CN1248926A - 样品制备用浇铸膜结构物 - Google Patents
样品制备用浇铸膜结构物 Download PDFInfo
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- CN1248926A CN1248926A CN98802852.2A CN98802852A CN1248926A CN 1248926 A CN1248926 A CN 1248926A CN 98802852 A CN98802852 A CN 98802852A CN 1248926 A CN1248926 A CN 1248926A
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Abstract
可用作吸附性介质或反应性介质或者用于基于尺寸的分离的复合结构和/或非填充结构(11)的就地浇铸方法。可使用任何特定的壳体尺寸或构型,而且在实现在聚合物中包含大量吸附性颗粒的同时仍能保持膜三维结构。在第一较好的实施方案中,该复合结构包含截留于一种多孔聚合物基质内的颗粒,而且就地浇铸到一种壳体例如移液管尖端部中,从而提供一种有效的微质量操作平台。随着颗粒化学的适当选择,实际上可以对各体积中低于1微克的样品质量负荷进行任何分离或纯化操作,包括选择性结合/洗脱色谱法操作。本发明也涵盖这些复合结构以及含有这些复合结构的样品制备装置。在第二较好实施方案中,自保持、自支撑的结构就地浇铸于适用壳体(12)中,而且可用于基于尺寸的分离,其中浇铸结构(11)起到一种半渗透膜阻挡层的作用。本发明也涵盖这些结构以及含有这些结构的壳体。
Description
发明背景
在生物化学技术方面已经开发了许多分析程序,其中要求去除肽溶液中的溶剂,以期得到可以有效地进行分析的更高浓度肽样品,或要求去除低分子量离子或溶质。也已经开发了很多不仅涉及肽而且也涉及一般大分子物种的其它分析程序,其中有必要使液体样品中的大分子成分浓缩和/或“脱盐”,因为生物化学/医药化学中通常需要没有盐类、洗涤剂及其它污染物的纯分析物。这些物质的存在可能是有害的,原因在于它们往往干扰随后的化学分析。环境技术上和化学分析中存在类似情况。
美国专利No.4,755,301公开了一种无需过滤至干的大分子浓缩用离心方法和装置。一张半透过性超滤膜将样品池与滤液杯隔离开,该膜下面的滤液导管从该膜外沿向里被充分抵销,因此,当该装置在一个固定角离心转子上使用时,一旦滞留物弯液面达到最外滤液导管的最外沿的离心径向水平,过滤就停止。
这样的超滤装置通常用于生物分子和天然产品的“纯化”和/或样品制备。为了使这样一种工艺能够成功,膜必须加以选择,使之能截留有益的分子但能让杂质通过。尽管这种情景对于大于约10,000分子量的分析物来说是相当直截了当的,但对于小于约5000分子量的物质来说问题就越来越多。理由是由于如下事实:截留约5000分子量分析物所需要的膜孔率是如此低,以致透水性(流量率)变得不良且加工时间太长。例如,使用了适合于30,000或更大的分子量的分析物的膜的装置,其典型的离心“自旋时间”是大约1小时,而对于约1000分子量的分析物则可能需要多达6小时。进而,对高g力的如此长期暴露经常导致设备损坏。
目前技术上常见的样品量在0.01~10μg范围。在如此低的负荷时,高效率样品处理对于避免损失来说是重要的。惯用的样品制备方法与装置对于处理如此小样品体积的“微量分离”来说是不实用的。此外,超滤只能有效地浓缩和脱盐,因而,这种规模的吸附技术的应用是微质量样品制备的一种全新思路。
制作样品制备装置的一种惯用方法,是首先把一个从诸如一种纤维性玻璃或纤维素片材得到的预开多孔塞插入一支移液管的尖端部,随后添加松散颗粒和第二个多孔塞,如图1中所示。这些塞子用来把这些颗粒保持固定在该移液管尖端部。然而,这些塞子也截留过量液体,从而造成死空间或体积(即未被介质或聚合物占据的空间,这会导致不良样品回收率、诸如样品带出引起的污染等)。然而,对于像移液管尖端部这样极小的液体输送装置无法使用这些程序,因为没有任何一种实用方法可用来要么装填塞子要么装填颗粒,以获得一种要用于以上提到的极小样品负荷的、含有10毫克或更少吸附剂的微量吸附装置。
此外,也可以通过把介质装入并固定于毛细管式移液管中来制作一种微量样品制备装置。然而,通过此类装置的流动通常是缓慢的。
进而,尽管从质量吸附观点来看,吸收性粉末提供最高的能力,但它们难以或确实不可能以毫克量操作。尽管基于聚合物的吸附膜片材相对容易操作,但它们的能力作为相对低的亚结构表面积的结果是较差的。
因此,本发明的一个目的是提供一种能使样品溶液中的分子浓缩、纯化和/或脱盐的样品制备装置。
本发明的另一个目的是提供一种能使非常少量样品溶液中的分子浓缩,纯化和/或脱盐的样品制备装置。
本发明的又一个目的是提供一种能使样品溶液中的分子浓缩、纯化和/或脱盐、呈各种各样几何形状的样品制备装置。
本发明的一个进一步目的是提供一种能使非常少量样品溶液中的分子浓缩、纯化和/或脱盐、呈各种各样几何形状的样品制备装置。
本发明的一个更进一步目的是提供一种制造起来简单而经济的样品制备装置。
本发明还有一个进一步目的是提供一种在一种有各种各样壳体尺寸或几何形状的壳体中浇铸颗粒的方法。
本发明的又一个进一步目的是提供一种呈现它浇铸于其中的壳体的形状而且不使用多孔塞就能保持在该壳体中的可浇铸膜。
本发明的再一个目的是提供有支撑体或基质的可浇铸膜。
发明概述
