的对上述方案的任意组合。
2.1磁铁相对于分离区的位置
图2A和2B是微滴操作机构200的侧视图和俯视图。在该实施例中,磁铁被设置于距离微滴中在分离操作时的断开点足够远的位置上,分离区224(或反之变然:也可表述为分离区域位于距离磁铁足够远的位置),以便在微滴分离操作中减少或消除小珠损失。还有,磁铁被放置于使小珠能沿微滴横向尺寸L处于中部位置(俯视图)。微滴操作机构200包含分开的第一基板210和第二基板212,以便形成间隙用来进行微滴操作,尽管只需要一块基板。一组微滴操作电极214与一板基板关联,或者与两板基板都关联,用来执行一个或多个微滴操作。微滴操作机构200可包括位于距微滴218/222足够近的距离,以便在微滴分离操作期间能够使磁响应小珠220固定。例如,磁铁可作为微滴操作机构的一个成分设置并且/或者距离微滴操作机构足够近的距离以便固定间隙中的微滴218/222中的磁响应小珠。微滴218/222可被填充液(图中未示)包围。微滴218/222包含被磁铁216固定的一定量的磁响应小珠220。
磁珠216相对于一个或多个微滴操作电极214定位,以便于将微珠220定位于微滴218/222中,形成微滴218而不允许在对微滴222进行分离操作的期间微滴218有损失。
在操作中,通过以下方式使分离操作中基本没有磁响应小珠220损失:如图201所示,提供一微滴操作机构200,电极处于启动(ON)状态,以便形成组合微滴218/222,并且磁铁216位于能够将基本上所有磁响应小珠220吸引到微滴218/222中某一区域,防止磁响应小220由微滴222中受到损失。磁铁216可设置为使被吸引的磁响应小珠220位于组合微滴218/222内沿横向直径L的中部位置,同时离开微滴分离区224。在如图202所示的微滴分离操作期间,一中间电极被关闭(OFF),使分离区域224处出现分离。基本上所有的磁响应小珠220都被保持在微滴218中,同时形成微滴222并且基本上不含磁响应小珠220,如图203所示。
在一实施例中,洗涤磁响应小珠220的过程可涉及:重复进行微滴融合(与一洗涤微滴融合)、小珠固定、分离、以及小珠悬置操作,直至达到可接受的洗涤程度。
2.2产生小珠柱的双磁铁布置
图3展示了微滴操作机构300的侧视图。微滴操作机构300大体上按图2所示设置,区别在于包含两块磁铁,磁铁310a和磁铁310b,分别位于微滴218之下和之上。磁铁可与微滴操作机构300形成一体并且/或者紧邻第一基板210和第二基板212外侧设置。总体来说,磁铁310a和磁铁310b可设置为反向磁极面向设置。在一实例中,磁铁310a的北极或正极面对磁铁310b的南极或负极设置,如图3所示。
磁铁310a和磁铁310b可是分离的两块磁铁,或者,磁铁310a和磁铁310b也可以是一块U型、C型或马蹄铁型永磁体或电磁铁相反的两个磁极。磁铁310a和磁铁310b的排列方式可使磁响应小珠220固定并保持为一簇柱状的形状。磁铁的排列最好使微滴218内的小珠处于离开保持小珠的组合微滴(图中未示)中的分离区域224一段距离的位置。更进一步,磁铁最好对齐,使小珠定位于沿组合微滴(图中未示)内横向直径L的中部。
2.3使小珠居中的多个磁铁对
图4A和4B展示了一微滴操作机构400的侧视图400。微滴操作机构400的设置大体上与图2中的微滴操作机构200相似,不同之处在于它包含4块围绕微滴设置的磁铁。一般来说,图中所示的实施例中的多个正/负板相向设置的磁铁对在分离操作前将小珠220定位于组合液滴的中部。如图4B所示,小珠大体上沿垂直尺寸V和横向尺寸L中部定位。在图中所示的实例中,微滴操作机构400包含4块磁铁,410a、410b、410c和410d。
磁铁410a和410b可靠近微滴、并在微滴各侧等距设置。例如,磁铁310a的北极可面向磁铁410b的南极设置。磁铁410c和磁铁410d可靠近微滴、并在微滴两侧等距设置,相反磁极相向设置。例如,磁铁410d的北极可面对磁铁410c的南要。磁铁对410a/410b可围绕微滴相对于磁铁对410c/410d呈直角对齐设置。在图中所示的实施例中,磁铁对410a/410b围绕微滴在垂直方向上设置,磁铁对410c/410d围绕微滴在水平方向上设置。任何围绕微滴的能够将微滴沿横向尺寸L和垂直尺寸V方向将微滴大致固定在中部的朝向都可以实现需要的中部固定。
