CN1173776C - 在微规模流体性设备里的高通过量的筛选分析系统 - Google Patents
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Abstract
本发明提供了用来进行高通过量筛选分析的微液体装置和方法。具体的是,本发明的装置和方法可用来筛选大量不同化合物对各种化学系统,优选的是生化系统的作用。该装置包括一系列管子(110,112),和任选的试剂管(114),它们组装在基片的表面里。这些管子的至少一种典型地有极小的截面尺寸范围,如0.1-500微米。该装置也包括处于且与管子末端流体连接的贮槽(104,106和108)。如图所示,样品管(112)用来将多个不同试验化合物引入装置。这样该管子通常与大量分开化合物源连接,从而可单个地引入样品管(112)并接着进入管(110)。
Description
本申请是美国专利申请08/671,987(1996,6,28提交)和美国专利申请08/761,575(1996,12,6提交)的部分续展申请,每篇文献都并入本文供参考。美国专利申请,律师文档号017646-0004200基本与本申请相同,1997,6,24提交到美国专利局。该申请也并入本文供参考。
发明领域
本申请涉及用来检测分子之间相互作用的装置和分析系统。该装置包括带有一个或多个相交管的基片和电渗透液移动组分,或用来使液体在基片上的相交管里移动的其它组分。
发明背景
人们长期需要快速分析化合物在各种生物过程中的作用的能力。例如,酶学家长期寻找更好的底物、更好的抑制剂或更好的催化剂用于酶反应。相似的是,在制药工业中,人们致力于鉴别出能阻滞、减少或甚至增加生物分子之间的相互作用的化合物。特别是,在生物系统中,受体和它的配体之间的互相作用常常直接地或通过一些下游事件对该系统,最终对接受治疗的病人产生有害的作用或有益的作用。因此,研究者长期在寻找能减少、阻滞或甚至增加该相互作用的化合物或混合物。相似的是,能快速地处理样品以便检测与诊断或法医分析有关的生物分子对于如诊断医学、考古学、人类学和现代犯罪调查具有很重要的价值。
现代新药发现研究被用来筛选具有这些所揭示的效果的化合物的分析通过量所限制。具体的是,筛选最大数量的不同化合物需要减少与每次筛选所用的时间和劳动。
对化学合成分子和天然产物(如微生物发酵肉汤)集合体的高通过量筛选在寻找用于开发新颖的药物的先导化合物中起关键的作用。对将组合化学和有关的技术用来产生和评价分子多样性所产生的极大的兴趣代表了药物发现进展中有重要的里程碑。参见Pavia等,1993,Bioorg.Med.Chem.Lett.3:387-396,在此并入供参考。今天,肽化学已经成为探索组合方法在配体鉴别的应用中的主要动力。见Jung和Beck,Sickinger,1992,
Angew.Chem.Int.Ed.Engl.31:367-383在此并入供参考。这归因于氨基酸单体的大而结构上多变的范围,相对普通的高得率的固相偶合化学和与用于产生重组肽库的生物学途径的协同作用。此外,许多低分子量肽的有效和特定的生物活性使这些分子成为治疗药物发现研究中的引入注目的起点。参见Hirschmann,1991,Angew.Chem.Int.Ed.Engl.30:1278-1301,和Wiley & Rich,1993,Med.Res.Rev.13:327-384,每篇文献并入本文供参考,但是,不良的药动学性质,如不良的口服生物利用度和快速的体内廓清率限制了肽类化合物更为广泛的开发成药物。这样的认知让人们近来得到灵感把组合有机合成延伸到肽化学以外来制造出已知的象苯并二氮杂那样的药效团(参见Bunin& Ellman,1992,J.Amer.Chem.Soc.114:10997-10998,这里并入本文供参考)及聚合物分子,如低聚的N-取代甘氨酸(“类肽”)和寡甲氨酸酯。参见Simon等,1992,Proc.Natl.Acad.Sci.USA 89:9367-9371;Zuckermann等,1992,J.Amer.Chem.Soc.114:10646-10647;和Cho等,1993,Science 261:1303-1305,每篇文献并入本文供参考。
在相似的开发中,和现代组合化学导致了许多可筛选的试验化合物数量的显著增加极为相似,人类基因组研究也揭露了大量新的靶分子(如,基因和基因产物,诸如蛋白质和RNA),需要筛选对它们有效用的试验化合物。
尽管用平行筛选方法和其它技术,如自动化和高通过量的检测系统改进了筛选方法,但目前的筛选方法仍有许多相关问题。例如,用目前的平行筛选方法来筛选大量样品需要很大的空间来容纳样品和设备,如机器人等,高成本的设备和高成本的试剂来进行这样的分析。另外,在许多情况下,反应体积必须极小以与少量可能得到的试验化合物匹配。这样小量的体积把与液体处理和测量有关的误差,如由于蒸发、小量分配的误差之类复合在一起。另外,部分由于这类小体积中表面张力作用,液体处理设备和方法典型地不能用来在可接受的精确水平上处理这样的体积范围。
解决这些问题的系统开发必须考虑分析方法的各个方面。这些方面包括靶和化合物来源、试验化合物和靶处理、特定的分析需要和数据的采集、减少贮存和分析,特别是,人们需要高通过量的筛选方法和能重复、准确地进行分析筛选并能在极少体积下操作的相关的设备和装置。
本发明满足这些和各种其它要求。特别是,本发明提供了进行筛选分析的新颖方法和装置,它们提供了这些问题的解决措施。
发明综述
本发明提供了筛选多个试验化合物对生物化学系统的作用的方法。这些方法典型地使用微组装基片,所述的基片至少有一个第一表面,和至少两个组装在该第一表面上的相交管。相交管中的至少一根的至少一个横截面的尺寸范围为0.1-500微米。该方法涉及将生物化学系统的第一组分流入至少两根相交管中的第一根管里。至少第一试验化合物从第二根管流入第一管中,从而使试验化合物与生物化学系统的第一组分接触。然后检测试验化合物对生物化学系统的作用。
在相关的一个方面,该方法包括连续地将生化系统的第一组分流入至少两根相交管的第一管里。不同的试验化合物被定期地从第二管引入第一管。然后检测试验化合物对生化系统的作用(如果作用的话)。
在另一方面,该方法使用有至少第一表面的基片,多个反应管组装入该第一表面。多个反应管的每根管与至少两根也装在该表面上的至少两根横向管流动性地连接。生化系统中的至少第一组分被引入多个反应管中,多个不同的试验化合物流经至少两根横向管的至少一根管。进而,多个试验化合物的每个以不连续的体积被引入横向管。多个不同的试验化合物的每一个都被引向分开的反应管,然后检测每个试验化合物对生化系统的作用。
本发明也提供了实施上述方法的装置。本发明的一个方面提供了用来筛选试验化合物对生化系统的作用的装置。该装置包括一个基片,所述基片有至少一个表面,在该表面中装有至少两根相交管。该至少两根相交管有至少一个截面其尺寸范围约为0.1-500微米。该装置也包括不同的试验化合物的源,所述的源与至少两根相交管的第一管流动性地连接,以及生化系统的至少一个组分的源,所述的源与至少两根相交管的第二根流动性地连接。该装置也包括液体导向系统供该至少一种组分在相交管里流动,并将不同的试验化合物从第一相交管引入第二相交管。该装置也可任选地在第二管里包括检测区供检测所述试验化合物对所述生化系统的作用。
在优选的方面,本发明装置包括液体导向系统,它包括至少三个电极,每个电极与至少两个相交管在由至少两个相交管形成的不同的相交面上进行电接触。该液体导向系统也包括用来在每个电极上同时施加可变电压的控制系统,从而控制了在至少两根相交管里的试验化合物或至少第一组分的移动。
在另一方面,本发明提供了检测试验化合物对生化系统的作用的设备,包括具有至少一个表面并在该表面中装有多个反应管的基片。该装置也具有至少两根装在该表面里的横向管,其中多根反应管的每一根与至少两根横向管的第一根在每个反应管的第一点上流动地连接,并在每个反应管的第二点处与第二横向管流动性地连接。该装置进一步包括与每个反应管流动性地连接的生化系统的至少一个组分的源,与第一横向管流动性连接的试验化合物源,和用来控制试验化合物和第一组分在横向管和多个反应管里移动的液体导向系统。如上所述,该装置在第二横向管里也任选地包括检测区供检测试验化合物对生化系统的作用。
附图简述
图1是本发明的可用于连续流动分析系统的微实验室筛选分析系统的示例性示意图。
图2A和2B显示了图1所示的装置在另外的分析系统中运行的示意图。图2A显示了用来筛选酶-底物相互作用的效应物的系统。图2B揭示了用于筛选受体-配体相互作用的效应物的装置。
图3是“系列输入平行反应”微实验室分析系统的示意图,其中待筛选的化合物被连续引入装置,但在装置里以平行的方向进行筛选。
图4A-4F显示了图3所示的装置在筛选多个球基试验化合物中操作的示意图。
图5显示了将掺入样品的连续流动分析装置分流,以进行延长的培养然后分离步骤的示意图。
图6A显示了用于液体基试验化合物的连续输入平行反应装置的示意图。图6B和6C显示了在图6A显示的装置里的液体流动模式的示意图。
图7显示了用多个微实验室设备、标记为LabChipsTM的总分析系统筛选试验化合物的示意图。
图8是用于连续流动分析筛选系统的薄片版面的示意图。
图9显示来自连续流动分析筛选的荧光数据,图9A显示来自定期将已知抑制剂(IPTG)引入在薄片版式里的β-半乳糖苷酶分析系统。图9B显示来自图9A的两个数据片段的重叠,直接将抑制剂数据与对照(缓冲液)数据比较。
图10显示在小薄片设备上进行酶抑制剂筛选分析的液体流动系统的操作参数。
图11显示了样品/间隔物在微液体装置管里取间隔的装置装载时机选择。
图12,小图A-G示意地说明了用于本发明装置中的电极。
优选技术方案的揭示
1.发明申请
本发明提供了为进行高通过量筛选分析有用的新颖的微实验室系统和方法。具体的是,本发明提供了将这类装置用于筛选大量不同的化合物对各种化学的,优选的是生化的系统的作用的流体的装置和方法。
本文使用的术语“生化系统”一般是指涉及一般在活的生物体里发现的分子的化学相互作用。这类相互作用包括在活体系统里发生的分解代谢和合成代谢反应的全部范围,包括酶反应、结合反应、信号反应和其它反应。进而,本文定义的生化系统也包括模拟特定生化相互作用的模型系统。实施本发明所关注的生化系统的实例包括,如受体-配体相互作用、酶-底物相互作用、细胞信号途径、供生物利用度筛选的涉及模型屏障系统(如细胞或膜部分)的传送反应和各种其它的一般系统。细胞或生物体的生存能力或活性也可用本发明的方法和装置来筛选,如,用于毒理学研究。被分析的生物材料包括,但不限于,细胞、细胞碎片(膜、细胞溶质制剂等)、细胞膜受体的激动剂和拮抗剂(如细胞受体-配体相互作用,如转铁蛋白、c-试剂盒、病毒受体配体(如CD4-HIV),细胞因子受体、趋化因子受体、白介素受体、免疫球蛋白受体和抗体,钙粘着蛋白族、整联蛋白族、选择蛋白族等;参见,如Pigott和Power(1993)
粘合分子手册(The Adhesion Molecule Facts Book)Academic出版社New York和Hulme(编辑)
受体配体相互作用实践 (Receptor Ligand Interactions A Practical Approach)Rickwood和Hames(系列编辑)IRL出版社(Oxford Press NY),毒素和毒液、病毒表位鉴定、激素(如,鸦片制剂、类固醇等)、细胞内受体(如调节各种小配体的作用的物质,包括类固醇、甲状腺激素、视网膜样物质和维生素D;综述参见,如Evan(1988)Science,240:889-895;Ham和Parker(1989),Ann.Rev.Physiol.,51:683-699;Truss和Beato(1993)Endocr.Rev.,14:459-479)、肽类、retro-inverso肽、α-、β-或ω-氨基酸(D-或L-)的聚合物、酶、酶底物、辅助因子、药物、植物血凝素、糖、核酸(线性和环状聚合物构型)、低聚糖、蛋白质、磷脂和抗体。也可以测试诸如杂聚合物的合成聚合物,其中已知药物与任何上述物质,如聚氨酯、聚酯、聚碳酸酯、聚脲、聚酰胺、聚乙烯亚胺、聚亚芳基硫、聚甲硅烷、聚酰亚胺和聚乙酸酯进行共价连接。其它也可用本系统分析的聚合物在本技术领域人员综观本发明后将会很显然。本技术领域人员通常熟悉生物学文献。对于生物系统的一般介绍参见Berger和Kimmel,分子克隆技术指南(Guide to Molecular Cloning Techniques),酶学的方法(Methods in Enzymology),卷152,Academic Press,Inc,.(美国加利福尼亚圣地亚哥)(berger);Sambrook等(1989)分子克隆-实验室手册(第二版)卷1-3,ColdSpring Harbor Laboratory,Cold Spring Harbor Press,纽约(Sambrook);分子生物学暂时草案(Current Protocols in Molecular Biology),F.M.Ausubel等编辑,CurrentProtocols,Greene出版协会公司和John Wiley & Sons,Inc.的合资单位(1997整年增补本)(Ausubel);Watson等(1987)