本发明克服了先有技术的问题,它提供可用作吸附性或反应性介质或用于基于尺寸的分离的复合型(有填料)和/或非填充型结构的一种就地浇铸方法。在一种实施方案中,这些结构是整体式的和/或连续式的。本发明适用于各种各样特定壳体尺寸和构型,并提供一种在各种各样体积的壳体中添加介质的手段。本发明使得大量介质(相对于所析出结构的表面积增加而言)能包含在该聚合物中,同时仍保持三维聚合物结构。
在第一种较好实施方案中,该复合结构包含截留于象图2B中所示那样的一种多孔聚合物基质内的颗粒,并就地浇铸到诸如图2A中所示的移液管尖端部等各种各样尺寸的壳体中,从而提供一种有效的微质量操作平台。随着颗粒化学的适当选择,实际上可以对少数几微升体积中小于1微米的样品质量负荷以及更大的质量负荷和体积进行任何分离或纯化操作,包括选择性结合/洗脱色谱法操作。本发明也涵盖复合结构,以及含有该复合结构的样品制备装置。
在第二种较好实施方案中,可以自保持和/或自支撑的无填充结构就地浇铸在一个适用壳体中,而且可以用于基于尺寸的分离,其中该浇铸结构充当一种半渗透阻挡层或用于吸附。本发明也涵盖这些结构以及含有这些结构的壳体,例如图3中所示那种。图3中的装置是一种离心装置,有一个液池、一个基础和一个密封于该液池与基础之间的多孔性织物。本发明的结构是就地浇铸在该多孔性织物上的。该装置在操作期间置于一个适用管形瓶中,该装置的通量受离心力驱动。
附图简要说明
图1是在两个多孔塞之间装配了颗粒的一种吸附性移液管尖端部的示意图;
图2A是按照本发明用一种就地浇铸工艺制备的一种吸附性移液管尖端部的示意图;
图2B是一种填充了颗粒的就地浇铸结构的扫描电镜微观照片;
图3是一种向其中添加了就地浇铸结构的壳体的一种进一步实施方案;
图4是一种用球形硅胶和聚矾粘结剂制备的颗粒填充膜的扫描电镜微观照片;
图5A说明作为本发明就地浇铸结构的一种适用壳体的一种多孔阵列;
图5B是一种可以与图5A的多孔阵列一起使用的集水系统的侧视图;
图5C是图5A多孔阵列的一个单孔的顶视图;
图5D是图5B集水系统的一个孔的横截面视图;
图6是一种5肽混合物的逆相色谱图;
图7是一种结合于含有就地浇铸C18二氧化硅的移液管尖端部并洗脱下来的5肽混合物的逆相色谱图;
图8是一种结合于含有就地浇铸涂有苯乙烯磺盐的二氧化硅的移液管尖端部并洗脱下来的5肽混合物的逆相色谱图;
图9是细胞色素C的逆相色谱图;
图10是对一种含有就地浇铸固定的胰蛋白酶珠的移液管尖端部暴露15分钟后细胞色素C的逆相色谱图;
图11是一种结合于含有就地浇铸固定的蛋白A珠的移液管端部并洗脱下来的兔免疫球蛋白-g样品的电泳凝胶;
图12是结合于含有就地浇铸二氧化硅的1000μl移液管尖端部并洗脱下来的超卷曲质粒DNA的电泳凝胶;
图13是结合于含有就地浇铸二氧化硅的200μl移液管尖端部并洗脱下来的、范围为200~1000bp的线型DNA碎片的电泳凝胶;
图14是结合于含有就地浇铸超微细二氧化硅的200μl移液管尖端部并洗脱下来的PCR放大DNA的电泳凝胶;
图15是结合于含有松散二氧化硅和就地浇铸膜阻挡层的200μl移液管尖端部并洗脱下来的线型DNA碎片的电泳凝胶;
图16A是一种含有用球形硅胶和聚砜粘结剂制备的就地浇铸填充颗粒的膜的移液管尖端部的一个纵向剖面的扫描电镜微观照片;
图16B是一种含有用球形硅胶和聚砜粘结剂制备的就地浇铸填充颗粒的膜的移液管尖端部的一个横截面的扫描电镜微观照片;
图17是一种含有就地浇铸无填充未切割膜的移液管尖端部的一个纵向剖面的扫描电镜微观照片。
本发明的详细说明
本文中使用的“膜”这一术语包括有适合于预期用途的孔率、有或无颗粒的透过性和半透过性三维结构物。本文中使用的“复合结构”这一术语包括填充膜。
在本发明的第一种较好实施方案中,熟悉本门技术的人员将认识到,很多不同的颗粒可以用于复合结构,这取决于所得到装置的预期目标。在吸收性装置的情况下,理想的装置将有迅速的吸附动力学、与用途相称的容量和选择性,而且能用适当脱附剂洗脱所结合的分析物。适用的吸附性复合结构是用聚合物粘结、填充了颗粒的吸附性膜结构,例如,那些包含用一种粘结剂粘合在一起的色谱珠的膜结构。图4中说明了一种适用的、用聚合物粘结、填充了颗粒的吸附膜。这种膜包含约80%(重量)二氧化硅和20%(重量)聚矾粘结剂,而且是Millipore公司生产的。图16A中显示一种就地浇铸于移液管尖端部50的类似膜。包含用其它官能团衍生的其它微米级(例如1~30微米)树脂颗粒的功能性复合结构也是有益的,其中包括基于苯乙烯-二乙烯基苯的介质(不改性或用诸如磺酸、季胺等衍生);基于二氧化硅的介质(不改性或用C2、C4、C6、C8或C18或离子交换官能团衍生),以容纳对肽、蛋白质、核酸及其它有机化合物的各种各样应用。熟悉本门技术的人员将认识到,也可以使用有替代选择性(例如疏水相互作用、亲合力等)的其它基体,尤其用于除肽以外的分子类别。本文中使用的“颗粒”这一术语意在涵盖有规则形状(如球形)或无规则形状的颗粒,以及碎片、纤维和粉末,包括金属粉、塑料粉(如粉末状聚苯乙烯)、正相二氧化硅、气相法二氧化硅和活性炭。例如,气相二氧化硅向聚砜聚合物中的添加导致增加活性表面积,而且适合于各种应用。Amoco公司以UDEL P3500和P1700名称销售的聚矾,从所形成复合结构对包括聚丙烯、聚乙烯及其混合物在内的聚烯烃壳体的粘合程度这一点来看,是特别好的。其它适用的聚合物粘结剂包括聚醚矾、乙酸纤维素、乙酸丁酸纤维素、丙烯腈PVC共聚物(商业上以“DYNEL”名称销售)、聚偏二氟乙烯(PVDF,商业上以“KYNAR”名称销售)、聚苯乙烯和聚苯乙烯/丙烯腈共聚物等。对壳体的粘合可以用熟悉本门技术的人员已知的手段来加强,或用这些复合结构达到类似效果,所述手段包括壳体刻蚀,例如用等离子体处理或化学氧化;壳体内部的环等机械辅助手段;以及把能促进这样的粘合的添加剂掺入壳体中。粘合使得在浇铸期间能均匀沉降。
