CN104614302A - 在声细胞计中的颗粒分析 - Google Patents

在声细胞计中的颗粒分析 Download PDF

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CN104614302A
CN104614302A CN201510064850.2A CN201510064850A CN104614302A CN 104614302 A CN104614302 A CN 104614302A CN 201510064850 A CN201510064850 A CN 201510064850A CN 104614302 A CN104614302 A CN 104614302A
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G.卡杜查克
M.D.沃德
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Abstract

本发明涉及在声细胞计中的颗粒分析。本文提供了根据尺寸分离颗粒的方法，此类方法包括：使颗粒在流动的流中流动；将径向声辐射压力导引至流动的流中；和根据尺寸按声分离颗粒。也公开了用于实施这些方法的装置。

Description

在声细胞计中的颗粒分析
本申请是申请日为2008年12月19日，申请号为200880127473.0(国际申请号为PCT/US2008/087579)，发明名称为“在声细胞计中的颗粒分析”的发明专利申请的分案申请。
相关申请的交叉参考
本申请要求2007年12月19日提交的美国临时专利申请序号61/008,422、2008年9月11日提交的美国专利申请序号12/283,461和2008年9月11日提交的美国专利申请序号12/283,491的权益，这些专利申请中各自的全部内容均通过引用结合到本文中。
技术领域
以下发明一般涉及颗粒分析领域。本发明也一般涉及细胞计和声学。
背景
早在流式细胞术的发展中就认识到，颗粒的光散射强度的角度相关性包含与颗粒的内在性质和外在性质有关的大量信息。例如，Mullaney等实验证明了约0.5度-约2度的前向光散射用于细胞尺寸估计的用途。在同一时期，也认识到，对于不具有平行于流动方向的轴对称性的颗粒，相对于入射光束的细胞定向可以引入影响群体分辨率和仪器灵敏度的人为结果。Loken等显示，固定的鸡红细胞形式的非球形颗粒产生与圆盘细胞结构的边上(rim-on)或面上(face-on)光照有关的双峰散射分布。也证明了由于出现于精细胞复杂几何形状中的不对称性导致的颗粒定向依赖性散射效应。一些研究者已经提出通过使样品喷嘴成型来定向颗粒的被动解决方案，以将不对称性引入流体动力学鞘系统的速度流场。已经显示，在流式细胞计数分拣中的有效X和Y精子区分中，最关键的方面是在光学散射平面中精子的定向。最近，新的喷嘴几何学已经证明，在分析速率接近2000颗粒/s时，在光学散射平面中高达60％的精子头部的合适定向戏剧性地影响分拣效率。其它研究者已经使用扫描流式细胞计(SFC)，通过在大的散射角排列上收集数据，以较低的颗粒分析速率(约400颗粒/s)为代价，解决了颗粒的不对称性。系统已经显示了跨越70度的连续角散射数据，但该数据是相对于任意颗粒定向而取得的，这对于不对称颗粒而言导致收集的角度谱产生大的变化。