基因的分子生物学(Molecular Biology of the Gene),第四版The Benjamin/Cummings出版公司,美国加利福尼亚;Watson等(1992)重组DNA第二版,Scientific American Books(美国纽约);Alberts等(1989)细胞的分子生物学,第二版(Molecular Biology of the Cell Second Edition)GarlandPublishing(美国纽约);Pattison(1994)
临床病毒学的原理和实践(Principles and Practice Of Clinical Virology);Darnell等(1990)
分子细胞生物学第二版 (Molecular Cell Biology Second edition),Scientific American Boods,W.H.Freeman and Company;Berkow(编辑)
诊断和治疗手册(The Merck Manual of Diagnosis and Therapy),Merck & Co.,Rahway,NJ;
内科学的哈里森原理 (Harrison’s Principles of Internal Medicine),第13版,Isselbacher等(编辑)(1994)Lewin
基因(Genes),第5版,牛津大学出版(1994);“Practical Approach”系列丛书(Rickwood和Hames编辑),在牛津大学的IRL出版社出版,纽约;AcademicPress的“FactsBook Series”;来自生物试剂和实验设备的产品说明书也提供了用于分析生物系统中的信息。这类制造商包括,如SIGMA chemical company(美国MO),R & D systems(美国明尼苏达),Pharmacia LKB生物技术(美国新泽西),CLONTECH实验室公司(美国加利福尼亚),Chem.Genes Corp.,Aldrich ChemicalCompany(美国WI),Glen Research,Inc.,GIBCO BRL生命技术公司(美国马里兰),Fluka Chemica-Biochemika Analytika(瑞典),Invitrogen(美国加利福尼亚)和Applied Biosystems(美国加利福尼亚),及许多其它对本技术领域公知的商业来源。
为了提供用于筛选化合物对生化系统的作用的方法和装置,本发明一般包含体外系统模型,所述的模型模拟作用物化合物所需的给定的生化体内系统。针对可筛选的化合物和作用物化合物所需的的系统的范围很广。例如,化合物可任选地筛选在阻滞、减缓或抑制与产生不良作用的生化系统有关的关键事件时的作用。例如,试验化合物可任选地筛选它们阻滞对疾病的发作负责的(至少部分责任的)或对疾病的特定症状的发生负责的系统的能力,包括,如遗传病、癌症、细菌或病毒感染等。在这些筛选分析方法中显示出有希望结果的化合物接着可进行进一步的试验来鉴定对于治疗疾病或疾病症状的有效的药理学制剂。
另外,可筛选化合物刺激、增加或诱发产生所需的功能的生化系统的能力,例如,治疗病人存在的缺陷。
一旦选定了模型系统,可将试验化合物库施加到这些模型系统上。通过体外鉴别这些对特定生化系统已有作用的试验化合物,人们可以发现对该系统体内有作用的潜在作用物。
在它们最简单的形式中,用于本发明方法和设备的生化系统模型将筛选试验化合物对生化系统的两个组分,如受体-配体相互作用、酶-底物相互作用等之间的相互作用的作用。在该形式中,该生化系统模型典型地包括寻找对它的作用物的系统的两个正常相互作用的组分,如受体及其配体或酶和它的底物。
首先决定试验化合物是否对该相互作用有效果,然后使系统与试验化合物接触,分析该系统的功能,如受体-配体结合或底物周转。然后将分析的功能与对照,如在没有试验化合物存在下或有已知作用物存在下进行相同的反应,进行比较。典型的是,这类分析涉及测量生化系统参数。“生化系统的参数”表示系统功能的一些可测量的证据,如存在或不存在标记的基团或分子量的改变(如,在结合反应、转移筛选中),存在或不存在反应产物或底物(在底物周转测量中),或电泳移动性的改变(典型地通过标记化合物洗脱时间的改变来检测)。
虽然阐述涉及到两组分的生化系统,但本发明的方法和装置也可用来筛选更复杂系统的作用物,其中系统的结果或最终产物是已知的,并在一定的水平上可分析,如酶途径、细胞信号途径等。另外,本文所述的方法和设备可任选地用来筛选与生化系统的单个组分相互作用的化合物,如特异性地与特定的生化化合物,如受体、配体、酶、核酸,结构大分子等结合的化合物。
生化系统模型也可包含在整体细胞系统中。例如,当人们在寻求筛选作用于细胞应答的试验化合物时,可任选地使用整体细胞的试验化合物。改良的细胞系统也可用于本文涵盖的筛选系统里。例如,嵌合的受体系统被任选地用作试验化合物对特定生化系统作用的指示剂。嵌合的受体系统典型地是将杂相受体系统整合到信号途径里,它标志受体与其配体结合。例如,受体被融合到异质蛋白质里,如活性很容易被分析的酶里。通过配体结合的受体激活活化了异质蛋白质,它然后可供检测。这样,替代的受体系统产生了容易检测的事件或信号,从而可以分析受体/配体结合。这类嵌合受体系统的例子在本技术领域已有所揭示。
另外,当人们对生物利用度(例如转运)进行筛选时,生物屏障被任选地包括生物屏障。术语“生物屏障”一般指在生物系统里的细胞的或膜的层,或它们的合成模型。这类生物屏障的例子包括上皮层和内皮层,如血管内皮层等。
生物应答常常通过受体与它的配体结合所引发和/或控制。例如,生长因子,即EGF、FGF、PDGF等与它们的受体相互作用刺激了大量生物应答,包括,如细胞繁殖和分化、调节酶的活化、信息子周转的刺激、离子流量的改变、酶的活化、细胞形状的改变和基因表达水平的改变。因此,控制受体和它的配体之间的相互作用能提供由该相互作用导致的生物应答的控制。
因此,一个方面,本发明可用于筛选对受体分子和它的配体的相互作用有作用的化合物。本文使用的术语“受体”一般指可特异性地彼此识别和结合的一对化合物中的一个成员。该一对物质里的另一个成员是“配体”。这样,受体/配体对可包括典型的蛋白质受体(通常与膜相关)和它的天然配体,如另一种蛋白质或小分子。受体/配体对也可包括抗体/抗原结合对、互补的核酸、与核酸缔合的蛋白质和它们的核酸配体。大量特异性相关的生化化合物在本技术领域也是公知的,它们可用来实施本发明。
传统上,对受体/配体相互作用的作用物筛选的方法涉及在试验化合物的存在下培养受体/配体结合对。受体/配体对的结合水平然后与阴性和/或阳性的对照比较。正常结合下降时,试验化合物被认为是受体/配体结合的抑制剂。结合增长时,试验化合物被认定为相互作用的增加剂或诱发剂。
在效率上,筛选分析被典型地建立在多坑反应板上,如多坑微板,这使得能同时平行地筛选大量试验化合物。
生化系统上相似和可能的重复包括酶和它们的底物之间的相互作用。本文使用的术语“酶”一般指作为催化剂诱发其它化合物或“底物”化学改变的蛋白质。
典型的是,通过使底物与酶在待筛选化合物存在下或没有所述化合物存在下,在最佳检测酶活性改变的条件下接触来筛选酶对其底物活性的作用物。在反应预定时间后,分析混合物中反应产物的存在量或底物量的减少量。已被催化的底物量与对照,即没有试验化合物存在下或有已知作用物存在下酶和底物接触,进行比较。如上所述,降低酶对其底物的活性减少的化合物是“抑制剂”,而加强该活性的化合物是“诱导剂”。
一般来说,本发明涵盖的各种筛选方法涉及将多个试验化合物引入微流体装置。一旦流入该装置,试验化合物用连续的系列或平行的分析取向筛选对生物系统上作用的。
本文使用的术语“试验化合物”是指待筛选影响特定生化系统能力的化合物的集合名词。试验化合物可包括各种不同的化合物,包括化学化合物、化学化合物的混合物,如多糖类、小的有机或无机分子,生物大分子,如肽、蛋白质、核酸,或从生物材料制备的提取物,如细菌、植物、真菌或动物细胞或组织,天然形成或合成的组合物。根据特定实施的技术方案,来提供试验化合物,如注射,在溶液里游离或任选地与载体或固体支持物,如球珠连接。许多合适的固体支持物被用来固定试验化合物。合适的固体支持物的例子包括琼脂糖、纤维素、右旋糖苷(市售可得,即Sephadex,Sepharose)、羧甲基纤维素、聚苯乙烯、聚乙二醇(PEG)、滤纸、硝基纤维素、离子交换树脂、塑料膜、玻璃珠、聚胺甲基乙烯基醚马来酸共聚物、氨基酸共聚物、乙烯-马来酸共聚物、尼龙、丝等。另外,对于本文所述的方法和装置,试验化合物被单个筛选或分组筛选。当有效试验化合物的命中率预计很低,结果人们在给定组中不能预期得到一个以上的阳性结果时,分组筛选尤为有用。或者当不同的试验化合物的效果在单个系统里分别检定时,可使用这类分组筛选,如通过这些效果的电泳分离或能分开检测的分别标记。
试验化合物是市售的,或从同上所述的对本技术领域熟练人员很明显的各种生物来源的衍生物。一方面,来自病人的组织匀浆或血样在本发明的分析系统里试验。例如,一方面试验血液中生物相关分子的存在或活性。例如,用本发明的分析系统通过向生物样品提供酶底物并检测产物的形成来检测酶的存在和活性水平,相似的是,感染病原体(病毒、细菌、真菌等)或癌样肿瘤的存在可通过监测标记配体对病原体或肿瘤细胞,或病原体或肿瘤组分,如蛋白质、细胞膜、细胞萃取物之类的结合来试验,或另外的方法是通过监测病人血液中的病原体或肿瘤的抗体的存在来试验。例如,来自病人血液的抗体与诸如HIV蛋白质的病毒蛋白的结合是检测暴露于该病毒的病人的通常试验方法。许多检测病原体感染的方法是公知的,它适合于本发明的分析系统。
用诸如静脉穿刺或组织分离术的已知的技术从病人中得到生物样品。当生物材料来自非人类动物,如市售的相关家畜类时,血样和组织样品常规地从家畜加工厂得到。相似的是,用于本发明分析的植物材料常规地来自农业或园林业。另外的方法是,生物样品可从贮存组织和/或血液的细胞库或血库得到,或从诸如细胞培养的体外来源得到。建立用作生物材料源的细胞培养技术和方法是本技术领域人员公知的。Freshney
动物细胞的培养,挤出技术手册,第三版(Culture of Animal Cells,a Manual of Basic Technique,Third Edition)Wiley-Liss,美国纽约(1994)提供了细胞培养的一般介绍。
II.分析系统
如上所述,本发明的筛选方法一般在微流体设备或“微实验室系统”里进行,所述的设备或系统集成了进行分析、自动控制、和使诸如蒸发、污染、人为误差等环境对分析系统的影响最小所需的部件。许多用来实施本发明分析方法的装置详述如下。但是,应当知道,这些装置的特定结构会根据分析的类型和/或分析所需的取向而改变。例如,在一些具体例子中,本发明的筛选方法可用有两个相交管的微流体设备来进行。对于更复杂的分析或分析取向来说,任选地使用多管/相交管设备。这些设备的小规模、完整性和自身包含性质使实际上任何分析取向可在微实验室系统的范围内进行。
A.电动材料传运
在优选方面,本文揭示的设备、方法和系统使用电动材料传运系统,更优选的是使用控制的电动材料传运系统。本文使用的“电动材料传运系统”包括使物质在相交管和/或含室结构里通过对该物质施用电场来转运和定向,从而使物质贯穿和在管和/或室之中运动,即,阳离子向阴极运动,而阴离子向阳极运动。
这类电动物质转运和定向系统包括那些依赖于带电荷物质在施加于该结构的电场里的电泳移动性的系统。这类系统特别可称为电泳物质转运系统。其它的电动物质定向和转运系统依靠在管或室结构里的流体和物质的电渗透流,它由跨越该结构施加电场而产生。简言之,当流体被放在管子里,它具有在蚀刻玻璃管或玻璃微毛细管上带有带电官能团,如羟基的表面,这些这些基团可被离子化。在羟基官能团的情况下,该离子化,如在中性pH下导致从表面上释放质子并进入流体,这样产生了在邻近流体/表面界面上的质子浓度,或在管中大量流体周围带有正电荷鞘。沿管子长度施加电压梯度将导致质子鞘,及其它所围绕的流体朝电压下降的方向运动,即向阴极运动。
