CN1685226A - 高分辨率流式细胞仪 - Google Patents
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Abstract
一种高分辨率的颗粒区分处理和分离系统，该系统根据所选颗粒的特征提供增强的颗粒分辨率。具体地说，本系统可包括分辨率增强的流式细胞仪。在一个实施方案中，本发明可包括至少一个流体源导管(24)，其可将流体源流(24)以一定角度导入分辨率增强的喷嘴(25)中，所述角度可通过细胞传感系统(13)使颗粒的分辨率增强。
Description
技术领域
本发明涉及根据颗粒的特征高分辨率地区分和分离颗粒。具体地说，本发明涉及高分辨率地将精子区分和分离成含X染色体的类群和含Y染色体的类群，或提高其同质性。
背景技术
随着安全、可靠地将精子分离成富含X染色体的类群和富含Y染色体的类群的方法的发展，已经在许多种哺乳动物中有效地实现了性别预选。按照本文及以下各国际专利申请公开，可以将含X染色体的精子与含Y染色体的精子分离开来，所述国际专利申请公开有例如WO98/34094、WO 99/33956、WO 99/42810、WO 00/06193、WO 01/40765、WO 01/85913、WO 02/43486、WO 02/43574，在此将其以参考的方式引入本文。
现在参考图1和图2，常规的流式细胞计数仪技术提供了颗粒或细胞源(1)，其用于安置或供应颗粒或细胞(16)(其可以是精子或精细胞，精子头部，常见的血细胞如白细胞、淋巴细胞、单核细胞、中性粒细胞、嗜碱性粒细胞、巨噬细胞、红细胞、血小板，或是罕见的细胞类型如母体血液循环中的胎儿细胞、带有病毒的细胞、癌细胞等，以及细胞的一部分如细胞器、线粒体、单个染色体，以及可结合有生物学组分的人造颗粒如小珠、微球或纳米球)，可以用至少一种荧光染料对这些颗粒或细胞进行染色以用于分析。通过将颗粒或细胞(16)导入液流或鞘液(3)中而将颗粒或细胞(16)导入喷嘴(2)中。液流(3)通常由某个流体源(4)供应，由此当颗粒或细胞源(1)将颗粒或细胞(16)供入液流(3)时，它们一起流经喷嘴(2)。
在此方式中，液流(3)构成了颗粒或细胞(16)的流体环境。由于以一定压力将各种流体供给流式细胞仪，所以它们于喷嘴开口(5)处排出喷嘴(2)。通过提供某种可由振荡控制器(7)高度精确调控的振荡器(6)，可在喷嘴(2)内形成压力波并传递给于喷嘴开口(5)处排出喷嘴(2)的液流(3)。由于振荡器(6)作用于鞘液(3)，于喷嘴开口(5)下形成的液流(8)最终有规律地形成液滴(9)。由于颗粒或细胞(16)为形成于喷嘴开口之下的液流(8)所包围，所以液滴(9)中可夹带有各自分开的颗粒或细胞(16)。
由于液滴(9)可以夹带单个的颗粒或细胞(16)，所以可采用流式细胞仪根据颗粒或细胞的特征分离这些颗粒或细胞(16)。这通过使用颗粒或细胞传感系统(10)来实现。该颗粒或细胞传感系统至少包括某种检测器或传感器(11)，其对包含于液流(8)中的颗粒或细胞(16)产生响应。颗粒或细胞传感系统(10)可以基于某一特征的相对存在或相对缺失而产生反应，所述特征有例如与颗粒或细胞或它们的组分相结合的荧光染料，所述组分如DNA、脂类线粒体或细胞内的细胞器，所述荧光染料可以被产生照射光束的照射源如激光(12)所激发，颗粒或细胞(16)可对所产生的照射光束产生响应。
尽管每一种颗粒、细胞或它们的组分可用至少一种类型的荧光染料染色，但是根据所用特定类型荧光染料的可用结合位点的数量，与各单个颗粒或细胞(16)结合的荧光染料量是不同的。仅举一例子来说，对于精子来说，Hoechst 33342染料结合位点的可利用率取决于各精子内所含的DNA量。由于含X染色体的精子的DNA含量比含Y染色体的精子的DNA含量要高，因此，一种哺乳动物的含X染色体精子可比同种哺乳动物的相应含Y染色体精子结合更多量的荧光染料。因此，测量所结合荧光染料在激发后所发射的荧光就能将含X染色体精子和含Y染色体精子区分开来。
为了根据颗粒或细胞的特征实现分开或分离，发射光可由传感器(11)接收并反馈到与液滴充电器相连的某种分离辨别系统(13)，所述充电器可根据液滴(9)内所含颗粒或细胞(16)的特征使各液滴(9)带上不同的电荷。通过这种方式，根据液滴(9)是否含有适当的颗粒或细胞(16)，分离辨别系统(13)使静电偏转板(14)将所述液滴(9)偏转。
结果，流式细胞仪通过将液滴(9)导向一个或一个以上的收集容器(15)中而使其中夹带的单个颗粒或细胞(16)得以分离。例如，当分离辨别系统(13)根据含X染色体精子和含Y染色体精子的相对DNA含量不同而区别精子时，可使夹带含X染色体精子的液滴带上正电荷并由此偏转到一个方向，而使夹带含Y染色体精子的液滴带上负电荷并由此偏转到另一个方向，可使废液流(其为未夹带颗粒或细胞(16)或夹带有不需要或不能分选的细胞的液滴)不带电荷，从而以未偏转的液流加以收集。用一些常规流式细胞仪可以同时确定各种偏转轨迹并进行收集。
尽管在过去几年中，用于细胞或颗粒分离的常规流式细胞仪得以改进，但是对于常规流式细胞仪的分辨能力来说仍存在显著的问题。
图1所示常规流式细胞仪的一个显著问题在于，流体源(4)和相关的流体源导管(23)将流体(3)以基本上与喷嘴(2)内的流体(3)流动相垂直的方向导入喷嘴(2)中。这两个流动方向可以使喷嘴(2)内层流的形成扰乱、变形或迟滞。特别是当定位、取向及颗粒间的分布对于单个颗粒或细胞(16)的精确分析来说很关键，以及要求单个液滴(9)正确夹带单个颗粒或细胞(16)时，那些相对于液流分子来说较大的颗粒或细胞(16)受可能产生涡流的流体运动的影响非常大，因此维持层流是很重要的一个方面，而这一点在常规流式细胞仪的设计中被忽视了。同样值得注意的是，振荡器(6)的主要功能是提供压力波以形成单个的液滴(9)，该振荡器(6)还会在喷嘴(2)内产生压力驻波，压力驻波会影响层流的特征，尤其是喷嘴设计不恰当时可导致谐波分散，如压力搏动或子振荡。
