CN106442039A - 用于样品采集的装置、溶液和方法 - Google Patents
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- CN106442039A CN106442039A CN201610647029.8A CN201610647029A CN106442039A CN 106442039 A CN106442039 A CN 106442039A CN 201610647029 A CN201610647029 A CN 201610647029A CN 106442039 A CN106442039 A CN 106442039A
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- G—PHYSICS
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- G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
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- A—HUMAN NECESSITIES
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- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
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Abstract
本发明涉及用于采集和处理含有细胞的体液样品的装置、溶液和方法(以及用于采集和处理和/或分析包括有毒和/或有害物质/流体在内的其它液体的实施方案)。另外,本发明总体上涉及功能基因组研究并涉及从唾液和其它体液(例如尿)中分离和保存细胞,用于细胞分析。对于体液采集装置,一些实施方案包括两个配合部分,盖和管(例如),其中在一些实施方案中,所述盖包括用于装有样品保存溶液的密闭的内部空间并与管配合以构成(密闭的)样品采集装置。一旦配合之后,保存溶液流入密闭的内部空间以保存在体液中的细胞。所述管设计成接收供体的体液(例如唾液、尿)样品,然后其可经历处理以提取多种细胞。多种细胞可被进一步处理以分离其中的一个和/或另一个细胞类型。可分析多种细胞以及所分离的细胞类型,用于功能基因组和表观遗传研究以及生物标记的发现。
Description
本申请是申请日为2012年6月19日,申请号为201280040239.0 (PCT/US2012/043176),发明名称为“用于样品采集的装置、溶液和方法”的发明专利申请的分案申请。
相关申请
本申请根据35 USC §119(e),要求于2011年6月19日提交的美国临时专利申请号61/498,584、2012年2月14日提交的61/598,601、和2012年2月14日提交的61/598,618的优先权。其各自的公开内容通过引用以其整体结合到本文中。
发明领域
本发明涉及用于采集体液或其它物质(包括有害的和/或有毒的物质)的样品,尤其是天然表达的体液(例如唾液、尿)的样品的装置、溶液和方法。另外,本发明总体上涉及功能基因组学并涉及从所述体液中分离并保藏细胞,用于研究以下任一个:功能基因组和表观遗传研究以及生物标记的发现(例如)。
背景
个性化医疗是为个人定制的治疗,与一种治疗全部的模式相反。个性化医疗包括根据患者的身体条件对他或她进行归类并且专门为了该类而设计最佳的健康解决方案。个性化医疗的发展取决于生物标记的发现、确认和商业化,所述生物标记对群体进行分层用于治疗并用于筛选和早期检测的诊断学的开发。
表观遗传研究已经到达医学研究的前沿并且涉及到包括以下在内的多种身体上的和精神上的疾病的病因学:癌症、肥胖症、糖尿病、精神分裂症和阿尔茨海默病(Alzheimer’s disease) (Alika等人, 2010;Grant等人, 2010;McGowen等人, 2009;McGowen和Szyf, 2010;Plazas-Mayorca和Vrana, 2011;和Portela和Esteller, 2010)。另外,表观遗传学可以在许多科学和医学领域上具有特别的前景,所述领域包括但不限于:癌症、糖尿病、药物整合(drug integration)、药物有效性、儿童期侵犯、自杀行为、老化、炎症、疼痛、肥胖症、精神分裂症和其它精神疾病(Abdolmaleky等人, 2005;Costa等人,2003;Iwamoto & Kato, 2009;Kuratomi等人, 2007;McGowan & Kato, 2007;McGowen和Szyf, 2010;Peedicayil, 2007;Petronis等人, 1999;McGowen和Szyf, 2010;Plazas-ˇMayorca和Vrana, 2011;和Zawia等人, 2009)。
在本领域的一个重大挑战包括对基于家庭的样品采集的合适原始材料的鉴定,其适合于大规模表观遗传研究(包括全-基因组-分析研究)。表观遗传学可能是理解基因-环境相互作用机制的关键,因为不断增加的证据表明表观遗传机制可能提供环境经历的分子记忆(Ho, 2010;Kappeler和Meaney, 2010;McGowen等人, 2009, McGowen和Szyf, 2010;Portela和Esteller, 2010;Richards, 2008;Russo等人, 2010;Tsai等人, 2010;和Vlaanderen等人, 2010)。来自某些人类的初步数据表明,外周血细胞中的独特甲基化模式与包括以下在内的社会性行为相关:儿童期侵犯、自杀行为和老化(Kappeler和Meaney,2010;McGowen等人, 2009;McGowen和Szyf, 2010;Portela和Esteller, 2010;Russo等人,2010, Tierling等人, 2010;Tsai等人, 2010;和Zhang等人, 2011)。
至少部分地因为人类疾病(尤其是精神疾病)的多样性,以及起作用的病因学因素的复杂相互作用,所以研究需要大的样品量以提供可靠的和显著的结果。然而,目前对于表观遗传研究的样品采集的研究选择不满足对“大的样品量”的这一需要。为在研究人类-环境相互作用中产生显著结果,对用于研究的大的样品量的需要同样是确切的,因为这些相互作用也具有非常复杂的特点,具有许多起作用的因素。进行大规模“群体量”(受试样品数量至少在数百至数千)表观遗传研究的能力可引入对人类-环境相互作用的新的理解并促进纵向研究的完成,便于开发对现代医学发展而言至关重要的基于表观遗传的筛选诊断学。这种表观遗传研究可导致对环境如何影响我们的表观基因组和这如何涉及个人健康后果的新的理解,这可进一步导致对被认为具有高度风险的个体预防性干预以及对这些健康差异的诊断学(包括但不限于诊断)的开发。