按照本发明的装置可以包含多种有不同官能团的树脂材料的复合材料,以便对因电荷、尺寸、亲合力和/或疏水性而异的分析物进行分级;此外,还可以组合使用多种含有不同个体功能膜的装置来达到类似结果。类似地,可以在一种适用壳体中浇铸一种或多种膜,而且可以在浇铸前后增加官能度。
按照本发明,本发明的结构物可以用聚合物换相(phase inversion)工艺、空气浇铸(蒸发)和热反转(thermal inversion)来成形。对于那些只有微小粘合力或无粘合力的系统,所形成的结构物可以单独制备、插入适当壳体中、用机械手段固定。在较好的方法中,所形成的结构物就地浇铸于合意的壳体中。这导致在聚合物基体中既能包含大量介质又能依旧保持三维多孔结构。这种膜亚结构充当一种兜住颗粒的支撑网络,从而消除对玻璃料或多孔塞的需要,因而最大限度减少或甚至消除死体积(该膜的吸附性可以或可不参与吸附过程)。然而,如果合意,也可以加多孔玻璃料塞子。较好的是,所形成的膜或复合结构的形态比(平均直径与平均厚度之比)为小于约20、更好的是小于约10、特别是小于1。例如,对于吸附性移液管尖端部来说,较好的是形态比为2或更小、更好的是小于1、特别是约0.005~0.5之间。这一范围内的形态比能提供操作期间样品在复合结构中的适用滞留时间。
在聚合物换相工艺中,该聚合物的溶剂必须能与骤冷相或反转相混溶。例如,N-甲基吡咯烷酮是聚砜、聚醚矾和聚苯乙烯的一种适用溶剂。在后一种情况下,聚苯乙烯粒料可以溶于N-甲基吡咯烷酮中和就地浇铸。所形成的结构显示出对聚烯烃基壳体的壁的良好粘合力,而且有类似于聚矾的吸附特征。二甲基亚砜(DMSO)、二甲基甲酰胺、丁酸丙酯和环丁砜也是适用溶剂。N,N-二甲基乙酰胺(DMAC)是PVDF的适用溶剂。水是较好的沉淀剂。聚合物换相工艺一般来说导致该结构膨胀到它在该壳体中的浇铸溶液体积的大约2~3倍。
在空气浇铸工艺中,使用了聚合物粘结剂的挥发性溶剂。例如,在乙酸纤维素的情况下,丙酮是一种适用的挥发性溶剂。空气浇铸一般来说导致一种比浇铸溶液体积小的结构。用这种方法,填充结构中的颗粒应当是至少约30μm,以便不必施加较高的推动力就能流过收缩后的间隙空间。
颗粒数量的上限受浇铸溶液粘度制约。因颗粒类型而异,可以向该聚合物中添加多达40%(重量)的颗粒而不导致浇铸溶液太粘,以致无法抽进该壳体中。用较高的温度,可以达到较高的颗粒添加量。适用的粒度包括有或无孔率、平均直径范围为约100纳米到约100微米的颗粒。
适用的壳体材料没有特别限定,而且包括塑料(例如聚乙烯和聚丙烯)、玻璃和不锈钢。当含有聚砜、尤其可购自Amoco公司的UDELP3500和P1700聚砜的复合材料就地浇铸于其中时,从与该复合结构产生的化学粘合力的观点来看,聚烯烃、尤其聚丙烯是较好的壳体材料。图16B用一种具有用球形硅胶和聚砜制备的、就地浇铸于其中的膜的聚丙烯移液管尖端部说明了这样的粘合力。
适用的壳体构型也没有特别加以限制,而且包括移液管尖端部、孔、多孔阵列、塑料和玻璃空腔、样品制备器具,例如可购自Millipore公司的MICROCON微量浓缩器,等。较好的壳体构型是大体上圆柱形的,因为操作期间的流动向量大体上是直的,类似于色谱法,因而最大限度减少或避免对于非圆形构型可能发生的稀释性冲洗。虽然体积介于约0.1μl与约5ml之间的壳体可以用于就地浇铸,但较好的是小于约100μl的体积,更好的是约0.1~50μl的体积,特别好的是约0.2~20μl的体积。可以使用体积小至约5微升的移液管尖端部几何形状。当复合结构对壳体壁的化学粘合是合意的但不显著或不存在时,可以用机械手段来把该复合结构保持在壳体中,例如使壳体或其一部分压扁、压装、热收缩,对壳体或其一部分进行等离子体处理,或者对壳体或其一部分进行化学处理,例如刻蚀,以促进粘合。与壳体壁粘合的一个优点是无需机械手段就能使该复合结构与壳体“密封”。这样的密封(无论用哪种方法)能防止样品在操作期间形成沟流或绕过该复合材料。较好的是,本发明的结构物的最终床高为约0.05~约5mm。这考虑了良好洗涤、每单位体积的良好密度、和导致塞子形成期间的均匀沉淀。
本发明的结构物也可以就地浇铸于有适用几何形状的惯用多孔阵列中。此外,如同图5A~5D中所示,多孔阵列10可以用来作为壳体,例如,通过在孔12中就地浇铸本发明的结构物11这样进行。此外,图5B显示一个集水系统亚组件13,后者有多个孔12(图5D中予以放大),以及其中包含的就地浇铸结构物。集水系统13可以进行适配,以通过任何适用手段永久性地或可拆卸地耦合到液池阵列10上,例如通过快速装卸设计,从而形成含有本发明结构物的可脱下“靴子”组件。为方便起见,每个集水系统13都可以含有一种有不同化学性质的颗粒的聚合物基体,从而用户可因用途而异来选择适当集水系统13。替而代之或除此之外,填充了颗粒的聚合物基体可以因孔而异。液池壳体10可以是多个开口孔,也可以包括一种膜。
复合结构物和含有复合结构物的本发明微量样品制备装置有种类繁多的应用,这取决于颗粒选择。例如,用途包括:肽和蛋白质分析前样品制备,碳水化合物中肽的脱除,氨基酸分析前净化,微体积反应用固定酶,微亲合力色谱法用固定配体,超卷曲和切割质粒的分离,PCR和DNA产物的净化,RNA分离用固定寡dT,染料终止区脱除,元素分析用样品制备等。熟悉本门技术的人员将能困所希望的用途而异来选择适当颗粒、聚合物粘结剂、颗粒化学性质和几何形态。在一些情况下,可以在相同的装置中使用颗粒混合物。替而代之或除此之外,多孔装置中每个独立的孔都可以有不同的化学性质。