图1所示常规流式细胞仪的另一个显著问题是，细胞源(1)和喷嘴(2)之间的细胞源导管(17)不是直的。细胞源导管(17)中的显著弯曲可使流体压力随细胞源导管的弯曲而发生变化，或可产生在横截面上流速完全不同的液流。这一问题可因细胞或碎片在细胞源导管(17)的弯曲处聚集而加剧。
图1所示常规流式细胞仪的第三个显著问题是细胞源导管(17)太长。常规流式细胞仪的细胞源导管(17)从细胞源(1)到颗粒或细胞注射入液流的位点(18)的长度可超过4英寸。常规长度的细胞源导管(17)可使细胞在细胞源导管中沉积或聚积，或是流经细胞源导管时使涡流增加，从而使细胞群的表观分辨率下降。
图1所示常规流式细胞仪的第四个显著问题是，细胞源导管(17)尤其是细胞源导管的颗粒注射器(19)部分不能单独地替换。这样，细胞源导管(17)或颗粒注射器(19)部分发生障碍或性能不佳时，必须得替换掉整个喷嘴(2)和细胞源导管(17)及流式细胞仪的其他与喷嘴(2)不可分离地连接在一起的组件。
常规流式细胞仪的第五个显著问题是，可能有一个连接器(20)接到细胞源导管(17)的颗粒注射器(19)部分的入口末端，以将注射器部分(19)和细胞源导管(17)连接起来。即使零死体积的连接器或接头也可使细胞源导管内表面产生变形或不同心度，从而足以使颗粒或碎片粘附、附着、贴着或以其他方式固定于连接器(20)的位置，导致在细胞源液流中传输的样品群间可能发生交叉污染，或导致细胞源流体通路受到阻滞或其结构发生改变。
常规流式细胞仪的第六个显著问题是，细胞源导管(17)的内表面或细胞源导管(17)的注射器(19)部分的内表面粗糙或不平整，足以使细胞或颗粒混合群的表观分辨率下降。此问题的一个方面是，所述使表面粗糙或不平整的表面部分有时可从细胞源导管的内表面脱落下来并可停留在流动通道内。有时，可以导致细胞源导管(17)受到阻滞或造成堵塞。此问题的另一方面是，颗粒与细胞源导管的粗糙或不平整部分相互作用，使液流的速度不均衡，从而引起使细胞群的表观分辨率下降的偏转力或涡流。
常规流式细胞仪的第七个显著问题是喷嘴(2)的横截面积太大。喷嘴(2)的横截面积越大，则泡沫或碎片或颗粒(16)可在其上面粘附的面积以及与喷嘴装置内流体动态相互干扰的面积越大，而且稳定于喷嘴(2)内的压力驻波和次谐压力波也越复杂。
常规流式细胞仪的第八个显著问题是，喷嘴(2)的主体包括第一喷嘴体元件(21)和第二喷嘴体元件(22)。这样就会使喷嘴内表面发生的变形或粗糙，从而足以使液流的层流受到干扰或消失，使得常规流式细胞仪的分辨能力下降；或者如果第一喷嘴体元件(21)和第二喷嘴体元件(22)的两种制造材料具有不同的弹性，则它们可以从振荡器(6)各自传递不同次谐波特征的压力波，这样会使颗粒流动通路的临界区域的层流在即将喷出喷嘴(2)之前在出口(5)处发生变形。
常规流式细胞仪的第九个显著问题是，难以精确测量颗粒或细胞内的DNA，所述颗粒或细胞如哺乳动物活精子，该哺乳动物活精子因DNA含量上的已知差异，其结合的荧光染料的量也不同，但是变异系数也很大，这使得测量结果不明显。例如，如Johnson等，《Theriogenology(动物生殖学)》，Vol.52，No.8：1326(1999)所揭示的，与Y染色体大小对活精子总DNA的影响相比，X染色体大小对活精子总DNA的影响由具体哺乳动物中X染色体和Y染色体的大小差别以及DNA的真正含量(所有其他染色体的数目和大小)所决定。具体来说，(X-Y)/X在人类中为2.8％，兔为3.0％，公猪(猪)为3.6％，公马(马)为3.7％，公牛(牛)为3.8％，狗为3.9％，公羊(羊)为4.2％，栗鼠高达7.5％。但是Welch等揭示，用常规方法分析精子，差异系数(CV)在0.9％时相当好，甚至可以高达1.97％(Welch等，《Theriogenology(动物生殖学)》，Vol.52，No.8：1348(1999))。因此，尤其是对于诸如(X-Y)/X数值为2.8％这样非常低的人类等物种来说，使CV降到小于1％非常关键，如果可能的话优选使之尽可能接近零。本发明说明书中所用的分辨率的定义指，根据从各单个精子所得的测量值与一已知值的接近程度，某装置将精子分辨成两个精子群的能力，其主要的负面决定性因素为所分析群体的高CV。
本发明解决了常规流式细胞仪装置在以下方面的分辨率低的各种问题：根据颗粒特征，将流动可分离的颗粒或细胞(16)、细胞尤其是精子分离成富集群，或者对于精子而言，将其分离成富含X染色体精子群及富含Y染色体精子群。
发明内容
因此，本发明的主要目的是提供分辨率得以提高的流式细胞仪，该流式细胞仪可以使所分离的群体的同质性得以提高，所述群体根据一种或一种以上的颗粒性质进行分离。
本发明此目的的第一方面是将来自流体源(4)的流体导入喷嘴(2)中，所述的导入方式使喷嘴(2)内液流(3)的层流的形成减少了扰乱、湍动、变形或迟滞，或是利用核心流来形成层流，所述核心流含有于注射位点(18)处导入喷嘴的颗粒或细胞(16)。
本发明此目的第二方面是在细胞源(1)和注射位点之间提供细胞源液流，该液流相对于细胞源导管(17)内细胞源液流的截面保持面积速度基本不变，或是基本消除了由于细胞源中的弧度、变形或弯曲而带来的细胞源液流速度的变化，或减少了细胞源导管(17)内的障碍、阻塞或颗粒聚积或集中的区域。
本发明此目的第三方面是提供可调节的细胞源液流结构，对于特定种类的颗粒或特定类型的颗粒差别特性来说，对于从细胞源(1)到注射位点(18)的颗粒(16)的流体，所述细胞源液流结构提供了一致的细胞源液流流量。
本发明此目的第四方面是提供可调节的同轴液流，对于特定种类颗粒或特定类型的颗粒差别特性来说，所述同轴液流提供了一致性更高的核心流，该核心流含有在喷嘴开口(5)下所形成的液流(8)中的颗粒(16)。