Doblhoff等进行了使用声力(acoustic force)分离生物细胞的最早大规模论证之一。在该系统中，将声辐射压力用于活的杂交瘤细胞的选择性保留，目的是从20升生物反应器中除去不能存活的细胞和较小的细胞碎片。该系统基于多平面转换器设计，并证明了高达99.5％的活细胞保留率，并且细胞碎片排除(rejection)具有不同的结果。早期的系统需要大功率的输入，典型地超过15W，因此需要用于驱动转换器的冷却单元。新近，Feke和合作者开发了依赖声辐射压力和次级声力的新的颗粒分离策略。在声驻波中，将高多孔性聚酯网状物(孔径比粒度大两个数量级)用作收集基质，其中将波节点位置的颗粒捕获于网孔内，且次级声力形成颗粒聚集物，并在网孔表面形成引力。在杂交瘤细胞保留的类似证明中，达到约95％的保留效率，且对细胞存活力的影响可忽略不计。该系统用仅数百毫瓦特(mWatts)的输入功率达到约1.5×108细胞/mL的高细胞密度。
概述
本发明的实施方案包括按声处理(acoustically manipulate)颗粒并停止颗粒流动的设备(apparatus)。该设备优选包含毛细管，该毛细管用于使其中含颗粒的流体流动；按声处理颗粒的产生声信号的转换器，和停止流动的装置(device)。该停止流动的装置优选为泵或一个或多个阀。该实施方案可包含颗粒分拣器、颗粒分级分离器(fractionator)和/或流式细胞计。该实施方案可还包含分析颗粒的分析器和/或成像器。
本发明的一个实施方案包括用于按声处理一种或多种颗粒的方法。该实施方案优选包括使其中含颗粒的流体流动、将声辐射压力施加至流体并按声处理一种或多种颗粒、使流体停止和检查至少一种颗粒。在本发明的该实施方案中，检查至少一种颗粒可以包括分析至少一种颗粒，和/或分拣至少一种颗粒。也可以使颗粒流动通过流式细胞计。
本发明的另一个实施方案包括按声处理颗粒并反转颗粒流动的设备。该设备优选包括用于使其中含颗粒的流体流动的毛细管、按声处理颗粒的产生声信号的转换器和逆流装置。该逆流装置优选包含泵和/或一个或多个阀。该实施方案的设备可还包含用于分析颗粒的分析器和/或成像器。该实施方案的设备可以任选包含分拣器、分级分离器和/或流式细胞计。
本发明的另一个实施方案包括用于按声处理一种或多种颗粒的方法。该实施方案包括使其中含颗粒的流体流动、将声辐射压力施加至流体并按声处理一种或多种颗粒、反转流动方向和检查至少一种在流动中反转的颗粒。在该实施方案中，检查颗粒可以包括分析至少一种颗粒，和/或分拣至少一种颗粒。该实施方案也可以包括使流体流动通过流式细胞计。
本发明的还另一个实施方案包括按声排列并在流动的流中定向颗粒的设备。该设备优选包含用于使其中含颗粒的流体流动的毛细管；按声处理、排列并定向颗粒的产生声信号的转换器和颗粒分析器。该实施方案的设备优选包含流式细胞计、颗粒分级分离器和/或颗粒分拣器，其中分拣器基于尺寸分拣颗粒。该设备可任选包括成像器。该实施方案的产生声信号的转换器优选在关于流动轴的偏振方向(polar direction)上排列颗粒，或在流动方向上排列颗粒。该实施方案的颗粒可以为红细胞、血小板或精子。
本发明的还另一个实施方案包括用于在颗粒分析器的流动的流中按声排列并定向颗粒的方法，该方法包括使颗粒流动通过流动的流，使颗粒经受声辐射压力，在颗粒分析器的流动的流中按声排列颗粒，和在颗粒分析器的流动的流中按声定向颗粒。在该实施方案中，颗粒分析器可为流式细胞计。该方法也可以包括其中颗粒不对称的非轴对称性场。另外，该实施方案任选包括选择颗粒的预定取向，其中该取向在光学散射平面内。该实施方案可以包括基于颗粒不对称性在颗粒的不同类型之间进行区分。该实施方案可还包括产生可重复的颗粒簇定向或分拣颗粒。颗粒的分拣可以包括基于尺寸预分析在线分离颗粒。此外，该实施方案可以在关于流动轴的偏振方向上排列颗粒，或在流动方向上排列颗粒。还另外，该实施方案可以任选包括分级分离颗粒。在该实施方案中，颗粒可为红细胞、血小板或精子。