磁铁410a和磁铁410b可以分别紧靠第一基板210和第二基板212的外侧设置,使磁铁410a和磁铁410b的磁场能够穿过微滴操作机构400的第一基板210和第二基板212之间的间隙。磁铁410a和磁铁410b设置对反向磁极相向设置。在一实例中,磁铁410a的北极面对磁铁410b的南极,如图4所示。类似地,磁铁410c和磁铁410d分别紧靠微滴操作机构400的第一侧和第二侧设置,使磁铁410c和410d的磁场能够穿过微滴操作机构400之间的间隙并垂直于磁铁410a磁铁410b的磁场。磁铁410c和磁铁410d被设置为相反磁极相向设置。在一实例中,磁铁410d的北极面对磁铁 410c的南极设置,如图4所示。
磁铁410a和磁铁410b可是分离的两块磁铁,或者,磁铁410a和磁铁410b也可以是一块U型、C型或马蹄铁型永磁体或电磁铁相反的两个磁极。类似地,磁铁410c和磁铁410d可是分离的两块磁铁,或者,磁铁410c和磁铁410d也可以是一块U型、C型或马蹄铁型永磁体或电磁铁相反的两个磁极。由于磁铁410a和磁铁410b以及磁铁410c和磁铁410d的磁场分别相交于微滴操作机构400内的液体流道的中部,磁响应小珠220被磁力固定并形成一簇于组合微滴内中部并在分离操作后保持在微滴218中。
2.4基本上无小珠损失的分离操作演示
图5A和图5B分别展示了微滴操作机构500在微滴分离操作的第一和第二阶段时的第一和第二俯视图。微滴操作机构500可以按微滴操作机构200、300、400中任意一种设置。图5A和图5B的微滴操作机构500利用正确设置的磁力用于例如磁响应小珠洗涤过程中进行的分离操作,使一个微滴中的小珠能够得以完全保留。
特别是图5A和图4B中展示了分离操作在距离被定位的小珠220足够远的位置进行,这样通过分离操作能够使磁响应小珠在微滴218中能够被完全保持并得到一基本上不含有磁响应小珠的微滴。磁面510被设置在能够使所有磁响应小珠220位于微滴内居中并被磁力固定,并且距离分离区域足够远从而能够实现将微滴218内的磁响应小珠220得到保持的适当位置。结果,在微滴分离操作期间,基本上没有磁响应小珠220与分离区域512连通,如图5A所示,并且基本上没有发生小珠损失。图5B展示了包含有基本上所有磁响应小珠的微滴218。换句话说,基本上发生在磁力范围以外的分离操作的操作结果是,由于基本上所有磁响应小珠220都被吸引、固定和保持在液体内中部,因而基本上没有发生磁响应小珠220损失。
3带有磁铁的微滴操作机构的设置
3.1具有磁屏蔽的微滴操作机构
图6是包含有用来减少磁场交叉的磁屏蔽的微滴操作机构600的侧视图。微滴操作机构600包含一顶板610和一底板614,其间形成一间隙618。电极622,例如电润湿电极,可以连接到底板614用来进行微滴操作,并且可以连接到与含有液体634的蓄液池630连接的蓄液电极626。可以由蓄液池630的液体634中分离出一个或多个微滴(图中未示),并沿电极622进行操作。此外,液体634和任何由此分离出来的微滴都可含有小珠(图中未示),这些小珠在某些情况下可以是磁响应小珠。
微滴操作机构600还包含一靠近一个或多个电极622设置的磁铁638。磁铁638可充分靠近电极622,以便能够固定磁响应小珠(图中未示),例如,位于微滴内电极之上。在一实例中,磁铁638的用处是在微滴分离操 作期间磁力固定并保持磁响应小珠,例如,可能在洗涤磁响应小珠时进行的分离操作。
此外,微滴操作机构600包含一足够靠近蓄液池630的磁屏蔽642,用来为蓄液池630屏蔽附近的磁场,例如磁铁638产生的磁场。举例而言,磁屏蔽642可以由具有足够高导磁率的镍铁高导磁合金(Mu-metal)材料,并且能够降低,最好是完全消除来自蓄液池630内磁铁的磁场的材料形成。在一实例中,磁屏蔽642可由McMaster-Carr公司(Elmhurst,IL)生产的镍铁高导磁合金形成。其它磁屏蔽642的例子包括坡莫合金、铁、钢和镍。
微滴操作机构600不仅限于一个磁屏蔽和一个磁铁,其上可以安装任何数量的磁屏蔽和磁铁。因此,利用一个或多个磁屏蔽可以将微滴内磁响应小珠(图中未示)在微滴操作机构600内暴露于磁场的区域限定在需要的区域之内。磁屏蔽可包含于微滴操作机构上任何表面上并以任何形式排列,只要有助于形成适当磁屏蔽。
在一应用实例中,微滴操作机构可用来进行多个并行的测定,并且随后可能会需要进行在多个电极通道内进行的大体上同步进行的对各种磁响应小珠的洗涤。在没有磁屏蔽的情况下,利用相关磁铁在某一位置上进行的洗涤操作或测定可能会受到远处磁铁的磁场的影响(例如:磁场的交叉)。相反,任何两块磁铁之间形成的磁场的交叉可以借助在微滴操作机构内对一个或多个磁屏蔽,例如磁屏蔽642的特定设置而减少,最好是完全消除。
3.2具有其它磁铁设置的微滴操作机构
