CN103323610B - 模块化现场护理装置及其应用 - Google Patents
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Abstract
本发明涉及模块化现场护理装置及其应用,本发明提供用于现场护理的装置和系统。本发明的方法和装置涉及自动检测体液中的分析物。装置组件是模块化的,可以配合公开的方法灵活且可靠地用于各种医学应用中。
Description
本申请是申请日为2008年10月2日,申请号为200880118646.2,名为“模块化现场护理装置及其应用”申请的分案申请。
交叉参照
本申请要求2007年10月2日提交的美国临时专利申请第60/997,460号的优先权,其内容通过参照整体结合于此。
发明背景
大量疾病生物标志的发现以及小型化医疗系统的建立,为在现场护理环境中进行疾病的预测、诊断和治疗监测开辟了新的道路。现场护理系统能够快速地将测定结果传递给医务人员、其他医疗专业人员和患者。对疾病或疾病进程的早期诊断能够让医务人员及时地开始或及时地修改治疗。
多重的生物标志检测能够提供患者状况的附加信息。例如,当监测药效时,可以平行测定3个或更多个的生物标志。典型地,已经在使用微量滴定板和其他类似器具进行多重基于分离的测定。一个微量滴定板(例如,384孔微量滴定板)能够平行进行大量测定。
在现场护理(POC)装置中,能够平行进行的测定的数量通常受到装置大小和待检测样品体积的限制。在许多POC装置中,能进行的测定数量是约2到10。需要有一种能对少量样品进行多重测定的POC装置。
许多多重POC测定装置的缺点是装置组件的制造成本高。如果装置是一次性的,组件的高成本会使得制造POC装置不切实际。此外,对于将所有所需试剂结合在装置上的多重POC装置而言,如果这些试剂中的任何一个显示出不稳定性,那么即使所有其他试剂都还是可以使用的,整个制造批号的装置也都必须丢弃。
当客户有兴趣定制针对一套特定分析物的POC装置时,多重POC测定系统的制造商通常要需要混合搭配该装置的测定方案和试剂。适合每个客户的多重POC测定会是非常昂贵、难以校准、并且难以维持质量控制的。
已经证明POC方法在监测疾病和治疗中是非常有价值的(例如,糖尿病治疗中的血糖系统,在采用苄丙酮香豆素的抗凝血治疗中的凝血素时间测定)。通过检测多个标记,可以对复杂疾病(例如癌症)和如癌症的多药物治疗等治疗进行更好的监测和控制。
发明内容
因而,对POC装置替换性设计的需求还没有得到满足。理想的设计提供模块化的捕获表面和测定孵育元件。此外,模块化的捕获表面和测定孵育元件需要整合到适合于即时生产(JIT)制造方法的一次性POC中。需要以对用户和制造商可行的成本提供定制化的POC装置。本发明针对的是这些需求并提供相关的优势。
在一个方面,揭示一种用于自动化检测体液样品中分析物的检测盒,包括:可寻址的测定单元的阵列,用于进行能产生指示分析物存在与否的可检测信号的化学反应;和可寻址的试剂单元的阵列,其中阵列中的独立可寻址的试剂单元编址为与测定单元阵列中的独立可寻址的测定单元相对应,且其中各试剂单元设计成在阵列被组装到检测盒上之前可以根据相对应的各测定单元进行校准的。该装置还可包括用于接收体液样品的样品收集单元。
在另一方面,揭示一种用于自动化检测体液样品中的分析物的检测盒,包括:用于接收体液样品的样品收集单元;测定单元阵列,用于接收来自样品收集单元的一部分的样品、并进行能产生指示样品中分析物存在的可检测信号的化学反应;含有用于进行该化学反应的试剂的试剂单元阵列;其中该测定单元阵列中的各测定单元和该试剂单元阵列的各试剂单元被设计成能移动进入液体连通,从而使得用于进行化学反应的试剂能与测定单元中的体液样品相接触。