本发明的一个实施方案包括分析颗粒的设备。该实施方案的设备优选包含用于使其中含颗粒的流体流动的毛细管；产生径向声信号的转换器，其在所述毛细管中按声定向非轴对称性颗粒；将所述颗粒传输通过讯问点的传输装置和颗粒分析器。在该实施方案中，产生径向声信号的转换器优选使颗粒排列在毛细管中，并使颗粒在毛细管中浓缩(concentrate)。产生径向声信号的转换器也可以形成排列颗粒的声场。该实施方案也可以任选包括排列颗粒的流体动力学鞘。该实施方案的设备可还包含成像器。
本发明的另一个实施方案包括用于在颗粒分析器中分析颗粒的方法。该方法优选包括使颗粒在流动的流中流动、将径向声辐射压力施加至流动的流、在流动的流中按声定向非轴对称性颗粒、将颗粒传输通过讯问点和分析颗粒。该实施方案也可以包括用声场或流体动力学集中(focus)在流动的流中排列颗粒。该方法也优选包括在流动的流中浓缩颗粒。
本发明的另一个实施方案包括分析流体中颗粒的设备。该实施方案的设备优选包含用于使其中含颗粒的流体流动的毛细管；产生声信号的转换器，该转换器不管流速在所述毛细管内按声维持颗粒集中；和用于分析颗粒的颗粒分析器。该设备可还包含停止流动的装置和/或逆流装置。该实施方案的设备也优选包含成像器。
本发明的还另一个实施方案包括分析流动的流中的一种或多种颗粒的方法。该实施方案优选包括用镧系元素标记颗粒、使颗粒在流动的流中流动；将声辐射压力施加至流动的流，以不管流速维持颗粒集中；和分析具有镧系元素的颗粒。该实施方案也可以包括使流动的流停止和/或反转。
本发明的还另一个实施方案包含按尺寸分拣颗粒的设备。该设备优选包含用于使其中含颗粒的流体流动的毛细管；和产生径向声信号的转换器，该转换器在所述毛细管中按尺寸按声分拣并分离颗粒。该实施方案可还包括流式细胞计和/或颗粒分析器和/或成像器。该设备也优选包含颗粒分拣器。
本发明的还一个实施方案包括用于按尺寸分拣颗粒的方法。该方法优选包括使颗粒在流动的流中流动、将径向声辐射压力施加至流动的流和按尺寸按声分拣并分离颗粒。该方法也优选包括将已分离的颗粒中的较大颗粒传输进入流式细胞计，并分析较大的颗粒。该实施方案的传输步骤优选将较大的依赖性(dependent)颗粒传输至流动的流的中心轴。该实施方案也优选包括在线分拣。
附图简述
加入说明书并形成说明书一部分的附图举例说明了本发明的一个或多个实施方案，并与文字描述一起用于解释本发明的原理。这些附图仅用于举例说明本发明一个或多个优选的实施方案的目的，不应视为限制本发明。
在附图中：
图1为举例说明线性驱动毛细管的本发明实施方案，其中使颗粒按声集中至毛细管的中心轴；
图2A为按照本发明的一个实施方案，在通过线源(linesource)驱动的圆形毛细管的横截面中，声力势(acoustic force potential)的密度图；
图2B举例说明按照本发明的一个实施方案，诱导的颗粒旋转，以处于稳定的力平衡平面内；
图3为举例说明线性驱动的声分级分离器的本发明实施方案，其中将大颗粒传输至毛细管轴，而较小的颗粒维持不受声场的影响；
图4A和4B举例说明按照本发明的一个实施方案，当声场关闭时，颗粒按随机定向流动通过毛细管，然后当声场激发之后，颗粒排列与毛细管轴一致；
图5A-5C举例说明按照本发明的一个实施方案，约1pm和约10pm的颗粒在线性驱动的毛细管中的选择性分级分离；
图6为举例说明样品输入流式细胞计内的本发明实施方案，其中将样品浓缩，降低其体积，并因此减少在流式细胞计量术应用中的分析时间。
例示性实施方案的详述
当用于本文时，″一″指一个(种)或多个(种)。