试图定量测定人群中环境和其它复杂的相互作用的某些表观遗传研究采用血液作为实验的原始材料。血液可限制研究人员进行大群体量研究的能力,因为它:
1. 通常需要医学监督,
2. 涉及有创性的采集程序,
3. 带有限制参与的烙印(stigma),和
4. 采集和运送昂贵。
天然表达的体液,例如唾液和尿,可以是基于家庭的样品采集的另外或替代的合适原始材料,因为它们:
1. 不需要有创性技术,
2. 没有像血液那样的烙印,
3. 不需要专业监督,和
4. 可以便宜地采集。
另外,已经证明至少唾液含有白细胞(Dos-Santos等人, 2009)。体液例如唾液、尿的使用,可使大规模“群体量的”表观遗传研究成为可能。另外,基于家庭的唾液或尿的样品采集,可以允许更宽范围的可用研究选择,因为这能大大增加参与者数量并可由受试者从世界的任何地方更容易地运送样品。例如,当样品来自没有实验室基础设施的国家时,从世界的任何地方更容易地运送样品的能力是特别有用的。
一个生物体的基因组是固定的序列,其含有它的遗传信息并且在该生物体的每个细胞中都是相同的。相反,生物体的表观基因组在各细胞类型间不同,而且随该生物体一生而变化。因此,表观遗传研究可包括单个细胞类型作为样品材料来源,以控制这些差异(Johnson和Tricker, 2010;Lister等人, 2009;和Rangwala等人, 2006)。例如,人的唾液含有大量细胞类型,包括上皮细胞、血液中正常存在的细胞(即T细胞和B细胞)、细菌和碎片(Dos-Santos等人, 2009和Viet和Schmidt, 2008)。对于表观遗传剖析(profile)而言最重要的唾液中的细胞是来自血流的那些,因为这些细胞携带来自整个机体的表观遗传信息(Kappeler和Meaney, 2010;McGowen和Szyf, 2010;McGowen和Szyf, 2010;Righini等人,2007;Rosas等人, 2011, Vlaanderen等人, 2010和Zhang等人, 2011)。
另外,使用全唾液DNA可能是不切实际的,因为在血液中不存在的唾液中细胞,例如构成唾液中细胞绝大部分的上皮细胞(Dos-Santos等人, 2009),通过抑制少数细胞的效应而具有“掩蔽”在T细胞(起源于血液中的细胞)中所见的表观遗传效应的能力(DosSantos等人, 2009, Lister等人, 2009;和Tierling等人, 2010)。为了解决这些问题,AboGen开发出一种方法,通过利用细胞特异性标记和分离技术(例如磁力)以分离和提取体液例如唾液中存在的不同细胞类型。该方法采用实用数量的体液(例如唾液),以得到富集的细胞,其可用于下游生物学应用,包括大规模功能基因组研究(例如表观基因组研究)。例如,唾液样品处理技术允许将所采集的样品处理成为单一细胞类型并使它们的表观基因组得以剖析。
此外,对于下游实验,唾液(和其它体液)作为原始材料进行血细胞的细胞分离可能是个挑战,原因如下:
1. 血液是运输液,而唾液是富含蛋白酶、酶和分泌物质的消化液,尿是由不想要的废品组成的排泄液。
2. 某些液体可具有宽的pH范围,而某些的pH值,例如对于唾液所报道的pH值,如果血液达到该pH值时就会导致死亡(唾液是6.2-7.4;尿是4.5-8;血是7.35-7.45)。
3. 某些液体与血液相比含有更多细菌。
4. 某些液体含有非细胞物质,其在个体间不同且干扰细胞分离。
5. 某些液体包含血细胞(例如T细胞),其可在血中含量丰富,但在其它天然表达的体液例如唾液或尿中可能稀少,并且被其它细胞类型例如上皮细胞的数量大大超过,不象在血液中。
6. 某些体液例如唾液中的淋巴细胞亚类,与在血液中的那些细胞类型的群体有很大差异。例如,已报道仅CD4+CD8- T细胞在唾液中存在。
7. 某些液体每天都在产生,例如唾液以每人每天大约0.5-1.5升的速率产生。
因此,需要新的方法用于从唾液和其它天然表达的体液中分离稀少细胞(即T细胞)。
为了从广泛地理分布的大量人群中采集唾液样品(实例:功能基因组研究),对于最佳的样品采集装置,可能需要满足若干要求。例如,具有将有毒保存溶液安全贮藏在密闭小室中的样品采集装置可能是有益的。另外,可将具有安全密闭的有毒溶液的样品采集装置送达供体。所述样品采集装置还可允许容易和安全地采集供体标本,例如人的唾液或尿,而供体无需冒着暴露给有毒溶液的风险。此外,所述样品采集装置可以允许供体安全地混合有毒溶液和标本(用于标本的保存),而供体无需冒着暴露给有毒溶液或任何其它危害的风险。所述样品采集装置还可允许供体在将所述样品采集装置安全密封之后将所述样品采集装置送到实验室,用于通常“按照原样(as-is)”进行处理。最后,所述样品采集装置可以进一步允许实验室技术人员接收所述样品采集装置并安全地打开它进行处理,而通常无需冒着暴露给任何危害的风险。
一些目前可用的样品采集装置包括,例如,美国专利号7,482,116,其描述了利用分离的屏障以允许装有供体样品的腔(cavity)和溶液之间的液体交流的装置,然而,该专利中包括的实施方案局限在使用尖锐突出物体和薄的可穿透的膜。因为任何错误操作(例如用指甲)可导致膜的穿透并释放溶液,因此所述薄的可穿透的膜可呈现出对样品供体的安全性风险。美国专利公布号2009/0216213 A1要求保护利用可穿透的膜以在含有溶液的腔和供体样品之间建立液体交流的装置。因为任何错误操作可导致膜的穿透并暴露溶液,因此这可呈现出对样品供体的安全性风险。所述装置还需要在将样品送给终端用户之前更换盖子。因为其将样品供体暴露给潜在有毒溶液,因此这可呈现出安全性风险。因此,需要更安全和更容易地使用样品采集装置。
另外,纯化过程需要细胞维持它们的抗原特性并且表观基因组剖析需要它们的表观基因组被维持。最终,有必要以这样的方式处理细胞,使其能够通常维持这些特征。目前可用的处理通常不满足这一需要。例如,美国专利7,267,980和7,749,757公开了含有赖氨酸、甘氨酸和甲醛的溶液,用于使来自血液的细胞稳定。然而,这些溶液不能保护细胞免于某些体液例如唾液中存在的蛋白酶作用。因此,需要新的溶液和方法,其能在其它体液例如唾液中保存细胞的抗原性和表观基因组。
发明概述
本发明的实施方案提供更安全和容易地使用用于天然表达的体液(例如)的样品采集装置,以及用于保存所采集样品的细胞的溶液和方法,并另外提供用于分离采集的和/或保存的特定细胞的方法。随后可分析所述分离的细胞(和甚至未分离的采集细胞),用于研究以下任一个:功能基因组和表观遗传研究以及生物标记发现(例如)。
本发明的样品采集装置提供优于现有可用的样品采集装置的若干优势。例如,在一些实施方案中,所述样品采集装置使用最小量的部件和不需要移除或更换其零部件或物体。在一些实施方案中,所述样品采集装置不需要由样品供体进行任何额外操作,除了将样品放置在所述样品采集装置中并关闭所述样品采集装置之外。在一些实施方案中,所述样品采集装置的使用对于样品供体和最终用户两者都提供了改进的安全性,因为例如,不包含尖锐物体并且限制在没有暴露给有毒溶液(例如样品保存溶液)的任何风险。