各试剂单元设计成可用于接收可移动的测定单元。在一些实施方式中,各测定单元包含一个测定尖端。在一些实施方式中,各测定单元设计成用于进行免疫测定。
体液样品可以是血液样品。在一些实例中,样品收集单元设计成用于接收约50、20、10、5或3微升或更少量的体液样品。在一个实例中,样品收集单元设计成用于接收相当于一滴血液的量的体液样品。
本发明所述的装置包括预处理单元,用于回收一部分的体液样品,以进行化学反应来检测分析物,而该预处理单元设计成用于从接收在样品收集单元中的全血样品中回收血浆。
在一个方面,本发明描述一种用于自动化检测体液样品中的分析物的系统,包括:如本发明所述的装置;和用于检测指示分析物存在与否的可检测信号的检测组合件。该系统还可包括一个可编程的机械装置,用于将各测定单元从第一位置移动到第二位置。在一些实例中,该系统包括液体转移装置。该液体转移装置可以是移液管,并且可以是自动化的。该系统还可包括用于传送基于待测分析物的实验设计的通讯组合件。在一些实例中,本发明的系统包括设计成接收各测定单元的加热模块,并且还可包括磁性模块,例如能用于从样品中分离红细胞。
在另一个方面,揭示一种用于自动化检测体液中的多个分析物的系统,包括:流体装置,包括:用于容纳体液样品的样品收集单元;测定单元阵列,其中所述测定单元阵列中的各测定单元设计成用于进行能产生指示被检测的所述多个分析物中的各分析物的信号的化学反应;和试剂单元阵列,其中所述试剂单元阵列的各试剂单元含有试剂;和包括多个端头的液体转移装置,其中该多个端头中的各端头用于接合各测定单元,且其中所述液体转移装置包含一个可编程处理器,用于引导体液样品从样品收集单元以及试剂从各试剂单元转移到各测定单元中去的液体转移。在一些实施方式中,引导液体转移的处理器设计成在测定单元阵列中进行一定程度的体液样品的稀释作用,使指示被检测的多个分析物的信号落在可检测的范围内,从而使所述多个分析物在所述系统中可以检测。
在一些实例中,体液样品包含至少2个分析物,其浓度相差至少2、5、10、15、50或100个数量级。该一定程度的体液样品稀释能使指示该至少2个分析物的信号落在可检测的范围内。
本发明所述的系统还包括用于检测可检测范围的检测信号强度的检测器。示例性的检测器是光电倍增器,而检测器的可检测范围可以是约2千万到1千万计数。
在一些实施方式中,其中液体转移装置的各端头设计成依附于各测定单元。各测定单元可以提供免疫测定反应的位点。在一些实例中,各测定单元是移液管尖端。液体转移装置可以是诸如空气置换式移液管等移液管。液体转移装置还可包括与可编程处理器连通的电动机,其中该电动机能基于来自所述可编程处理器的实验设计来移动所述多个端头。
在另一个方面,本发明描述一种用于自动化检测全血样品的血浆部分中的多个分析物的系统,包括:用于自动化地接收和处理全血样品来产生血浆部分的装置,由此在该装置之上生成指示感兴趣的分析物存在与否的可检测信号;和用于检测指示分析物存在与否的可检测信号的检测组合件。
在一个方面,本发明提供一种检测体液样品中分析物的方法,包括:向如本发明所述的装置提供血液样品;使所述样品在至少一个测定单元中反应;并检测从收集在所述体液样品中的所述分析物生成的所述可检测信号。体液样品可以是血液,方法可以包括从血液中回收血浆。