当用于本文时，″毛细管″指具有选自以下形状的流动通道或室：矩形、椭圆形、扁圆形、圆形、八角形、七角形、六角形、五角形和三角形。
在本发明的一个实施方案中，声辐射压力优选使颗粒集中至毛细管的中心。该实施方案确保按可以在流动的流中分析或处理单细胞或颗粒的方式，发生根本变化。该样品递送实施方案通过改善样品制备和纯化的分析或预分析或两者，扩展了流式细胞计的分析能力。
在图1中举例说明了声颗粒集中装置的非限制性实施方案。该装置优选包含按声驱动的毛细管10，其中平行于流动方向定向的声颗粒收集器包含线源12和含有颗粒/细胞16的流体18。该实施方案可确保除去与流体动力学集中有关的高速鞘流，并允许延长颗粒在光讯问区的传输时间，同时由于固有的在线颗粒浓缩作用而维持高颗粒分析速率。另外，颗粒流的按声集中提供停止并反转流动方向而不使颗粒流散开的能力，同时维持颗粒记录(registration)。增加的颗粒传输时间提供了使用低功率光源和较低灵敏性光学组件的高灵敏性光学测量机会。流动方向和流速的控制允许高显著性目标的再分析，因此可最小化与系统水平波动有关的散射数据的不确定性。
按声驱动的流动室的附加性质是可在流动的流内形成非轴对称性力场。力不对称性在流动室内定向非球形细胞或颗粒，以便产生一致的散射讯号，该一致的散射讯号用标准流体动力学流动系统通常是不可能的，可通过在光学散射平面内，按预定的取向，定位不对称颗粒而产生。在该实施方案中，与特异性颗粒定向有关的光学散射数据可以例如基于颗粒的不对称性在细菌的不同类型之间进行区分，并改善不规则细胞类型例如RBC细胞和精细胞的分析和分拣。不对称性力场也可产生由多个微球或细胞的聚结而形成的可重复的颗粒簇定向，例如由两个颗粒的凝集形成的“哑铃”形状。由于簇相对于散射平面的唯一诱导的定向，可以通过脉冲形状分析和角形散射判读容易地进行颗粒簇的区分，例如诱导的定向可引起“哑铃”的中心轴平行于流动轴。
本发明的按声线性驱动的毛细管实施方案可产生针对流式细胞计检测系统的颗粒和细胞分析新模式，并可用于在线样品制备的颗粒或细胞分离。声辐射压力的主要优点是它可以用于有高体积通量的相当大的室。声场类似地作用于大多数生物颗粒，因此固有地是非特异性的，因此将大多数生物颗粒传输至相同的空间位置。然而，场的大小是高度尺寸依赖性的，并在需要高通量的应用中，在根据尺寸的颗粒预分析在线分离中，例如在法医分析中在分离精子与阴道细胞(vaginal cell)、分离病毒与细菌或分离完整细胞与细胞碎片中，使声辐射压力成为优异的候选者。在上面的描述中，有圆柱形几何形状的线性驱动的毛细管可用作按声集中装置，但使用声辐射压力定位颗粒的一般几何形状(正方形、矩形、椭圆形、扁圆形等)装置可以用于颗粒分离、碎片排除、颗粒排列和样品纯化的应用中。
声辐射压力
因声辐射压力引起的对颗粒的力取决于刺激的频率、介质内的压力幅值和颗粒与宿主介质之间的密度/压缩率对比。在声驻波内，它是时间平均的漂移力，将颗粒传输至波节或波腹的位置。在声驻波中在球形颗粒上声辐射力势U的表达通过以下给出：
U = 4 3 &pi;a 2 [ ( &beta; 0 < p 2 > 2 ) f 1 - 3 2 ( &rho; 0 < v 2 > 2 ) f 2 ]
此处，α是颗粒半径，β0是周围流体的压缩率，ρ0是周围流体的密度。分别由p和v描述在缺乏颗粒时声场的压力和速度，且括号对应于时间平均的量。术语f1和f2是确定颗粒的力学性质如何与背景介质不同的对比术语。它们通过以下给出：
f 1 = 1 - &beta; p &beta; 0
f 2 = 2 ( &rho; p - &rho; 0 ) ( 2 &rho; p - &rho; 0 )