在所述样品采集装置的一些实施方案中,所述样品采集装置可具有两个主要的配合部分(mating bodies),盖和管。所述盖可包括装有保存溶液的密闭的腔,其可与所述管配合以构成密闭的样品采集装置。所述管可被设计为用于接收供体标本。所述盖和管被设计使得当供体放置标本并用所述盖关闭所述管时,装有保存溶液的腔可被打开,以释放保存溶液并允许将它与供体标本混合。
在某些实施方案中,提供了用于采集天然表达的体液的体液样品采集装置并且所述装置包括盖,所述盖具有带有接合构件(engagement member)的外壁以及装有液体的内部小室。所述小室可包括限定内部空间和孔隙的内壁,其中所述孔隙经设计用于被可移动的封闭构件密封。所述封闭构件可包括第一连接构件,其用于接合在管中的相应的第二连接构件,从而在将所述盖连接到所述管时导致所述封闭构件的移除和孔隙的打开。所述装置还包括管,其包括限定体液样品采集池的容器壁(containment wall)、与所述盖的接合构件互补的接合构件和所述第二连接构件。
在一些实施方案中,样品采集装置可提供以下部件中的一种和/或另一种:
- 可移动的封闭构件是盘状构件,其螺纹接合所述孔隙;
- 第一连接构件包括中心地位于所述封闭构件底部中的凹痕(indentation),第二连接构件中心地位于所述管中;
- 第一连接构件包括偏离中心地位于所述封闭构件底部中的凹陷(recess),第二连接构件偏离中心地位于所述管中;
- 所述可移动的封闭构件包括其中具有排列于其上的螺纹的环形构件,其中所述环形封闭构件完全覆盖所述孔隙,并且所述盖的内壁包括互补的螺纹,使得可将所述环形构件螺旋拧到内部空间中以打开孔隙;
- 锁闭机构,以将所述盖锁闭到所述管(或将任意两个组件锁闭在一起),所述锁闭机构可包括楔子和互补的凸缘;
- 密封机构,其可包括与所述盖的接合构件相关联的密封物质,其中当所述盖一旦连接到所述管之后,所述密封物质至少流入所述盖的接合构件;
- 用于确定所述盖是否已被打开的防拆封工具,其可包括其第一部分与所述盖的开口端整合的环,其中当所述盖一旦连接到所述管时,所述环位于所述管附近;这样,在一些实施方案中,一旦所述盖与所述管脱离,第一部分被破坏并且所述环仍然基本上在所述管附近;和/或
- 所述盖小室内的液体包含用于保存细胞的溶液。
在一些实施方案中,提供了用于采集天然表达的体液的体液样品采集装置,并且所述装置包括盖和管,所述盖具有用于装有液体的内部小室和第一接合构件,所述管包括限定样品采集池的容器壁和用于接合第一接合构件的第二接合构件。在一些这样的实施方案中,所述盖包括具有第一接合构件的外壁,所述小室包括限定装有液体的内部空间和孔隙的内壁,所述孔隙经设计用于被可移动的封闭构件密封。另外,在一些实施方案中,所述封闭构件包括第一连接构件,用于接合所述管的相应的第二连接构件,一旦所述盖连接到所述管时,所述封闭构件被移动且孔隙打开。
在某些实施方案中,提供了用于采集天然表达的体液(或有毒或有害液体)的样品的方法,并且所述方法包括:提供所公开的样品采集装置实施方案中任一个的体液采集装置,将体液放入所述小室中,并将所述盖和管配合在一起使得所述相应的接合构件接合,其中所述封闭构件移动且保存液体流入含有体液的池中,使得体液中含有的细胞得以保存用于分析。在一些这样的实施方案中,进一步的步骤可包括以下至少一个(对于体液):对于体液中的多种细胞类型,分离一种或多种细胞类型,并分析所采集的细胞。
正如本领域技术人员所理解,在一些实施方案中,可从所采集/保存的细胞(不管是分离的细胞还是未分离的细胞)中提取DNA、RNA和蛋白质中的至少一种。
在一些实施方案中,提供了用于采集天然表达的体液(或有毒和/或有害液体)的试剂盒,并且所述试剂盒包括依据所公开的样品采集装置的多个样品采集装置。
另外,本发明涉及功能基因组研究,包括表观遗传研究。更具体地讲,本发明还涉及从体液(例如唾液和尿)中分离细胞,用于这些研究。因此,本发明的一些实施方案包括用于保存细胞的抗原性和表观基因组的方法,并且本文公开了从体液例如唾液和尿中分离稀少细胞(包括但不限于T细胞)的方法。
如本文所用,“体液”的采集通常是指天然表达的体液的采集(尽管一些实施方案可用于静脉内采集方法例如血液的采集)。因此,对于本发明的实施方案,“体液”是指天然表达的体液,包括例如唾液和尿。
例如,在一些实施方案中,提供了用于保存体液例如唾液和尿中的细胞的溶液,用于进一步分离成细胞类型和下游分析,其允许唾液中的细胞在贮存期间保留它们的抗原性和细胞结构。所述溶液可含有至少一种化学固定剂例如但不限于低聚甲醛,和至少一种蛋白酶抑制剂。在一些实施方案中,所述溶液可进一步含有例如以下的一种或多种:至少一种抗微生物剂、来自人和/或其它动物物种的血清蛋白。所述溶液可被缓冲在pH介于大约6.4至约8.4之间,在一些实施方案中介于大约7.2至约7.6之间。
在一些实施方案中,用于保存一种或多种体液中的细胞的方法包括使所采集的细胞与本发明的一个和/或另一个实施方案的溶液接触,例如所述溶液允许所述细胞保留它们的抗原性和表观基因组。
在一些实施方案中,用于从采自体液例如唾液或尿的经化学固定的细胞中分离细胞的方法,并且包括离心所述细胞以便从细胞、细菌和碎片的沉淀中分离例如DNA和/或其它可溶性材料,从沉淀的其它内容物中富集白细胞,并且使用靶向细胞特异性标记的缀合到磁珠的抗体来分离特定细胞(例如白细胞)。
在一些实施方案中,用于从一种或多种体液(例如唾液和/或尿)中分离特定类型的细胞例如一类白细胞(例如淋巴细胞)的方法,并且包括一个或多个以下步骤(并且,根据实施方案,若干或所有以下步骤):提供包含化学固定的细胞的体液样品,任选离心所述体液样品以获取包含细胞的沉淀,任选将所述沉淀重悬于缓冲液中,使重悬的沉淀经历密度梯度分离,以获取一层白细胞类型混合物(包括淋巴细胞),使细胞类型混合物与含有对特定类型的白细胞上存在的表位具有特异性的结合剂的溶液接触,并且从白细胞类型混合物中分离所述特定类型的白细胞(包括淋巴细胞)。
在一些实施方案中,所述特异性结合剂可以是连接到抗体上的磁珠,所述抗体对特定类型的白细胞上存在的表位具有特异性,并且在分离步骤中可随后包括例如从白细胞类型混合物中经磁力分离特定类型的白细胞(包括淋巴细胞) (尽管其它细胞分离技术在本发明的范围之内)。
在一些实施方案中,可将体液(例如唾液、尿)与化学固定溶液混合,并可从沉淀中除去混合物。然后可将所述沉淀重悬于缓冲液中。重悬的沉淀可以任选地经离心和在缓冲液中洗涤一次或多次。然后将经洗涤的沉淀施加到亲水性多糖混合物中,以形成梯度。该梯度可以是不同于对于血液所用的,因为在用于保存的化学固定之后,在其它体液(例如唾液、尿)中的细胞密度可以是不同的,这是因为对于通过该密度梯度而待处理的细胞而言,所保存细胞的不同密度需要时间、温度、和/或梯度密度上的改变。