在本发明结构物没有填充颗粒的实施方案中,对称或不对称的半渗透结构物,或者对称和不对称的半渗透结构物的组合,均可形成。在这种实施方案中,较好的成形方法是就地浇铸于适当壳体中,形成一种适用于基于尺寸或吸附作用的分离(取决于聚合物同一性)的自保持、自支撑结构。可以给这样一种膜加上官能度,从而不使用颗粒就能执行吸附分离。例如,乙酸纤维素可以用碱处理以形成纤维素,随后用一种氧化剂处理以使之有反应性。
在就地成形工艺(要么有填充要么无填充的结构)中,较好的成形方法包括借助于溶剂交换的沉淀,例如,利用任何适用手段(例如在压力是推动力的情况下利用毛细管作用或利用真空源)把浇铸溶液引进壳体中。在壳体是移液管尖端部的实施方案中,较好的推动力是一种手持移液管管理器。一旦壳体中所希望的体积充满了浇铸溶液,就让壳体中的浇铸溶液接触一种聚合物不溶于其中的液体、较好是水,从而使该聚合物在壳体中析出。这可以通过把该壳体浸入该液体中,和/或用一种推动力例如借助于真空把该液体吸进该壳体中来实现。通过用水交换出溶剂,该结构物便析出。熟悉本门技术的人员将会知道,用来制备浇铸溶液的溶剂和非溶剂可以含有各种各样的添加剂。
在聚合物与沉淀剂刚一接触时,实际上有瞬时沉淀,从而形成一种半渗透屏障或“皮层”。图17中把这样一种屏障图示为壳体62中的元件60。这一屏障减慢了该亚结构进一步沉淀的速度。一旦沉淀完成,就可以诸如通过在该屏障以上的一点切断该壳体或通过磨蚀露出的聚合物,取下最初的半渗透屏障60。该半渗透屏障60可以任选地留在原位,以便用无填充结构进行基于尺寸的分离,因为该屏障层起到一种微滤膜的作用。
这种就地浇铸结构取该壳体的形状,而且导致一种类似于色谱柱的自保持均匀结构,提供适用于结合/洗脱色谱法(例如,当聚合物基体中包括颗粒时)或适用于其它分析技术或生物化学技术的大表面积。适用的推动力包括离心作用、重力、压力或真空。
下列实例非限制性地说明本发明的目的和优点。
实例1:20μl移液管尖端部中的强阳离子交换(SCX)二氧化硅
在一个适用小容器中,用N,N-二甲基乙酰胺制备5克7%(重量)PVDF溶液(Pennwalt公司,KYNAR 761)。向此溶液中添加1克SCX、200、15μl(Millipore,PN 85864)球形二氧化硅,用刮铲充分混合。让混合物在室温平衡2小时,然后再次混合。把一支20μl有槽纹的聚丙烯一次性移液管尖端部插入一个常用P-20 Pipetman(Gilson,Ranin等)中,把体积调整设定到20μl。将活塞推到底,把该移液管的尖端部放进浇铸溶液中。一边仔细观察,一边缓缓提升活塞,以使尖端部充满约0.5~1μl浇铸溶液。一旦该尖端部含有足够液体,就保持等压,并将移液管尖端部取下、在60℃的去离子水浴中浸渍约5秒钟。在这个短暂时期之后,释放活塞上压力,让水吸进尖端部中以使聚合物沉淀。当水位达到聚合物高度以上约0.5cm处时,把该尖端部推入该浴中,并使溶剂交换能进行约5分钟。从水浴中取出该尖端部,磨去位于外部的任何沉淀聚合物。把该尖端部重新插入吸移管管理器中,排出液体。如果流动差,就用一把锋利的剃刀片切掉端部约0.25mm。为了确保除去所有溶剂,把约5~20μl去离子水吸进和排出若干次。
实例2:普通200μl移液管尖端部中的C18二氧化硅
在一种适用小容器中,用N-甲基-2-吡咯烷酮制备5克6%(重量)聚砜溶液(Amoco,P3500)。向此溶液中添加2克C18、200、15μm球形二氧化硅(Millipore,PN 85058),用刮铲充分混合。让混合物在室温平衡2小时,然后再次混合。把一支200μl有槽纹的聚丙烯一次性移液管插入一个普通P-200 Pipetman(Gilson,Ranin等)中,并将体积调整设定到200μl。把活塞推到底部,把移液管端部放进浇铸溶液中。一边仔细观察一边缓缓提升活塞,使该尖端部充满约2~5μl浇铸溶液。一旦尖端部含有足够液体,就保持等压,并把尖端部取出、浸入处于室温的去离子水浴中约5秒钟。在这一短暂时期之后,释放活塞上的压力,将水抽进该尖端部分中使聚合物沉淀。当水位达到该聚合物高度以上约0.5~1cm时,把该尖端部推入该浴中,使溶剂交换能进行约5分钟。把尖端部从水浴中取出,拧掉位于外部的任何沉淀聚合物。把尖端部重新插入吸移管管理器中、排出液体。如果流动差,则可以用一把锋利的剃 刀片切掉端部约0.5mm。为确保除去所有溶剂,把约50~200μl去离子水吸进、排出若干次。
实例3:大膛孔1000μl移液管尖端部中的60、10μm正相二氧化硅
在一个适用的小容器中,用N-甲基-2-吡咯烷酮制备6克6%(重量)乙酸纤维素溶液(伊斯门·柯达公司,398-60)。向此溶液中添加1克60、10μl粒状硅胶(Davison,Grade 710),用一把刮铲充分混合。让混合物在室温平衡2小时,然后再次混合。把一支大膛孔1000μl聚丙烯移液管插入一个常用P-1000 Pipetman(Gilson,Ranin等)中并将体积调整设定到1000μl。把活塞压到底,将移液管端部放进浇铸溶液中。一边仔细观察,一边缓缓提升活塞,以使该尖端部充满约10~25μl浇铸溶液。一旦该尖端部含有足够的液体,就保持等压力,并将尖端部移出、浸入去离子水浴中约5秒钟。在这个短暂时期之后,释放活塞上的压力,使水吸进该尖端部以使该聚合物沉淀。当水位达到聚合物高度以上约1cm处时,把尖端部推入水浴中,使溶剂交换能进行约5分钟。把尖端部从水浴中取出,擦掉位于外部的任何沉淀聚合物。把尖端部重新插入吸移管管理器中,排出液体。如果流动差,就用一把锋利的剃刀片切掉端部约0.5mm。为确保除去所有溶剂,要吸进、排出约200~1000μl去离子水。