本发明此目的第五方面是提供可替换的细胞源导管(28)的颗粒注射器部分(31)。
本发明此目的第六方面是除去接在细胞源导管(17)的注射器部分(19)入口末端的连接器(20)。
本发明此目的第七方面是消除或显著减少细胞源导管(17)内壁的粗糙或不平整。
本发明此目的第八方面是提供连续而完整的整体喷嘴，从而实质上消除或减少喷嘴内部圆形横截面的不同心度，或实质上消除或减少喷嘴内表面的变形。
本发明另一重要目的是提供可在整个流式分选过程中维持哺乳动物精子更大存活力的精子分离装置或方法。
本发明的其他重要目的在下面的发明描述和附图中自然得以明确。
附图说明
图1为常规流式细胞仪的示意图。
图2为常规流式细胞仪的示意图。
图3为本发明中分辨率增强的流式细胞仪的一个具体实施方案。
图4对常规流式细胞仪的喷嘴装置(图4a)和常规流式细胞仪的注射器部分(图4b)与本发明中分辨率增强的流式细胞仪中相应的喷嘴装置(图4c)和本发明中分辨率增强的流式细胞仪中分辨率增强的注射器部分(图4d)进行比较。
图5对利用常规流式细胞仪处理牛精子核样品所得的分辨率(图5a)和利用本发明中分辨率增强的流式细胞仪处理同样的牛精子核样品所得的分辨率(图5b)进行比较，两者速率均为每秒25,000次事件。
图6对用常规流式细胞仪以每秒50,000次事件的速率处理牛精子核样品所得的分辨率(图6a)和用本发明中分辨率增强的流式细胞仪以每秒60,000次事件的速率处理同样的牛精子核样品所得的分辨率(图6b)进行比较。
图7对用常规流式细胞仪以每秒100,000次事件的速率处理牛精子核样品所得的分辨率(图7a)和用本发明中分辨率增强的流式细胞仪以每秒110,000次事件的速率处理同样的牛精子核样品所得的分辨率(图7b)进行比较。
图8为本发明的颗粒注射器的一个具体实施方案。
图9为本发明的内部喷嘴体的一个具体实施方案。
图10为本发明的外部喷嘴体的一个具体实施方案。
图11为图10所示本发明的外部喷嘴体具体实施方案的截面B-B。
具体实施方式
本发明涉及一种高分辨率的流式细胞仪，在根据各种细胞或颗粒的个别特性或其组合来将混合的细胞群、精子群或颗粒群相互分离的时候，该流式细胞仪可增强分辨能力。
同样，尽管本发明提供了分离精子或分离牛或马的完整活精子的具体实施例，但是应理解，所述分辨率得以增强的技术可以应用于各种类型的流动可分离颗粒的分离，所述流动可分离颗粒包括但不限于以各种方式收集、处理或储存的细胞、精子或精子核。
还应当理解，含X染色体的精子群和含Y染色体的精子群包括由精子经流式分离或分选所得的富含群体，所述精子得自哺乳动物的雄性个体，这些哺乳动物包括但不限于人类；其他哺乳动物有例如牛科、马科、鹿科、ovids、犬科、猫科、羊、猪或骆驼；海洋动物如鲸目动物(各种鲸或海豚)；尤其包括濒临灭绝的哺乳动物；和以下种属的特定个体：动物学样本、稀有或珍贵样本以及提供动物养殖、兽群管理系统、人工授精方案、低温储存中所用精子的哺乳动物样本；或是例如由Wilson，D.E.和Reeder，D.M.，《Mammal Species of the World(世界哺乳动物物种)》，Smithsonian InstitutionPress，(1993)所列的哺乳动物，在此将其以参考的方式引入本文。
列出此动物清单是为了示例可以获得精子的从大量不同的哺乳动物，或其精子可用本文所述的分辨率得以增强的流式细胞仪的发明进行流式分选的大量不同的哺乳动物，而不是将所述分辨率得以增强的流式细胞仪的发明局限于分析或流式分离任一特定的颗粒或来自特定类型哺乳动物或单个哺乳动物的精子。
用本文所述分辨率得以增强的流式细胞仪的发明所获得的细胞、精子或颗粒可以应用于包括但不限于人工授精方案的各种用途或产品中；或作为商用方法的一部分，所述的商用方法有例如专利合作条约申请PCT/US01/18879或PCT/US99/17165所述的方法；或在专利合作条约申请PCT/US98/27909所述低剂量授精方案中使用；或用于如专利合作条约申请PCT/US01/45237所述包括人类在内的动物的卵母细胞体外受精，在此将上述所提及的各申请或文献以参考的方式引入本文。
术语“纯度”应理解为具有特定差别特征或所需特征组合的被分离精子群的百分数。例如，当精子群根据含X染色体而不含Y染色体进行分离时，纯度为90％的含X染色体精子群包括其中有90％的精子个体含有X染色体的精子群，而该精子群中的10％有可能含有Y染色体。同样，就根据本发明而产生的含X染色体精子群或含Y染色体精子群的纯度来说，可以具有比常规流式分离装置更高的纯度，或可具有以下纯度：约70％～99％，或者可选自90％～约100％、约91％～约100％、约92％～约100％、约93％～约100％、约94％～约100％、约95％～约100％、约96％～约100％、约97％～约100％、约98％～约100％、约99％～约100％。
重要的是，尽管本说明书包括本发明的大量实施方案，其中一些可包括分离的含X染色体和含Y染色体的精子群，而且尽管本说明书还进一步公开了分辨率增强的精子分离装置或方法如何增强混合精子群的分辨率的具体方面，但应当理解，本发明的基本思想可应用于具有类似或不同颗粒差别特征或事件差别特征的其他类型的颗粒或事件。应理解本发明可应用于各种情况，包括分辨光生信号的微小差别的能力需要增强的情况。
另外，尽管本公开内容描述了将含X染色体的精子与含Y染色体的精子进行流式分离的装置和方法的实施方案，但对本发明这些实施方案的描述并不意味着将本发明的范围缩小到仅限于精子的流式分离，或仅限于分辨率高的或分辨率增强的流式细胞仪精子分离系统，而是指这些实施方案是以可行的方式示例性说明本发明的基本思想，以便其可应用于多种颗粒或用途中。