另外,在一些实施方案中,白细胞在梯度中可形成一层。可从梯度中提取白细胞层并放在另一离心管中,其中可将其在缓冲液中洗涤并重新沉淀,以除去残留的梯度混合物。然后可将沉淀重悬并在含有抗体的缓冲液中孵育,所述抗体缀合在磁珠上并且对所分离的细胞类型的特异抗原具有特异性。在一些实施方案中,所分离的细胞类型是T细胞,所述抗原是T细胞-特异性抗原。在一些实施方案中,所述抗原是CD4。在缓冲液中重悬的细胞可被所述抗体结合并经历磁场,所述磁场将与抗体-缀合的磁珠结合的细胞磁性吸引到管的侧面。然后可从管中去除残余液体并将管在缓冲液中洗涤。然后所分离的T细胞依旧吸引在管的侧面,并准备进一步处理,例如冷冻用于后期下游实验(例如)。
在一些实施方案中,用于在天然表达的体液中保存细胞的方法包括使体液与所公开的实施方案的任一个的保存溶液接触。
根据以下附图、详述和权利要求书,将会更好地理解样品采集、保存、分离和分析的装置、溶液和方法。在不同附图中的同样的参考符号表明同样的要素。
值得注意的是,尽管阐明了本文所公开的样品采集装置的一些实施方案用于采集体液,但同样也可具体用于采集任何其它物质,包括有害和/或有毒液体。
附图简述
图1显示本发明的一些实施方案的样品采集装置,其包括盖和管。
图1A是沿着图1的线1A-1A的横截面视图,显示依据本发明的一些实施方案的盖的内部小室,其包括限定内部空间和孔隙的内壁。
图1B是沿着图1A的线1B-1B的横截面视图,显示依据本发明的一些实施方案中心地位于管内的连接构件。
图2A显示依据本发明的一些实施方案的样品采集装置的纵向横截面视图,其中盖含有具有可移动的封闭构件的内部小室,所述构件具有偏离中心位置的连接部件,其可与偏离中心地位于管内的连接构件配合。
图2B是沿着图2A的线2B-2B的横截面视图,显示依据本发明的一些实施方案偏离中心地位于管内的连接构件。
图3A显示依据本发明的一些实施方案的样品采集装置的盖的实施方案,其中所述盖含有具有可移动的环形构件的内部小室,所述环形构件可覆盖内壁中的孔隙。
图3B显示依据本发明的一些实施方案的样品采集装置的实施方案,其中将所述盖连接到管,并且将可移动的的环形构件移至不覆盖内壁中的孔隙的位置。
图3C是图2B中所示的管的俯视图,显示依据本发明的一些实施方案位于管内的连接构件。
图4A显示依据本发明的一些实施方案的样品采集装置的实施方案,所述装置包括位于盖和管内侧的锁闭机构,当所述盖连接到管之后,所述锁闭机构阻止了至少供体移动盖。
图4B显示图4A中所示的依据本发明的一些实施方案的样品采集装置中的锁闭机构,其显示锁闭的结构和未锁闭的结构。
图5A显示依据本发明的一些实施方案的样品采集装置,所述装置包括位于盖和管外表面上的锁闭机构,当所述盖连接到管之后,所述锁闭机构阻止了至少供体移动盖。
图5B显示图5A中所示的依据本发明的一些实施方案的样品采集装置中的锁闭机构,显示锁闭的结构和未锁闭的结构。
图6显示依据本发明的一些实施方案的进一步包括含有密封溶液的密封腔的样品采集装置,当所述盖连接到管时所述溶液释放到盖和管的接合部件,当所述盖连接到管之后,其阻止了至少供体移动盖。
图7A显示依据本发明的一些实施方案的“防拆封的(tamper-evident)”盖,其中当盖已在管上旋转/螺旋之后而移除盖时,所述盖底部的环形构件可与盖断开。
图7B显示图7A中所示的依据本发明的一些实施方案的“防拆封的”盖,显示环形构件与盖断开。
图8显示依据本发明的一些实施方案,在室温下贮存在化学固定溶液中0、1、2和7天之后的样品中DNA收率的时间进程,以及从各样品的T细胞中提取的DNA。
图9是显示与从血液中提取的T细胞收率相比每ml原料(例如体液样品)中提取的T细胞的相对收率的图。
图10显示依据本发明的一些实施方案,每ml唾液中分离的T细胞DNA的微克数的唾液剂量曲线。
实施方案的详述
本发明的实施方案包括用于采集样品例如体液的装置、溶液和方法,以及用于从采集的细胞(经化学固定或其它)中分离一种或多种细胞类型的方法。例如,在一些实施方案中,所述样品采集装置提供优于现有可用的样品采集装置的若干优势,并且另外,依据一些实施方案的样品采集装置使用最小量的零件并且所述装置不需要移除或更换其零部件或物体。此外,在一些实施方案中,所述样品采集装置可通常不需要由样品供体进行额外操作,除了放置样品并关闭采集装置之外。依据一些实施方案的样品采集装置包括对于样品供体和最终用户两者的改进的使用安全性,至少部分地是因为消除了尖锐物体并且暴露给有毒溶液的有限风险,正如以下所更详述。
在一些实施方案中,对于功能基因组和表观遗传研究以及生物标记发现,提供了用于从体液中保存和分离细胞的方法。另外,本发明提供了用于从体液(即唾液、尿)中分离稀少保存的细胞例如T细胞的装置、溶液和方法,亦正如以下所更详述。
样品采集装置的一些实施方案可包括两个配合部分,例如盖和管。在一些实施方案中,所述盖可包括用于装有保存溶液(其可以是有毒的)的密闭的腔,例如内部空间,其与所述管配合以构成密闭的样品采集装置。所述管可被设计为接收供体标本,例如一种或多种体液(例如唾液、尿)。在一些实施方案中,所述盖和/或管可以被设计使得当供体放置标本并用所述盖关闭所述管时,可装有保存溶液的盖中的腔可被打开,以释放保存溶液并允许将它与供体标本混合。
本领域技术人员将会理解,对于本文所述的采集装置的一些实施方案,所述装置可与附件组合使用,所述附件便于将标本放置在采集装置内,包括例如用于唾液采集的口腔适配器,用于尿采集的漏斗和软管等。
在一某些实施方案中,所述样品采集装置可包括具有内部螺纹的外壁的盖。另外,所述样品采集装置可包括用于装有液体的内部小室,所述小室包括壁,其限定内部空间和壁内带螺纹的孔隙。壁内的孔隙可以被可螺旋移动的封闭构件密封,其中所述封闭构件可包括用于接合在管中的连接构件的接合构件,从而在将盖螺旋拧到管上时(在一些实施方案中)导致所述封闭构件移动并打开孔隙。在一些实施方案中,所述样品采集装置可以进一步包括管,其包括限定用于样品采集的内腔或池的容器壁、与盖的外壁的内部螺纹互补的外部螺纹和形状与盖的接合构件互补的连接构件。
在一些实施方案中,所述可螺旋移动的封闭构件可以是盘状构件,当将盖旋转或螺旋拧到管上时,所述盘状构件是推进、旋转、螺旋、螺纹和/或配合到内部小室的孔隙中的至少一种,并且可以是通过盖的接合构件和管的连接构件之间的相互作用而推进、旋转、螺旋、螺纹和/或配合到小室中的至少一种。所述接合构件可以中心地或者偏离中心地位于盘状构件中,其中所述连接构件分别是中心地或偏离中心地位于所述管中的至少一种。
本文所公开的术语推进、旋转、螺旋、配合以及螺纹、连接和附加,以及其任何相应的时态和复数(正如额外包括术语“部件),相当于用于连接(永久的或临时的)两个(或更多个)组件(例如“螺旋工具”、“配合工具”、“连接部件”、“接合部件”)的结构(本领域技术人员众所周知的)。例如,对于“推进”,这样的工具可包括“扣合(snap-fit)”型的结构;旋转工具可包括这样的工具:其中当将一个组件相对于另一个而旋转时,突出构件被相应的凹陷接纳。“螺旋”和“可螺旋地”包括螺旋螺纹的接合等。因此,这些术语(或其时态)的任一个的使用亦可包括具有任何这类工具或其等同物的这类连接。