下标ρ对应于颗粒的内在性质。作用于颗粒上的力F与力势梯度有关，其通过以下给出：
F = - &dtri; U
颗粒优选位于力势U显示为最小值的位置。对于圆形横切面的毛细管，当按偶极型模式驱动时，力势最小值与毛细管的轴一致，形成图1中的颗粒收集器。其它模式存在，且对于选择的应用而言，有利于在除毛细管轴之外的位置中颗粒的空间定位。
声线性驱动的毛细管
因声辐射压力引起的力优选为使颗粒位于类似于流体动力学集中的排列中而不需要鞘流的有效手段。本发明的线性驱动的毛细管可有效替换鞘。具有比线接触大的源孔径的毛细管可以产生相似的结果。该实施方案已证明了具有源孔径的按声驱动的毛细管，该源孔径具有沿跨距大于约45度的毛细管圆周延伸的接触长度。它可由毛细管构成，该毛细管由压电陶瓷源与其外壁接触而驱动。结构的振动沿其中形成轴颗粒收集器的中心轴产生局部压力波节点。在图1中给出了该装置的图。稀悬浮液中的颗粒从顶部进入装置，当它们流动通过系统时经受的径向力将它们传输至压力波节点。在本发明的实施方案中，将包含于样品中的颗粒同时浓缩和排列成单行，然后将它们传输通过讯问激光(interrogation laser)。通过各种传输装置将颗粒传输通过讯问激光，该传输装置包括但不限于泵和/或一个或多个阀。
声颗粒集中的实现优选允许新流式细胞计量术和方法因颗粒在样品细胞内放置方式的基本变化而进行发展。不像常规的流体动力学鞘集中系统那样需要具有不同流速的同心流动的流。可以使按声集中的样品流停止、减缓、反转或其任何组合，而没有降低颗粒流在流动室内的排列。在声场内增加的驻留时间产生其集中实际上改善了的颗粒流。此外，流动可以反转而对流动室内的颗粒排列没有不良影响，允许稀少的目标重复分析或停止，以便扩展分析例如散射/荧光讯号的光谱解析。
本发明的独特流动能力之一可以是选择样品传递速率的能力。通过减慢细胞/颗粒传输时间，该传输时间可比常规系统慢例如约20-100倍，更高灵敏度光学测量和需要更长讯问时间的光子事件例如发光的测量是可能的。
在驻声波场中的颗粒定向
当颗粒通过讯问区时已知的颗粒定向确保散光测量或荧光测量或两者，提供细胞结构和内在光学性质的显著了解。通过将它们校准至细胞/颗粒的特定取向来增加目前的散光测量值和允许合理地考虑新的散射角作为测量参数，证明几个旋转自由度的去除是流式细胞计量术的无价之工具。本发明的声线性驱动的毛细管和将声辐射压力引导入流动细胞内的其它方法，是在流动方向和关于流动轴的偏振方向上旋转和排列颗粒以产生用于非球形颗粒的角形校准散射数据的有效手段。按声驱动的管中的颗粒经受的力通常为在流动平面的横切面内非轴对称性的。对于集中至管轴的颗粒，声力分布性质上是偶极的，在平面内产生力反射对称。图2(a)中显示以偶极型模式作为该方法的一个实例计算线性驱动的管中的颗粒的声力势U，其中声力Fu可以通过以下方程得到：
F = - &dtri; U
其中流动方向为穿入页面(into the page)。面内力势具有关于贯穿中心轴的两个平面的反射对称。对称的第一平面贯穿中心轴20和线性驱动22，而对称的第二平面与第一平面垂直。虽然在显示的二维声力势内存在两个对称平面，但是相对于颗粒旋转，只有一个导致稳定平衡24部位。所有的规则颗粒在流场内的小扰动下快速旋转进入稳定平衡24，如图2(b)所示。
将第三维结合入力场计算(轴成分)产生由声力场诱导的颗粒旋转自由度的附加限制。计算显示杆状颗粒(有两个相等的短轴和一个长轴的颗粒)的长轴通常与毛细管的轴对齐。两侧对称的颗粒例如红细胞，通常排列一个长轴平行于流动轴，而其它长轴平行于稳定的对称平面，由图2(a)中的白色虚线所示。
细胞和细胞碎片的声分离