本文使用的“受控的电动物质转运和定向”指上述的电动系统,它使用施加在多个电极,即多于两个电极上的电压的活性控制。改述之,这类受控的电动系统同时调节施加在至少两根相交管上的电压梯度。受控的电动物质转运如公开的PCT申请WO 96/04547(Ramsey)所述,在此全文并入本文供参考。具体的是,本文所述的优选的微流体装置和设备包括主要部分结构,它包括至少两根相交管或流体导管,如相交的封闭室,其中管包括至少三个不交叉的端点。两根管子的交叉是指在一点处两根或多根管互相通过流流相连,包括“T”相交、交叉相交、多个管子的“货车轮”型相交,或两根或多根管子进行流体相通的任何其它几何学图形。管子不相交的末端是管子不与另一根管子进行诸如“T”相交的端点处。优选的是,该装置包括至少三根相交管,它们有至少四个不相交的端点。在基本的跨管结果中,其中单个水平管是相交的,且与单根垂直管交叉,受控的电动物质转运通过在相交处提供来自其它管的约束流来控制物质定向地流动经相交处。例如,假定人们想要将第一物质运送经水平管,如从左到右,穿过与垂直管的相交处。穿越相交处的该材料的简单电动物质流可通过沿水平管的长度施加电压梯度来实实,即在该管子的左端施加第一电压,在该管子的右端施加较低的第二电压,或让右端飘移(不施加电压)。但是,该类型的流经相交处的物质流导致在相交处的大量扩散,这是由于被转运物质在使用的介质里的天然的扩散性质及在相交处的对流性所导致的。
在受控的电动物质转运中,被转运穿越交叉点的物质通过来自侧管,如顶部和底部管的低水平流动所限制。这通过沿着物质流的途径,如从垂直管的顶部或底部末端流向右末端的物质流施加平缓的电压梯度而实现。结果是物质流在交叉处“收缩”,这防止物质扩散入垂直管里。交叉处收缩的物质的体积然后可通过施加穿越垂直管长度,即从顶端到底端来施加电压梯度来流入垂直管。为避免物质在注入期间从水平管渗出,低水平的液流被导回侧管,导致物质从交叉处被“拉回”。
除了收缩注入方案外,使用受控电动物质转运以产生不包括机械或运动部件的虚拟的阀。特别是,参照上述内容,可通过控制垂直管的流动,如垂直管中从底管到顶管的流动来有效地调节、停止和再引发物质从一根管子的部分流向另一根管子,如从水平管的左臂流向右臂。具体是,在“关闭”模式下,通过在左端和顶端处施加电压梯度,物质从左侧管,经过交叉处转运顶管。通过沿着该途径(从底端到顶端)施加相似的电压梯度使限制的流动从底管流向顶管。然后通过将施加的电压梯度从左到顶转换成,从左到右,使计量量的物质从水平管的左臂分配到右臂。时间和施加电压梯度的量确定了以该方式分散的物质量。虽然用四通道、截面交叉来供阐述用,这些受控的电动物质转运系统可容易地适合更复杂的相交管网络,如相交平行管的排列。
B.连续的流动分析系统。
一方面,本发明优选的方法和装置用连续的流动分析系统来筛选试验化合物。一般来说,连续的流动分析系统可容易地用来筛选酶活性的抑制剂或诱导剂,或受体-配体结合的激动剂或拮抗剂。简单来说,连续的流动分析系统涉及沿着微组装管的特定生化系统的连续流。本文使用的“连续”表示连续流动的特定组合物不间断或接连流动。例如,连续流动可包括有一定速度的恒定的液流,或换言之,包括整个系统里的流动速度中止,结果该中止不干扰流动的液流。该系统的功能通过可检测的事件或信号来显示。在优选的技术方案中,这类可检测信号包括与所用的特定模型系统的功能有关的可光检测的发色信号或荧光信号。对于酶系统,这类信号通过酶催化作用的产物,如在发光团或发荧光底物上产生。对于结合系统,如受体配体相互作用,信号典型地涉及受体与标记的配体的缔合,或反之亦然。
各种其它的检测信号和标记物也可用于本发明的分析和装置中。除了上述的发光团和发荧光标记外,也可常规性地测量放射活性衰变、电子密度、pH、溶剂粘度、温度和盐浓度的改变。
更通常的是,标记物可通过光谱、光化学、生化、免疫化学或化学手段来检测。例如,有用的核酸标记物包括32P、35S、荧光染料、光电子密集试剂、酶(如通常用于ELISA中)、生物素(biotin)、二氧化素(dioxigenin)或半抗原和蛋白质,可从中得到抗血清或单克隆抗体。各种适合标记生物组分的标记物是已知的,在科学和专利生物里得到广泛的报道,一般可应用于本发明来标记生物组分。合适的标记物包括放射性核苷酸、酶、底物、辅助因子、抑制剂、荧光部分、化学发光团部分、磁性颗粒等。标记试剂任选地包括,如单克隆抗体、多克隆抗体、蛋白质或诸如亲和基质的其它聚合物(matrices)、碳水化合物或脂质。用各种已知方法进行的检测包括光谱测量或放射活性或荧光标记物的光学追踪,或根据分子大小、电荷或亲和性进行追踪的其它方法。可检测部分可为有可检测的物理或化学性质的任何材料。这类可检测标记物在凝胶电泳、柱层析、固体底物、光谱技术等领域里是已得到很好的开发,一般来说用于这类方法的标记物也可用于本发明。因此,标记物是可被光谱、光化学、生化、免疫化学、电学、光热或化学手段检测的任何组合物。用于本发明的标记物包括荧光染料(如荧光素异硫代氰酸酯,Texas红,若丹明等),放射标记物(如3H、125I、35S、14C、32P或33P)、酶(如LacZ,CAT,辣根过氧化酶,碱性磷酸酯酶和其它通常用作可检测的酶,如标记产物或ELISA中使用的酶)、核酸嵌合剂(如溴化3,8-二氨基-5-乙基-6-苯基菲啶鎓)和比色标记物,如胶体金或着色玻璃或塑料(如聚苯乙烯、聚丙烯、胶乳等)珠。
荧光标记物是尤为优选的标记物。优选的标记物典型的特征在于下列一个或多个:高灵敏度、高稳定性、背景弱、环境敏感性低和标记中的高特异性。
引入本发明标记物的荧光部分一般是已知的,包括1-和2-氨基萘、p,p’-二氨基芪、芘、季菲啶盐、9-氨基吖啶、p,p’-二氨基苯酮亚胺、蒽、氧杂羰花青、部花青、3-氨基quilenin、苝、双-苯并噁唑、双-对-噁唑基苯、1,2-苯并吩嗪、视黄醇、双-3-氨基吡啶鎓盐、嚏根苷配基、四环素、甾族苯酚(sterophenol)、苯并咪唑基苯胺、2-氧基-3-色烯、吲哚、占吨、7-羟基香豆素、苯并噁嗪、calicylate、strophanthidin、卟啉、三芳基甲烷和黄素。在本发明装置或分析中具有官能团可连接在要检测的元素上或通过改性可结合这类官能团的的单个荧光化合物包括,如,丹酰基氯;荧光素,如3,6-二羟基-9-苯基占吨醇;若丹明异硫代氰酸酯;N-苯基1-氨基-8-磺化萘;N-苯基2-氨基-6-磺化萘;4-乙酰氨基-4-异硫代氰酸酯基-芪-2,2’-二磺酸;芘-3-磺酸;2-甲苯氨基萘-6-磺酸酯;N-苯基-N-甲基-2-氨基萘-6-磺酸酯;溴化3,8-二氨基-5-乙基-6-苯基菲啶鎓;stebrine;亚金胺-0,2-(9’-蒽基)棕榈酸酯;丹酰磷脂酰基乙醇胺;N,N’-二十八烷基氧杂羰化青;N,N’-二己基氧杂羰化青;部花青、4-(3’-芘基)硬脂酸酯;d-3-氨基脱氧-马萘雌酮;12-(9’-蒽基)硬脂酸酯;2-甲基蒽;9-乙烯基蒽;2,2’-(亚乙烯基-对-亚苯基)双苯并噁唑;对-双(2-(4-甲基-5-苯基-噁唑基))苯;6-二甲基氨基-1,2-苯并吩嗪;视黄醇;双(3’-氨基吡啶鎓)-1,10-癸二基(decandiyl)二碘化物;嚏根苷配基的磺基萘基腙;氯代四环素;N-(7-二甲氨基-4-甲基-2-氧基-3-色烯基)马来酰亚胺;N-(对-(2-苯并咪唑基)-苯基)马来酰亚胺;N-(4-荧蒽基)马来酰亚胺;双(高香草酸);刃天表;4-氯-7-硝基-2,1,3-苯并噁二唑;部花青540;试卤灵;玫瑰琼脂;和2,4-二苯基-3-(2H)-呋喃酮。许多荧光剂标记物由SIGMA化学公司(美国MO),Molecular Probes,R & D systems(美国明尼苏打),Pharmacia LKBBiotechmology(美国新泽西),CLONTECH Laboratories,Inc.(美国加利福尼亚),Chem GenesCorp.,Aldrich Chemical Company(美国WI),Glen Research,Inc.,GIBCO BRL LifeTechnologies,Inc.(美国马里兰),Fluka Chemica-Biosystems(美国加利福尼亚)及其它本技术领域公知的市售来源。
需要的是,荧光标记物吸收300纳米,优选的是约350纳米,更优选的是约400纳米以上的光,通常以比吸收光大10纳米的波长发射。应当注意的是,结合的标记物的吸收和发射特征可能不同于未结合的标记物。因此,当谈及各种标记物的波长范围和特征时,是指所使用的标记物而不是没有结合的并在任意的溶剂中表征的标记物。
荧光标记物是一类优选的可检测标记物,部分是因为通过用光照射荧光标记物,人们可得到多个发射。因此,单个标记物可得到多个可测量的事件。用化学发光和生物发光源也可提供可检测的信号。化学发光源包括通过化学反应而激发电子的化合物,然后发射的光可作为检测信号或给予荧光受体提供能量。现已发现,各种化合物的家族在不同的条件下有化学发光。一类化合物是2,3-二氢-1,4-2,3-二氮杂萘二酮。最常用的化合物是鲁米诺,它是5-氨基化合物。其它化合物家族成员包括5-氨基-6,7,8-三甲氧基-和二甲氨基{ca}苯基类似物。这些化合物可用碱性过氧化氢或次氯酸钙和碱变得发光。另一类化合物是2,4,5-三苯基咪唑,用lophine作为母体产物的通名。化学发光类似物包括对-二甲氨基和-甲氧基取代物。化学发光剂也可用草酸酯,通常是草酰基活性酯,如对-硝基苯基酯,和过氧化物,如过氧化氢在碱性条件下得到。其它有用的化学发光化合物也是已知和可得的,包括N-烷基吖啶鎓酯(碱性H2O2)和dioxetane。可替换的是,荧光素可与荧光素酶或光泽精结合以得到生物发光。
根据本技术领域公知的方法将标记物直接或间接地与要被检测的分子(产物、底物、酶等)偶合。如上所述,可使用各种标记物,根据所需的灵敏度、与化合物结合的容易性、稳定性要求、可得的设备和弃置规定来选择标记物。非放射活性标记物通常通过间接手段来连接。一般来说,配对分子(如生物素)被共价连接到聚合物上。然后配体结合到抗-配体(如,streptavidin)分子上,它可被固有地检测出或共价连接到信号系统,如可检测的酶、荧光化合物或化学发光团化合物上。有许多配体和抗-配体可供使用。当配体具有天然的抗配体时,如生物素、甲状腺素和皮质醇,它可用来与标记的抗配体结合。可替换的是,任何半抗原或抗原化合物可用来与抗体结合。标记物也可直接与信号产生化合物结合,如与酶或荧光结合。作为标记物的酶主要为水解酶,特别是磷酸酯酶,酯酶和糖苷酶,或氧化还原酶,特别是过氧化酶。荧光化合物包括荧光素和它的衍生物,若丹明和它的衍生物、丹酰基、7-羟基香豆素等。化学发光化合物包括荧光素和2,3-二氢-2,3-二氮杂萘,如鲁米诺。检测标记物的手段是本技术领域公知的。因此,例如,当标记物是放射性标记物时,检测设备包括放射闪烁计数器或放射性自显影法中的照相膜。当标记物是荧光标记物时,可通过用合适的光波长来激发荧光发光团来检测所得的荧光,如通过显微镜、肉眼观察、通过照相膜、通过使用诸如数字照相机的电子检测器、电荷偶合装置(CCDs)或光电倍增管和光电管等。荧光标记物和检测技术,特别是显微镜和光谱学是优选的。相似的是,通过给酶提供合适的底物并检测所得的反应产物来检测酶标记物。最后,简单的比色标记物常简单地通过观察与标记物有关的颜色来检测。例如,结合的金色一般为粉红,而各种结合的珠表现出是珠的颜色。
在优选情况下,连续系统产生恒定的信号,它只是在影响系统的试验化合物被引入后发生改变。特别是,当系统组分沿管流动时,它们在检测带或管窗处产生相对恒定的信号水平。试验化合物被定期引入管子,并与系统组分混合。当这些试验化合物对系统有作用时,就导致了检测窗处恒定的信号水平发生偏离。该偏离然后与特定的筛选试验化合物进行关联。
图1显示了在系列或连续的分析设备中使用的设备的一个技术方案。如图所示,总体设备100被组装在平面基片102上。合适的基片材料根据它们与特定操作条件的匹配性来选择。这类条件包括pH、温度、盐浓度和施加电场的端值。另外,基片材料也可根据它们对由设备进行分析或合成的关键组分的惰性来选择。
有用的基片材料的例子包括,如玻璃、石英和硅及其聚合基片,如塑料。若是导体或半导体基片,通常需要在基片上包含绝缘层。当在设备中结合入电气部件时,如电气材料和流体导向系统、传感器等时这点尤为重要。对于聚合基片,基片材料是任选的刚性、半刚性或非刚性,不透明、半透明或全透明,这根据它们的用处而定。例如,包括光或肉眼检测元件的设备通常用,至少部分用,透明的材料组装,以便于检测。可替换的是,玻璃或石英的透明窗被任选地并入设备中作为这些类型的检测元件。另外,聚合材料可为直链或支链骨架,它们可任选地交联或非交联。特别优选的聚合物材料例子包括,如聚二甲基硅氧烷(PDMS)、聚氨酯、聚氯乙烯(PVC)、聚苯乙烯、聚砜、聚碳酸酯等。