在一个方面,本发明提供按需组装用于自动化检测体液样品中分析物的检测盒的方法,其中所述装置包括机架,所述机架包含:可寻址的测定单元阵列,其中该阵列的各测定单元设计成用于进行能产生指示分析物存在与否的可检测信号的化学反应;和可寻址的测定单元阵列,其中该阵列的各试剂单元被编址为对应于各测定单元,所述方法包括:(i)根据待测分析物,将可寻址的测定单元阵列放入机架内,阵列中的各测定单元设计成用于进行检测所述最终用户定制的感兴趣的分析物的化学反应;(ii)根据待测分析物,将试剂单元阵列放入机架内,阵列中的各试剂单元对应于个测定单元;和(iii)将(i)和(ii)的阵列固定在装置的机架内。该方法可包括选择待测分析物。在一些实施方式中,该方法包括将检测盒密封。在一个实施方式中,该方法包括用表示待测分析物的可读标签对检测盒进行标记,例如用条形码或RFID。
在一个方面,提供一种用于自动化检测体液样品中多个分析物的方法,包括:向流体装置提供体液样品,其中该流体装置包括:用于容纳体液样品的样品收集单元;测定单元阵列,其中所述测定单元阵列的各测定单元用于进行产生指示被检测的所述多个分析物中的各分析物的信号的化学反应;和试剂单元阵列,其中所述试剂单元阵列的各试剂单元含有试剂;用液体转移装置接合(engage)各测定单元;用该液体转移装置将体液样品从样品收集单元转移到各测定单元中;以及将试剂从各试剂单元转移到各测定单元中,因此使试剂与体液样品发生反应,产生指示被检测的多个分析物中各分析物的信号。
在一个实施方式中,液体转移装置包含多个端头,其中所述多个端头中的各端头设计成用于接合各测定单元;且其中所述液体转移装置包含一个可编程处理器,用于引导体液样品从样品收集单元、以及试剂从各试剂单元转移到各测定单元中去的液体转移。该方法还可包括向该可编程处理器提供指令,其中所述指令可以引导向各测定单元转移体液样品的步骤。
在一个实施方式中,转移体液样品的步骤使体液样品在各测定单元中发生一定程度的稀释作用,以使指示被检测的多个分析物中的各分析物的信号落在可检测的范围内。体液样品可包含至少2个独立分析物,其浓度相差至少2、5、10、15、50或100个数量级。在一些实例中,体液样品的稀释度使指示该至少2个独立分析物的信号落在可检测的范围内。在一个实施方式中,使用光电倍增器时可检测的范围为每秒约1000到约100万次计数
在一个实施方式中,各试剂单元中的试剂是用于免疫测定的酶底物,而本发明的方法还包括在产生指示被检测的多个分析物中的各分析物的信号的反应完成之后,重复从各试剂单元中转移试剂的步骤,由此引起产生指示各分析物的第二信号的第二反应。可以对指示各分析物的信号强度和第二信号的第二强度求平均值,来计算指示各分析物的信号的最终强度。
在一个方面,本发明描述一种用于测定液体样品体积的方法,包括:将液体样品中已知量的对照分析物与试剂反应,产生指示对照分析物的可检测信号;将所述可检测信号与一个预期的可检测信号进行比较,其中该预期的信号指示液体样品的预期体积,且其中所述比较提供被检测的所述液体样品的所述体积的测定值。在一些实例中,在所述液体样品中通常不存在可检测量的对照分析物。该方法可包括当样品体积的测定值在液体样品预期体积的约50%之内时,校验所述液体样品的体积。在一个实施方式中,该方法还包括:使含有目标分析物的体液样品与试剂进行反应,产生指示目标分析物的可检测信号;用指示目标分析物的所述可检测信号的强度和所述液体样品的体积的测定值来测定体液样品中目标分析物的量。液体样品和体液样品可为同一样品,且对照分析物不与体液样品中的目标分析物发生反应。在一些实例中,液体样品和体液样品为不同的液体样品。对照分析物可以是例如荧光素标记的白蛋白、荧光素标记的IgG、抗-荧光素、抗-地高辛、地高辛标记的白蛋白、地高辛标记的IgG、生物素化的蛋白、非人IgG。