对于按照本发明的一个实施方案发生在按声驱动室内的颗粒传输，声力必须足够大，以克服颗粒在悬浮介质内的布朗运动。颗粒经受的声辐射压力的大小与颗粒体积、声场的驱动水平、介质和颗粒的力学性质和声场的空间梯度直接成比例。因为该原因，(由于颗粒半径的三次方关系)较大的颗粒可以在比较小的颗粒更低的压力幅值和激发频率(更小的梯度)下，在声场中传输。这对于在其力学性质方面相对于背景介质具有较大相对差异的颗粒，通常也是真实的。
本发明声分离系统的一个实施方案的一个方面是它可以无阻塞(无过滤器)操作，并且跨越单元的压力降几乎为零。由于在声辐射力和热颗粒运动中固有的尺寸依赖性，本发明的实施方案可以基于粒度和力学对照在流动的流的前端分离样品。为了选择性地收集留下的未受影响的背景碎片，声力通过在特定的位置浓缩目的分析物而用于纯化样品。该系统通过大大地减少颗粒计数和提高数据质量，在流式细胞计上，用高颗粒背景，减少样品分析时间。例如，Bossuyt显示，在通过所选择溶解方法制备的全血样品内的细胞碎片可以产生在流式细胞计上的CD45细胞计数中说明最高达所有事件的80％的散射事件。Macey指出，由于存在残留的细胞碎片，用于制备用于流式细胞计量分析的淋巴细胞的某些全血溶解方法可以导致差的前向散射和侧散射分别率。在本发明的一个实施方案中，在线纯化装置例如线性驱动的毛细管恰好位于如图3所示的流式细胞计的样品入口之前，用于将目的大颗粒30(其可为例如淋巴细胞)传输至样品流的中心轴32，同时较小的颗粒34例如包含于溶胞产物内的细胞碎片和蛋白质维持不受影响。对于有比目的颗粒更少的力学对照的细胞碎片，这尤其是真实的。然后将样品流的中心核进料至流式细胞计内，并丢弃剩余的溶胞产物，消除样品的大颗粒浓缩。应该指出，该样品制备方法可以用作任何类型颗粒/细胞分析的样品纯化步骤，其中背景颗粒计数的减少是有利的。
在驻声波场中的颗粒定向
实施例1：
为了证明声场对诱导决定性的颗粒定向的作用，用线性驱动的毛细管，使用长宽比大于整体(unity)的颗粒进行实验。在一个实施例中，毛细管由玻璃制备并具有约500μm的内径和约1000μm的外径。声源附接至毛细管的外表面，与毛细管的轴平行，并在约1.78MHz和约10Vpp下操作。用注射泵将圆柱形碳纤维在去离子水中的悬浮液沿着管传输。然后通过显微镜将颗粒成像。纤维具有约8μm的短轴尺寸，并具有不同的更大长轴尺寸。
图4A举例说明了样品从左至右流动通过毛细管。当不存在声场时，看到随机取向的纤维，因为它们被夹带于流体中并传输通过系统。在毛细管的声刺激之后，纤维被传输和旋转至一致的排列，并与毛细管的轴平行，见图4B所示。这里显示的排列是由于声辐射压力使颗粒的长轴沿毛细管的轴排列。
用于在线样品纯化和分离/浓缩的基于场的粒度选择
通过在按声驱动的毛细管中改变声源的驱动电压和/或激发频率，可以达到根据尺寸的颗粒两次分级分离。该作用是由于声力对颗粒半径的三次方相关性，由较小的颗粒感受到的减少声力的结果。在应用中，将包含于毛细管中心核内的较大颗粒进料至较小的、同轴毛细管内，将含同心流场的小颗粒丢弃。可以取得纯化的样品，用于进一步的样品制备步骤，或实时进料至流式细胞计或其它分析工具内。根据应用，也可认为中心核外面的流体是有价值的样品，将其收集并用于分析。
实施例2：
图5A-5C举例说明了来自初步实验的结果证明尺寸选择能力为驱动水平的函数。在该实施例中，使按声驱动的毛细管在约1.78MHz下振荡。将含约1μm直径的荧光球和约10μm直径的无荧光的球的胶乳微球悬浮液泵送通过驱动的毛细管。颗粒的体积分数为约2.5x 10-5。毛细管由约500μm的内径和约1000μm的外径来限定。