图1显示的装置包括一系列管子110、112和任选的试剂管114,它们组装在基片的表面上。这些管子中至少一根具有极小的截面尺寸,如约0.1-500微米。优选的是,管子的截尺寸径范围为约0.1-200微米,更好的是约0.1-100微米。在特别优选的情况下,每个管子的至少一个截面尺寸范围为约0.1-100微米。虽然一般是如显示的直管,但应当明白,为了最大限度地使用基片空间,S字曲线、锯齿形或其它管子几何图形可使有效的更长管子占据更短的距离。
将这些微规模元件制备入基片表面一般可通过本技术领域公知的任何数目的微组装技术进行。例如,石版印刷的技术可任选地用于如玻璃、石英或硅基片的组装中,它可采用半导体制造工业,如光石版印刷蚀刻、等离子蚀刻或湿化学蚀刻的公知方法。可替换的是,诸如激光钻孔、微研磨等的微机械方法也可任选地采用。相似的是,对于聚合基片,也可使用公知的制造技术。这些技术包括注入模塑或冲压模塑方法,其中大量基片任选地用如滚动冲压来生产出大张的微规模基片或用聚合物微压延技术,这时基片在微机械铸模里进行聚合。
该装置典型地包括另外的平面元件,它与装了管子的基片重叠,密闭并液封各种管子以形成管道。用各种方法,包括如热粘合、粘合剂或对于某些基片,如玻璃或半刚性和非刚性的聚合基片,在两个部件之间进行天然的粘合,这样将平面遮盖元件连接上去。平面遮盖元件另外可带有入口和/或贮槽供引入各种用于特定筛选所需的液体组分。
图1所示的装置也包括贮槽104、106和108,它们放置并流体地连接在管子110和114的末端。如图所示,样品管112用来将多种不同的试验化合物引入装置。这样,该管子通常可液体地与大量分离的试验化合物源连接,所述的试验化合物将被各个引入样品管112并接着进入管子110。
由许多方法可将大量单个分离的体积的试验化合物引入样品。例如,微吸移管被任选地用来将试验化合物引入装置。在优选的情况下,使用液体地连接于样品管112的电子吸移管。美国专利申请08/671,986,1996,6,28提交(律师文档号:017646-000500)揭示了这类电子吸移管的一个例子,在此并入本文供参考。一般来说,该电子吸收移管用本文揭示的电渗透流体定向来交替地对许多试验化合物或“主题材料”和间隔的化合物进行取样。吸移管然后将单个的,物理上分离的样品或试验化合物体积移送入主题材料区,按序进入样品管供装置里作随后的操作。各个样品典型地由低离子强度间隔液体来分离。这些低离子强度间隔区域在其长度上的电压落差大于较高离子强度的主题材料或试验化合物区域的电压落差,从而驱动了电动泵。在试验化合物或主题材料区域(它们典型地处在较高离子强度的溶液里)的每一侧面上是液体区域,称为第一间隔区域(也称为“防护带”),它们与主题材料区的界面接触。这些第一间隔区域典型地包括高离子强度溶液以防止样品组分迁移入较低离子强度的液体区域,或第二间隔区域里,从而导致电泳变斜。美国专利申请08/671,986,1996,6,28提交(律师文档号017646-000500)更详尽地揭示了对这类第一和第二间隔区域的使用,在此并入本文供参考。
另外的方法是,样品管112通过独立的管子被任选地各个液体地连接到多个分开的贮槽。该分开的贮槽每个含独立的试验化合物,并带有另外的贮槽用来提供适当的间隔化合物。试验化合物和/或间隔化合物然后用合适的材料定向方案从各个贮藏运送到样品管。在每个情况下一般都需要用合适的间隔区域来分开不连续的样品体积,或试验化合物。
如图所示,该装置也包括检测窗或检测带116,在此可任选地监测来自生化系统的信号。该检测窗典型地包括透明的覆盖物供肉眼或光学观察并检测分析结果,如比色的或荧光的应答的观察。
在特别优选的情况下,用光学检测系统在检测窗监测信号。例如,荧光基的信号典型地用,如使用了适当波长的激光源来激活系统里的荧光指示剂的激光激活荧光检测系统来监测。然后用合适的检测元件,如光电倍增管(PMT)来检测荧光。相似的是,对于使用比色信号的筛选,可任选地使用将光源导向样品的分光光量计检测系统,提供样品的吸收性或透光率的测量。
在另外的情况下,检测系统可包括非光学检测器或传感器供检测安置在检测窗116里的系统的特定性状。这类传感器包括温度、传导性、电位计(pH、离子)、电流计(amperometric)(对于氧化或还原的化合物,如,O2、H2O2、I2、可氧化/可还原的有机化合物等)。
在操作时,生物系统的可流动的第一组分,如包括受体或酶的液体被放在贮槽104中。该第一组分流经主管110,经过检测窗116,流向废物贮槽108。生化系统的第二组分,如配体或底物同时从侧管114流入主管110,在此第一和第二组分混合并相互作用。用多种方式加入这些组分。例如,酶和底物或受体和配体溶液可通过在平面遮盖物上的开口或可密封的入口进入本装置。另外的方法是,这些组分在制造装置时便被任选地加入到它们各自的贮槽里。对于这种预加入的组分,需要提供这些组分的稳定形式以延长本装置的使用寿命。例如,酶/底物或受体/配体组分在装置中以冻干形式存在。使用前,这些组分通过向贮槽里加入缓冲液来再构建。可替换的是,组分与合适的缓冲盐一起冻干,从而只要向样品中加水家即可完成再构建。
如上所述,第一和第二组分之间的相互作用通常伴随可检测的信号。例如,在第一组分是酶,第二组分是底物的技术方案里,当酶作用于底物上时,底物是生色的或生荧光的底物,它产生光学可检测的信号。若第一组分是受体,第二组分是配体,配体或受体可任选地包括可检测信号。在每种情况下,化合物的混合和流动速率典型地是稳定的,结果第一和第二组分混合物流经检测窗116时会产生稳态信号。“稳态信号”通常表示具有规则的、可预见的信号强度曲线。这类稳态信号可包括有恒定信号强度的信号或具有规则的周期性强度的信号,相对于它们,正常信号曲线中的变化就可以测量。这个后者的信号是在液体流被周期性地干扰,如在连续流动系统中所述的加入了另外的试验化合物时产生。虽然上述酶系统里产生的信号会沿管的长度改变,即随着酶将生荧光的底物转换成荧光产物的暴露时间而增加,但在给定的恒定流速下,沿管子上任何特定点处的信号将是恒定的。
试验化合物从样品管112周期性地或连续地进入主管110并进入第一和第二组分的流体里,此时液体区域含试验化合物,也称为“主题材料区”。当这些试验化合物对第一和第二组分的相互作用有影响时,它在相应于主题材料区的检测窗处检测到的信号将产生偏差,如上所述,典型的是,经管112被注入的各种不同的试验化合物将被第一,甚至第二间隔流体区域分离,以将一种试验化合物的作用与另一种区别开,或确定没有作用。在使用电渗透流体定向系统的具体技术方案中,间隔流体区域也可减少试验样品里发生的电泳偏斜。使用这些间隔区域来驱动电渗透流体流动,并消除样品里或试验化合物里或主题材料区里的电泳偏斜,这在美国专利申请08/671,986,1996,6,28提交(律师稳定号017646-000500)中得以揭示,前面已并入本文供参考。
举例说明,流经主管110的稳定、连续的酶流和产荧光底物在检测窗116处将产生恒定的荧光信号。当试验化合物抑制酶时,在主题材料区里引入试验化合物在相应于该主题材料区的检测窗处会产生瞬间的,但可检测到的信号下落。信号下落的时间测定可根据已知的注入对检测的时间框架与特定的试验化合物进行关联。特别是,注入化合物产生可观察到的效果所需要的时间可用阳性对照的方法很容易地测定出。
对于受体/配体系统,也可在稳态信号里观察到相似的变化。特别是,可以使受体和它的荧光配体沿管子有不同流速。这可这样来实施:在管子中装入尺寸排阻基质,或在电渗透方法里,改变两个化合物之间的相对电泳迁移性,使受体更快地向下流动。再者,通过使用尺寸排阻基质或通过在管子里使用不同表面电荷,会导致电荷改变的化合物的流动速率分化。当试验化合物与受体结合时,它会在荧光信号中产生一个暗的,接着一个较亮的脉冲。不为特定的操作理论所约束,据信稳态信号是游离荧光配体和结合到受体的荧光配体已与受体结合的结果。该结合的配体以与受体相同的流速运动,而未结合的配体运动较缓慢。当试验化合物抑制受体-配体相互作用时,受体将不会“携带”荧光配体,从而在流动方向稀释荧光配体,过量的游离配体被留在后面。这导致稳态信号的暂时下降,然后是荧光的暂时增加。另外的方法是,使用与酶系统相似的方案,其中信号反映了受体与它的配体之间的相互作用。例如,指示pH对受体-配体结合的影响的pH指示剂即以封人小室的形式结合人生化系统的装置,从而可检测到产生自结合的轻微的pH改变。参见Weaver等,Bio/Technology(1988)6:1084-1089。另外,人们可以监测由受体-配体结合导致的酶活化,如激酶的活化,或检测这类酶在活化时构象的改变,如通过掺入荧光,它由于酶在活化时的构象改变而活化或淬灭。
通过各种方法在微规模流体装置里让流体流动和定向。例如,装置可包括完整的微流体结构,如微泵和微阀,或外部元件,如泵和转换阀供将各种液体泵经整个装置并定向。微流体结构的实例如下列文献所述:如美国专利5,271,724,5,277,556,5,171,132和5,375,979。也可参见公开的英国专利申请2 248 891和公开的欧洲专利申请568 902。
虽然微组装的流体泵和阀门系统可很容易地用于本发明的装置,但与其制造和操作有关的成本和复杂性通常抑制了它们在本发明大量生产的一次性装置中的使用。鉴于该理由,本发明优选的装置典型地包括电渗透流体定向系统。这类流体定向系统综合了没有移动部件的液体定向系统的优点与制造、对液体的控制和放置的容易性等优点。特别优选的电渗透流体定向系统的例子包括,如国际专利申请WO 96/04547(申请人:Ramsey等)在此并入本文供参考。
简单地说,这些流体控制系统典型地包括放置在贮槽里的电极,所述的贮槽被放在与组装在基片表面里的多个相交管连接的流体交接处。贮藏在贮槽里的材料经管系统运送,将适当体积的各种材料移送到基片上的一个或多个区域以进行所需的筛选分析。
流体和材料的运送和定向由电渗透或电运动来实施。简单地说,当合适的材料,典型地包括流体,被放在表面上存在官能团的管子里或其它流体导管里时,这些基团可离子化。例如,当管子的表面包括羟基官能团时,质子可离开管子的表面进入流体。在这类条件下,表面将具有净负电荷,而流体具有过量的质子或正电荷,特别是在管子表面和流体之间的界面附近。通过沿着管子的长度施加电场,阳离子流向阴极。流体中正电荷离子拉动溶剂共同运动。该流体运动的稳态速度由下式算得:
其中v是溶剂速度,ε是流体的介电常数,ξ是表面的Z电位,E是电场强度,η是溶剂粘度。这样,从该等式中可知,溶剂速度与表面电位成正比。
为了提供合适的电场,该系统通常包括能同时对每个贮槽,包括接地施加可选择的电压水平的电压控制器。这类电压控制器可用多电压分配器和多重继电器得到可选择的电压水平来实施。可替换的是,任选使用多个独立的电压源。电压控制器与每个贮槽通过放置或组装在多个贮槽里的每一个的电极进行电连接。
将电渗透流体定向系统结合入如图1所示的装置涉及将电极装入每个贮槽104、106和108、在样品管112末端或在任何与之连接的流体管的末端处,从使而电极与放置在各个贮槽或管子中的流体电接触。也可选择基片材料来产生有所需表面电荷的管子。对于玻璃基片的情况,蚀刻的管子具有净负电荷,它从自然存在在表面的离子化羟基得到。可替换的是,任选地用表面改性以提供合适的表面电荷,如涂覆,衍生化,如硅烷化或浸渍表面以在表面上得到合适的带电荷的基团。暂时申请60/015,498,1996,4,16提交(律师文档号017646-002600)揭示了这类处理的例子,在此并入本文供参考。
简单地说,合适的基片通常根据它们与使装置运行的特定操作条件的匹配性来选择。这类条件可包括pH、温度和盐浓度的端点值。另外,基片材料也可根据它们对用该装置进行的分析或合成的关键组分的惰性来选择。聚合物基片材料根据它们的用途,可为刚性、半刚性或非刚性,不透明、半透明或全透明。例如,包括光学或肉眼检测元件的装置一般至少部分由透明的聚合材料组装以便于检测。可替换的是,如玻璃或石英的透明窗可装入装置作为检测元件。另外,聚合材料可为直链或支链骨架,可为交联或非交联的。聚合材料的例子包括,如丙烯酸类,特别是PMMA(聚甲基丙烯酸甲酯);丙烯酸类的例子包括,如Acrylite M-30或Acrylite L-40,CYRO Industries出售(美国新泽西),或PLEXIGLAS VS UVT,Autohass North America出售;聚碳酸酯(如Makrolon CD-2005,Plastics和Rubberdivision of Mobay Corporation或Bayer Corporation出售,或为LEXAN OQ 1020L或LEXAN OQ 1020,两者都是GE Plastics出售),聚二甲基硅氧烷(PDMS),聚氨酯、聚氯乙烯(PVC)、聚苯乙烯,聚砜,聚碳酸酯等。许多塑料的光学、机械、热学、电学和化学耐受性质是公知的(一般可从制造商那里得到)或可通过标准分析很容易地测定。