在另一个方面,本发明还提供一种从血液样品中回收血清的方法,包括:在样品收集单元在可磁化颗粒的存在下对血液样品进行混合,其中,可磁化颗粒包含用于结合血液样品中非血浆部分的抗体捕获表面;在血浆收集区域上方向混合后的血液样品施加一个磁场,使血液样品中的非血浆部分悬浮在血浆收集区域顶部。在一些实例中,样品收集单元是毛细管。血液样品可以是少于约20微升,且回收的血浆可以是少于约10微升。在一些实例中,血液样品未经稀释。在一些实例中,混合是在存在没有结合到固体表面的抗体的情况下进行的。混合作用可以包括用注射作用进行混合。
在又一个方面,本发明提供一种使用自动化免疫测定来检测全血样品的血浆部分中存在的分析物的方法,包括:将全血样品提供给用于在机内自动接收并处理全血样品来产生血浆部分的装置,由此在机内产生指示感兴趣的分析物存在与否的可检测信号;检测指示所述体液样品中分析物存在与否的所述信号;以及将(b)的结果传送给最终用户。免疫测定可以是ELISA。在一些实例中,结果是无线传送的。
在一些实施方式中,本发明所述的方法是在如本发明所述的系统中实施的。
引用结合
本说明书提及的所有出版物和专利申请通过引用结合到本发明中,等同于指出将每个独立出版物或专利申请明确且单独地通过引用结合到本发明中。
附图简要说明
本发明的许多新颖特征具体地在所附权利要求书中做出了阐述。通过参考以下对说明性实施方式予以阐述的详细说明部分以及附图,就可以更好地理解本发明的特征和优点,本发明的许多原理在这些实施方式中得到了利用,而附图之中:
图1是一个本发明的示例性装置,包括测定单元、试剂单元和该装置的其他模块化部件。
图2是图1所示的示例性装置的两个侧剖视图,包括在该装置的机架中其形状适于容纳测定单元、试剂单元和样品尖端的腔体。
图3A显示了一个包括小尖端或管状结构的示例性测定单元。
图3B显示了如本发明所述的样品尖端的实施例。
图4A和4B是包括杯状物的试剂单元的2个实施例。
图5显示了包括一个装置和液体转移装置的系统的实施例。
图6是一个本发明的示例性系统,包括用于温度控制的加热模块和检测器。
图7显示了一个示例性系统,其中患者将血液放到一个装置,然后该装置插入读数器。
图8是建立用于评估患者的医疗状况的流程图。
图9A-9E显示了血浆分离方法的实施例,其中,将全血样品吸入样品尖端,磁性试剂与样品混合并且悬浮,然后对全血样品和磁性试剂混合物施加一个磁场。然后将分离的血浆样品分配到装置的孔中。
图10显示了包含已知量的对照分析物的如本发明所述的对照测试的一个示例性方法。
图11是当液体排出并吸入另一种液体时尖端内的一个薄膜,例如污染。
图12是进行VEGFR2测定的测定单元和试剂单元相关的校准曲线。
图13是对于用光度计测得的在系统中进行P1GF测定得到的测定单元和试剂单元结果做相关性处理的校准曲线。
图14是CRP浓度对测定信号(光子计数)作图,数据拟合至一个5项多项式函数从而产生校准函数。
图15显示了如本发明所述在模型和参数Smax、C0.5和D值之间实现拟合。
图16显示了依据使测试尖端中达到终浓度的稀释作用得到的数据。
图17是归一化的测定响应(B/Bmax)对相对稀释作用的归一化浓度(C/C0.5)的对数作图,稀释作用为1:1(实线)、5:1(虚线)和25:1(点线)。
图18和19以在不同的归一化的浓度示出与图17相似的实施例。
图20显示了在经过了以下步骤后的对照分析物的测定响应:去除探测抗体、洗涤测定单元、添加底物,用光谱光度计读数0.5秒测得。
图21显示了测定结果,是通过测量在本发明所述的系统中在约10秒内产生的光子数来评估的。
发明的详细说明
在此描述的本发明的各实施方式和各方面涉及用于自动化检测体液样品中分析物的装置、系统和方法。本发明能够对与特定的生物学过程、生理状况、病症或病症的阶段、或生物制剂或治疗剂的效果相关联的分析物进行检测和/或定量。在此描述的本发明的实施方式和实施例并非意在限制本发明的范围。