现主要参见图3，本发明可包括至少一个流体源导管(23)，该流体源导管将流体源流(24)相对于喷嘴(25)内流动的液流(26)成一定角度导入分辨率增强的喷嘴(25)，该喷嘴(25)通过细胞传感系统(13)来增强颗粒的分辨率。导入的角度可根据所要区分的颗粒群类型的不同而不同。就本发明的一些实施方案来说，流体源导管(23)可以将流体源流(24)以与分辨率增强的喷嘴(25)的中心纵轴成约0度～约45度的角度导入。对于本发明的一些实施方案来说，多个流体源导管(23)可以将多个流体源流(24)导入分辨率增强的喷嘴(25)。
还是主要参见图3，本发明还可包括在细胞源导管(28)内速度对称的细胞源液流(27)。速度对称的细胞源液流提供了具有以下速度的细胞源液流(27)，该速度在穿过细胞源液流(27)的垂直截面上基本达到对称，这种对称可包括与接近或处于细胞源导管(28)内表面处的速度下降相关的预期的对称，而且避免或减少穿过细胞源液流(27)垂直截面的速度不对称。为了形成细胞源液流(27)的速度对称，本发明的某些实施方案可使用一种基本为直线的细胞源导管(28)。直线细胞源导管(28)给细胞源液流(27)提供了一条基本上没有弧度、弯曲或回折的直线形流动通路，或者比常规技术更为笔直的流动通路，而细胞源液流(27)流过这种具有弧度、弯曲或回折的流动通路时，会使细胞源液流(27)的一部分速度下降或一部分速度升高。同样，与常规技术相比，速度对称的细胞源液流(27)给下列如图1所示常规类型细胞源液流(29)所带来的问题提供了解决方案。
现主要参见图1所示的常规技术，当液流速度不对称时，导入细胞液源液流(29)的细胞可分别以不同的速率穿行，由细胞源(1)进入常规细胞源液流(27)的颗粒的起始分布受到影响，导致注射位点(18)处存在的细胞分布显著不同，从而可影响颗粒群的表观分辨率。
对于常规技术的具体问题，细胞源导管(17)可能有例如90°的弯曲，迫使常规细胞源液流(29)对小半径的弧度或弯曲发生响应。在这些回折处，在细胞源液流(29)的整个截面区域或其中一部分，细胞源液流(29)的速度可能突然下降。在小内径的弯曲处细胞源流(29)的速度下降，对于邻近较大外径的液流的速度下降而言，其下降将显著减少。在一些情况下这会造成颗粒在细胞源导管(17)内的弧度或弯曲处堆积或聚积，从而进一步加剧细胞源液流(29)内的不对称，并进一步干扰注射位点(18)处的颗粒递送分布。有时侯，这些颗粒可以使细胞源液流(29)的流动部分或完全中断，导致流式分离过程完全失败。
本发明的一些实施方案可以单独包括或与本发明其他方面一起包括一个在细胞源液流(27)和细胞源导管(28)内部之间的低阻力界面。对于诸如塑料或金属等材料，所述低阻力界面可以包括抛光的或使之变光滑的细胞源导管(28)的内表面。可以将内表面抛光或使之变光滑，直到所观察到的分辨率增量提高到最大值或所需的值。此外，可通过替换用于制造细胞源导管(28)的材料来实现所述界面的低阻力或变形。例如，玻璃管或Telfon管可取代金属或其他类型的塑料管。还可通过对细胞源导管(28)的内表面进行化学处理来获得低阻力细胞源导管(28)。在本发明的这些实施方案中，塑料或玻璃材料可以例如硅烷化，而金属可进一步用酸洗液来使之钝化。
还是主要参见图3，本发明的实施方案可包括具有可调节的同轴液流特性的细胞源液流(27)。由于颗粒的分辨率可依赖于诸如以下操作参数所产生的液流特征：温度、液流速度、液流压力、液流在其中流动的导管的构造、液流中的颗粒的注射位点以及注射入液流中的颗粒的类型等，因此为了获得、维持或增强颗粒群的分辨率，控制液流特征很重要。同样，细胞源导管(28)的直径或长度、注射位点(30)在细胞源液流(27)的喷嘴(25)内的位置，可以单独或共同影响颗粒群的分辨率。
在本发明的一些具体方案中，颗粒注射器(31)可以具有选择性可变调节元件(35)，该可变调节元件(35)可以实现调节或改变喷嘴开口(5)与颗粒注射器(31)在液流(26)中的位置之间的距离，颗粒注射器(31)在该位置将来自细胞源(1)的颗粒(16)夹带入液流(26)。在从第一套操作条件变为第二套操作条件时，无论操作条件的改变是否包括鞘液、精子种类、温度、液流压力、液流温度或其他变化，颗粒注射器(31)的选择性可变调节均可改变液流特性，以便补偿所述操作条件的变化。重要的是，根据细胞的特征，通过调节颗粒注射器(31)和喷嘴开口(5)之间的距离可以使分辨率得到提高。如图5～7所示，对于精子来说，利用本发明可以提高根据含有X染色体或含有Y染色体来分离精子的分辨率。
为了调节注射位置(30)，可以通过各种途径来实现颗粒注射器(31)的选择性可变调节。首先，如图3b所示，啮合于颗粒注射器(31)和喷嘴体(25)之间的一对匹配的螺旋丝(36)可以对颗粒注射器(31)进行旋转调节，从而改变注射位点(30)的位置。其次，如图3c所示，可通过提供可滑动接合(37)而在颗粒注射器(31)和喷嘴体(25)之间实现可调的接合。第三，如图3、4d和8a所示，多个可交换颗粒注射器(31)可以具有替代的长度，该长度由与喷嘴体(25)相匹配的销接制动器(38)所确定。
现主要参见图3和图4，本发明可进一步包括整体喷嘴(25)(图4d)。与图1和图4a所示的喷嘴(2)不同，本发明可以消除在匹配两个或两个以上的分离的喷嘴元件时所产生的不同心度，所述分离的喷嘴元件如图1和图4b所示的第一喷嘴元件(21)和第二喷嘴元件(22)。
还是主要参见图3和图4，本发明可进一步包括压力套管连接器(32)，以取代常规技术中的连接器(20)。压力套管连接器(32)的一个具体方案可包括细胞源导管(28)的终末端，细胞源导管(28)具有足够的回弹性来与颗粒注射器(31)的管相配合。本发明的此具体方案可包括细胞源导管，该细胞源导管包含Silastic或其他具有Silastic样性质的材料，或者细胞源导管(28)具有足够的弹性，如Teflon，或足够的回弹性，如Tygon，从而与颗粒注射器(31)的管的外表面相配合。