在一些实施方案中,可螺旋移动的环形构件可以不匹配所述孔隙,而是从内部小室外部覆盖孔隙。在这样的实施方案中,所述环形构件可具有与内部小室或内部空间的外面上的螺纹互补的内部螺纹。环形封闭构件的连接部件和管的连接构件之间的相互作用可导致环形构件被螺旋拧到内部小室的外面,远离所述孔隙。
在一些实施方案中,所述样品采集装置可以进一步包括锁闭或密封工具,使得一旦由例如供体已经将盖连接或螺旋拧到所述管上之后,供体就不能从所述管上移动所述盖。合适的锁闭构件可包括盖上的楔子和管上的配合凸缘,或者反之亦然。楔子和凸缘可在盖和管的内部,或在盖和管的外部。合适的密封工具包括含有密封溶液例如粘合剂的密封腔,其中当盖被推进、旋转或螺旋拧到管上时,所述密封溶液被释放并随后固化以阻止盖和管之间脱开。在一些实施方案中,所述密封溶液可以是双组分粘合剂,例如环氧树脂,其中一组分密封到盖中,而另一组分密封到管中,使得当将盖螺旋拧到管上时两种组分在螺纹内混合。在其它实施方案中,所述密封溶液可以是单组分,例如基于氰基丙烯酸盐的粘合剂,其可以在盖或管中的密封腔中,使得当将盖螺旋拧到管上时所述密封溶液被释放到螺纹中。在一些实施方案中,所述密封溶液可在盖和管之间接合后不久就固化,使得通常可阻止用户将管和盖之间脱开。
替代地,或另外,一些实施方案可以进一步包括在盖基部的环形构件,其部分地固定到盖上,使得当盖已被螺旋拧到管上之后盖的移除破坏了盖和环形构件之间的结合,从而指示管已被打开。该“防拆封的”实施方案类似于用于将盖连接到苏打瓶的那些。
依据一些实施方案的样品采集装置可由任何合适的塑料(例如聚丙烯、聚苯乙烯和聚碳酸酯)制造。可修改所述装置的尺寸以适应样品将会经历的特定处理。在某些实施方案中,典型的尺寸包括以下。对于盖的内部小室,体积为约3 ml至约10 ml,典型地约6 ml。对于管的内腔,体积为约15 ml至约50 ml,典型地约25 ml。其它体积在本发明的一些实施方案的范围之内。
对于附图,图1是包括盖12和管14的样品采集装置10的实施方案的图示。所述管可被设计用于采集一种或多种样品体液,所述盖可被设计用于贮存一种或多种保存液体。另外,盖12和管14可被设计为彼此牢固配合,以便提供至少样品体液的牢固密封容器以贮存和运送。此外,为了牢固配合盖12和管14,在样品采集装置10中可被应用的机构可阻止盖12和管14之间脱开。阻止盖12和管14之间脱开的一个好处是它至少可阻止例如管内含有的样品的污染和任何保存溶液(其可能有毒)对样品供体的暴露,所述溶液例如盖12中含有的那些。
图1A显示依据一些实施方案的盖12的内部小室16的实例,其可以由至少一个外壁24和至少一个内壁18限定。所述至少一个内壁18可以进一步限定内部空间20和孔隙22。另外,外壁24可包括沿着外壁24的至少一侧的一个或多个盖接合部件34,用于接合管14。例如,和如图1A所示,外壁24的内表面26可包括一个或多个盖接合部件34,例如螺纹,用于与连接在管14上的一个或多个互补的管接合部件38例如螺纹接合和配合。管14可包括至少一个容器壁32,其可限定用于采集和贮存样品体液例如唾液或尿的池40。容器壁32的外表面30可包括一个或多个管接合部件28,例如螺纹。
盖12可以进一步包括孔隙22,其具有一个或多个孔隙接合部件42,例如螺纹。另外,盖12可包括封闭构件46,其可具有一个或多个封闭构件接合部件44,例如螺纹,用于接合孔隙接合部件42。例如,封闭构件46可以可移动地连接到孔隙22,使得当所述封闭构件被锁紧到孔隙时,盖的内部空间20中可含有一种或多种流体或材料。然而,一旦封闭构件46与孔隙22脱开之后,一种或多种流体或材料可从盖12的内部空间20中释放出来。例如,一旦盖12至少部分地锁紧到管14之后,封闭构件46可与孔隙22脱开,然后允许内部空间20中的液体或材料释放到管14的池40中。在至少贮存和运送期间,盖12的内部空间20中含有的一种或多种流体或材料可以有助于保存管14的池40中含有的样品体液。本文所讨论的任何接合部件可以是任何数量的接合部件,用于允许样品采集装置10的两个部分或部件之间的临时的或永久的接合,并且不限于本发明中讨论的实例。
封闭构件46还可包括一个或多个连接部件48,其可允许包含管14的一部分的一个或多个连接构件50与连接部件48接合和连接。连接部件48和连接构件50之间的连接可有助于封闭构件46与孔隙22脱开。例如,当盖12被锁紧到管14时,连接构件50可与封闭构件46的连接部件48接合并相互作用,例如类似于螺丝刀头与螺丝头相互作用。封闭构件46可与带螺纹的孔隙接合部件螺纹接合,并且连接部件48和连接构件50的连接和相互作用可导致封闭构件46和孔隙22之间的螺纹接合被释放。封闭构件46和孔隙22之间的螺纹接合可被释放,例如,因为封闭构件46相对于孔隙22而旋转。任何数量的可释放的接合都可用于使封闭构件46与孔隙22接合,使得在将盖锁紧到管14之后,封闭构件46和孔隙22之间的接合可被释放。同样,可将任何数量的部件整合到样品采集装置10中,其可允许在盖12或管14的一部分中容纳溶液,使得所述溶液不被释放,直到盖至少部分地锁紧到管14。
以实例的方式显示了图1A中的管14,其具有呈现方钉(square peg)形状的连接构件50,所述方钉与在封闭构件46中包括连接部件48的方形凹痕互补。此外,连接构件50可中心地位于管14中,并且连接部件可中心地位于所述封闭构件46的底部。因此,一旦盖12和管14之间螺纹接合之后,方钉连接构件50可延伸到封闭构件46中的方形凹痕连接部件48并与之接合,因此阻止封闭构件46相对于连接构件50旋转。然而,尽管可阻止封闭构件46相对于连接构件50旋转,但封闭构件46可相对于孔隙22旋转并且可与孔隙22脱开,例如释放封闭构件46和孔隙22之间的螺纹接合。图1B显示通过不止一个十字形构件54而锁紧到管14的容器壁的内表面52的连接构件50的实例。一个或多个十字形构件54可有助于锁紧连接构件50的位置,同时又允许液体或材料流入池40的空间。
使用样品采集装置10的实例方法可包括样品采集装置10,其在盖12的内部空间20中供应有样品保存液体,并具有与孔隙22螺纹接合的封闭构件46,以在内部空间20中包含样品保存液体。然后,可由供体将样品液体例如唾液或尿放入管14的池40中。然后可将盖12螺旋拧到管14上。将盖12螺旋拧到管14上可导致管14中的连接构件50接合封闭构件46的连接部件48并将封闭构件48从孔隙22上旋开并进入盖12的内部空间20。将封闭构件48与孔隙22脱开可允许样品保存液体流入管40的池40中。将样品保存液体释放到管14的池40中之后,所述样品保存液体可与供体的样品液体混合,从而保存供体的样品液体。
尽管在本图中显示为方钉,但是管14的连接构件50可以是在形状上与封闭构件46的连接部件48互补的任何形状,使其允许封闭构件46与孔隙22脱开。连接部件48可在封闭构件46中或管14中,并且互补的连接构件50可相应地在管14中或封闭构件46中。其它形状对于本领域技术人员而言将是显而易见的,包括但不限于狭缝和条状(tab),像普通螺丝刀和螺丝一样,或十字形的一对,像十字螺丝刀和螺丝一样。