图7展示了包含有磁极相向设置以便减少磁场交叉的磁铁的微滴操作机构700的俯视图。微滴操作机构700包括一系列电极710,例如,电润湿电极,用来在一个或多个微滴(图中未示)上进行微滴操作。此外,磁铁714靠近电极710的第一的通道排列,磁铁718靠近电极710的第二的通道排列,磁铁722靠近电极710的第三的通道排列,磁铁726靠近电极710的第四的通道排列。磁铁714、718、722和726可充分靠近电极710设置,以便能够将位于一个或多个电极之上的一个或多个微滴(图中未示)内的磁响应小珠(图中未示)固定。
为了减少,最好是消除相邻磁铁之间的磁场的交叉,相邻磁铁的极性相反排列,使邻近磁场抵消。例如,请再次参见图7,磁铁722的北极向上设置,磁铁726的南极向下设置。这样,磁场被抵消并且磁铁714、718、722和726之间的磁场交叉可减少,最好基本上消除。
图8展示了按照图7的方式排列的磁场分布图800。
4其他技术
本发明还提供减少微滴操作机构内遗留物的技术,以及改进检测操作的技术。
4.1减少微滴操作机构内遗留物的技术
图9展示了微滴操作机构900的俯视图,可以借助其进行减少微滴检测区域遗留物的操作。微滴操作机构900包含一组电极910,例如,电润湿电极,用来对微滴进行微滴操作。此外,微滴操作机构900包含一指定的检测区域914,例如,位于某电极910上。检测区域914用来检测在微滴操作中位于其上或由此穿过的微滴。在一实例中,利用与检测区域914连接的光电增倍管(PMT)或光子计数PMT进行微滴检测。PMT(图中未示)被用来测量当微滴处于与检测区域914关联的电极上时由微滴发射的(例如:由于荧光或化学光)光线(例如:检测光子)。
在一些情况下,由于遗留物的原因,在检测区域,例如检测区域914会积累物质,例如小珠或其他在微滴操作期间在表面和/或填充液中残留的其他物质。遗留物可干扰对来自后续微滴信号的精确检测和/或由于对电极的影响而干扰微滴操作。
请再次参阅图9,本发进而微滴排序操作借助提供一系列变化的测定微滴918和洗涤微滴922减少、最好是基本消除检测区域914的遗留物。在一实例中,测定微滴918a穿过检测区域914,随后是洗涤微滴922a,随后是测定微滴918b,随后是洗涤微滴922b,随后是测定微滴918c,随后是洗涤微滴922c,随后是测定微滴918d,随后是洗涤微滴922d。由于测定微滴918a、918b、918c、918d具有因交叉而弱检测区域914的功能降级的潜在可能性,洗涤微滴922a、922b、922c、922d对与检测区域914相关的表面进行清洁操作。本发明的清洁过程不限于图9所示序列。只要该序列包含了适当数量的洗涤微滴用来适宜地清洁检测区域,任何序列都是可能的。例如,根据某特定测定的需要,可在测定微滴之间提供多个洗涤微滴和/或在洗涤微滴之间提供多个测定微滴,例如:AAWAAWAAW、AAAWAAAWAAAW、AWWAWWAWW、AWWWAWWWAWWW、AAWWAAWWAAWW、AAAWWWAAAWWWAAAWWW等等,其中A=测定微滴,W=洗涤微滴。应该注意,测定微滴和洗涤微滴的大小不必相同。可以是测定微滴较大,或者是洗涤微滴较大。较大的微滴可作为鼻涕虫状微滴接受微滴操作(例如:一占有4个电极的鼻涕虫状微滴),或是作为一个大的微滴接受微滴操作(例如:一自然占有尽量多电极但没有形成鼻涕虫状的4X倍微滴)。每种排列布置都会带来不同的清洁结果。测定微滴和洗涤微滴没有必要经过相当的路径。例如,它们的路径可以在需要清洁的位置重叠。
图10A和图10B展示了微滴操作机构1000的俯视图,借助该微滴操作机构1000可进行另一减少遗留物的操作。微滴操作机构1000包括一组电极1010,例如,电润湿电极,用来在一个或多个微滴上进行微滴操作,例如在测定微滴1014和1018(图10A)和洗涤微滴1022(图10B)上。此外, 磁铁1026靠近某一电极1010设置。磁铁1026可足够靠近该电极1010以便能够在固定一个或多个微滴内的磁响应小珠,例如测定微滴1014内的磁响应小珠1030。
例如,在微滴分离操作中,发生分离的位置点上可能会留下一些“伴生”微滴。例如,参见图10A,在由测定微滴1018分离而形成的测定微滴1014的微滴分离操作中,可产生一定数量的伴生微滴1034遗留在某一电极1010上。伴生微滴,例如伴生微滴1034可能是一个个微滴遗留物(交叉污染)的来源,而这是不希望出现的。图10B展示了洗涤微滴,如洗涤微滴1022可在对例如测定微滴1018和1014的测定操作后沿电极1010被搬运,以便将伴生微滴1034捕获并在下一测定操作开始前将其运走。这样,电极1010就在测定操作之间得到了清洁。本发明清洁过程不限于图10A和图10B中所示的序列。只要序列中包含有适当数量的洗涤微滴以便适宜地清洁电极,任何序列都是可以的。