实例4:大膛孔200μl移液管尖端部中的气相法二氧化硅
在一个适用的小容器中,用N-甲基-2-吡咯烷酮制备8克7.5%(重量)聚砜溶液(Amoco,P3500)。向此溶液中添加0.5克气相法二氧化硅(Degussa,Aerosil 200),用一把刮铲充分混合。让混合物在室温平衡2小时,然后再次混合。把一支200μl大膛孔聚丙烯移液管插入一个常用P-200 Pipetman(Gilson,Ranin,等)中并将体积调整设定到200μl。把活塞压到底,将移液管端部放进浇铸溶液中。一边仔细观察一边缓缓提升活塞,使该尖端部充满约10~25μl浇铸溶液。一旦该尖端部含有足够液体,就保持等压,并将该尖端部移出、浸入去离子水浴中约5秒钟。在这一短暂时期之后,释放活塞上的压力,让水吸进该尖端部以使该聚合物沉淀。当水位达到聚合物高度以上约1cm处时,把该尖端部推进水浴中,让溶剂交换进行约5分钟。把该尖端部从水浴中取出,擦掉位于外部的任何沉淀聚合物。把该尖端部重新插入吸移管管理器上,将液体排出。如果流动差,就用一把锋利的剃刀片切掉端部约0.5mm。为了确保除去所有溶剂,吸进、排出了约200~1000μl去离子水。
实例5:填充了C18、15μm二氧化硅颗粒的就地浇铸膜
在一个小容器中,用N-甲基-2-吡咯烷酮制备5克6%(重量)聚矾溶液(Amoco,P3500)。向此溶液中添加2克C18、200、15μm二氧化硅(Millipore,PN 85864),用一把刮铲充分混合。让混合物在室温平衡2小时,然后再次混合。用一支移液管或眼药水滴管,把25~50μl浇铸溶液分配到适用的器具中。这样的器具实例包括(但不限于)Millipore Microcon或96孔过滤板的孔。当用这种方法制备器具时,每个室都必须含有一个能截留溶液的半渗透阻挡层(例如聚丙烯纤维、膜等)。一旦添加,该单元就会缓缓排液,以确保该溶液覆盖整个阻挡层表面。该器具浸入水中约2小时,而且每15分钟轻轻搅拌一次,以促进溶剂交换。在这一时期之后,把这些单元取下来,视情况而定,或者放进离心机中或者放进抽真空装置中。这种就地浇铸结构物用500~1000μl去离子水冲洗,以确保溶剂脱除。
实例6:含有松散30μl二氧化硅的大膛孔1000μl移液管尖端部中的浇铸多孔端塞
在一个适用小容器中,用N-甲基-2-吡咯烷酮制备5克7.5%(重量)聚矾溶液(Amoco,P3500)。让混合物在室温平衡2小时,然后再次混合。把一支1000μl大膛孔聚丙烯移液管插入一个常用P-1000 Pipetman(Gilson,Ranin等)中并将体积调整设定到1000μl。把活塞压到底,并将移液管端部放进浇铸溶液中。一边仔细观察一边缓缓提升活塞,使其尖端部充满约2~10μl浇铸溶液。一旦尖端部含有足够液体,就保持等压,将该尖端部移出、浸入去离子水浴中约5秒钟。在这一短暂时期之后,释放活塞上的压力,让水吸进该尖端部中以使聚合物沉淀。当水位达到聚合物高度以上约0.5cm处时,将该尖端部推入水浴中,让溶剂交换能进行约5分钟。把该尖端部从水浴中取出,擦掉位于外表的任何沉淀聚合物。该尖端部再次插入吸移管管理器中,将液体排出。如果流动差,则用一把锋利的剃刀片切掉端部约0.5mm。为确保去除所有溶剂,吸进、排出约100~500μl去离子水。拨下移液管,用棉签除去上室中任何过量的水。称取5~10mg(250)30μm硅胶,小心添加到该移液管的后端中。让移液管放流,从而使二氧化硅停留在就地浇铸阻挡层顶上。如有必要,在上室中配一个适用多孔塞(棉花或聚丙烯),以防颗粒损失。
实例7:过滤用浇铸半渗透膜塞
在一个适用容器中,用N-甲基-2-吡咯烷酮制备5克7.5%(重量)聚砜溶液(Amoco,P3500)。让混合物在室温平衡2小时,然后再次混合。把一支1000μl大膛孔聚丙烯移液管插入一个常用P-1000Pipetman吸移管管理器(Gilson,Ranin等)中并将体积调整设定到1000μl。把活塞压到底,并将移液管端部放进浇铸溶液中。一边仔细观察一边缓缓提升活塞,使该尖端部充满约2~10μl浇铸溶液。一旦该尖端部含有足够的液体,就保持等压,并把该尖端部移出、拭去过量聚合物溶液,再把该尖端部浸入去离子水浴中约5秒钟。在这一短暂时期之后,释放活塞上的压力,让水吸进该尖端部中以使聚合物沉淀。当水位达到聚合物高度以上约0.5cm处时,把该尖端部推入水浴中,让溶剂交换进行约5分钟。将该尖端部再次插入吸移管管理器中,把液体排出、用100~200μl去离子水洗涤。当以这种方式浇铸时,沉淀的聚合物在移液管出口处形成一个半渗透皮膜,这可以用来作为过滤介质。
实例8:蒸发法制备的多孔30μl二氧化硅塞子
在一个适用容器中,用丙酮制备5克10%(重量)乙酸纤维素溶液(伊斯门·柯达,398-60)。向此溶液中添加1克甲醇、0.5克去离子水和1克250、30μm二氧化硅。让该混合物在室温平衡2小时,然后再次混合。把一支1000μl大膛孔聚丙烯移液管插入一个常用P-1000 Pipetman吸移管管理器(Gilson)中并将体积调整设定到1000μl。把活塞压到底,将移液管端部放进浇铸溶液中。然后缓缓提升活塞,使该尖端部充满约5~10μl浇铸溶液。一旦该尖端部含有足够液体,就保持等压,并将该尖端部移去、拭去过量流体、把该尖端部放到一个支架上,使溶剂蒸发约16小时。在这段时间之后,该尖端部用约10μl蒸馏水洗涤。