样品采集装置100的另外的实施方案在图2A和2B中以实例的方式显示。样品采集装置100可包括一个或多个连接构件50和互补的连接部件48,其可以偏离中心地位于盖12或管14。如图2B所示,该实施方案可需要较少的材料和部分而正确运转,例如连接构件50仅通过一个十字形构件54就可维持正确定位。尽管连接构件50被显示为仅通过从管14的容器壁32延伸出的一个十字形构件54就可保持定位,但是任何数量的构造和十字形构件54可用于定位连接构件50,而不偏离本发明的范围。
样品采集装置200的另一实施方案在图3A-3C中以实例的方式显示。更具体地讲,图3A显示在连接到管14之前的盖12的横截面。盖12可包括外壁24和沿着外壁24的内表面26的盖接合构件34。盖12的内壁18或外壁24中的至少一个可以至少部分地限定内部空间20。此外,内壁18可包括沿着内壁18表面的接合部件60,例如螺纹。内壁18可以进一步限定孔隙22,其可被打开或关闭,取决于环形封闭构件62相对于孔隙22的位置。当孔隙22被关闭,使得所述环形封闭构件62覆盖孔隙22时,可不允许内部空间20中含有的液体或材料例如样品保存液体或材料70进入内部空间20的外面,如图3A所示。然而,当孔隙22被打开,使得所述环形封闭构件62不覆盖孔隙22时,可允许内部空间20中含有的液体或材料70进入内部空间20的外面,例如进入管14的池40中,如图3B所示。内部空间中含有的液体或材料70对于保存位于管14的池40中的样品72例如体液(即唾液、尿等)而言可以是有益的,类似于如上所述。此外,任何数量的机构都可阻止样品保存液体或材料72从内部空间20中释放出来,直到盖12至少部分地被锁紧到管14上。
在图3A-3C中以实例的方式显示的实施方案中,环形封闭构件62可被设计为与一个或多个部件例如管14的连接构件50相互作用,使得当盖12被牢固地连接到管14上时,管14或者环形封闭构件62的一个或多个部件可导致环形封闭构件62从环形封闭构件62覆盖孔隙22的位置移至环形封闭构件62不覆盖孔隙22的位置上,从而允许样品保存液体或材料72从内部空间20释放出来并与样品72相互作用。
图3C显示管14的横截面,具有限定用于样品采集的池40的容器壁32。管14可包括连接构件50,用于结合环形封闭构件62的连接部件48。
使用样品采集装置200的实例方法可包括样品采集装置200,其在在盖12的内部空间20中供应有样品保存液体70,并具有覆盖孔隙22的环形封闭构件62,以阻止样品保存液体70通过孔隙22。在该实施方案中,可将样品液体72例如唾液或尿放入管14的池40中。然后可将盖12牢固连接例如螺纹接合到管14上,导致环形封闭构件62的连接部件48接合管14的连接构件50。然后,环形封闭构件62可螺纹接合沿着内壁侧面的接合部件,例如螺纹。这可导致环形封闭构件62离开孔隙22,使其不再覆盖孔隙22。这反过来又可将至少一些样品保存液体70释放到管14的池40中,在池40中其可与样品液体72混合,从而保存后者。
在一些实施方案中,所述样品采集装置300,如在图4A和4B中以实例方式所示,盖12包括至少一个连接部件或楔子90,其经成型和设计以与管14的互补的连接部件或凸缘92相互作用。在该实施方案中,楔子90和凸缘92沿着盖12和管14的内表面而延伸。例如,当盖12连接到管14上时,楔子90可接合凸缘92并在盖12和管14之间形成牢固接合。此外,一旦楔子90和凸缘92彼此完全接合,例如在图4B以实例方式所示的锁闭结构96,至少样品供体不可释放楔子90和凸缘92之间的接合。因此,一旦盖12接合到管14上使得楔子90和凸缘92彼此牢固接合,至少样品供体再不能将盖12从管14上脱开。这可阻止至少样品供体污染放置在管14中的样品体液,以及保护样品供体不接触样品保存溶液。图4B显示在楔子90和凸缘92之间的未闭锁结构94和已闭锁结构96的样品实施方案。
在一些实施方案中,样品采集装置400,如图5A和5B以实例方式所示,楔子90和凸缘92分别沿着盖12和管14的外表面延伸。图5B显示在楔子90和凸缘92之间的未闭锁结构94和已闭锁结构96的样品实施方案。
在一些实施方案中,样品采集装置500,如图6以实例方式所示,其中盖12包括含有密封物质112例如粘合剂的一个或多个密封腔110。任何一个密封腔110可以是操作性连接或者位于临近盖12上的接合部件34例如螺纹,使得当盖12连接到管14时,一个或多个密封腔110可被管12的一个或多个部件或末端150破坏。一旦密封腔110被破坏,密封物质112例如粘合剂可从密封腔110中释放出来并导致盖12被永久地锁紧到管14上。
盖12或管14可包括任何数量的部件,其可有助于阻止盖12从管14上不合需要的脱开,例如以防止污染。另外或代替地,盖12或者管14可包括“防拆封的”部件160,其可被改变使得如果盖12已从管14上不利地脱开,对用户或样品采集者而言是已知的。如图7A和7B中以实例方式所示,盖12可包括防拆封的部件160,其可包括可释放地连接到盖12的开口端162的环,使得当盖12从管14上不利地脱开时,防拆封的部件160可永久地释放它与盖12的连接,如图7B所示。一旦防拆封的部件160从盖12上永久地脱开之后,盖12的任何观察者都可确定盖12已从管12上不利地脱开,因此给出了例如样品污染的警告。
本领域技术人员将知道,许多等同实施方案可用于获得由本文所公开的样品采集装置所提供的益处。例如,尽管本说明书涉及盖12中的某些要素和管14中的其它要素,但是本领域技术人员将知道,将盖12中的要素转换为管14中的要素和反之亦然,都将是等同方案。
在一些实施方案中,公开了用于保存在一种或多种体液例如唾液和尿中的细胞的溶液。所述保存细胞的溶液对于进一步分离细胞类型和下游分子分析而言是有益的,其允许贮存体液中的细胞以保留它们的抗原性和细胞结构。所述溶液可含有至少一种化学固定剂,例如但不限于低聚甲醛,和至少一种蛋白酶抑制剂。在一些实施方案中,所述溶液可以进一步含有至少一种抗微生物剂的一种或多种,以及来自人和/或其它动物物种的血清蛋白。可将所述溶液在pH介于约6.4至约8.4之间、优选介于约7.2至约7.6之间缓冲。
为了本发明的目的,“保存细胞”是指使细胞免于其抗原被降解,使得可根据其抗原而纯化或富集它们,并且阻止细胞表观基因组上的改变。“表观基因组”是指通过DNA或与DNA结合的蛋白质的共价修饰的基因组DNA的改变状态或模式。这类改变的实例包括在CpG二核苷酸中的胞嘧啶的5位上的甲基化、组蛋白的赖氨酸残基的乙酰化以及并非由基础DNA序列中的变化所致的其它遗传的或非遗传的变化。
在一些实施方案中,以下描述中的试剂浓度可以是样品保存溶液本身的浓度。根据体液,并且就唾液而言,可将大约等体积的溶液和体液混合在一起。这优选地导致来自体液的细胞在室温下保持它们的抗原性和DNA完整性达至少一周。
在本发明的一些实施方案中,装在所述装置中并使用的保存溶液的体积可以是介于大约100和大约500ml之间,其是例如对在尿中细胞的保存相关。这样,对于尿的保存溶液可以是介于大约10倍(10x)浓缩的溶液到1.5倍(1.5x)溶液之间的任何浓度(对于尿而言)。