4.2改进微滴操作机构的检测操作
图11A、11B、和11C展示了微滴操作机构1100的侧视图,可以通过该微滴操作机构1100进行提高微滴检测灵敏度的相关操作。微滴操作机构1100包含一顶板1110和一底板1114,其间具有一间隙1118。可与底板1114关联一电极1122,例如电润湿电极,用来在微滴1126上进行微滴操作。可将PMT窗1130关联到顶板1110,借助它使用PMT(图中未示)对微滴1126发射的光线(例如:检测光子1134)进行测量。
图11A展示了一种通过平铺一微滴例如微滴1126以增加其暴露在PMT窗1130下的表面积,从而提高可被检测到光子1134数量,进而提高微滴检测灵敏度的方法。可以根据微滴的体积在一个或多个电极1122上直线平铺微滴。对于小体积微滴来说,可加入一缓冲微滴使微滴变大,只要缓冲微滴造成的稀释能被增加的暴露在PMT下的微滴面积补偿即可。例如,图11B展示了被连续地平铺在多个电极1122上的微滴1126,这样就增加了可到达PMT窗1130并可被PMT检测到的的光子1134的数量。
图11C展示了微滴1126被分离为多个微滴1126时的情景,例如多个电极1122上的微滴1126a、1126b、1126c、1126d。暴露在PMT窗1130下的表面再次增加了,从而增加了可能会到达PMT窗1130并会被PMT检测到的光子1134的数量。或者,再次参见图11A、11B、11C,微滴,例如微滴1126的平摊不仅限于线性方向的平摊。可在两个维度上对微滴进行平铺,例如横穿格栅或阵列或电极1122,以便增加暴露在PMT窗口1130下的表面积。或者,可提供一个或多个大面积电极,可在其中平铺一个或多个微滴。
图12展示了用来提高微滴检测灵敏度的微滴操作机构1200的俯视图。微滴操作机构1200包含一组电极1210,例如电润湿电极,用来在多个微滴 1214上进行微滴操作。
此外,微滴操作机构1200可包括设置有PMT(图中未示)的微滴检测区域1218用来测量由某一微滴1214发射的光线。为了减少,更好是消除由远处微滴1214向微滴检测区1218遗留的光,在微滴检测区域1218和外周和任何微滴操作机构1200内的远处微滴1214之间在各个方向上都保持最小距离d,如图12所示。最小距离d的值足够大,以便减少,更好的是消除由远处微滴1214留给微滴检测区域1218的光遗留物。结果,在包含多微滴1214的微滴操作机构中,在检测期间被测量的目标微滴1214和远处微滴1214之间保持一个间距,这样由远处微滴1214向微滴检测区域1218遗留的光就减少了,最好是完全减去。作为一特殊情况,距离d是单位电极尺寸的整倍数m,并且微滴检测可在一组以m相位的总线电连接的电极上进行。或者,图13(下文描述)展示了具有微滴操作机构的基板面受到限制,因此如图12所示,微滴之间可以实现足够的空间。
在一替换实施例中,利用光学成分消除由附近微滴造成的交叉,例如一个或多个透镜,只聚焦来自被传感器检测的微滴的光线并消除来自其他微滴的信号。
图13展示了用来提高微滴检测灵敏度的微滴操作机构1300的侧视图。微滴操作机构1300包括顶板1310和底板1314,二者之间形成间隙1318。一组电极1314,例如电润湿电极,可与底板1314关联,以便对微滴进行微滴操作,例如微滴1326和微滴1330。PMT窗1334可与顶板1310关联,通过其利用PMT(图中未示)测量由例如微滴1326发射的光线(即检测光子1338)。由于,例如,在PMT窗1334的微滴1326与远处微滴1330之间的间距还不足以避免由微滴1330向PMT窗1334的遗留物,因此在顶板1310上提供遮罩1342。遮罩1342的目的在于阻挡来自远处的微滴光线使其不会到达作为目标微滴的检测区域的PMT窗1334。
遮罩1342可通过一层任何类型的吸光材料形成于顶板1310之上,只要该材料与电润湿工艺兼容并且不会不适当地干扰微滴操作机构的操作即可。在一实例中,遮罩1342可通过在顶板上1310涂覆一层黑漆形成,这样一个或多个窗,例如PMT窗1334只存在于微滴操作机构1300上选定的检测区域。在图13所示的实例中,遮罩1342减少,更好的是基本上消除由远处微滴1330向PMT窗1334处的目标微滴1326的遗留光线。在另一实例中,遮罩1342由顶板1310上面向微滴一侧上的不透明导体形成。例如,该导体可以是铝、铬、铜或铂。该导体还可作为参考电极。
5具有磁组件的微滴操作机构