实例9:热换相法制备的多孔聚乙烯中30μl二氧化硅端塞
在一个适用容器中,添加5克珠状聚乙烯和100克矿物油。混合物在一块加热板上搅拌加热到250℃。当该塑料液化时,添加4克250、30μm二氧化硅,充分混合。用一支有填料泡的1ml刻度玻璃移液管吸进50~100μl该熔体。一旦该尖端部含有足够液体,就保持等压,并将该尖端部移出、拭去过量塑料、让该尖端部冷却到室温。把移液管转移到二氯甲烷浴中1小时,以提取矿物油。然后将其移出、把二氯甲烷排出、使之风干。
实例10:肽样品制备用C18二氧化硅200μl移液管尖端部
由GlyTyr(1)、ValTyrVal(2)、甲硫氨酸脑啡肽(3)、亮氨酸脑啡肽(4)和血管紧张素II(5)组成的混合物(在100μl 0.1%TFA中)中每种肽各约2.5μg吸附到一支含有约5μl浇铸C18、200、15μm球状二氧化硅的P200移液管尖端部。将该溶液吸进、排出4次。然后,该尖端部用200μl 0.1%TFA洗涤。结合的肽用80%乙腈的0.1%TFA/水溶液洗脱。洗脱的肽用4份0.1%TFA稀释,用逆相HPLC(20分钟时间的线性乙腈梯度为5~30%)分析。然后,把得到的色谱图与原混合物的色谱图比较(见图6和7)。如所预料的,较小且相对亲水的GlyTyr、ValTyrVal并没有结构到C18上。其余3种(吸附)肽洗脱后的回收率范围为70~85%。
实例11:强阳离子交换二氧化硅200μl移液管尖端部
由5种肽(见实例10)组成的混合物(100μl 10%冰醋酸溶液)中每种溶质各约2.5μg吸附到一支含有约5μl浇铸、包覆了苯乙烯磺酸盐、300、15μm球形二氧化硅的P 200移液管尖端部上。吸附是在4个完整的吸进-退出循环期间进行的,随后用100μl 20%甲醇/10mMHCl冲洗。结合的样品用2×25μl体积的1.4N氢氧化铵/50%甲醇洗脱。洗脱的样品用逆相HPLC分析,得到的色谱图与原混合物的色谱图加以比较(见图6和8)。强阳离子交换的尖端部结合了除GlyTyr外的所有样品成分。这样的表现是与磺酸离子交换树脂的选择性一致的。
实例12:200μl移液管尖端部中的固定酶
胰蛋白酶以共价方式偶合到一种醛活化的300、15μm球形二氧化硅上,并就地浇铸(20μl)到蛋白质消解用P 200尖端部中。该尖端部内的胰蛋白酶活性是通过用HPLC监测细胞色素的消解来评价的。在15分钟内使细胞色素C的样品(100μl 100mM Tris、1mMCaCl2、37℃pH8溶液中10μg)吸收到该尖端部中,利用对一支Eppendorf管的排出/吸进循环,使反应物混合4次。消解物用HPLC分析,采用了在30分钟内5~45%乙腈的线性梯度(见图10)。得到的色谱图显示,15分钟后消解了细胞色素C的90%以上(未消解细胞色素C的情况见图9)。
实例13:200μl移液管尖端部中的固定蛋白质A
将重组体蛋白质A偶合到预浇铸的、含有醛活化的300、15μm球形二氧化硅、兔免疫球蛋白(IgG)分离用的P 200尖端部中。RIP缓冲剂(150mM NaCl,1%NP-40,0.5%DOC,0.1%SDS,50mMTris,pH8.0)中1mg/ml IgG和BSA的样品100μl,通过一支含有40μl含有蛋白质A固定珠的浇铸体积的尖端部循环6次。然后,该尖端部在洗脱前用4倍体积的RIP缓冲剂洗涤。结合的IgG的脱附是用(2×25μl体积)的6M脲进行的。脱附的样品用50μl 2×SDS Laemmli样品缓冲剂稀释,并在电泳分析之前煮沸3分钟。这个实验方案也对只含有聚砜而不含有珠子、起背景对照作用的空白尖端部进行。电泳是在所示的10~16%丙烯酰胺凝胶(见图11)进行的。样品如下:道9:(分子量刻度);道1~4:蛋白质A尖端部洗脱样品的数量递增;和道5~8:从空白聚矾尖端部洗脱的IgG/BSA的数量递增。这些结果表明IgG对蛋白质A尖端部的选择性结合有微不足道的非专一性吸附。进而,在洗涤剂(RIP缓冲剂)的存在下,空白尖端部(道5~8)无论对IgG还是对BSA都不显示吸附作用。
实例14:超卷曲DNA用60、10μm 1000μl移液管尖端部
含有质粒pUC 19的大肠杆菌株JM 109在3~5ml含有100μg/ml氨苄青霉素的Luria液体培养基中在37℃生长12~16小时。1.5ml过夜培养物在室温下在以最大g力旋转的微型离心分离管中沉降30秒钟。除去残余生长介质,而保持细菌性片状沉淀物原封不动。然后,利用改进的Birnboim和Doly的碱性溶菌程序(Birnboim,H.C.and Doly,J.(1979),Nucleic Acids Res 7.,1513)分离质粒DNA。简而言之,这种细菌性片状沉淀物通过涡旋重新悬浮于50μl 50mM葡萄糖、25mM Tris-HCl(pH8.0)、10mM EDTA和10μg/ml核糖核酸酶A中。其次添加100μl 0.2N NaOH、1%硫酸十二烷酯钠。得到的悬浮液在室温下温育2小时。在添加100μl 3M乙酸钠溶液(pH4.8)之后,悬浮液通过涡旋混合,然后在微型离心分离管中以最大g力旋转2分钟。把清澈的溶菌产物转移到一支新的微型离心管中,向其中添加pH5.6、在200mM 2-(N-吗啉代)乙烷磺酸(MES)中的7M盐酸胍(GuHCl),使最终浓度和体积分别为4.4M和700μl。把所得到的溶液用吸移管管理器吸进一支有约60μl含有约60、10μm硅胶的浇铸膜的1000μl聚丙烯移液管尖端部中。用2~2.5分钟时间将该溶液吸进-排出,以使DNA溶液与二氧化硅膜基体之间有长时间相互作用。然后,该尖端部用400μl 80%试剂级醇冲洗一次。残留的醇通过重复驱赶到纸巾上来去除。用100μl 10mM Tris-HCl(pH 8.0)、1mMEDTA(TE),通过吸进-排出三遍,从该尖端部上洗脱质粒DNA。洗脱液级分用TE调整到最终体积为100μl。评估了6个尖端部。为了定量质粒DNA回收率,用琼脂糖凝胶电泳(见图12)分析了20%的洗脱液以及20%的未结合滤液。该凝胶上包括的是已知浓度的pUC 19质粒DNA样品(道1~4)。这些实验的结果表明,平均回收了2.5mg超卷曲质粒(道5、7、9、11)。