装置
在本发明的一个方面,自动化检测体液样品中分析物的装置包括:可寻址的测定单元阵列,用于进行能产生指示分析物存在与否的可检测信号的化学反应;以及可寻址的试剂单元阵列,其中的每一个试剂单元被编址成对应于所述装置中的一个或多个可寻址的测定单元,从而在诸阵列被组装到该装置上之前,可以参照相对应的测定单元对各个试剂单元进行校准。
在本发明的另一个方面,自动化检测体液样品中分析物的装置包括:测定单元阵列,用于进行能产生指示分析物存在与否的可检测信号的化学反应;以及包含用于进行该化学反应的试剂的试剂单元阵列,其中至少一个测定单元和至少一个试剂单元是可以在该装置中相对于彼此移动的,从而使进行化学反应的试剂自动地接触测定单元中的体液样品。
在本发明装置的一个实施方式中,可以根据配置的测定单元所要进行的化学反应,为测定单元或试剂单元阵列编址。在另一个实施方式中,至少一个测定单元和至少一个试剂单元是可以在装置中相对于彼此移动的,从而使进行化学反应的试剂自动地接触测定单元中的体液样品。
在一个实施方式中,本发明的装置是自给自足的,并且包含平行进行多个测定所需的所有试剂,液相和固相试剂。需要时,可以将该装置设计成能够进行至少2,3,4,5,6,7,8,9,10,20,30,40,50,100,200,500,1000或更多测定。如果需要,也可以在装置中加入一个或多个对照测定来平行进行。.
测定可以是定量免疫测定,并且能够在短时间内进行。也可以用本发明的装置执行其它类型的测定,包括但不限于核酸序列测定、和诸如胆固醇等代谢物测定。在一些实施方式中,测定在不超过一小时内完成,优选少于30、15、10或5分钟。在其它实施方式中,测定在不足5分钟内完成。测定检测的持续时间可以根据用本发明的装置来执行的测定的类型进行调整。例如,如果需要较高的灵敏度,可以将测定孵育超过一小时或直至超过一天。在一些实施例中,需要较长持续时间的测定在诸如家庭使用等其它POC应用中要比在临床POC背景中更有实行性。
任何怀疑含有感兴趣的分析物的体液都可以结合本发明的系统或装置使用。普遍采用的体液包括但不限于血液、血清、唾液、尿液、胃液和消化液、眼泪、粪便、精液、阴道液、来源于肿瘤组织的间质液、和脑脊髓液。
体液可以用各种方式从患者提取、然后提供给本发明的装置,包括但不限于:切口、注射、或移液管吸取。如本发明所用,术语“对象”和“患者”可以在此互换使用,指脊椎动物,优选为哺乳动物,更优选为人。哺乳动物包括但不限于鼠科动物、猿猴、人、家畜、运动动物和宠物。在一个实施方式中,用柳叶刀切开皮肤,并使用例如重力、毛细作用、吸力或真空力等提取样品。柳叶刀可以是本发明装置的组成部分、或系统的组成部分、或是一个独立部件。需要时,可以用各种机械的、电的、电机的、或任何其它已知的激活机制或这些方法的任意组合来激活柳叶刀。在另一个不需要激活机制的实施方式中,患者可以简单地向装置提供体液,例如对于唾液样品即是如此。可以将收集的液体放在装置的样品收集单元中。在又一个实施方式中,装置还包含至少一个刺破皮肤的微针。
用于装置的体液的体积通常小于约500微升,典型地在约1到100微升之间。需要时,可以采用装置以1-50微升、1-40微升、1-30微升、1-10微升或甚至1-3微升的样品进行分析物的检测。
在一个实施方式中,采用本发明装置或系统进行分析物检测的体液量是一滴液体。例如,从刺破的手指提取的一滴血可以提供用于本发明所述的装置、系统或方法分析的待测体液样品,
可以从对象收集体液样品,并且如下文所述传递给本发明的装置。