图14A和图14B展示了模块化微滴操作机构组件1400的俯视图,是用来将磁铁组件对向滴操作机构正确朝向的通用组件的一个非限制性的实 例。模块化微滴操作机构组件1400可包含,例如,一装配件1410、一磁铁组件1420、一微滴操作机构1430。图14A展示了解体状态的模块化微滴操作机构组件1400。图14B展示了组装状态的模块化微滴操作机构组件1400。
磁铁组件1420可包含基板1424,其上安装一块或多块磁铁1428,如图14A所示。磁铁1428可以永久性在固定在基板1424上,也可以是活装于基板1424之上。活装磁铁1428使用户可以选择具有需要属性的磁铁,例如需要的磁强度。在一实施例中,微滴操作机构被提供一个包含有装配件1410和没有磁铁的磁铁组合1420的微滴操作机构组件1400。在另一实施例中,还可以向用户提供具有特定属性的磁铁,用户可将该磁铁固定在磁铁组件1420上。在另一实施例中,还可以向用户提供一组具有不同特性的磁铁,这样用户可以选择具有需要属性的一块或一套磁铁并将其固定在磁铁组件1420上。
还可以为磁铁标记或编号(例如:将磁铁打上色标)以便帮助选择具有适宜属性的磁铁,并且为显示磁铁磁场的朝向而进行标记(例如:打上色标或标记出磁铁的北极和南极)。类似地,可将磁铁组件1420打上标记以便显示出插入其中的磁铁应该具有的朝向,并且在一些实施例中,可以使磁铁具有某种形状,使其只有在朝向正确时才能够固定在磁铁组件1420上。
还有,在另一实施例中,可向用户提供已经固定有磁铁的磁铁组件,而每个磁铁组件1420都具有不同的磁铁设置,例如,一组具有不同属性的磁铁。用户可选择具有与用户需要的属性相配的磁铁设置。磁铁组件1420可以被标记或打上色标以帮助用户选择。例如,可以根据用户选择的小珠的属性来选择磁铁的属性。
微滴操作机构1430可包含基板1434,其上布置有电极1438,例如电润湿电极,如图14A所示。还可包含第二基板(图中未示)。
磁铁组件1420被设计为将磁铁1428与向滴操作机构1430上的某相关电极1438基本上对齐。例如,在一些实施例中,可以存在平行设置的磁铁,用来在微滴操作机构1430上进行并行的测定步骤。例如,可以根据本说明书中描述的各种配置和朝向确定磁铁的配置和朝向。
装配件1410可用作安装磁铁组件和微滴操作机构的通用平台,例如磁体组件1420、和向滴操作机构1430。在一实施例中,装配件1410被设置为能够接受多种不同的磁铁组件1420和多种不同向滴操作机构1430。磁铁组件1420可包括按多种模式中的任意一种设置并采用多种磁铁属性中的任意一种磁铁的一块或多块磁铁。图14展示了一排磁铁,但磁铁还可以置于栅格中或任何一种能够将磁铁置于相对于微滴操作机构1430正确位置以便于在微滴操作机构上进行需要的操作的设置方式。
在一实例中,磁铁组件1420和微滴操作机构1430可通过对应的配件1418和1414被安装到装配件1410中。例如,配件可以是能够配合装配件1410的槽、装配件1410上用来接收磁铁组件1420上的凸柱的开口或反之亦然、装配件1410上用来接收磁铁组件1420上的螺丝的开口、用来接收螺栓的带螺纹凸柱、各种弹簧机构、凹座、配件等等。任何有助于充分固定使装置能够按其本预定的功能正常工作的机构都可以使用。
还有,装配件1410可包括用于磁铁组件1420和/或微滴操作机构1430的多个可能位置,和/或在一个装配件中安装多个磁铁组件1420和/或多个微滴操作机构1430的多个配件。还有,装配件1410可以设置为允许磁铁组件1420安装在微滴操作机构1430之上、之上、和/或旁边,即任何与微滴操作机构的位置关系都允许。微滴操作机构1430安装在模块化装配件1410内时,任何相关的磁铁组件,例如磁铁组件1420都可以插入到模块化微滴操作机构组件1400,例如,通过插槽的方式。
图15展示了模块化微滴操作机构组件1500的侧视图,该组件是另一个用来将磁铁组件相对于微滴操作机构正确放置的通用组件的非限定性实例,与图14中展示的组件1400类似,不同之处在于装配件1410被装配件1510替换。装配件1510包含凹座,磁铁组件1420和微滴操作机构1430可以装配于其中,从而提供一种“滴入”(drop in)式的加载方法。
参见图14A、14B、和图15,本发明的一个方面在于插槽或其他固定机构用来正确地朝向磁铁基板和微滴操作机构,以便将磁铁组件上的磁铁与微滴操作机构上的电极或电极通道正确地对准。采用这种方式,当不需要磁铁进行测定时,就可以将磁铁取下。此外,还可提供具有不同磁铁分布的磁铁装配件,用于不同类型的测定或不同的微滴操作机构的我布局。
6磁铁
除了前文已经描述过的各个方面,应注意本发明所使用的磁铁可以是永久磁铁或电磁铁。微滴中的小珠中的磁响应物质与磁力强度/拉力之间具有一定关系。因此,磁铁的磁力强度/拉力可以相对磁珠的反应度进行选择,使其:
相对于小珠的磁响应度足够强大,能够基本上将磁响应小珠固定。
相对于小珠的磁响应度尚不够强大,能够明显磁化小珠,从而导致不可逆的珠簇的形成。
相对于小珠的磁响应度尚不够强大,当去除磁场时重新悬置的情况发生得不好。
相对于小珠的磁响应度尚不够强大,小珠被一起拉出微滴。
在一些实施例中,磁铁可以具有很高的磁强度(按泰斯拉计)较小的拉力(按磅计)。在一实例中,磁铁是钕永久磁铁,其表面场强大约为1泰 斯拉(T)。在另一实例中,磁铁是电磁铁,其表面场强大约为1泰斯拉,可以通过电气开关启闭。使用永久磁铁时,在需要去除磁场的影响时,可将磁体移离含有磁响应小珠的微滴。尽管不受下面给出的范围的限制,应理解通常包含本发明的有效强度磁力强度的范围包含:较宽的范围,0.01T-100T(脉冲)或45T(连续);中间范围为0.01T-10T;较窄范围为0.1T-1T(优选0.5T)。
7微滴组分
含有磁珠并要接受分离操作的微滴可包括各种利用小珠进行测定的样品、试剂、缓冲剂。例如,在洗涤时,微滴可包含缓冲剂,例如适用于含磁免疫测定的含有表面活性剂的磷酸盐缓冲盐水(PBS)缓冲液。适宜的表面活性剂在磁力固定后有助于小珠的固定和/或重新悬置。可以调节表面活性剂及其用量,以便能够提供相比没有表面活性剂的对照溶液而言对重新悬置有所改善。在一实施例中,微滴中含有具有约0.01% 20的PBS缓冲液。
亲水聚合物和/或表面活性剂可包含于微滴之中,在分离操作中帮助磁响应小珠的保持和重新悬置。微滴可包含各种不能与填充液混合的液体。缓冲剂的包括(但不限于)磷酸盐缓冲盐水(PBS)缓冲液和三羟甲基氨基甲烷缓冲液。在一实施例中,微滴液中包含缓冲液,例如PBS缓冲液,和任何适用于含磁免疫测定的表面活性剂。
优选的亲水聚合物和表面活性剂在小珠被磁力固定后有助于小珠重新悬置。可以调节表面活性剂及其用量,以便能够提供相比没有表面活性剂的对照溶液而言对重新悬置有所改善。适合在含磁免疫测定中使用的表面活性剂包括,但不限于,聚山梨酸酯20,商品名为 20和Triton X-100。例如, 20可由Pierce Biotechnology,Inc.(Woburn)提供。 X-100可由Rohm & Hass Co(philadelpia,PA)提供。在一实例中,微滴操作机构内的微滴液是PBS与 20的混合物,其范围大约在0.001%-0.1%之间。在另一实例中,微滴操作机构内的微粒液是PBS与大约0.01%的 20的混合物。
其他实例包含聚醚(pluronic)表面活性剂、聚乙二醇(PEG)、甲氧基聚乙二醇(MPEG)、聚山梨酸酯(聚氧化乙烯山梨聚糖一油酸或 )、聚氧乙烯辛基苯基醚(Triton X- )、聚乙烯吡咯烷酮、聚丙烯酸(以及交联聚丙烯酸如卡波姆)、聚糖苷(非离子化糖苷如辛基吡喃葡萄糖苷)和可溶多糖(及其衍生物)如肝磷脂、右旋糖苷、甲基纤维素、丙基甲基纤维素(以及其他纤维素脂和醚)、糊精、麦芽糊精、半乳甘露聚糖、阿拉伯半乳聚糖、β-葡聚糖、藻酸盐、琼脂、角叉藻聚糖、以及植物胶如黄原胶、车前草、瓜尔豆胶、胺黄树胶、刺梧桐胶、印度胶、阿拉伯树胶。可选择 特定的添加剂以获得与某特定微液试样的最佳相容性。
8微滴操作机构
适用于本发明的微滴操作机构的实例参见:2005年6月28日授予Pamula等人的名称为“Apparatus for Manipulating Droples byElectrowetting-Based Techniques”美国专利第6,911,132号、2006年1月30日递交的名称为“Apparatuses and Methods for ManipulatingDroplets on a Printed Circuit Board”美国专利申请11/343,384号、2004年8月10日授予Shenderov等人的名称为“Electrostatic Actuatorsfor Microfluidics and Methods for Using Same”美国专利第6,773,566号和2000年1月24日授予Shenderov等人的名称为“Actuators forMicrofluidics Without Moving Parts”美国专利第6,565,727号、以及2006年12月11日由Pollack等人提交的名称为“Droplet-BasedBiochemistry”的国际申请号PCT/US06/47486,本发明全文引用以上内容。固定磁珠和/或非磁珠的微滴操作机构在前述国际申请中有描述,并在以下专利文献中有描述:Sista等人于2007年2月9日提交的名称为“Immobilization of magnetically-responsive beads during dropletoperations”的美国专利申请号60/900,653、Sista等人于2007年9月4日提交的名称为“Droplet Actuator Assay Improvements”的美国专利申请号60/969,736、Allen等人于2007年8月24日提交的名称为“Beadwashing using physical barriers”的美国专利申请号60/957,71,本发明全文引用以上内容。这些技术的组合均在本发明的范围之内。