现主要参见图4a至图4d，其对常规的喷嘴装置(图4a和4b)和本发明的喷嘴装置(图4c和图4d)进行了比较。比较图1与图3以及图4b与图4d可以理解，常规技术需要在细胞源(1)和注射位点(1 8)之间使用较长的流动通路(见图4b中较长的颗粒注射器管)，并且在流体源和注射位点(18)之间使用较长的液流通路(3)。常规技术所使用的较长流动通路导致了如图5a、6a和7a所示的使不同细胞群分辨率下降的操作条件，与此相对的是，本发明使用较短的流动通路导致了如图5b、6b和7b所示的使不同细胞群分辨率提高的操作条件。
对于本发明的一些实施方案来说，可通过缩短细胞源(1)和注射位点(30)之间的细胞源导管(28)的总长度来缩短细胞液流(27)的长度，直到分辨率提高到最高为止。细胞源(1)和注射位点(30)之间的距离可以被制成显著短于常规技术的长度，如图4c和4d所示，其长度可短于4英寸。
对于本发明流式细胞仪的具体配置以及所要分离的颗粒群类型来说，可以单独或联合使用本发明的不同实施方案以提高颗粒群、细胞群或精子群之间的分辨率。具体地说，对于如图5b、图6b和图7b所示的本发明用于分离牛精子的实施方案来说，使用自细胞源(1)至注射位点(30)之间流动通路更短但保持注射位点(30)与喷嘴开口(5)距离不变的连体喷嘴(25)，可以显著提高含X染色体的精子群(39)与含Y染色体的精子群(40)之间的分辨率。但是，此实施例并不是在分析精子时将本发明可调节注射位点(30)限制于分辨牛精子群所用的位置。对于本发明分析其他种类哺乳动物物种精子的实施方案来说，注射位点可以离喷嘴开口更近或更远，以提高分辨率或初步分辨精子群。
再次主要参见图4，本发明可以包括喷嘴(25)内的面积缩小的液流(26)。对于本发明的一些实施方案来说，可将喷嘴(2)内液流的常规截面积(如图4a和4b所示)充分缩小，例如可如图4c和图4d所示那样缩小。对于本发明的一些实施方案来说，当与图4a和4b所示作为尺度的常规技术(Cytomation SX MoFlo喷嘴)相比较时，液流(26)截面积可缩小到常规液流(33)的截面积的四分之一至六分之一，或更小。另外，对于本发明如图4c和4d所示的某些实施方案，可将常规喷嘴(2)的长度充分缩短，以提供更短的液流流动通路。具体地说，对于牛精子的流式分离来说，图4c所示为液流截面积缩小为约占常规技术的液流截面积的五分之一。
现主要参见图5、6和7，其示范了本发明用于区分含X染色体的牛精子核和含Y染色体的牛精子核的分辨率增强的流式细胞仪的实例之一。
本发明分辨率增强的流式细胞仪按如下条件设置：
液流压 50.0psi(磅/平方英尺)
喷嘴开口 70μm
激光功率 150mW
光电倍增管电压 220/230V
标准品 新鲜公牛精子核
样品 Equinox批号19901
但是使用30～40psi的较低液流压也可获得基本上相同的结果，并提高精子的生育力。
由图5、图6和图7可以理解，将常规技术(图5a、图6a和图7a)和本发明高分辨率流式细胞仪(图5b、图6b和图7b)以每秒约25,000次事件、每秒约50,000～约60,000次事件或每秒约100,000～约110,000次事件这三个不同事件速度所取得的数据进行了比较。当用荧光染料染色的精子发出可检测的荧光发射时就记录为一次事件。事件的速度越快，则通常根据所检测荧光发射的强度不同来区分精子越困难。对于所有的事件速率来说，利用本文所述的高分辨率流式细胞仪发明可以更好地区分含X染色体的牛精子核群和含Y染色体的牛精子核群的混合群。
现主要参见图8～11，这些图显示了本发明实施方案的组件。图8显示了长度缩短、可替换的颗粒注射器(31)的具体方案，所述颗粒注射器(31)具有与喷嘴体(25)相匹配的销接制动器和带斜面的尖端(41)。对于本发明的一些实施方案来说，颗粒注射器的直径可为约1毫米～约2毫米，孔内径约0.2毫米～约0.3毫米。带斜面的尖端可以与垂直于颗粒注射器纵轴的平面相交成约84度，斜面的末端宽度约为0.5毫米～约0.7毫米。销接制动器(38)可包括平台(42)，以使旋转方向一致。
图9和图10显示了通过平台销接以便以滑动方式支撑和固定颗粒注射器(31)的内部喷嘴体(43)的具体方案。内部喷嘴体(43)插入如图10所示的外部喷嘴体(44)中。外部喷嘴体还包括至少一条来自流体源(45)的流动通路(图10所示的本发明实施方案中显示2条)，并且可将该外部喷嘴体设置为用压力接头或防漏接头将流体源导管与外部喷嘴体(44)相连。
图11提供了附加的图11a和图11b，其中附加的图11a显示外部喷嘴体(44)的截面B-B，其显示鞘液通路的具体结构，图11b提供了所述外部喷嘴体的透视图。
由图4c、图4d、图9和图11可以理解，整体喷嘴(25)与外部喷嘴体(44)接合，并可用固定环(45)固定到位。本发明的喷嘴装置可用于取代图1、图2、图4a及图4b所示的常规喷嘴，以提供如图6b、图7b和图8b所示的增强的分辨率。
对于不对称的颗粒类型如精子来说，本发明的喷嘴装置可以使喷嘴体中的不对称颗粒更好的取向，从而在进行分析时提供更好的一致性，尤其是当所述分析包括测定所发射的荧光的量或细胞量(volume)时更是如此。
另外，根据所分析的颗粒、细胞或精子的类型，可在每秒20,000次事件～100,000次事件这样非常高的事件速度实现分辨率的提高。结果在每秒内有更多数量的精子可以得以分离、分选、收集或回收。该方法可以在每个单位时间内生产更多的产品，并减少了单位生产成本，这是由于流式细胞仪或细胞分选仪可占生产分离颗粒的总体成本中的很大一部分。
当本发明的喷嘴装置采用低压液流操作时，甚至在高于每秒1000次分选的分选速度下，所收集的经分离或经分选的精子可具有强的运动力、存活力和生育力(精子生育力特征)，而且对于某些类型的精子来说，这些经分离或经分选的精子具有与从精液中新鲜收集的精子基本相同的精子生育力特征。