在一个实施方式中,测定单元和试剂单元阵列被设置成一套可混合装配的部件。测定单元可以包括至少一个能与体液样品中的分析物反应的捕获表面。测定单元可以是在尖端内带有捕获表面的管状尖端。在此描述了本发明的尖端的实施例。试剂单元通常储存了进行检测给定分析物的测定所需的液体或固体试剂。每个测定和试剂单元可以独立地针对测定功能进行配置。为了装配装置,可以将单元以即用即装的方式进行装配,用于集成式检测盒中。
可以制备液相的和固相的独立部件,然后进行性能测试,并存储。在一个实施方式中,在制造场所以按需方式进行装置的装配。装置可以是模块化的,并且包括诸如机架等通用于所有测定的部件;测定单元,比如尖端;和试剂单元,比如装有液体试剂的各种易碎的或仪器可操作的容器。在一些实例中,对组装后的装置随后进行测试以验证校准情况(系统响应对已知分析物水平的关系)。可以从预制的、校准过的零件库中按需组装测定装置。在一些实施方式中,装置中的液体流经途径可以是简洁的,排除任何滞留气泡的机会,提供在诸如ELISA等试剂过量测定中洗去多余的标记试剂的有效途径。
本发明装置的机架可以用聚苯乙烯或其它可模塑的或可机械加工的塑料制成,并且具有确定的位置来放置测定单元和试剂单元。在一个实施方式中,机架带有能去除多余液体来吸干尖端或测定单元的手段。这种吸干手段可以是多孔膜,例如醋酸纤维素,或者是一片吸水材料,例如滤纸。
在一些实施方式中,装置的至少一个部件是由聚合材料构成的。聚合材料的非限制性例子包括聚苯乙烯、聚碳酸酯、聚丙烯、聚二甲基硅氧烷(PDMS)、聚氨酯、聚氯乙烯(PVC)、聚砜、聚甲基丙烯酸甲酯(PMMA)、丙烯腈-丁二烯-苯乙烯共聚物(ABS)和玻璃。
装置或装置的次级部件可以用各种方法制造,包括但不限于冲压、注模、轧花、浇铸、吹塑、机械加工、焊接、超声焊接、和热融合。在一个实施方式中,装置是由注模、热融合和超声焊接的方式制造的。装置的次级部件可以通过下列方式相互固定:热融合、超声焊接、摩擦拟合(压力拟合)、粘合,或者对于诸如玻璃、或半刚性和非刚性聚合基材等特定基材而言,以两个部件之间的天然粘附。
在图1中示出了一个本发明的示例性装置。装置100有时候在本发明中也可以称为检测盒100。装置100包括机架130,该机架有容纳测定单元121和试剂单元103、122、124、125的位置。在图1的示例性实施方式中,测定单元121占据装置100的机架130的中心行。测定单元121可任选地包括至少一个校准单元126。在一个实施例中,测定单元121类似于移液管尖端,被称为测定尖端121,校准单元126在本发明中被称为校准尖端126,然而,测定单元121可以为能被本发明所述的装置100广泛容纳的任何形状和大小。测定单元121和校准单元126是示例性的测定单元121,在此有更为详细的描述。图1中的测定单元121可以包含捕获表面,并且能够进行诸如核酸测定和免疫测定等化学反应。测定单元121可以根据指令或使用者想要对样品进行的测定装配到机架上。
如图1所示,装置100的机架可以包含用于容纳样品的样品收集单元110。诸如血液样品等样品能够放入样品收集单元110中。样品尖端111(例如连接至在此更详尽描述的液体转移装置的移液尖端)能够占据机架130的另一个部分。当要进行测试时,样品尖端111能够将样品分配到预处理试剂单元或预处理单元103、104、105、106、107或测定单元121中。示例性的预处理单元103、104、105、106、107包括但不限于:混合单元107,稀释剂或稀释单元103、104,以及——如果样品是血液样品——血浆去除或回收单元105、106。预处理单元103、104、105、106、107可以是同一类型的单元或不同类型的单元。进行化学反应所需的其它预处理单元103、104、105、106、107可以整合到装置100中,这对于具有本发明领域的的知识的技术人员而言是显而易见的。诸单元103、104、105、106、107可以含有各种量的试剂或稀释剂,易适应于任何在现有检测盒100上进行测定的需要。