根据一些实施方案,“化学固定剂”是用于改变细胞组分使细胞耐受降解的化学交联化合物。化学固定剂也可起到将组蛋白和其它DNA-结合蛋白与DNA交联的作用。这样的试剂在本领域中可以是已知的并且包括但不限于低聚甲醛、甲醛、福尔马林、醛、醇、氧化剂、Mercurials、Picrates、Hepes-谷氨酸缓冲剂-介导的有机溶剂保护效应(HOPE)、固定组合例如Zambonis固定剂、醛的组合和合成的交联剂。在一些实施方案中,化学固定剂是低聚甲醛。在一些实施方案中,化学固定剂的浓度大约为1% (v/v)。
为了保护细胞免于被体液中存在的蛋白酶降解,在一些实施方案中,所述溶液可含有至少一种蛋白酶抑制剂。在一些实施方案中,所述蛋白酶抑制剂可选自天冬氨酸蛋白酶抑制剂、半胱氨酸蛋白酶抑制剂、金属蛋白酶抑制剂、丝氨酸蛋白酶抑制剂(例如serpins)、苏氨酸蛋白酶抑制剂、胰蛋白酶抑制剂和Kunitz STI蛋白酶抑制剂。一些具体的非限制性实例包括叠氮化钠、PMSF、抑肽酶、亮抑酶肽、胃酶抑制剂、天然的或合成的蛋白酶抑制剂和蛋白酶抑制剂的混合物。这些抑制剂的合适浓度可包括但不限于大约0.1-1 mM的PMSF (苯基甲基磺酰氟)丝氨酸蛋白酶、大约1 mM的苯甲脒丝氨酸蛋白酶、大约1 μg/ml的胃酶抑制剂A酸性蛋白酶、大约1 μg/ml的亮抑酶肽硫醇蛋白酶、大约5 μg/ml的抑肽酶丝氨酸蛋白酶和大约1 μg/ml的抗蛋白酶硫醇蛋白酶。在一些实施方案中,蛋白酶抑制剂是浓度大约0.01% (w/v)的叠氮化钠。
为了防止细胞因微生物污染而被破坏,所述溶液的一些实施方案含有至少一种抗微生物剂。合适的抗微生物剂包括但不限于抗细菌的和抗真菌的抗生素。
血清蛋白的存在增强细胞结构的维持,在一些实施方案中可任选将所述血清蛋白加入到所述溶液中。另外,血清蛋白可用于中和细胞和溶液之间的渗透压差异。这些蛋白可来自人类或其它动物来源。在一些情况下,可使用全血清。例如,在某些实施方案中,可添加胎牛血清,浓度大约1% (v/v)。
本发明的溶液可包括上述实施方案的任何组合。
在本发明的一些实施方案中,公开了用于在一种或多种体液中保存细胞的方法。保存细胞的方法可包括使体液与本发明的溶液接触。体液可含有多种细胞类型并且体液中的细胞可通过本发明的溶液来保存。尽管对本发明并非关键,但是通常使用溶液与体液的比例为大约1比1。
以下实施例意图进一步说明用于保存体液中的细胞的溶液和方法的一些实施方案,并且不得解释为限制本发明的范围。
例如,可以与唾液1:1的比例加入PBS pH 7.4、1%低聚甲醛、1% FBS和0.01% NaN3的溶液,然后可纯化T细胞并提取DNA。这类方法的结果示于图8。这些结果可表明T细胞的抗原性和DNA的完整性维持至少一周。
在本发明的一些实施方案中,公开了方法,其提供包含化学固定的细胞的一种或多种体液例如唾液或尿的样品,和任选离心所述体液样品以便从包括细菌和碎片在内的细胞沉淀中分离DNA和其它可溶性材料。所述方法可进一步包括从沉淀的其它内容物中富集白细胞,包括淋巴细胞。另外,使用靶向细胞特异性标记的缀合到磁珠的抗体可以分离特定细胞。
在一些实施方案中,本发明提供了用于从体液(即唾液、尿等)中分离特定类型的白细胞(尤其包括但不限于淋巴细胞)的方法,所述方法包括例如一个或多个以下步骤(并且在一些实施方案中,若干或所有步骤):提供包含化学固定的细胞的体液样品,任选离心所述体液样品以获取包含细胞的沉淀,任选将所述沉淀重悬于缓冲液中,使重悬的沉淀经过密度梯度分离以获取一层白细胞类型(包括淋巴细胞)的混合物,使细胞类型的混合物与含有对特定类型的白细胞上存在的表位具有特异性的结合剂的溶液接触,并且从白细胞类型混合物中分离所述特定类型的白细胞(包括淋巴细胞)。
在一些实施方案中,所述特异性结合剂可包括偶联到抗体上的磁珠,所述抗体对特定类型的白细胞上存在的表位具有特异性,并且分离可包括从白细胞类型混合物中经磁力分离特定类型的白细胞(包括淋巴细胞),但用于彼此分开细胞类型的任何方法(和相应的系统/装置)都在本发明的范围之内。磁力分离仅仅是这么做的一种方法。
在经历本发明的方法之前,所述细胞可经化学固定。可通过例如使唾液样品与化学固定溶液接触而使细胞经化学固定。这样做是为了在环境温度下将细胞保存额外的时间。这还可允许完成表观基因组的研究,因为它允许自所放置的体液样品研究组蛋白修饰和其它蛋白-DNA相互作用。必须将组蛋白化学固定到DNA上,以便研究。如果不固定,组蛋白通常不能保持与DNA的结合并且所述蛋白质可随时间而降解。
在一些实施方案中,所述缓冲液可包含叠氮化钠,所述缓冲液可包含磷酸缓冲盐水和叠氮化钠。在一些实施方案中,所述缓冲液可进一步包含胎牛血清。在一些实施方案中,所述缓冲液的pH在大约7.2至约7.6之间。
在一些实施方案中,在缓冲液中将细胞洗涤一次。这在实际上去除了可溶性材料并且就唾液而言,这去除了被分类为“口颊”层(“buccal” layer)的材料(Dos-Santos等人,2009)。
在一些实施方案中,将所述白细胞混合物在缓冲液中洗涤一次或多次,然后分离。优选进行这一步以从细胞类型混合物中除去任何残余密度梯度溶液。
在该过程中,抗体可结合到特定类型的白细胞上,从而使特定类型的白细胞结合到磁珠上。然后,可通过将磁珠放在磁场中将特定类型的白细胞与任何其他细胞类型分开,并除去任何残余液体,以获得特定类型的白细胞的分离细胞。
在一些实施方案中,所述特定类型的白细胞可以是淋巴细胞,其中所述淋巴细胞可以是T细胞。在这样的实施方案中,所使用的抗体可以对T细胞特异性的抗原(例如抗原是CD4)具有特异性。在一些实施方案中,然后可在进一步处理之前,例如表观遗传分析之前,将所述分离的血细胞冷冻。
以下实施例意图进一步说明本发明的实例方法实施方案,并且无意限制本发明的范围。
实施例:从体液(例如唾液)中分离T细胞
采集唾液,将唾液与保存溶液混合。然后通过离心沉淀细胞并除去处理溶液。之后将细胞重悬于大约6 ml缓冲液(PBS, pH 7.4)、1% FBS、0.01 % NaN3)中,然后在缓冲液中洗涤一次并重沉淀。将沉淀重悬于大约6 mL PBS-15 FBS-0.01%NaN3中并使用1.082 -1.072 g/ml Ficoll® (GE Healthcare)经历密度梯度离心。将白细胞旋转到多糖和缓冲液的界面上,同时将细菌、碎片和任何其它颗粒物质沉淀到管底部。从管中提取细胞并放入新管中。再将细胞在Hank氏平衡盐溶液中洗涤一次,然后在PBS-NaN3-FBS缓冲液中洗涤一次以除去可能在从界面上提取白细胞时被带出的残余密度梯度溶液。