如本文所述,本发明装置中使用的电动流体控制系统通常使用表面上有带电荷官能团的基片,如玻璃表面上存在着的羟基。如本文所述,本发明的装置也可使用塑料或其它聚合基片。一般来说,这些基片材料具有疏水表面。结果,用于本发明中使用的聚合基片的装置中使用电动流体控制系统典型地使与流体接触的基片表面改性。
聚合基片的表面改性可用各种不同的形式进行。例如,可用合适的带电荷材料涂覆。例如,带有带电荷基团和疏水末端的表面活性剂是所需要的涂覆材料。简单地说,疏水末端将定位在基片的疏水表面上,从而使流体层上存在带电荷的头部基团。
在一个技术方案中,制备在基片上的带电荷表面涉及让待改性的表面,如管子和/或反应室暴露于合适的溶剂,所述的溶剂部分溶解或软化该聚合基片的表面。然后使清洁剂与部分溶解的表面接触。清洁剂分子的疏水部分将与部分溶解的聚合物缔合。然后,如用水从表面上洗去溶剂,从而聚合物表面硬化,同时清洁剂被植入表面,在流体界面上存在带电荷的头部基团。
在另外方面,诸如聚二甲基硅氧烷的聚合物材料可通过等离子体辐照来改性。特别是,等离子体辐照PDMS使甲基氧化,释放出碳并在其位置上留下羟基,从而在聚合物材料上有效地制造出玻璃样的表面,具有缔合的羟基。
聚合基片根据使用的特定装置可为刚性、半刚性、非刚性或刚性和非刚性元件的结合,在一个技术方案中,基片由至少一种较软的弹性基片元件和至少一种较硬的更刚性的基片元件制成,其中的一种制成管子和室的表面。在匹配两种基片时,选用较软的元件可形成管子和室有效的液体密封性,排除了与刚性较大的塑料组件粘合或熔融在一起的问题。
许多另外的元件被加到聚合基片上以提供电动流体控制系统。这些元件可在基片形成过程,即模塑或冲压步骤中加入,或它们可在下一个分离步骤中加入。这些元件典型地包括给各种流体贮槽施加电压的电极,在一些技术方案中,在各个管子相交处放置电压传感器以监测施加的电压。
电极可作为模塑加工的一部分装入。特别是,电极可在模具中成形,使得在聚合材料引入模具时,电极可被合适地放置。可替换的是,在基片形成后用公知的微组装方法,如喷溅或受控蒸汽沉积方法,然后用化学蚀刻加入电极和其它元件。
不论是使用聚合基片或其它基片,调制电压被同时施加到各个贮槽以影响所需的流体流动特性,如受体/酶、配体/底物向废物贮槽的连续流动,同时定期引入试验化合物。特别是,施加在各个贮槽上的电压调制可移动并指导流体以受控的方式流经装置的相交管结构,使流体流至所需的筛选分析和装置。
图2A显示了在典型的分析筛选期间流体定向的示意图。特别是,所显示的是将试验化合物(在主题材料区里)注入酶-产荧光底物混合物的连续流。如图2A所示,并参照图1,酶的连续流从贮槽104流出沿主管110流动。由合适的间隔区域121,如低例子强度间隔区域分离的试验化合物120被从样品管112引入主管110。一旦引入主管,该试验化合物将与流动的酶流相互作用。混合的酶/试验化合物区域然后沿主管110流动,经过与管子114的相交处。存放在贮槽106中的产荧光或生色底物的连续流被引入样品管110,从而它与酶的连续流、包括含试验化合物122的主题材料区接触和混合。酶与底物的作用会使荧光或彩色信号水平增加。当它接近监测窗时该增加的信号在主管里由增加的阴影来表示。在对酶/底物相互作用没有影响的试验化合物或主题材料区,如试验化合物126也会发生该信号趋势。当试验化合物对酶和底物的相互作用确有影响时,产生的信号将会有变化。例如,假设产荧光底物,抑制酶和其底物相互作用的试验化合物会使主题材料区里产生的荧光产物较少。这将导致在物流经过相应于主题材料区的检测窗116时无荧光,或可检测到的荧光减少。例如,如图所示,含试验化合物128(它是酶-底物相互作用公认的抑制剂)的主题材料区显示出荧光比周围物流的荧光低的可检测荧光。这由缺少主题材料区128的阴影来表示。
与检测窗相邻的检测器监测由产荧光或生色底物上酶活性产生的荧光信号。该信号对于对酶-底物相互作用没有影响的试验化合物保持相对恒定。但是,在筛选抑制剂化合物时,其荧光信号有暂时的下落,这代表抑制了酶对底物的活性。相反,筛选诱导剂化合物时荧光信号产生暂时的上升,这相应于酶对底物的活性增加。
图2B提供了筛选受体-配体相互作用物的相似示意图,如图2A所示,受体的连续流从贮槽104流出经主管110。被合适的间隔流体区域121分离的试验化合物或主题材料区150从样品管112引入主管110,来自贮槽106的荧光配体的连续流从侧管114里引入。在管子里用阴影表示荧光。如图2A所示,荧光配体和受体的连续流经过检测窗116,产生了恒定的信号强度。物流中的主题材料区(含有对受体-配体相互作用没有影响的试验化合物)会提供与余下的周围物流,如试验化合物或主题材料区152的荧光水平相同或相似的荧光水平。但是,当存在对受体-配体相互作用有拮抗或抑制活性的试验化合物时会导致带有这些化合物的这些部分的物流,如试验化合物或主题材料区154的相互作用的水平降低。进而,与荧光配体结合的受体和游离的荧光配体的不同的流动速度导致相应于由未结合、更快移动的受体的荧光稀释产生的的荧光水平可检测性下落。荧光的下落后,继而在荧光156处有增加,这相应于较慢移动的未结合的荧光配体的积聚。
在某些实例中,希望提供一种用于将主题材料区(subject material region)的反应混合物从操作缓冲液(running buffer)和/或间隔区域(spacer regions)中分流或提取出来的附加管。这可能是下述的这种情况,即希望在反应过程中将反应成分保持含在不连续的流体区域中,而同时在获取数据的阶段中使这些成分分开。如上所述,通过在样品之间加入合适的间隔流体区域(spacer fluid region),可以将各种反应成分一起保持在在反应管中移动的主题材料区中。通常对这种间隔流体区域进行选择以将样品保留在其初始的主题材料区中,即不允许将样品涂抹到间隔区域中,即使在延长的反应期间内。然而,这个目的对于下述这些试验可以有所不同,所述试验为基于对试验成分的分离,例如如上所述的配体-受体试验,或其中的反应产物必须在毛细管中分离的试验。这样,可能希望除去那些在流体方向的初始部分中阻碍这种分离的成分。
为进行这个样品或主题材料的分流(shunting)或提取所用的装置500的一个例子的示意图图示于图5中。如图所示,通过样品管512将主题材料或试验化合物504引入装置或片(chip)中。再者,一般通过合适的注入装置506如毛细吸移管管理器引入这些材料或化合物。选择离子强度和第一间隔区域508和第二间隔区域502的长度,使得那些电泳迁移性最高的样品在使样品沿反应管下移的期间内不会从第一间隔区域508迁移到第二间隔区域502。
假定受体配体试验系统,试验化合物进入装置500,再进入反应管510,在此处它们先与受体混合。以主题材料区形式的试验化合物/受体沿反应管流入培养区510a中。在此初始培养之后,试验化合物/受体混合物与标记的配体(例如荧光配体)混合,此时这个混合物沿反应管510的第二个培养区510b流动。培养区的长度和系统的流动速度(由施加在各贮槽514,516,518,520,522以及试验管512末端处的电压确定)决定了受体与荧光配体和试验化合物的培养时间。选择含受体和荧光配体的溶液的离子强度,以及材料从容纳这些成分的贮槽进入样品管的流动速度,以便不干扰第一和第二间隔区域。
在如贮槽514,516,518以及样品管512的末端施加电压,使包含受体、荧光配体和试验化合物的分隔的主题材料区沿反应管510流动。在贮槽520和522,在分离管524的相对的两端也施加电压,使与转移管两端的电压相匹配,从而使通过转移管的净流动为零。当主题材料区在反应管510和转移管526的交叉处通过时,使电压在贮槽518和522上漂移(float),此时施加在贮槽514,516,520上和样品管512末端上的电压会使主题材料区从转移管526分流到分离管524中。一旦在分离管中,在所有的贮槽上都施加初始电压以终止通过转移管526的净流体流动。对于各后继的主题材料区,可以重复主题材料的转移。在分离管中,使主题材料区处在与反应管的条件不同的条件下。例如,可以使用不同的流动速度,可以运用毛细管处理来分离带有不同电荷或具有不同大小的物质,等等。在一种较好的情况中,使主题材料分流到分离管中,将主题材料放到用高离子强度缓冲液充满的毛细管中,即除去低离子强度的间隔区域,从而在最初的主题材料区边界的外部分离各种样品组分。例如,在上述受体/配体筛选的情况下,在转移管中的受体/配体配合物可以具有与配体自身不同的电泳迁移性,从而使配合物从配体中及在其后继的检测中能更为显著地分离出来。
这种改进具有广泛的应用,尤其是需要分离反应(如断裂反应,裂解反应,PCR反应等)后的反应产物。
C.
平行试验系统中的系列
在本发明的范围内,也可以制出更为复杂的系统。例如,一种使用“系列输入平行反应(serial input parallel reaction)”结构的替换实例的示意图图示于图3中。如图所示,装置300也包括如上所述的平面基材302。组装入基材302表面的是一系列平行的反应管312-324。该图也图示了三个与这些平行反应管中的每个管以流体方式相连接的横向管。该三个横向管包括样品注入管304,任选的播种管(seeding channel)306和收集管308。再者,基材和各管通常使用如上所述的材料来制造并制成如上所述的大小。尽管所图示和所描述的是以一系列平行的管来表示,但也可以以各种不同的取向来制造反应管。例如,除了制造一系列与单个横向管以流体方式连接的平行管外,还可以任选地将管制成连接到并从中心贮槽向外径向延伸,或任选地将管以某些其它非平行的方式来放置。另外,尽管图示了三个横向管,但应明白的是可以使用更少的横向管,其中如生化系统组分可被预先置于装置中。类似地,在需要时,任选地可以使用更多的横向管,以在给定的试验筛选(assay screen)中引入更多的成分。因此,本发明的平行装置中的系列一般包括至少两个,较好为三个,四个,五个或更多个横向管。类似地,尽管图示了7个反应管,但容易明白的是视具体筛选的要求,本发明的微型装置将能包含7个以上的管。在较好的情况下,该装置可以包含从10个到约500个反应管,更好地包含从20个到约200个反应管。
这个装置尤其可用于筛选连续注入到装置中的试验化合物,但一旦将样品引入到装置中,它使用平行的试验结构,以提高通过量。
在操作中,将不连续主题材料区中的试验化合物连续地引入到如上所述分隔开的装置中,而后沿横向样品注入管304流动,直到分开的主题材料区靠近样品管304与平行的反应管310-324的交叉处。如图4A-4F所示,试验化合物以任选地在单个珠上固定化的形式提供。在试验化合物固定在珠上的情况下,任选地将平行管制成包括位于反应管与样品注入管304的交叉处的珠停留井(bead restingwells)326-338。箭头340表明在这种类型的样品/珠注入过程中的净流体流量。由于各珠沉降到停留井中,故通过那个特定管的流体流量通常将受到限制。在系列中下一个珠跟随未受限制的流体流,而后流到下一个可利用的停留井中沉降到位。
一旦在靠近平行反应管和样品注入管交叉处的位置上,通过重新使流体流沿管而下,试验化合物被导入其各自的反应管中。同样地在那些试验化合物在珠上固定化的情况下,固定化一般通过可断裂的连接基如对光不稳定的、对酸或碱不稳定的连接基而产生。因此,试验化合物一般必须从珠上释放出来,这例如可通过将之暴露在释放剂如光、酸、碱或类似物下,之后使试验化合物向下流入反应管中。
在平行管中,试验化合物将与寻找效应化合物(effector compound)的生化系统相接触。如图所示,使用与试验化合物所述的相类似的技术将生化系统的第一个组分放到反应管中。尤其是,生化系统一般经一个或多个横向播种管306加入。箭头342说明在播种管306中流体流动的方向。生化系统任选地是溶液基的,例如如上所述的连续流动的酶/底物或受体-配体混合物,或如图4A-4F所示,可为全细胞(cell)或珠基系统,例如酶/底物系统在其上固定化的珠。