因为利用该喷嘴体装置可以获得高的分辨率，所以即使是分选速度高于常规喷嘴所能达到的速度，所分选的颗粒的纯度也可得以提高。
本发明的喷嘴装置较少发生颗粒注射器(31)的部分或完全阻塞的情况。因此，不能操作典型流式细胞仪或细胞分选器的时间较少。
在注射管发生阻塞的情况下，本发明的喷嘴装置允许快速移去注射管而不必将整个喷嘴装置拆开或卸下来。然后可以很容易地对注射管进行检查、清洗和重新安装，使得此类清洗工作带来的停工期短得多，从而使分选仪器有更多时间用于生产。
本发明的喷嘴装置还允许由不熟练(或半熟练)的操作工来清洗注射管，而不需要熟练的检修员。这就是意味着可以减少排除注射管部分或完全阻塞故障的劳动力成本，也意味着操作工可以立即排除这类故障而不必浪费时间去寻找合适的维修人员。
本发明的喷嘴装置可使操作工观察到分离分辨率的下降并立即加以修正。使用常规喷嘴装置时，部分阻塞不会使仪器发生中止，但是阻塞逐步增加，可导致仪器在多个小时、多天或甚至多个星期内分辨能力慢慢丧失，而在分辨率变差的喷嘴在运行的整段时间内，仪器通常产出纯度低得多的产品，尤其是在需要以低得多的分选速度运行时可产出的产品量更少(产率下降)。实际上，经常是在熟练技术人员更换或清洗喷嘴并即刻发现有所改善时，操作工才会注意到这种产率下降。
注射管可以很容易地加以替换，使得注射管可以是一次性使用或只使用一段非常短时间的管子。在流式细胞仪的一些用途中，如分选诸如人胚胎细胞、人精子、人骨髓细胞之类的材料时，需要使用复杂、冗长的CIP(原位清洗)方案来确保消除样品间的交叉污染，如果用以下方案替换CIP过程，那就方便和有益了，所述方案为替换所有与样品接触的部分，这需要替换样品注射管。
本发明的注射管更短，喷嘴也更小，这样可以防止在检查或装配过程中该管发生某种变形，例如弯曲，并使该管在喷嘴内更难自由移动(振动)。这样就可使注射管的尖端更靠近喷嘴内的所需注射位点，减少注射管在特定喷嘴几何结构中谐波共振的数量和振幅。
本发明中直线形的注射管可以使注射管可深、可浅地插入喷嘴内，从而使用户可调节样品被注射入液流的位点与喷嘴开口位点之间的确切距离。可以通过观察分辨率数据来影响注射管在喷嘴内的定位的确定(反馈控制环路)，于是，当仪器操作的其他方面或样品发生改变时，可以确定可动态变化的注射点位置。
大部分喷嘴装置均为昂贵的组件，通常是由产商小量生产，他们不能制造出完全相同的亚组件。因此，在实践中，必须仔细测试每一喷嘴装置，如果不精确的话需要重新制造甚或丢弃。本发明简化了喷嘴装置的许多部件，有助于更可靠地生产喷嘴装置的各种亚组件，并使得注射管很容易地得以替换，而更换注射管正是喷嘴工作状态不好的较常见原因之一。所有这些均可以降低制造成本，更有效地利用各部件，由此又可以降低一个或一个以上生产仪器的维护成本，所述生产仪器的生产设置为每天24小时、每周7天(24/7)运转。
本发明还可包括利用本发明任意实施方案所分离或处理的精子而产生的哺乳动物胚胎或哺乳动物；或可包括根据本发明各种实施方案所分离的精子而产生的性别预先选定的哺乳动物胚胎或哺乳动物；或可包括利用根据本发明制备的精子授精样品所产生的哺乳动物胚胎或哺乳动物，所述精子授精样品具有富含X染色体的精子群或富含Y染色体的精子群；或根据本发明任意实施方案所产生的哺乳动物胚胎或哺乳动物，其中精子授精样品中的精子数量少于给该特定种类哺乳动物授精的典型精子用量。
从上文中可以很容易地理解，本发明的基本思想可以用不同途径来具体实施。本发明涉及高分辨率的精子处理系统，该系统包括技术和装置，其中的一些实施方案用于提供高分辨率或分辨率增强的流式细胞仪系统，该流式细胞仪系统可用于各种颗粒、细胞或精子，所述的技术和装置用来根据选定颗粒的特征将所述颗粒高分辨率地分开并分离成富含群体。
在此申请中，通过所述各种装置所得的部分结果和应用中的固有步骤公开了各种精子处理技术。它们只是利用所述目标装置的自然结果。另外，尽管公开了一些装置，但是应该理解，这些装置不仅实现了某些方法，而且这些装置可以以多种方式加以变更。重要的是，如前所述，所有这些方面应理解为包括于本公开内容中。
这份临时申请中所包括的讨论，其目的是为了提供基本的描述。读者应当清楚，具体的讨论可能并未明确地描述所有可能的实施方案，许多替代方案是隐含的。它也可能没有充分地解释本发明的普遍性质，也可能没有明确地显示各个性质或元件实际上如何代表大量不同功能或大量替代方案或等同元件。同样，这些也隐含地包括在本发明的公开内容中。当从装置术语的角度描述本发明时，装置的每一元件隐含地执行一种功能。装置权利要求不仅可包括所述的装置，还可以包括用于实现本发明及每个元件所执行的功能的方法或过程的权利要求。所有描述及术语均并非是对权利要求范围的限制，权利要求的范围包含在整个专利申请中。
同时应当理解的是，可以进行各种变更而不会背离本发明的本质。这些变更也隐含地包括在本说明中。它们仍属于本发明的范围。广泛的公开内容包括于本发明的公开内容之内，其中包括已经展示的显式实施方案、大量隐含的替代实施方案及广泛的方法或过程等，当撰写完整专利申请的权利要求时可以依赖这些公开内容。应当理解，当申请人以后(在所需最后期限之前提交)根据此临时提交文件欲提交专利时，所述语言变更和广泛的权利要求将会完成。随后提交的完整专利申请将会要求对权利要求的基础进行审查，所述权利要求的基础与申请人权益所认为的一样广泛，并将其设计为产生独立覆盖本发明许多方面及作为一个综合系统的专利。