实例15:线型DNA用大膛孔200μl移液管尖端部中的60、10μm二氧化硅
评价了含有约20μl浇铸的、填充了60、10μm二氧化硅的膜的200μl聚丙烯大膛孔移液管尖端部结合线性化DNA碎片(pBR 322或者用BstNI或者用MspI消解,以产生DNA碎片梯子)或者用PstI和HamHI限制的质粒pBR 322 DNA(产生大的线性限制碎片)的能力。5μg线性化质粒DNA与MES中的GuHCl,pH5.6合并,达到最终浓度为0.5M,体积为150μl。使用前,含有二氧化硅膜的P-200尖端部用(2%)200μl MES中0.5M GuHCl,pH5.6预平衡。把DNA/GuHCl溶液吸进移液管尖端部,并且吸进-排出循环1.5~2.0分钟,使得在DNA结合混合物与二氧化硅填充膜基体之间能长时间相互作用。然后,这些尖端部用125μl 80%试剂级醇洗涤,以除去盐及其它污染物。结合的DNA是用100μl TE通过吸进-排出3遍而从尖端部基体洗脱下来的。为了测定DNA回收率,用琼脂糖凝胶电泳(见图13)分析洗脱液和滤液。为了定量DNA的回收量,在道1~4中测定了代表起始原料的100%、75%、50%和25%的样品。道5、7、9和11是洗脱液。带强度的估计值表明回收率超过95%。
实例16:PCR放大DNA用大膛孔200μl移液管尖端部中的气相法二氧化硅
评价了PCR放大的DNA(500bp)纯化用的、含有约20μl固定于聚砜基体中的气相法二氧化硅的200μl大膛孔聚丙烯移液管尖端部的能力。使用前,尖端部用100μl TE缓冲剂冲洗2遍,然后与500μl200mM MES缓冲剂(pH6.4)中的3M NaI平衡。然后,把取自所收集的PCR料液的50μl样品(约3μg DNA)与7M NaI合并,使最终NaI浓度为3.0M。添加NaI溶液后的总体积是150μl。用2~3分钟时间,将此样品吸进和排出含有填充了气相法二氧化硅的浇铸膜的P-200尖端部,使得能与该基体长时间接触。然后,每个尖端部用125μl80%试剂级醇洗涤,以除去盐及其它污染物。通过把尖端部内容物排到纸巾上,除去残留的醇。结合的PCR产物用50μl TE(pH8.0)洗脱。为了估计DNA回收率,用琼脂糖凝胶电泳(见图14)分析了洗脱液和滤液。作为对照,在道1~4中显示了代表起始原料的100%、75%、50%生25%的负荷。请注意,较低带的存在表明轻微的引物二聚体污染。固定的气相法二氧化硅与NaI一起使用显然使放大的DNA回收率超过90%。此外,显然引物二聚体污染物也减少了(见道5、7、9、11)。
实例17:DNA分离用200μl移液管尖端部中含有松散30μl二氧化硅的浇铸多孔端塞
含有约5~10μl浇铸(7.5%)聚砜作为多孔端塞和2~4mg松散250、30μm二氧化硅的200μl移液管尖端部,进行了其结合线型和超卷曲质粒DNA的能力的试验。关于线型DNA,大约5μg pBR 322首先在45μl TE(10mM Tris-HCl,1mM EDTA)、pH8.0溶液中用MspI消解,然后与100μl 200mM MES缓冲剂(pH5.6)中的7M盐酸胍(GuHCl)合并。该溶液中GuHCl的最终浓度是4.7M。所得到的溶液(一次)吸进200μl移液管尖端部中,通过使吸移管管理器与插入的尖端部颠倒约2分钟,使之能长时间接触二氧化硅。然后,如同实施例15中所述,使吸附到尖端部上的DNA洗涤和洗脱下来。作为对照,在道1~4中做了代表起始原料的100%、75%、50%和25%的负荷。利用这种格式的实验结果表明可以达到75%以上的DNA回收率(见图15道5和7)。
Claims (31)
1.一种界定某一体积的壳体,所述壳体在所述体积的一部分中含有一种三维结构,其中包含许多截留在一种多孔聚合物基体中的吸附性颗粒,所述结构的形态比小于约10。
2.权利要求1的壳体,其中所述壳体有第一个开口端和与所述第一个开口端隔开的第二个开口端,且其中所述三维结构是与所述第二开口端邻接的。
3.权利要求1的壳体,其中所述形态比小于5。
4.权利要求1的壳体,其中含有所述结构的所述体积的所述部分是约0.1微升~约10毫升。
5.权利要求1的壳体,其中所述壳体是一支移液管尖端部,该端部有一个第一端和一个与所述第一端隔开的第二端以及介于两者之间的所述结构。
6.权利要求5的壳体,其中所述第一端的内径大于所述第二端的内径。
7.权利要求1的壳体,其中所述聚合物是从聚砜、聚醚砜、聚四氟乙烯、乙酸纤维素、聚苯乙烯、聚苯乙烯/丙烯腈共聚物和PVDF组成的一组中选择的。
8.权利要求7的壳体,其中所述聚合物是聚砜、且其中所述壳体包含一种聚烯烃。
9.权利要求8的壳体,其中所述聚烯烃是聚丙烯。