样品现在包括具有最少细菌和最少碎片的高度富集的白细胞。该步骤还可极大地降低其它细胞类型,例如上皮细胞。然后可将所述细胞与靶向CD4并缀合到磁珠(Dynabeads® Invitrogen®)的抗体一起在缓冲液(PBS-NaN3-FBS)中孵育。然后可将样品放入磁场中,磁珠到达管侧,并除去液体。液体可含有未通过抗体与珠子结合的任何东西。T细胞可结合到抗体上并且因磁场而不会被除去。可将珠子和所吸附的细胞在缓冲液中洗涤,以消除体液例如唾液或尿中存在的任何非特异性或弱结合的其它细胞、细菌或其它碎片。然后将细胞冷冻,用于随后的下游处理和分析。可通过光学显微镜检查证实T细胞的分离(与上皮细胞和细菌相比,T细胞非常独特) (参见图9)。另外,使用针对CD3、CD4和CD8的抗体,流式细胞术和F.A.C.S.分析可证实所分离细胞的视觉评价。然后可自体液滴定(tittered)T细胞,以确定每单位体液(ml)中的T细胞数量,来测定对于用于下游实验的足够数量的细胞而言体液例如唾液或尿的量(参见图9和10)。分离的细胞可显示具有无降解的DNA并且适用于下游应用(参见图8)。
本申请中出现的出版物或其它文件(包括但不限于专利、专利申请、文章、网页、书籍等)的任何和所有引用,通过引用以其整体结合到本文中。
尽管以上已经详细描述了少数变动,但是其它修改也是可能的。例如,附图中所描绘的和本文所描述的任何逻辑流程不需要所示的特定顺序或序贯次序,以获得所需结果。其它实施可以在至少一些以下示例性权利要求的范围之内。
本文已经描述了装置、系统和方法的实例实施方案。正如在别处所述,仅用于说明性目的而非限制性目的而描述了这些实施方案。其它实施方案是可能的并且被本发明所覆盖,根据本文所含有的教导,这些实施方案将是显而易见的。因此,本发明的宽度和范围应当不受任何上述实施方案的限制,而应仅由本发明及其等同方案所支持的权利要求书来限定。此外,本发明的实施方案可包括方法、系统和装置,其可以进一步包括任何其它公开的方法、系统和装置的任何和所有要素,包括对应于从体液(例如唾液、尿)中细胞的采集、保存、分开和分离以及其它物质(包括有毒和/或有害物质/流体)的采集(及其组分的保存、分开和分离)的任何和所有要素。换句话说,来自一个或另一个所公开的实施方案的要素与来自其它所公开的实施方案的要素是可互换的。
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Claims (33)
1.用于保存在体液中的细胞的溶液,用于进一步分离细胞类型和下游表观遗传分析,其允许在体液中贮存细胞,以保留它们的抗原性和细胞结构,所述溶液包含至少一种化学固定剂和至少一种蛋白酶抑制剂,缓冲在pH约6.4至约8.4之间。
2.权利要求1的溶液,进一步包含至少一种抗微生物剂和来自人和/或其它动物物种的血清蛋白中的一种或多种。
3.权利要求1的溶液,其中所述化学固定剂选自醛类。
4.权利要求3的溶液,其中所述化学固定剂是低聚甲醛。
5.权利要求1的溶液,其中所述化学固定剂的浓度为大约1% (v/v)。
6.权利要求1的溶液,其中所述抗微生物剂选自抗细菌的和抗真菌的抗生素。
7.权利要求1的溶液,其中所述蛋白酶抑制剂选自:天冬氨酸蛋白酶抑制剂、半胱氨酸蛋白酶抑制剂、金属蛋白酶抑制剂、丝氨酸蛋白酶抑制剂、苏氨酸蛋白酶抑制剂、胰蛋白酶抑制剂、Kunitz STI蛋白酶抑制剂和以上的任意组合。
8.权利要求1的溶液,其中所述蛋白酶抑制剂选自:叠氮化钠、PMSF、抑肽酶、亮抑酶肽、胃酶抑制剂、天然的或合成的蛋白酶抑制剂、天然的和合成的蛋白酶抑制剂的混合物和以上的任意组合。
9.权利要求1的溶液,其中所述蛋白酶抑制剂是叠氮化钠。
10.权利要求1的溶液,其中所述溶液缓冲在pH约7.2至约7.6。
11.权利要求1或10的溶液,其中所述缓冲液选自:巴比妥、三羟甲基氨基甲烷磷酸盐、柠檬酸盐、甲次砷酸盐、其它非磷酸盐缓冲液和以上的任意组合。
12.权利要求1或10的溶液,其中所述缓冲液是磷酸盐缓冲液。
13.用于在天然表达的体液中保存细胞的方法,包括使体液与权利要求1-12中任一项的保存溶液接触。
14.用于从天然表达的体液中分离一类白细胞的方法,包括:
提供包含化学固定的细胞的体液样品;
离心所述体液样品以获取包含细胞的沉淀;
将所述沉淀重悬于缓冲液中;
使重悬的沉淀经过密度梯度分离,以获取一层多个白细胞类型;和
从多种白细胞中分离第一类型的白细胞。
15.权利要求14的方法,其中分离包括:
使细胞类型混合物与含有与对第一类型的白细胞上存在的表位具有特异性的抗体偶联的磁珠的溶液接触,和
从多个白细胞类型中磁力分离第一类型的白细胞。
16.权利要求14的方法,其中所述体液选自:唾液、尿及其组合。
17.权利要求14的方法,其中所述缓冲液包含叠氮化钠。
18.权利要求14的方法,其中所述缓冲液包含磷酸盐缓冲盐水和叠氮化钠。
19.权利要求14的方法,其中所述缓冲液进一步包含胎牛血清。
20.权利要求14的方法,其中所述缓冲液的pH为约7.2至约7.6。
21.权利要求14的方法,其中将所述白细胞类型混合物在缓冲液中洗涤一次或多次,然后分离。
22.权利要求14的方法,其中所述第一类型的白细胞是淋巴细胞。
23.权利要求14的方法,其中第一类型的淋巴细胞细胞是T细胞。
24.权利要求15的方法,其中所述抗体对T细胞特异性抗原具有特异性。
25.权利要求24的方法,其中所述抗原是CD4或CD3中的至少一种。
26.用于从体液中分离白细胞的方法,包括:
提供包含化学固定的细胞的体液样品;
使所述样品经历密度梯度分离以获取一层多个白细胞类型;和
从多个白细胞类型中分离第一类型的白细胞。
27.权利要求26的方法,其中分离包括:
使多个细胞类型与含有与对第一类型的白细胞上存在的表位具有特异性的抗体偶联的磁珠的溶液接触;和
从多个白细胞类型中磁力分离所述第一类型的白细胞。
28.权利要求26的方法,进一步包括离心体液样品以获取包含细胞的沉淀,并将所述沉淀重悬于缓冲液中,然后使所述样品经历密度梯度分离。
29.用于从体液中分离包括但不限于淋巴细胞在内的特定类型的白细胞的方法,包括:
提供包含化学固定的细胞的唾液样品;
使所述样品经历密度梯度分离以获取一层白细胞类型的混合物,所述白细胞类型包括淋巴细胞;和
从多种白细胞中分离第一类型的白细胞。
30.权利要求29的方法,其中分离包括:
使细胞类型混合物与含有对特定类型的白细胞上存在的表位具有特异性的结合剂的溶液接触;和
从白细胞类型混合物中分离特定类型的白细胞。
31.权利要求29的方法,进一步包括离心体液样品以获取包含细胞的沉淀,并将所述沉淀重悬于缓冲液中,然后使所述样品经历密度梯度分离。
32.用于从体液样品中分离一类白细胞的系统,包括:
用于离心体液样品以获取包含细胞的沉淀的离心机;
用于将沉淀重悬于缓冲液中的重悬工具;
用于使重悬的沉淀经历密度梯度分离以获取一层多个白细胞类型的工具;和
用于从多种白细胞中分离第一类型的白细胞的分离工具。
33.权利要求32的系统,其中分离工具包括:
用于使细胞类型混合物与含有与对第一类型的白细胞上存在的表位具有特异性的抗体偶联的磁珠的溶液接触的工具,和
用于从多个白细胞类型中磁力分离第一类型的白细胞的磁力分离工具。
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