而且，本发明及权利要求的每个不同元件还可以用多种方式获得。本公开内容应理解为包括每一个这样的变化，不论它是任意的装置的实施方案、方法或过程的实施方案的变更，还是甚至仅仅是其中任意元件的变更。特别是，应该理解，由于本发明公开内容涉及本发明的元件，每个元件的文字可以用等同的装置术语或方法术语来表达——甚至仅仅是相同的功能或结果。应认为这些等同的、更广泛的甚至是更上位的术语包含于各元件或动作的描述中。当需要对本发明所包括的隐含的广泛范围进行明确时，这些术语可加以替换。仅举一个例子来说，应该理解的是，所有的动作均可以用执行该动作的装置或促使产生该动作的元件来表达。类似地，每一公开的物理元件应理解为包含了对所述物理元件执行的动作的公开。就此最后一方面来说，仅举一个例子，“流式分选仪”的公开内容应理解为包含了“流式分选”动作的公开内容，无论其是否明确讨论过；反过来说，当有“流式分选”动作的有效公开时，这样的公开内容应理解为包括了“流式分选仪”，甚至包括了“流式分选装置”的公开。这些变化及替代术语应理解为明确包括在说明书内。
本专利申请中提及的任何法律、法令、规章或准则的条款，或此专利申请中提及的专利、出版物或其他参考文献均以参考的方式引入本文。另外，对于所用的每一术语，应当理解，除非其在本申请中的应用与通用词典中的解释不一致，否则应当认为，本文引入了通用词典中对各条术语的定义。在此以参考的方式引入例如《Random House Webster’s UnabridgedDictionary(兰登书屋韦氏大词典)》第二版的所有定义、替代术语和同义词。最后，以参考方式引入该临时专利申请的参考文献列表中所列出的所有文献或其他与该申请同时提交的信息声明均在此附上，并以参考的方式引入；但是，对于上述每一项来说，这些以参考方式引入的信息或声明可被认为与此/这些发明的专利权不一致，很清楚这样的声明不能认为是本申请人所做出的。
因此，应理解为申请人至少主张如下权利：i)本文所公开和描述的各种精子处理装置；ii)所公开和描述的相关方法；iii)这些装置和方法的类似、等同甚至是隐含的变化；iv)可以完成所公开和描述的所示各个功能的替代设计；v)完成每一所示功能的替代设计和方法，其为隐含的完成所公开和描述的功能的替代设计和方法；vi)作为分开的和独立的发明所显示的各个性质、元件及步骤；vii)由所公开的不同系统或组分而改进的申请；viii)由此类系统或元件所生成的最终产品；以及ix)基本在上文中并参考任何所附实施例所描述的方法和装置，x)所公开元件的各种组合及排列，及xi)从属于每个或其中任何一个独立权利要求或概念的每个从属的潜在的从属权利要求或概念。就这点上，应理解的是出于实践的原因及为了避免增加数以百计权利要求的可能性，申请人最终仅提交了具有最初的从属权利要求的权利要求。支持应当被理解为达到有关新实体法规(newmatter laws)所要求的程度，以便能够在一项独立权利要求或概念之下增加各种的从属权利要求或其他要素，作为任何其他独立权利要求或概念的从属权利要求或要素，上述法规包括但不限于《欧洲专利公约》第123条(2)款和美国专利法35 USC 132或其他此类法律。而且，如果使用或当使用表示转接关系的措词“包含”时，根据习惯上对权利要求的解释，使用该词是为了保持本文权利要求为“开放式”。因此，除非上下文需要，术语“包含”或诸如“包括“或“含有”等变化形式应理解为，它们意指包括所声明的要素或步骤或者要素或步骤的组，而不排除任何其他的要素或步骤或者要素或步骤的组。这样的术语应以其最广泛的形式来解释，以使申请人获得法律许可的最广泛的范围。
Claims (26)
1.一种流式细胞计数方法，该方法包括以下步骤：
a.从哺乳动物的雄性个体获取精子；
b.在注射位点将所述精子注入液流中；
c.在所述液流中形成大量液滴；
d.在所述大量液滴的一部分液滴中夹带所述精子中的一个精子；
e.分析所述大量液滴的所述部分液滴中的精子；
f.根据至少一种精子特征区分所述精子，从而产生两个精子群；
g.调节所述精子在所述液流中的所述注射位点，以提高所述至少两个精子群的分辨率。
2.如权利要求1所述的流式细胞计数方法，其中所述哺乳动物的雄性个体选自牛、马、羊、犬、猫、猪、海洋动物或鹿。
3.如权利要求1所述流式细胞计数方法，其中所述液流包含鞘液。
4.如权利要求3所述的流式细胞计数方法，其中所述鞘液包括选自含柠檬酸盐缓冲液、磷酸盐缓冲液或HEPES缓冲液的鞘液。
5.如权利要求1所述的流式细胞计数方法，其中所述从哺乳动物的雄性个体获取精子的步骤包括获取第一种哺乳动物的精子和获取第二种哺乳动物的精子；所述调节所述精子在所述液流中的所述注射位点以提高所述至少两个精子群的分辨率的步骤包括确定第一注射位点以提高所述至少两个精子群的分辨率，所述第一注射位点为所述第一种哺乳动物的所述精子在所述液流中的第一位置，以及确定第二注射位点以提高所述至少两个精子群的分辨率，所述第二注射位点为所述第二种哺乳动物的所述精子在所述液流中的第二位置。
6.如权利要求1所述的流式细胞计数方法，其中所述调节所述精子在所述液流中的所述注射位点以提高所述至少两个精子群的分辨率的步骤包括调节颗粒注射器将所述精子导入所述液流的位置。
7.如权利要求1所述的流式细胞计数方法，其中所述调节颗粒注射器将所述精子导入所述液流的位置的步骤包括，在所述颗粒注射器和喷嘴体之间提供可调节的滑动连接。
8.如权利要求1所述的流式细胞计数方法，其中所述调节颗粒注射器将所述精子导入所述液流的位置的步骤包括，操控位于所述颗粒注射器和喷嘴体之间的一对匹配的螺旋丝。
9.如权利要求1所述的流式细胞计数方法，其中所述调节所述精子在所述液流中的所述注射位点以提高所述至少两个精子群的分辨率的步骤包括，用第二颗粒注射器取代所述颗粒注射器以改变所述精子被注射入所述液流中的所述注射位点与所述液流所流经的所述喷嘴开口之间的距离。
10.如权利要求1所述的流式细胞计数方法，其中所述调节所述精子在所述液流中的所述注射位点以提高所述至少两个精子群的分辨率的步骤包括，调节所述精子被注射入所述液流中的所述注射位点与所述液流所流经的喷嘴开口之间的距离。