通常,测定单元121可以与机架130分开制造,然后用拾放法插入到机架130中。测定单元121可与机架130紧密配合或与机架130松散配合。在一些实施方式中,机架130制造成能在例如运输和操作检测盒的过程中将试剂单元103、122、124、125和/或测定单元121紧密夹持定位。图1中显示的试剂单元103、122、124、125包含共轭试剂122(例如,用于免疫测定)、洗涤试剂125(例如,从捕获表面洗去所述共轭物)、和底物124(例如,酶底物)。在此描述装置100的其它实施方式和图1实施例中的部件。试剂单元103、122、124、125可以与机架130分开制造并充填,然后安装到机架130上。以这种方式,可以模块化的形式构建检测盒100,从而提高检测盒100用于各种测定的灵活性。可以根据要进行的测定,选择试剂单元103、122、124、125中的试剂。在此描述示例性的试剂和测试。
例如图1所示的实施例,装置还包括进行化学反应可能需要的其它特征。例如,如果测定单元121是在此描述的测试尖端121,则装置还包括尖端除余垫112,用于在用例如本发明所述的装置进行液体转移后从测定尖端121或样品尖端111去除多余样品或试剂。机架130还可在装置100内包含放置使用过的尖端或单元的单元或区域101、102,例如,以便避免样品尖端111或测定单元121的交叉污染。在图1中,装置100包括用于在装置100的单元之间转移样品的样品尖端111。如图1所示,装置100还包括预处理尖端113,用于将已经在装置100的一个单元中经过预处理的样品转移到装置100的其它单元中进行化学反应。例如,样品尖端111可用于从样品收集单元110中移出血液样品并将血液样品转移到所述的预处理单元103、104、105、106、107中。在预处理单元103、104、105、106、107中可以去除血液样品中的红细胞,然后可以用预处理尖端113从预处理单元103、104、105、106、107中收集血浆,并将血浆转移到另一个预处理单元(例如,稀释剂单元)103、104、105、106、107和/或至少一个测定单元121。在一个实施方式中,样品尖端111为样品收集单元110。在另一个实施方式中,样品收集单元110类似于孔,并用于容纳使用者接收到的样品。
如图1所示,测定单元121和试剂单元103、122、124、125能够编址,来指示单元在检测盒100上的位置。例如,如图1所示,检测盒100的一个列能容纳一个进行用于检测C反应蛋白的测定的测定单元121,且该列可以在同一列中包含用于该项测定的相应试剂单元103、122、124、125,其中诸单元可以编址为相互对应。例如,各个地址可以输入并存储在计算机系统中,并且可以给检测盒100加一个标签,比如条形码。当扫描使用检测盒100的条形码时,如本发明所述,计算机系统可以把单元的地址输送给在此所描述的系统,根据输入计算机的地址转移液体并进行反应。地址可以是传送用于对系统进行操作的协议的一部分。地址可以采用任意配置,并且在需要改变进行测定的协议时加以改变,而这又向检测盒的使用者提供了一种测定协议或步骤的改变,这是本领域以前的POC装置中通常没有的。在一些实施方式中,机架130和各单元构建成如图1所示的6×8的单元阵列。单元的分布可以是任何格式的,例如长方形阵列或随机分布。检测盒100可包含任意数量的单元,例如在1到约500个之间。在一些实施方式中,检测盒100有5-100个单元。如图1所示的实施例中,检测盒100有48个单元。