10.权利要求1的壳体,其中所述颗粒是从聚苯乙烯-二乙烯基苯珠、官能化聚乙烯-二乙烯基苯珠、二氧化硅、气相法二氧化硅、衍生化二氧化硅和活性炭组成的一组中选择的。
11.权利要求1的壳体,其中所述三维结构包含一个半渗透阻挡层(屏障)。
12.在一个壳体中浇铸一种复合结构的方法,所述方法包括:
形成一种聚合物溶液;
把颗粒添加到所述溶液中,形成一种浇铸溶液;
把所述浇铸溶液引进所述壳体中;和
使所述浇铸溶液发生换相,从而使所述聚合物形成一种包含所述颗粒的多孔聚合物基体。
13.权利要求12的方法,其中所述溶液是通过使所述聚合物溶解在一种溶剂中形成的。
14.权利要求12的方法,其中所述溶液是通过使所述聚合物溶解在所述聚合物的一种溶剂和非溶剂的混合物中形成的。
15.权利要求12的方法,其中所述换相是通过使所述壳体中的所述浇铸溶液接触一种所述聚合物不溶于其中的液体引起的。
16.权利要求12的方法,其中所述换相是通过所述溶剂的蒸发引起的。
17.权利要求12的方法,进一步包括人所述壳中取出所述多孔聚合物基体,并将所述多孔聚合物基体引进到第二个壳体中。
18.在一个壳体中浇铸一种膜的方法,所述方法包括:
形成一种聚合物溶液;
把所述溶液引进所述壳体中;和
使所述溶液发生换相,从而使所述聚合物在所述壳体中沉淀。
19.权利要求18的方法,其中所述溶液是通过使所述聚合物溶解在一种溶剂中形成的。
20.权利要求18的方法,其中所述换相是通过使所述壳体中的所述溶液接触一种所述聚合物不溶于其中的液体引起的。
21.权利要求18的方法,进一步包括取出在所述沉淀期间形成的任何半渗透阻挡层。
22.一种界定某一体积的壳体,所述壳体在所述体积的一部分中含有一种三维结构,该结构包含一种多孔聚合物基体,所述结构的形态比小于约10。
23.权利要求22的壳体,其中所述壳体有一个第一开口端和一个与所述第一开口端隔开的第二开口端,且其中所述结构是与所述第二开口端邻接的。
24.权利要求22的壳体,其中所述形态比小于5。
25.权利要求22的壳体,其中含有所述结构的所述体积的所述部分是约0.1微升~约10毫升。
26.权利要求22的壳体,其中所述壳体是一支移液管尖端部,该端部有一个第一端和一个与所述第一端隔开的第二端以及介于两者之间的所述结构。
27.权利要求26的壳体,其中所述第一端的内径大于所述第二端的内径。
28.权利要求22的壳体,其中所述聚合物是从聚砜、聚醚矾、聚四氟乙烯、乙酸纤维素、聚苯乙烯、聚苯乙烯/丙烯腈共聚物和PVDF组成的一组中选择的。
29.权利要求28的壳体,其中所述聚合物是聚砜,且其中所述壳体包含一种聚烯烃。
30.权利要求29的壳体,其中所述聚烯烃是聚丙烯。
31.权利要求22的壳体,其中所述三维结构包含一种半渗透阻挡层。
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CN110505906A (zh) * | 2017-01-10 | 2019-11-26 | 得克萨斯州A&M大学系统 | 甲磺酸介导的共轭多孔聚合物网络的无溶剂合成 |
CN108970659A (zh) * | 2017-05-31 | 2018-12-11 | 希森美康株式会社 | 固液分离方法和装置及在其中使用的移液器吸头、粒子及试剂盒 |
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US20020185428A1 (en) | 2002-12-12 |
US6048457A (en) | 2000-04-11 |
IL155971A0 (en) | 2003-12-23 |
IL131315A (en) | 2003-11-23 |
AU6186198A (en) | 1998-09-18 |
JP4320140B2 (ja) | 2009-08-26 |
WO1998037949A1 (en) | 1998-09-03 |
AU722581B2 (en) | 2000-08-10 |
DE69807240T2 (de) | 2003-03-27 |
CA2279363C (en) | 2002-08-20 |
JP2000515066A (ja) | 2000-11-14 |
CA2279363A1 (en) | 1998-09-03 |
EP1015098A1 (en) | 2000-07-05 |
IL155971A (en) | 2007-03-08 |
JP3941842B2 (ja) | 2007-07-04 |
JP2002263451A (ja) | 2002-09-17 |
US6200474B1 (en) | 2001-03-13 |
DE69807240D1 (de) | 2002-09-19 |
IL131315A0 (en) | 2001-01-28 |
US6830717B2 (en) | 2004-12-14 |
IL153737A (en) | 2006-07-05 |
ATE222141T1 (de) | 2002-08-15 |
EP1015098A4 (en) | 2000-08-09 |
US6635201B1 (en) | 2003-10-21 |
CN1137761C (zh) | 2004-02-11 |
US6875354B1 (en) | 2005-04-05 |
EP1015098B1 (en) | 2002-08-14 |
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