11.如权利要求1所述的流式细胞计数方法，其中所述液流具有液流特征；并且其中，调节所述精子在所述液流中的所述注射位点以提高所述至少两个精子群的分辨率的步骤包括，根据所述液流特征调节所述精子的所述注射位点。
12.如权利要求1所述的流式细胞计数方法，其中所述液流具有改变的液流特征；并且其中，调节所述精子在所述液流中的所述注射位点以提高所述至少两个精子群的分辨率的步骤包括，根据所述改变的液流特征调节所述精子的所述注射位点。
13.如权利要求1所述的流式细胞计数方法，该方法还包括将所述精子分离成第一精子群和第二精子群的步骤。
14.如权利要求1所述的流式细胞计数方法，其中根据至少一种精子特征区分所述精子从而产生两个精子群的步骤包括，根据性别特征区分所述精子，其中所述第一精子群含有X染色体，所述第二精子群含有Y染色体。
15.一种流式细胞仪，该流式细胞仪包括：
a.液流；
b.所述液流在其中流动的喷嘴体；
c.所述液流喷出所述喷嘴的喷嘴开口；
d.颗粒源；
e.与所述颗粒源流控相连的颗粒注射器，该颗粒注射器在所述液流中的一个位置掺入至少一个颗粒；和
f.选择性的可变调节元件，该选择性的可变调节元件用以改变所述喷嘴开口和所述液流内所述位置之间距离，所述颗粒注射器在所述位置掺入所述至少一个颗粒。
16.如权利要求15所述的流式细胞计数仪，其中所述颗粒包括细胞。
17.如权利要求15所述的流式细胞计数仪，其中所述颗粒包括精子。
18.如权利要求15所述的流式细胞计数仪，其中所述精子从哺乳动物的雄性个体获得，所述哺乳动物选自牛、马、羊、犬、猫、猪、海洋动物或鹿。
19.如权利要求15所述的流式细胞计数仪，其中所述选择性的可变调节元件包括位于所述颗粒注射器和所述喷嘴之间的可调节的滑动接合，所述选择性的可变调节元件用以改变所述喷嘴开口和所述液流内所述位置之间距离，所述颗粒注射器在所述位置掺入所述至少一个颗粒。
20.如权利要求15所述的流式细胞计数仪，其中所述选择性的可变调节元件包括接合于所述颗粒注射器和所述喷嘴之间的一对匹配的螺旋丝，所述选择性的可变调节元件用以改变所述喷嘴开口和所述液流内所述位置之间距离，所述颗粒注射器在所述位置掺入所述至少一个颗粒。
21.如权利要求15所述的流式细胞计数仪，其中所述选择性的可变调节元件用以改变所述喷嘴开口和所述液流内所述位置之间距离，所述颗粒注射器在所述位置掺入所述至少一个颗粒，所述选择性的可变调节元件包括用第二颗粒注射器取代所述颗粒注射器，所述第二颗粒注射器在所述液流的第二个位置掺入所述所述至少一个颗粒。
22.一种流式细胞仪，该流式细胞仪包括：
a.液流；
b.所述液流在其中流动的喷嘴体；
c.所述液流喷出所述喷嘴的喷嘴开口；
d.颗粒源；
e.与所述颗粒源流控相连的颗粒注射器，该颗粒注射器在所述液流中的选择性可变位置掺入至少一个颗粒。
23.一种流式细胞仪，该流式细胞仪包括：
a.液流；
b.所述液流在其中流动的喷嘴体；
c.所述液流喷出所述喷嘴的喷嘴开口；
d.颗粒源；
e.与所述颗粒源流控相连的颗粒注射器，该颗粒注射器在所述液流中的一个位置掺入来自所述颗粒源的至少一个颗粒，其中调节所述颗粒注射器而使喷嘴开口与所述液流内所述位置之间的距离发生改变，所述颗粒注射器在该位置掺入所述至少一个颗粒。
24.一种流式细胞仪，该流式细胞仪包括：
a.液流；
b.所述液流在其中流动的喷嘴体；
c.所述液流喷出所述喷嘴的喷嘴开口；
d.颗粒源；
e.将所述颗粒源与所述喷嘴流控相连的导管；
f.与所述导管相连的颗粒注射器，该颗粒注射器在所述液流的一个位置掺入至少一个颗粒；
g.选择性的可变调节元件，该选择性的可变调节元件用以改变所述喷嘴开口和所述液流内所述位置之间距离，所述颗粒注射器在该位置掺入所述至少一个颗粒。
25.一种流式细胞仪，该流式细胞仪包括：
a.具有喷嘴开口的喷嘴体；
b.在所述喷嘴内可调节位置的颗粒注射器，通过调节所述颗粒注射器的位置使所述颗粒注射器的注射位点与所述喷嘴开口之间的距离发生改变。
26.一种流式细胞计数的方法，该方法包括下列步骤：
a.在喷嘴中产生液流；
b.从喷嘴开口喷出所述液流；
c.确定所述液流中的颗粒注射位点与所述喷嘴开口之间的距离；
d.在所述注射位点将细胞掺入所述液流中；
e.调节颗粒注射器在所述喷嘴内的位置；
f.根据细胞的至少一个特征分析所述细胞；
g.调节颗粒注射器在所述喷嘴内的位置。
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| US7981682B2 (en) | 2011-07-19 |
| MXPA05001654A (es) | 2005-10-18 |
| US7855078B2 (en) | 2010-12-21 |
| BRPI0313476B1 (pt) | 2015-06-23 |
| US20110091963A1 (en) | 2011-04-21 |
| US20060141628A1 (en) | 2006-06-29 |
| CA2534394A1 (en) | 2004-02-26 |
| WO2004017041A3 (en) | 2004-07-15 |
| AU2003265471A1 (en) | 2004-03-03 |
| AU2003265471B2 (en) | 2009-08-06 |
| WO2004017041A2 (en) | 2004-02-26 |
| JP2005535346A (ja) | 2005-11-24 |
| CA2534394C (en) | 2013-01-08 |
| CN100570360C (zh) | 2009-12-16 |
| BR0313476A (pt) | 2005-08-02 |
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