9液体
可接受本发明的微滴操作液体参见本说明书第8节中列出的美国专利文件,特别是2006年12月11日递交的名称为“Droplet-BasedBiochemistry”的国际申请号PCT/US06/47486。在一些实施例中,微滴是样本液体,例如:全血、淋巴液、血清、血浆、汗液、眼泪、唾液、痰液、脑脊髓液、羊水、精液、阴道分泌物、浆液、滑液、心包液、腹膜液、胸膜液、渗出液、渗出物、囊液、胆汁、尿液、胃液、肠液、粪便样品、液化组织、液化有机体、生物棉签和生物洗涤剂。在一些实施例中,加载的液体包含试剂,例如水、去离子水、盐溶液、酸性溶液、碱性溶液、清洁液和/或缓冲液。在一些实施例中,加载的液体可包含试剂,例如用来进行生化试验方案,例如核酸放大试验方案、基于亲合力的测定试验方案、序列试验方案、和/或用来分析生物流体的试验方案。
10填充液
正如所见,间隙中通常充满了填充液。举例而言,填充液可以是低粘度油,例如硅油。其它填充液的例子参见国际申请PCT/US06/4748,名称为 “Droplet-Based Biochemistry”,2006年12月11日递交。
11磁响应小珠的洗涤
对于使用小珠的试验方案来说,可利用微滴操作将含有小珠的微滴与一个或多个洗涤微滴结合。然后,在保持小珠(例如:采用物理的或磁力手段)的同时,利用本发明的磁铁设置,可利用微滴操作将融合的微滴分离成两个或更多的微滴:一个或多个微滴含有小珠而一个或多个微滴基本上不含小珠。在一实施例中,利用微滴操作将融合后的小滴分离为一个含有小珠的微滴和一个基本上不含小珠的微滴。
通常每个洗涤试验方案的执行都会保持足够多的小珠,以便在对测定结果没有有害影响的情况下进行需要的测定。在一些实施例中,每次对融合小珠的分离都导致多于小珠总量90%、95%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99%、99.9%、99.99%、99.999%、99.9999%、99.99999%或99.999999%的小珠得到保持。在另一实施例中,每次为实现预期的减少移除物质的浓度和/或数量而执行的洗涤试验方案导致多于小珠总量99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99%、99.9%、99.99%、99.999%、99.9999%、99.99999%或99.999999%的小珠得到保持。在另一实施例中,被保持的小珠的数量被计算出来并得到相应的调节。
在一些实施例中,可在同时含有含小珠微滴与洗涤微滴的蓄液池中对小珠进行洗涤,小珠被保持(例如借助磁铁、物理结构、静电力),并且利用微滴操作将不含小珠的微滴由蓄液池分出。例如,可借助稀释-分发方案对小珠进行洗涤,向蓄液池中加入洗涤缓冲剂将溶液稀释,使用磁铁将磁响应小珠定位于蓄液池内部,并且大多数溶液由蓄液池分出,并且重复这一循环,直至达到合格的洗涤标准。
作为举例,磁响应小珠的洗涤大致可包含以下步骤:
(1)在一磁铁附近提供含有磁响应小珠和游离物质的微滴;
(2)使用微滴操作将洗涤微滴与上述含有磁响应小珠微滴结合;
(3)利用磁场将小珠固定;
(4)使用微滴操作将环绕在小珠周围的部分或全部微滴移除,产生一个含有小珠的微滴,游离成分的浓度有所减少,并产生一个包含游离成分的微滴;
(5)去除磁场将小珠释放;
(6)重复步骤(2)到(3)或(2)到(4),直到达到预定的纯度。
采用这种方式,游离物质如污染物、副产物或多余的制剂都可与小珠分离开来。每次循环都产生一个含有小珠的微滴,但是微滴不需要物质的浓度在下降。所有洗涤周期都不需要步骤(5),但是,该步骤通过将污染物 释放,可能对加强洗涤有用。这些步骤可以按不同的顺序进行,例如,步骤(2)和(3)可以互掉。洗涤试验方案可以在微滴操作机构上利用前述的微滴操作完成。