图5A是通过荧光显微镜取得的照片，其中作为大的圆形内含物观察到约10μm颗粒，作为颗粒状背景观察到约1μm颗粒。来自约1μm颗粒的荧光信号太低而在实验的操作条件下观察不到。在约7Vpp(图5B)的低声驱动水平下，约10μm颗粒快速传输至毛细管的轴。约1μm颗粒维持随机分布。将驱动电压加倍至约16Vpp导致两种尺寸的颗粒有效传输至毛细管的中心轴，见图5C所示。沿圆柱体轴的亮线是由于大的、局部的荧光增强的结果，该荧光增强是由于约1μm荧光颗粒在那个部位的浓缩。
在按声集中的流动室中，声集中/定向例如反射对称对光散射参数的影响
本发明的实施方案解决了与由于声辐射压力而在光学散射平面排列的颗粒有关的角形散射。在流动细胞中用按声驱动的颗粒排列替代流体动力学鞘流优选导致改善的光散射数据并产生取决于颗粒的几何形状和取向的新参数。在流式细胞计量分析中，除不对称性生物颗粒例如RBC细胞、精细胞和细菌的颗粒取向的重要性之外，由多个微球或细胞聚结形成的复杂几何形状，例如由两个颗粒的凝集形成的′哑呤′形也有利于颗粒定向。颗粒簇优选通过使其定向固定于散射平面内来更容易的区分。定向微球′双联体′以因它们如何通过散射平面而产生可重复的和独特的散射讯号，将提供一种方法来通过利用用于接触球的逆散射问题的解决方案隔离其在光散射数据中的贡献，用于数据舍弃或数据接受。按声定向的颗粒在流动的流中的应用也可适用于成像的场，其中检查颗粒的所选择取向在测定细胞形态学、细胞成分的定位或其它颗粒/细胞特征中是有价值的。
在按声集中的流动室中，在减慢流动、停止流动和反转流动条件下提高检测能力
本发明的另一个实施方案还解决了因用声颗粒排列替代鞘流引起的在流式细胞计量检测中减慢流动、停止流动、反转流动和增加分析时间的影响。在第一种情况下，停止和反转样品流的流动方向的能力允许颗粒的再分析。使用各种停止流动的装置和逆流装置包括但不限于泵或一个或多个阀，使流动停止和/或反转。峰扩散(增加的CV的)和在分析平面中为离群值的数据点是系统依赖性的量，该系统依赖性的量是激光稳定性、颗粒排列的质量、电子噪声、检测器噪声、测定的稳定性(开/关速率等)等的函数。通过明显多于一次分析颗粒，可以改善数据质量，尤其是在瞬时性人为结果的情况，且可以在稀有事件分析中使统计不确定性最小化。
用于在线样品纯化和颗粒分离的基于声场的粒度选择
虽然通过在检测系统中替换鞘流而使声集中可用于颗粒或细胞分析，但是本发明的还另一个实施方案扩展声力在按声驱动的毛细管中的应用，以在流式细胞计量系统或一般的样品制备和纯化中用于逆流、在线样品调理的颗粒和/或细胞分离。图6举例说明了利用本发明，在分析阶段之前，在流式细胞计的入口处，通过相对于背景介质的粒度和/或力学对比，实时按声、按尺寸分级分离并浓缩样品。基于粒度/力学性质的直接分级分离减轻了对有劳动强度的样品制备步骤包括离心和过滤的需要。对于流式细胞计量应用，在全血测定中，尤其在包括细胞溶解的无洗涤(nowash)测定中，这可用于减少与细胞碎片、蛋白质和其它分子成分有关的背景。在样品递送至流式细胞计之前的样品制备包括细胞碎片排除步骤，可以大大地减少与碎片的散射/荧光有关的人为结果。
虽然已经具体参考这些优选的实施方案详细地描述了本发明，但是其它实施方案可以获得相同的结果。本发明的变化和修改对本领域的技术人员来讲将是显而易见的，且将包括所有此类修改和等同实施方案。在上面和/或在附件中引用的所有参考文献、申请、专利和出版物以及相应申请的全部内容均通过引用结合到本文中。

Claims (36)

1.一种用于按声处理一种或多种颗粒的方法，所述方法包括：
使流体流动，所述流体中含有一种或多种颗粒；