在那些生化系统以颗粒状(例如细胞或珠)加入的情况下,平行管可以包括颗粒滞留区344。一般来说,这种滞留区包括颗粒筛分或过滤基体,例如多孔凝胶或能保留颗粒状材料但使流体自由流动的微结构。此过滤所用的微结构的例子包括如那些在美国专利5,304,487中所述的内容,在此为所有的目的对其全部内容进行参考引用。关于连续的系统,通常使用微制的流体定向结构如泵和阀来控制更为复杂的系统中流体的方向。然而,当系统变得越来越复杂时,这种系统将很难以控制。因此,如上所述的电渗系统对控制这些更为复杂系统中的流体通常是较好的。一般来说,这种系统在位于各种横向管末端的贮槽中加入电极,以控制流过装置的流体。在某些情况下,希望在所有各种管的末端都装上电极。这通常提供更为直接的控制,但随着系统越是复杂,也就越难控制。为了使用较少的电极以便减少潜在的复杂性,常常希望在平行系统中,例如二种流体希望以类似的速度在平行管中移动的系统中,调节各种流动管的几何形状。尤其是,当管的长度增加时,沿管的电阻也提高了。这样,应将电极之间的流动长度(flow lengths)设计成基本上相同,而不管所选择平行的通道。这通常防止了横向电场的生成,从而促进了所有平行管中相等的流动。为了在电极之间达到基本上相同的电阻,可以改变管结构的几何形状,以提供相同的管长度,进而提供相同的管电阻,而不管所走过的通道。或者,任选地通过改变通道的横截面大小来调节管的电阻,从而产生均匀的电阻量,而不管所采用的通道。
当试验化合物通过它们各自的平行反应管时,它们将与上述所讨论的生化系统相接触。如上所述,特定的生化系统一般包括指示该系统的相对功能的可流动的指示剂系统,例如可溶性指示剂如生色或产荧光底物,标记的配体或类似物,或以颗粒为基的信号(particle based signal),例如沉淀物或键合在珠上的发信号基团(signalling group)。然后可流动的指示剂流过各自的平行管进入收集管308,在此来自各平行管的信号连续地流动通过检测窗116。
参照图3,图4A-4F说明了注入试验化合物和生化系统组分进入“系列输入平行反应”装置的进程示意图,将系统与试验化合物接触,所得的信号流出平行反应管并通过检测窗。尤其是,图4A说明了通过样品注入管304加入在珠346上固定化的试验化合物。类似地,通过播种管306将生化系统组分348加入反应管312-324中。尽管如上所述图示了与试验化合物一道加入装置中,但是任选地在制造过程中已将待筛选的模型系统(model system)的组分加入反应管中。再者,这种组分任选地以液体形式或以冻干形式提供,以提高特定筛选装置的贮藏寿命。
如图所示,生化系统组分包括在多孔状(cellular)或以颗粒为基的系统中,然而,如在此所述,也可以使用流体组分。如上所述,当颗粒组分流入反应管时,它们任选地留在任选的颗粒保留基体344上。
图4B说明了将珠与释放剂接触而使试验化合物从珠346上释放。如图所示,将珠暴露在能产生足以光解连接基的某一波长光的合适的光源352的光下,从而释放通过对光不稳定的连接基连接到它们各自的珠上的化合物。
在图4C中,释放的试验化合物沿箭头354所示的方向流入并沿平行反应管流动,直到它们与生化系统组分相接触。然后生化系统组分348在试验化合物的存在下发挥其功能,如酶反应,受体/配体相互作用等。当生化系统的各种组分在固体载体上固定化时,从其载体上释放组分可以为该系统提供起始事件(initiatingevent)。然后产生了与生化系统的功能相对应的可溶性信号(soluble signal)356(图4D)。如上所述,所产生的信号量的变化表明特定的试验化合物是特定的生化系统的效应物。这可由信号358的较淡的阴影表示。
在图4E和4F中,可溶性信号然后流出反应管312-324进入检测管308,并沿检测管通过检测窗116。
再者,位于检测窗附近的上述检测系统将监测信号量。在一些实例中,任选地回收载有试验化合物的珠以鉴定存在于其上的试验化合物。这一般可通过在珠上的试验化合物合成的过程中加入标记基团来完成。如图所示,任选地将已释放出试验化合物的废珠(spent bead)360通过用于鉴定已连接到其上的试验化合物的孔362从管结构中转移出来。这种鉴定任选地是经下述方法在装置的外部完成的,即将珠送入分部收集器,从而任选地通过鉴定标记基团或通过鉴定残留化合物来鉴定存在于珠上的试验化合物。先前已经描述过在组合化学方法中使用译码的核苷酸序列或氯化/氟化芳族化合物作为标记基团来加入标记基团。例如,参见公开的PCT申请No.WO 95/12608。或者,任选地将珠转移到在装置本身分开的试验系统中,在此进行鉴定。
图6A说明了另一个“系列输入平行反应”装置的实例,它可用于与以珠为基的系统不同的以流体方式为基的系统。如图所示,装置600通常包含至少两个如图3和4所示的横向管,即样品注入管604和检测管606。这些横向管由将样品管604连接到检测管606上的系列平行管612-620相互连接起来。
所示的装置也包括用于使流体试验化合物流入反应管的附加的一组管。尤其是,附加的横向抽吸管634通过一系列平行抽吸管636-646以流体方式连接到样品管604上。抽吸管包括在其末端的贮槽650和652。平行管636-646的交叉处隔着样品管604与平行管612-620的交叉处交错排列,即错开一半的距离。类似地,横向抽吸管608通过平行抽吸管622-632连接到检测管606上。再者,平行抽吸管622-632与检测管606的交叉处和反应管612-620与检测管606的交叉处相交错排列。
这个系统的操作示意图示于图6B-6C中。如图所示,使用如上所述的方法将物理上在分开的主题材料区域中相互分开的一系列试验化合物引入样品管604中。对于电渗系统,在样品管604的末端以及贮槽648上施加电压。在贮槽650:652,654:656和658:660上也施加电压。如图6B所示,这会导致流体沿横向管634,604,606和608如箭头所示的方向上流动,并且使通过连接这些横向管的平行管排列的净流动为零。一旦包含试验化合物的主题材料区与平行反应管612-620相连,将样品管604连接到检测管606上,如图6B中阴影部分所示,通过撤去施加在各管末端贮槽上的电压,流动在所有横向方向上都停止。如上所述,可以改变管的几何形状以最大程度地利用基材上的空间。例如,当样品管是直的时候,反应管之间的距离(从而可以在大小受限制的基材上进行的平行反应数)受主题材料区之间的距离限定。然而,这些限制可以通过采用有所改变的管的几何形状而得以消除。例如,在某些情况下,可以采用蛇形、方波形、锯齿形或其它往复式管的几何形状来调节第一和第二间隔区域的长度。这就使得在有限的基材表面上能包括最大数目的反应管。
如图6C所示,一旦与平行反应管相连,通过将第一电压施加到贮槽650和652上,同时将第二电压施加到贮槽658和660上,样品或主题材料就流到平行反应管612-620中,从而流过平行抽吸管636-646的流体迫使主题材料流入平行反应管612-620中。在这个过程中,在贮槽648,654,656上,或样品管604的末端上不施加电压。一般对平行管636-646和622-632的长度进行调节,从而使管的总长,因而从贮槽650和652到管604和从贮槽658和660到管606的电阻量对任何所采用的通道都是相同的。电阻通常可通过调节管的长度和宽度而得到调节。例如,管可通过采用折叠或蛇形的几何形状而加长。尽管并未如此图示,但为了达到这个相同的管长,管636和646可以是最长,而管640和642可以是最短,以产生对称的流动,从而迫使样品流入管中。可以看出,在样品流过管612-620的过程中,这些管中的电阻是相同的,原因是各管的长度是相同的。
在筛选反应后,通过将电压从贮槽650和652施加到贮槽658和660上,同时使其余贮槽上的电压漂移,从而使主题材料区/信号成分流到检测管606中。通过将电压施加到贮槽654和656上,同时在其它横向管的末端施加合适的电压以防止沿各种平行管的任何流动,从而使主题材料区/信号连续地流过检测窗/检测器662。
尽管如图所示,管以直角相交,但是其它角度也适合于连续进料的平行反应。例如,USSN 08/835,101(1997年4月4日申请)描述了对抛物线型几何形状和管的优点,可改变管的宽度以控制流体流动。简洁地讲,在电渗透系统中的流体流动可以由电极间的电流控制,并因此与电极间的电流有关。流体管中的电阻随路径长和路径宽度变化,因此不同长度的管有不同的电阻。如果该电阻差未得到校正,会导致产生横向电场,它会抑制设备使流体流向特定区域的能力。电流和由此的流体流动总是流过电阻最小的路径,如最短的路径。通过采用分开的电系统(即在每个平行管的终端使用分开的电极)可缓和这类横向电场问题,但是配有所有这些电极的设备的生产以及用于控制在每个电极上施加的电压的控制系统可能很复杂,特别是在一个小规模的设备(如1-2厘米2)上有数百至数千个平行管的情况更是如此。因此,通过保证流过多个平行管的电流处于合适水平,以确保通过那些管或管网的所需流动模式,本发明提供了用于进行从连续到平行转变的微流体设备。为达到这些目的的许多方法和基材/管的设计都是合适的。
对本发明设备的管的抛物线型的一个例子中,基材包括一个主管。一系列平行管的终端在主管上。这些平行管的另一端连接到抛物线管。电极排列在这些抛物线管的终端。通过调节平行管长在每个平行管中的电流保持恒定或相同,使连接每个平行管到其电极为抛物线管结构。通过调节管宽度以适应由这些平行管造成的平行流路径所导致的管流变化,保持在平行管间的抛物线管内的电压降恒定。管的抛物线设计,与其圆锥形结构相结合,使得电阻沿所有平行管相等,导致相等的流体流动,而不管所选择的路径如何。一般,可通过已知的方法来确定管道大小,保证可按照要求控制管内的电阻,管大小的确定一般取决于诸如通过基材的流体构成等因素。
尽管根据本发明公开的内容,就筛选分析描述了影响特定相互作用的化合物的鉴别,但是,认为上述的微型实验室系统也可以用于筛选能与生物化学系统的组分专一地相互作用,而不会影响该组分与生物化学系统中另一种元素的相互作用的化合物。这样的化合物一般包括键合化合物(一般在如诊断和治疗应用中用作治疗的目标基团或标志基团,即放射性核素、染料等)。例如,这些体系可任选用于筛选能与生物化学系统中的给定组分键合的试验化合物。
II.
微型实验室系统
尽管对个别设备进行了一般性描述,为易于操作,所述的系统一般是较大系统的一部分,该系统既可以在个别的基准上,也可以在平行、多设备的筛选中能监测和控制设备的功能。图7所示为这样的系统的一个例子。
如图7所示,该系统包括一个试验化合物的处理体系700。图7所示的体系包括平台702,该平台可以固定许多不同的测定片或装置704。如图所示,每个片包括许多分开的测定管706,每个板有一分开的界面708,如吸移管管理器,用于将试验化合物导入该装置。这些界面可用于将试验化合物吸入该装置,试验化合物通过吸入第一和第二间隔流体来分隔。在所示的系统中,片的界面通过开口710插入平台702的底部,平台702可以升高或降低板,使界面与试验化合物或洗涤液/第一间隔流体/第二间隔流体接触,这些流体含在如多井微板711中,711微板放在平台的下面,如在传输器体系712上。在操作中,含有大量不同试验化合物的多井板在传输器系统的端层叠为714。这些板被放在传输器上,由合适的缓冲剂容器716和718分开,这些容器中放有缓冲剂体系720。这些板下降到传输器,试验化合物抽样到片中,由合适的间隔流体区域相间。在片上加上试验化合物后,然后在系统的相对端将多井板收集层叠为722。总的控制系统包括许多单个的微型实验室系统或装置,如图7中所示。每个装置连接到计算机系统,合理地编制该计算机程序,以控制在不同片内的流体流动和方向,并且监测,记录和分析由不同装置进行的筛选分析产生的数据,这些装置一般可通过中间适配器模块(intermediate adapter module)连接到计算机,该模块提供计算机和各个装置之间的界面,用于由计算机向装置提供操作指令,和由装置向计算机报告数据。例如,适配器一般包括在每个装置上相应元件合适的连接件,如连接到容器中用于电渗透流体流动的电极的电线、检测系统(电的或光学纤维的)电源入口和数据出口、和安装到该装置的其它传感器元件的数据中继站。该适配器设备还提供了对各个装置的环境控制(当这样的控制是必要时),如使各个装置在最佳温度下进行特定的筛选分析。
如图所示,每个装置还配有合适的流体界面,如微量吸移液管理器,用于将试验化合物导入各个装置。这些装置能容易地连接到自动控制系统,使试验化合物从许多多井板上取样,这些多井板沿传输器系统移动。通过间隔溶液容器还可以导入插入的间隔流体区域。
III.