在使用磁响应小珠的实施例中,本发明人发现,磁场的使用尽管对于临时固定小珠、移动小珠和/或固定小珠十分有用,但有时会导致不希望的小珠的聚集。前文已经提到,在一实施例中,加入亲水聚合物和/或表面活性剂防止或减少小珠的聚集。亲水聚合物和/或表面活性剂的选用量应减少或消除小珠的聚集并尽量少非特定吸附,同时不会引起微滴内目标分析物或试剂的大量流失。在一实施例中,亲水聚合物和/或表面活性剂减少了处于非气态填充液中的微滴内的小珠的聚集,并且不会减少微滴成分对微滴操作机构表面的分子吸附。
另一种减少或消除小珠聚集凝结的方案是使用较少数量尺寸较大的小珠。在一次或多次微滴操作期间,微滴中可包含任意数量的小珠。在一些实施例中,磁响应小珠的数量可在一到数十万之间。例如,在一实施例中,每个微滴使用1至100个磁响应小珠。例如,每个微滴中使用1、2、3、4、5、6、7、8、9、10…100个磁响应小珠。在一实施例中,磁响应小珠数量为1到10。使用较少数量的微滴就意味着可以使用较大的微滴。例如,在一实施例中,每个微滴使用1到100个磁响应小珠,小珠的平均直径在大约25到100微米之间。在另一实施例中,每个微滴使用1到10个磁响应小珠,小珠的平均直径在大约50到100微米之间。
9结束语
以上结合反应本发明特定实施例的附图对实施例进行了详细描述。
将说明书分为了几个部分仅仅是为了方便读者。不能将这些标题理解为对本发明的限制。此外,对说明书内容的描述也仅仅是为了展示发明内容,并非对发明的限制。本发明的范围由后附的权利要求确定。
Claims (15)
1.一种提供与磁响应小珠接触并具有减少的物质量的微滴的方法,其特征在于该方法包括以下步骤:
(a)提供一微滴操作机构,其包含:
(i)一基板,包含电极结构,用来在一表面上进行微滴操作;和
(ii)一初始微滴,包含:
(1)一个或多个磁响应小珠;
(2)一定初始量的物质;和
(3)一初始体积;
(b)将上述一个或多个磁响应小珠磁性固定于离开目标微滴分离区一定距离的位置;和
(c)进行一次或多次微滴操作,包含选定的将初始微滴分离成一组微滴的分离操作,该组微滴包含:
(i)一微滴,包含所有上述一个或多个磁响应小珠并具有相对于初始浓度减少的物质量;和
(ii)缺少磁响应小珠的微滴;
在步骤(b)中,一个或多个磁响应小珠磁性固定是通过设置于所述初始微滴之上和之下的两个磁铁设置为反向磁极面向设置实现的。
2.根据权利要求1所述的方法,其特征在于其中所述的初始微滴包含具有一初始浓度的物质,并且所述一次或多次微滴操作产生一包含与初始浓度和初始量相比具有减少的浓度和量的物质的微滴。
3.根据权利要求1所述的方法,其特征在于还包含进行一次或多次微滴操作以便将洗涤微滴与步骤1(a)提供的微滴融合,形成一复合微滴。
4.根据权利要求1所述的方法,其特征在于还包含在步骤1(c)之后将一个或多个微滴释放或重新悬置。
5.根据权利要求4所述的方法,其特征在于还包含在微滴中提供表面活性剂,以便较没有亲水聚合物的微滴而言提高其重新悬置能力。
6.根据权利要求4所述的方法,其特征在于还包含在步骤1(c)后使用超声波仪对一个或多个小珠进行搅动。
7.根据权利要求1所述的方法,其特征在于其中:
(a)步骤1(b)包含以下步骤:将邻近一个或多个电极的所述磁铁的磁场附近的含有小珠的微滴定位;并且
(b)对磁场的强度和位置进行选择,以便在一离开目标分离区域一定距离将微滴中的磁响应小珠固定,足以将基本上全部磁响应小珠保持在一个微滴内。
8.根据权利要求1所述的方法,其特征在于其中:
(a)步骤1(b)包含以下步骤:将邻近一个或多个电极的所述磁铁的磁场附近的含有小珠的微滴定位;并且
(b)对磁铁的位置进行选择,以便将磁响应小珠沿微滴的横向居中定位。
9.根据权利要求1所述的方法,其特征在于其中:
(a)步骤1(b)包含以下步骤:将邻近一个或多个电极的所述磁铁的磁场附近的含有小珠的微滴定位;并且
(b)对所述磁铁的位置进行选择,以便将磁响应小珠沿微滴的垂直方向居中定位。
10.根据权利要求1所述的方法,其中步骤1(b)包含利用一装置将一个或多个磁响应小珠磁性固定的步骤,该装置包含:
(a)所述磁铁;和
(b)将该磁铁移进或移出所述一个或多个电极附近的装置。
11.根据权利要求1所述的方法,其特征在于其中步骤1(c)是依赖电极完成的。
12.根据权利要求1所述的方法,其特征在于其中步骤1(c)是依赖电润湿完成的。
13.根据权利要求1所述的方法,其特征在于其中步骤1(c)是依赖介电电泳完成的。
14.根据权利要求1所述的方法,其特征在于其中步骤1(c)是依赖电场完成的。
15.根据权利要求1所述的方法,其特征在于所述初始微滴周围围绕设置有相反磁极相向设置的多个磁铁对。
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