将声辐射压力导引至所述流体，并按声处理所述一种或多种颗粒；
使所述流体停止；和
检查至少一种所述颗粒。
2.权利要求1的方法，其中检查包括分析至少一种所述颗粒。
3.权利要求1的方法，其中检查包括分拣至少一种所述颗粒。
4.权利要求1的方法，所述方法还包括使所述流体流动通过流式细胞计。
5.一种用于按声处理一种或多种颗粒的方法，所述方法包括：
使流体流动，所述流体中含有一种或多种颗粒；
将声辐射压力导引至所述流体，并按声处理所述一种或多种颗粒；
使所述流体的流动方向反转；和
检查至少一种在流动中反转的颗粒。
6.权利要求5的方法，其中检查包括分析至少一种所述颗粒。
7.权利要求5的方法，其中检查包括分拣至少一种所述颗粒。
8.权利要求5的方法，所述方法包括使所述流体流动通过流式细胞计。
9.一种用于在颗粒分析器的流动的流中按声定向颗粒的方法，所述方法包括：
通过流动的流使颗粒流动；
将声辐射压力导引至所述颗粒；和
在颗粒分析器的流动的流中按声定向所述颗粒。
10.权利要求9的方法，其中所述颗粒分析器是流式细胞计。
11.权利要求9的方法，其中所述声辐射压力不对称。
12.权利要求9的方法，其中所述颗粒不对称。
13.权利要求9的方法，所述方法还包括选择所述颗粒的预定取向。
14.权利要求13的方法，其中所述取向在光学散射平面内。
15.权利要求9的方法，所述方法还包括基于颗粒的不对称性来在颗粒的不同类型之间进行区分。
16.权利要求9的方法，所述方法还包括产生颗粒簇的可重复取向。
17.权利要求9的方法，所述方法还包括分拣所述颗粒。
18.权利要求17的方法，其中所述分拣包括基于尺寸的颗粒的分析前在线分离。
19.权利要求9的方法，所述方法包括使所述颗粒排列在关于流动轴的偏振方向上。
20.权利要求9的方法，所述方法包括使所述颗粒排列在流动方向上。
21.权利要求9的方法，所述方法还包括分级分离所述颗粒。
22.权利要求9的方法，其中所述颗粒是红细胞或血小板。
23.权利要求9的方法，其中所述颗粒是精子。
24.一种用于在颗粒分析器内分析颗粒的方法，所述方法包括：
使一种或多种颗粒在流动的流中流动；
将径向声辐射压力导引至所述流动的流；
在所述流动的流中按声定向不对称颗粒；
使各颗粒传输通过讯问点；和
分析各颗粒。
25.权利要求24的方法，所述方法还包括使所述颗粒排列在所述流动的流中。
26.权利要求25的方法，其中排列是用声场。
27.权利要求25的方法，其中排列是用流体动力学集中。
28.权利要求24的方法，所述方法还包括使所述颗粒在所述流动的流中浓缩。
29.一种分析流动的流中的一种或多种颗粒的方法，所述方法包括：
用镧系元素标记一种或多种颗粒；
使所述颗粒在流动的流中流动；
将径向声辐射压力导引至所述流动的流，以使所述颗粒沿流动的流的方向排列；和
分析至少一部分所述用镧系元素标记的颗粒。
30.权利要求29的方法，所述方法还包括使所述流动的流停止。
31.权利要求29的方法，所述方法还包括使所述流动的流反转。
32.一种用于根据尺寸分离颗粒的方法，所述方法包括：
使颗粒在流动的流中流动；
将径向声辐射压力导引至所述流动的流；和
根据尺寸按声分离所述颗粒。
33.权利要求32的方法，所述方法还包括将所分离颗粒中的较大颗粒传输进入流式细胞计内。
34.权利要求33的方法，所述方法还包括分析所述较大的颗粒。
35.权利要求33的方法，其中所述传输步骤将所述较大的颗粒传输至所述流动的流的中心轴。
36.权利要求32的方法，所述方法还包括在线分离所述颗粒。
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