防止微片中化学物质的降解的流体电极界面
通过电渗透或电泳泵抽液体或其它物质通过本发明的装置时,如果施加高电压或电流,或长时间施加电压,流体中的化学物质可以降解。阻止化学物质从电极运动到管进口,或阻止化学物质向电极的运动的设计,通过减少样品中化学物质不希望的降解,提高了化学分析的性能。在长时间(如几小时到几天)施加电压的分析系统特别优选这类设计。
由图12的A-G的考虑说明本发明的分析中减少化学物质降解的电极设计。该设计可阻止化学物质从电极向管进口的运动或阻止化学物质向电极的运动,这种设计提高了化学分析的性能。图12A所示为一典型的电极设计,其中电极1211部分浸在容器1215中,该容器流体连接到流体管1217。
与之比较,图12B使用了有玻璃料1219的电极和流体连接到流体管1223的流体容器1221之间的盐桥。
图12C减少了化学物质的降解,通过提供浸在第一流体容器1227的电极1225,由大管1231将容器1227流体连接到第二容器1229,管1231限制了扩散,但是有低的电渗透流动。
图12D提供了类似的两部分容器,其中电极1235浸在第一流体容器1237中,通过小管1243将1237流体连接到第二容器1241,管1243处理成减少或消除电渗透流动。
图12E提供了另一种类似的两部分容器,其中电极1245浸在第一容器1247中,由管1253将容器1247流体连接到第二容器1251。管1253充有如凝胶、琼脂、玻璃珠或其它降低电渗透流动的基体的物质。
图12F提供了不同的两部分容器系统,其中电极1255浸在第一容器1257中,由管1261将容器1257流体连接到第二容器1259。第二容器1259中流体水平高于第一容器1257中的流体水平,可迫使流体流向电极1255。
图12G提供了第二类不同的两部分容器系统,其中电极1265浸在第一容器1267中,由管1271将容器1267流体连接到第二容器1269。第一容器1267的直径很小,足以由毛细管力将流体吸入第一容器1267。
对在此所述的方法和设备可进行各种修改,而不会偏离按权利要求书的本发明的范围,本发明可用于许多不同用途,包括:
微流体系统的使用,该系统含至少一个有第一管和与所述的第一管交叉的第二管的第一基材,所述的管中至少一个有至少一个在0.1-500微米范围的横截面,以试验多个试验化合物中的每一个对生物化学系统的作用。
如前所述的微流体系统的使用,其中所述的生物化学系统基本上连续地流过一个所述的管,使其能连续试验所述的多种试验化合物。
如前所述的微流体系统的使用,其中在所述第一基材中的许多反应管使得多种试验化合物能平行地暴露在至少一个生物化学系统中。
如前所述的微流体系统的使用,其中,每一个试验化合物与相邻的试验化合物物理地分离。
通过用所述管将所述试验材料与生物化学系统一起流动,将带有交叉管的基材用于筛选试验材料对生物化学系统的作用。
如前所述的基材的使用,其中至少一个所述的管具有至少一个在0.1-500微米范围的横截面。
使用上述任何一个微流体系统或基材的分析。
本发明提供了用于检测试验化合物对生物化学系统的作用的设备,该设备包括一个基材,该基材有至少一个表面带有多个安装在该表面的反应管。如前所述的设备,有至少两个安装在该表面的横向管,该设备中多个反应管的每一个,在每一个反应管的第一点上流体连接到至少两个横向管的第一个上,在每一反应管的第二点流体连接到第二横向管上,还提供了包括如前面所述的设备的分析设备。
实施例
下列实施例仅提供说明用途,而不是限制。本领域技术入员会很容易认识到,许多非临界参数可以改变或修改,得到基本上相似的结果。
实施例1-酶抑制剂的筛选
在一个平片格式(planar chip format)上证实进行酶抑制剂分析筛选的效果。使用一个6-口(port)平片,有如图8所示的布局。靠近管的数字表示每个管的长度(毫米)。在片的出口上施加两种电压状态。第一种状态(状态1)使酶与缓冲剂从顶部的缓冲剂井流到主管。第二电压状态(状态2)导致从顶部井的缓冲剂流动中断,并由抑制剂井将抑制剂连同酶导入主管。还进行了对照试验,其中将缓冲剂放在抑制剂井中。
施加两种电压状态的每一种,在每个口施加的电压如下:
状态1 状态2
顶部缓冲剂井(I) 1831 1498
抑制剂井(II) 1498 1900
酶井(III) 1891 1891
底物井(IV) 1442 1442
底部缓冲剂井(V) 1442 1442
检测/废物井(VI) 0 0
为证实该系统的效果,设计的分析为,使用下列酶/底物/抑制剂试剂筛选β-半乳糖苷酶的抑制剂:
酶: β-半乳糖苷酶(180U/ml在50mM Tris/300μg/ml BSA)
底物: 荧光素-二半乳糖苷(FDG)400μM
抑制剂: IPTG,200mM
缓冲剂: 20mM Tris,pH8.5
在两种电压状态下,通过主管从其相应出口连续泵出酶和底物。通过在电压状态1和电压状态2之间的交替,交替地分别从其相应的井将抑制剂和缓冲剂送入主管。当在主管的检测端不存在抑制剂时,产生荧光产物的基线水平。在引入抑制剂时,荧光信号极大减弱,表明抑制了酶/底物的相互作用。由交替输送抑制剂和缓冲剂至主管获得的荧光数据示于图9A。图9B是从图9A的两个数据段的叠加,将抑制剂数据直接与对照(缓冲剂)数据比较。对照数据表明荧光信号仅有很小的波动,很明显是由于酶底物混合物的稀释作用,而抑制剂的筛选表明荧光信号明显减弱,表明清楚的抑制。
实施例2-多重试验化合物的筛选
进行分析筛选,以鉴别酶反应的抑制剂。将使用的片的示意图示于图10。该片具有5厘米长的反应管,它包括1厘米的保温区和4厘米的反应区。在样品管开端的容器充以酶溶液,边上的容器充以产荧光底物。稀释每一酶和底物,为分析系统在检测器提供在线性信号范围内的稳态信号。在容器(样品源、酶、底物和废物)中的每一个上施加电压,达到施加200V/cm的电场。这一施加的电场产生2毫米/秒的流动速度。在给定样品通过该片的过程中,一般样品会有扩散性扩展。例如,在小分子样品的情况,如,1mM苯甲酸可观察到约0.38mm扩散性扩展和0.4mm电泳移动。
将150mM NaCl中含试验化合物的主题材料区导入样品管,样品管分隔成150mM NaCl的第一间隔区域和5mM硼酸盐缓冲剂的第二间隔区域。一旦显示导入样品管,主题材料区需要12秒通过样品管长,到达反应管的保温区。这正是2mm/秒的流动速度的结果,估计需1秒使样品吸移管管理器从样品移动到间隔化合物。考虑了这些间断,净的流动速度为0.68mm/秒。另外需要12秒使酶/试验化合物混合物通过保温区到达与底物管的交叉部分,在那里底物连续流入反应管的反应区。然后含有试验化合物的每一主体材料区需要48秒穿过反应区长度,并且通过荧光检测器。对主体材料区/间隔区域加载的时间安排示于图11。上部的图表明管内的主体材料/第一间隔区/第二间隔区的分布,而下部的图表明管加载所需要的时间。如图所示,该示意图包括高盐(HS)第一间隔流体(“A”)的加载(吸入)、将吸移管管理器移到样品或主体材料(“B”),吸样品或主体材料(“C”),将吸移管管理器移动到高盐第一间隔区流体(“D”),吸第一间隔流体(“E”),将吸移管管理器移动到低盐(LS)或第二间隔流体(“F”),吸第二间隔流体(“G”),并回到第一间隔流体(“H”)。对另外的每一试验化合物重复该过程。
在没有试验化合物存在时,在检测器中建立恒定的基础荧光信号。当导入试验化合物时,观察到荧光的减弱,与图9A和9B类似,根据时间延迟,它对应于各个具体的试验化合物。该试验化合物假设被鉴别为该酶的抑制剂,进行进一步的试验,以确定该抑制剂并定量其效果。
前面对本发明的详细描述仅达到说明和理解的目的,通过阅读这些公开内容,本领域的技术人员能清楚地理解在不偏离本发明范围下可对本发明的形式和细节进行各种变动。在本发明中列举的出版物和专利全部引用作为参考,与分别指出各出版物或专利的目的相同。
Claims (93)
1.一种用来筛选试验化合物对生化系统的作用的装置,包括:
一个主体,有组装在其中的至少两个相交管,所述至少两个相交管中的至少一根至少一个的截面尺寸为0.1-500微米;
与所述至少两根相交管的第一相交管以流体连接的多个不同试验化合物源;
与所述至少两根相交管的第二相交管以流体连接的所述生化系统的至少一个组分源;
供所述至少一种组分在所述至少两个相交管的所述第二相交管里流动,并将所述不同化合物从所述至少两个相交管的所述第一管子引入所述第二管中的液体导向系统;和
在所述第二管中用于检测所述试验化合物对所述生化系统的作用的检测带。
2.根据权利要求1所述的装置,其中所述的液体导向系统沿所述至少两个相交的管的所述第二管产生所述至少第一组分的连续流,并定期地从所述第一管将试验化合物注入所述的第二管。
3.根据权利要求1所述的装置,它进一步包括所述生化系统的第二组分源,第三管组装在所述主体里,所述的第三管将至少两个相交管的至少一根管子与所述生化系统的所述第二组分源以流体地连接。
4.根据权利要求3所述的装置,其中所述的液体导向系统沿所述至少两个相交的管的所述第二管产生所述第一组分和所述第二组分的混合物的连续流,并定期从所述第一管将试验化合物注入所述第二管。
5.根据权利要求1所述的装置,其中所述液体导向系统连续地从所述至少两个相交的管的所述第一管将多个不同试验化合物流入所述至少两个相交的管的所述第二管里,多个不同试验化合物的每一个被流体间隔物分开。
6.根据权利要求1所述的装置,其中所述液体导向系统包括:
至少三个电极,每个电极与所述至少两个相交的管在由所述至少两个相交的管形成的相交处的不同面上进行电接触;和
用于同时将可变电压施加到所述每个电极上,从而控制在所述至少两个相交的管里的所述试验化合物或所述至少第一组分的运动的控制系统。
7.根据权利要求1所述的装置,其中所述检测系统包括在所述第二管中的检测窗。
8.根据权利要求7所述的装置,其中所述的检测系统是荧光检测系统。
9.根据权利要求1所述的装置,其中所述的主体通过将第一玻璃基片加热层压到第二玻璃基片上而制成,第一玻璃基片有至少两个蚀刻入该第一玻璃基片的管,第二玻璃基片遮盖蚀刻入第一玻璃基片里的至少两个管。
10.根据权利要求1所述的装置,其中所述的主体包括蚀刻玻璃。
11.根据权利要求1所述的装置,其中所述的主体包括蚀刻硅。
12.根据权利要求11所述的装置,它进一步包括安置在所述蚀刻硅基片上的绝缘层。
13.根据权利要求1所述的装置,其中所述的主体包括模塑的聚合物。
14.根据权利要求1所述的装置,其中所述的生化系统的至少一个组分包括酶和酶底物,所述的酶底物当与所述酶反应时产生可检测的信号。
15.根据权利要求14所述的装置,其中所述的酶底物选自生色的和产荧光的酶底物。
16.根据权利要求1所述的装置,其中所述的生化系统的至少第一组分包括受体/配体结合对,其中所述受体或配体的至少一个具有与之相关联的可检测信号。
17.根据权利要求1所述的装置,其中所述的生化系统的第一组分包括受体/配体结合对,其中所述受体与所述配体的结合产生可检测信号。
18.根据权利要求1所述的装置,该装置进一步包括在多个贮槽中的多个电极,所述的贮槽与所述相交管的一个管或多个管以流体连接,和用于同时对每个所述电极施加电压的控制系统,从而控制所述第一组分在所述至少两个相交管中的运动。
19.根据权利要求18所述的装置,其中该装置使存在于所述贮槽或所述相交管里的化学物质的降解达到最小。
20.根据权利要求19所述的装置,其中该装置进一步包括用于减少电渗透流的一种或多种组件,它选自:
在一个或多个电极上的玻璃料,该玻璃料减少了向一个或多个电极的电渗透流;
在所述贮槽中至少两个贮槽之间的大管,该大管限制了所述化学物质的扩散,该管的电渗透流很低;
在所述贮槽中至少两个贮槽之间的窄管,该窄管限制了所述化学物质的扩散,该窄管被处理以减少电渗透流;
在所述贮槽的至少两个贮槽之间的填充管,该填充管包含基质以限制所述的化学物质经填充管运送,从而其电渗透流很低;
液体水平高于至少一个低位贮槽的高位贮槽,该高位贮槽与所述的低位贮槽以流体连接,该低位贮槽包括电极,其中高位贮槽和低位贮槽之间的流体压力减少了电渗透流流向电极;和
双贮槽系统,其第一贮槽通过连接管与窄直径的第二贮槽以流体连接,后者适合接受多个电极中的一个,所述的窄直径第二贮槽通过毛细管电泳将流体拉向该一个电极,从而电渗透流在连接管里相抵销。
21.一种用来检测试验化合物对生化系统的作用的装置,包括:
一个主体,有组装入其中的多个反应管;
组装在其中的至少两个横向管,多个反应管的每根管与所述至少两个横向管的第一管在所述反应管的第一点以流体连接,在所述反应管的第二点处与所述至少两个横向管的第二管以流体连接,所述至少两个横向管和所述多个反应管中的每根管的至少一个截面尺寸为0.1-500微米;
所述生化系统的至少一种组分源,所述的生化系统的所述至少一种组分源与所述多个反应管的每根管以流体连接;
与所述至少两根横向管的所述第一管以流体连接的试验化合物源;
供控制所述试验化合物和所述的至少一种组分在所述的至少两个横向管和所述的多个反应管里运动的液体导向系统;和
用于检测所述试验化合物对所述生化系统的作用的检测系统。
22.根据权利要求21所述的装置,其中所述的液体控制系统包括:
许多单个电极,每个与所述至少两个横向管的每个端点进行电接触;和
控制系统,用于同时将可变电压施加到每个所述电极上,从而使所述试验化合物或所述至少第一组分在所述的至少两个横向管和所述多个反应管中的运动得到控制。
23.根据权利要求21所述的装置,其中所述多个反应管的每个反应管在所述多个反应管的第一点处包含珠停留井。
24.根据权利要求21所述的装置,其中所述生化系统至少一种组分源与所述多个反应管通过第三横向管以流体连接,所述第三横向管的至少一个截面尺寸范围为0.1-500微米,在所述反应管的第三点处与所述多个反应管的每一管以流体连接。
25.根据权利要求21所述的装置,其中在所述反应管里的所述的第三点在所述反应管的所述第一点和第二点中间。
26.根据权利要求25所述的装置,它进一步包括在所述多个反应管的每个反应管里的颗粒保留带,它在所述多个反应管的第三点和第二点之间。
27.根据权利要求26所述的装置,其中所述的颗粒保留带包括颗粒保留基质。
28.根据权利要求26所述的装置,其中所述的颗粒保留带包括微结构滤器。
29.根据权利要求21所述的装置,其中所述多个反应管包括组装在所述主体里的多个平行反应管,所述至少两个横向管在每个所述平行反应管的相反端连接。
30.根据权利要求21所述的装置,其中所述至少两个横向管以内和外同心管各自被组装在所述基片的所述表面上,所述的多个反应管从所述内同心管辐射状延伸到所述的外同心管。
31.根据权利要求30所述的装置,其中所述检测系统包括在所述第二管中的检测窗。
32.根据权利要求30所述的装置,其中所述检测系统是荧光检测系统。
33.根据权利要求21所述的装置,其中所述的主体通过将第一玻璃基片加热层压到第二玻璃基片上而制成第一玻璃基片有至少两个蚀刻入该第一玻璃基片的管,第二玻璃基片遮盖蚀刻入第一玻璃基片里的至少两个管。
34.根据权利要求21所述的装置,其中所述主体包括蚀刻玻璃。
35.根据权利要求21所述的装置,其中所述主体包括蚀刻硅。
36.根据权利要求21所述的装置,它进一步包括安置在所述蚀刻硅上的绝缘层。
37.根据权利要求21所述的装置,其中所述主体由第一聚合基片模塑而成,该第一聚合基片有至少两个横向管蚀刻在其中,主体进一步包括层压在该第一聚合物基片上的第二基片。
38.根据权利要求21所述的装置,其中所述生化系统的至少一种组分包括酶和酶底物,所述的酶底物当与所述的酶反应时产生可检测信号。
39.根据权利要求38所述的装置,其中所述的酶底物选自生色的和产荧光的底物。
40.根据权利要求21所述的装置,其中所述生化系统的至少第一组分包括受体/配体结合对,其中所述受体或配体的至少一种具有与之相关联的可检测信号。
41.根据权利要求21所述的装置,其中所述生化系统的所述第一组分包括受体/配体结合对,其中所述受体与所述配体的结合产生可检测信号。
42.一种测定样品是否含能影响生化系统的化合物的方法,包括:
提供包括有至少两个相交管组装在其中的主体结构的微流体装置,所述至少两个相交管中的至少一个管子的至少一个截面尺寸范围为0.1-500微米;
将生化系统的第一组分流入所述至少两个相交管的第一管中;
将所述样品从第二管流入所述第一管,从而所述样品与所述生化系统的第一组分接触;和
检测所述至少一种样品对所述生化系统的作用。
43.根据权利要求42所述的方法,其中生化系统的所述的至少第一组分包括抗体/抗原结合对的至少一个成员,其中所述抗体与所述抗原特异性地进行免疫反应。
44.根据权利要求42所述的方法,其中生化系统的所述至少第一组分包括抗体和与抗体进行特异性反应的抗原。
45.根据权利要求42所述的方法,其中所述抗体或抗原的一种包括可检测的标记基团。
46.根据权利要求42所述的方法,其中所述生化系统的至少第一组分包括受体/配体结合对中的至少一个成员。
47.根据权利要求42所述的方法,其中所述生化系统的至少第一组分包括受体和能与所述配体特异性结合的配体。
48.根据权利要求42所述的方法,其中所述样品来自病人。
49.根据权利要求42所述的方法,其中所述样品来自血液。
50.根据权利要求42所述的方法,其中所述检测步骤包括在有或没有所述样品存在下测量所述生化系统的参数,并将在有所述样品存在下测得的参数与在没有所述样品存在下测得的参数进行比较,所述参数的改变表示所述的样品对所述生化系统有作用。
51.一种用来筛选试验化合物对生化系统的作用的方法,包括:
一种主体,包括至少两个相交管组装在其中,所述至少两个相交管中的至少一个管子的至少一个截面尺寸范围为0.1-500微米;
与所述至少两个相交管的第一管以流体连接的样品源;
与所述至少两个相交管的第二管以流体连接的所述生化系统的至少一种组分源;
一种液体定向系统,用于使所述至少一种组分在所述至少两个相交管的所述第二管里流动,并将所述样品从所述第一管引入所述两个相交管的第二管中;和
在所述第二管中用来检测所述样品对所述生化系统的作用的检测带。
52.一种用来筛选多个试验化合物对生化系统的作用的方法,包括:
提供有至少两个相交管组装在其中的主体,所述至少两个相交管中的至少一个管子的至少一个截面尺寸范围为0.1-500微米;
将生化系统的第一组分流入所述至少两个相交管的第一管里;
将至少第一试验化合物从第二管流入所述第一管,从而使所述第一试验化合物与所述生化系统的所述第一组分接触;和
检测所述至少第一试验化合物对所述生化系统的作用。
53.根据权利要求52所述的方法,其中所述生化系统的至少第一组分产生标志了所述生化系统的功能的可检测信号。
54.根据权利要求52所述的方法,其中所述至少第一组分进一步包括与所述第一组分相互作用时产生标志所述生化系统的功能的可检测信号的指示剂化合物。
55.根据权利要求52所述的方法,其中所述生化系统的第一组分包括酶和所述酶的底物,其中所述酶对所述底物的作用产生了可检测信号。
56.根据权利要求52所述的方法,其中所述生化系统的第一组分包括受体/配体对,其中所述受体或配体的至少一种有与它相关联的可检测信号。
57.根据权利要求52所述的方法,其中所述生化系统的所述第一组分包括受体/配体结合对,其中所述受体与所述配体的结合产生了可检测信号。
58.根据权利要求52所述的方法,其中所述生化系统的所述至少第一组分是生物屏障,所述至少第一试验化合物的所述作用是所述的试验化合物横越所述的屏障的能力。
59.根据权利要求58所述的方法,其中所述的屏障选自上皮或内皮层。
60.根据权利要求52所述的方法,其中所述生化系统的所述至少第一组分包括细胞,所述的检测步骤包括测定所述试验化合物对所述细胞的作用。
61.根据权利要求60所述的方法,其中所述细胞能产生相应于细胞功能的可检测信号,所述的检测步骤包括通过检测所述可检测信号的水平来测定所述试验化合物对所述细胞功能的作用。
62.根据权利要求60所述的方法,其中所述的检测步骤包括检测所述试验化合物对所述细胞生活力的影响。
63.一种用来筛选多个试验化合物对生化系统的作用的方法,包括:
提供有至少两个相交管组装在其中的主体,所述至少两个相交管中的至少一个管子的至少一个截面尺寸范围为0.1-500微米;
将生化系统的第一组分连续地流入所述至少两个相交管的第一管里;
将不同试验试验化合物定期地从所述的至少两个相交管的第二管引入所述第一管;和
检测所述试验化合物对所述生化系统的作用。
64.根据权利要求63所述的方法,其中所述定期引入步骤包括使多个不同的试验化合物从所述至少两个相交管的第二管流入所述的第一管,多个不同的试验化合物的每个化合物物理上彼此分开。
65.根据权利要求63所述的方法,其中所述生化系统的所述至少第一组分产生代表所述生化系统功能的可检测信号。
66.根据权利要求65所述的方法,其中所述的检测包括监测来自所述连续流动第一组分在所述第一管上的一个点上的可监测信号,所述的可监测信号具有稳态强度,其中所述第一组分和所述试验化合物之间的相互作用的所述影响包括所述可检测信号的所述稳态强度发生偏差。
67.根据权利要求65所述的方法,其中所述至少第一组分进一步包括与所述第一组分互相作用以产生代表所述生化系统的功能的指示剂化合物。
68.根据权利要求67所述的方法,其中所述生化系统的第一组分包括酶,所述指示剂化合物包括所述酶的底物,其中所述酶对所述底物的作用产生了可检测信号。
69.根据权利要求65所述的方法,其中所述生化系统的至少第一组分包括受体/配体结合对,其中所述受体或配体的至少一种具有与之相关联的可检测信号。
70.根据权利要求69所述的方法,其中所述受体和所述配体沿所述第一管以不同的速度流动。
71.根据权利要求65所述的方法,其中所述生化系统的第一组分包括受体/配体结合对,其中所述受体与所述配体的结合产生了可检测信号。
72.根据权利要求63所述的方法,其中所述生化系统的第一组分包括细胞,所述检测步骤包括测定所述试验化合物对所述细胞的作用。
73.根据权利要求72所述的方法,其中所述细胞能产生相应于细胞功能的可检测信号,所述的检测步骤包括通过检测所述可检测信号的水平来检测所述试验化合物对所述细胞功能的影响。
74.根据权利要求72所述的方法,其中所述的检测步骤包括检测所述试验化合物对所述细胞生活力的影响。
75.一种用来筛选多个不同试验化合物对生化系统的作用的方法,包括:
提供有多个反应管组装在其中的主体,所述多个反应管的每根管子与组装在所述表面里的至少两个横向管以流体连接;
将生化系统的至少第一组分引入所述多个反应管;
使多个不同试验化合物流经至少两个横向管的至少一根管,所述多个试验化合物中的每个试验化合物被引入在分开主题材料区里的所述至少一个横向管里;
使所述多个不同的试验化合物的每个流入所述多个反应管里的分开的一个;和
检测每个所述化合物对所述生化系统的至少一种组分的作用。
76.根据权利要求75所述的方法,其中所述生化系统的至少第一组分产生了代表所述生化系统的功能的可流动的可检测信号。
77.根据权利要求76所述的方法,其中多个反应管的每个管产生的所述可检测的可流动信号流入并经过所述第二横向管,所述多个反应管的每个产生的可检测的可流动信号相互物理学上分开,从而使每个所述的可检测的可流动信号能被分开检测。
78.根据权利要求76所述的方法,其中所述的可流动信号包括可溶信号。
79.根据权利要求78所述的方法,其中所述的可溶信号选自荧光或比色信号。
80.根据权利要求75所述的方法,其中生化系统的所述至少第一组分进一步包括与所述第一组分相互作用以产生代表所述生化系统的功能的可检测信号的指示剂化合物。
81.根据权利要求80所述的方法,其中所述生化系统的第一组分包括酶,所述指示剂化合物包括所述酶的底物,其中所述酶对所述底物的作用产生了可检测信号。
82.根据权利要求75所述的方法,其中生化系统的生化系统的所述至少第一组分包括受体/配体结合对,其中所述受体或配体的至少一种具有与其相关联的可检测信号。
83.根据权利要求75所述的方法,其中所述生化系统的第一组分包括受体/配体结合对,其中所述受体与所述配体的结合产生了可检测信号。
84.根据权利要求75所述的方法,其中所述生化系统的至少第一组分包括细胞,所述检测步骤包括测定所述试验化合物对所述细胞的作用。
85.根据权利要求84所述的方法,其中所述细胞能产生相应于细胞功能的可检测信号,所述的检测步骤包括通过检测所述可检测信号的水平来检测所述试验化合物对所述细胞功能的影响。
86.根据权利要求85所述的方法,其中所述检测步骤包括检测所述试验化合物对所述细胞的生活力的影响。
87.根据权利要求75所述的方法,其中多个不同试验化合物的每个试验化合物在分开的珠上固定,使每个所述多个不同试验化合物导向进入所述多个反应管的各个分开管的步骤包括:
将所述分开珠的一个装载到所述第一横向管与所述多个反应管的每个反应管的交叉处;和
可控制地将来自每个所述分开珠的所述试验化合物释放入每个所述多个反应管里。
88.含至少第一基片的微流体系统的用途,所述第一基片有第一管和与所述第一管相交的第二管,所述管的至少一个的至少一个截面尺寸为0.1-500微米,以便试验多个试验化合物对生化系统的作用。
89.根据权利要求88所述的用途,其中所述的生化系统基本连续地流经所述管中的一根,使得能连续地试验所述多个试验化合物。
90.根据权利要求88或89所述的用途,其中在所述第一基片里的多个反应管使多个试验化合物能平行地暴露于至少一种生化系统。
91.根据权利要求88或89所述的用途,其中每个试验化合物与相邻的试验化合物被物理上分开。
92.携带相交管的基片在筛选试验材料对生化系统的作用中的用途,它通过使用所述管子使所述试验化合物和生化系统一起流动。
93.根据权利要求92所述的用途,其中所述相交管的至少一个的至少一个截面尺寸为0.1-500微米。
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US10065403B2 (en) | 2009-11-23 | 2018-09-04 | Cyvek, Inc. | Microfluidic assay assemblies and methods of manufacture |
CN103649759A (zh) * | 2011-03-22 | 2014-03-19 | 西维克公司 | 微流体装置以及制造方法和用途 |
CN103649759B (zh) * | 2011-03-22 | 2016-08-31 | 西维克公司 | 微流体装置以及制造方法和用途 |
US10228367B2 (en) | 2015-12-01 | 2019-03-12 | ProteinSimple | Segmented multi-use automated assay cartridge |
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US20050241941A1 (en) | 2005-11-03 |
JP3788519B2 (ja) | 2006-06-21 |
US20030134431A1 (en) | 2003-07-17 |
CA2258489C (en) | 2004-01-27 |
US20040028567A1 (en) | 2004-02-12 |
US6413782B1 (en) | 2002-07-02 |
WO1998000231A1 (en) | 1998-01-08 |
CA2258489A1 (en) | 1998-01-08 |
EP0907412A1 (en) | 1999-04-14 |
US6274337B1 (en) | 2001-08-14 |
US6306659B1 (en) | 2001-10-23 |
JP2001502790A (ja) | 2001-02-27 |
NZ333346A (en) | 2000-03-27 |
US6630353B1 (en) | 2003-10-07 |
US6479299B1 (en) | 2002-11-12 |
EP0907412B1 (en) | 2008-08-27 |
US6429025B1 (en) | 2002-08-06 |
CN1262629A (zh) | 2000-08-09 |
US6558960B1 (en) | 2003-05-06 |
US6267858B1 (en) | 2001-07-31 |
US7067263B2 (en) | 2006-06-27 |
US20040241733A1 (en) | 2004-12-02 |
US7091048B2 (en) | 2006-08-15 |
BR9710054A (pt) | 2000-01-11 |
US6399389B1 (en) | 2002-06-04 |
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