在图2是图1中示例性装置200的两个侧剖视图。在装置的机架220中形成腔体,以纵向(机架横向)容纳测定单元(例如测试尖端)201,使其凸起部朝向装置200顶部。如图2所示,还可以形成腔体以容纳试剂单元210、212或样品收集单元或尖端202。在机架220中可以有精确捕获单元并将它们安全夹持的特征。此类特征还可以设计成用移动尖端的机构操作,例如尖端的提取和放落。在另一个实施方式中,样品收集单元包括可弯曲或遮断的零件,用于在运输过程中保护小收集管以及在毛细管内保持活塞装置定位。在图2中还显示了如本发明所述的试剂单元210、212的两个示例性的实施方式。机架220的底部可用于收集废液,例如通过机架220上的一个洞转移到底部的使用后的洗涤试剂。机架220可包含用于收集废液的吸收垫。测定单元201和样品单元202可以定位成配合穿过装置200的机架220的腔体并延伸越过内部支撑结构。如图2所示,试剂单元210、212紧密地安装到机架上,且不延伸到越过内部支撑结构。机架220和将测定单元201和试剂单元210、212保持并定位于其中的区域可以适应各种模式。
在一些实施方式中,每个尖端提供给单个测定,并能与适当的试剂配对或相对应,例如进行指定的测定所需的试剂。一些尖端提供给对照测定单元,且具有已知量的分析物或是在制造过程中或是在测定进行的过程中结合在其捕获表面上。对于对照测定单元而言,单元设计成用于进行用作比较的对照测定。对照测定单元可以包括例如捕获表面和处于固态或液态的分析物。
在许多实施方式中,装置包含有测定所需的所有试剂和液体。例如,对于发光ELISA测定,装置内的试剂可以包括样品稀释剂、检测共轭物(例如,3个酶标记的抗体)、洗涤溶液、和酶底物。其它试剂可以根据需要提供。
在一些实施方式中,可以在装置中引入试剂以提供样品预处理。预处理试剂的例子包括但不限于:白细胞裂解试剂、从样品中的结合因子上释放分析物的试剂、酶和去垢剂。预处理试剂还可以加到装置中所包含的稀释剂中。
各试剂单元可设计用于接受可移动的测定单元。在一些实施方式中,各测定单元包括一个包含捕获表面的末端开放的中空圆柱元件和一个反应管。圆柱形测定单元在本发明中可称为测试尖端。在一些实施方式中,各测定单元用于进行免疫测定。图3A显示了包括小尖端或管状构造的测定单元301。在一些实例中,尖端301设计成提供内部圆柱形捕获表面311和能够与装置的机架相接合的凸起部321。在一些实例中,凸起部321和尖端301设计成接合移动尖端301的机构,例如如本发明所述的系统或例如液体转移装置。如图3A所示的测试尖端301可包括在尖端的底部的开口331。开口331可用于从测定单元301和向其转移液体或试剂。在一个实施方式中,所述的测定单元301是或类似于移液尖端,其改进之处在于测定单元301包括用于检测样品中分析物的捕获表面311。
尖端301可以用注塑法制造。在一个实施方式中,用于化学发光测定的尖端301是用透明的聚苯乙烯制成的。如图3A所示,示例性的尖端301包含一个凸起部(示为尖端301较大的上半部分),其能与机架相接合、并且能与例如液体转移装置和/或移液器装置的锥形元件相接合,以便形成气密性密封。同样如图3A所示,示例性尖端301包括一个较小的圆柱形部分。在许多实施方式中,测定捕获表面被包含在这个较小的圆柱形部分内。测定捕获表面可以是在尖端301内或尖端301外侧的任意位置。尖端301的表面可以是许多种几何形状的,包括但不限于管状、立方体、金字塔形。在以化学发光和荧光为基础的测定中,尖端301可用作将测定产品递呈给测定光学器件的便利方式。
图3B显示了包括样品尖端302的示例性样品收集单元302。如图3B所示的样品尖端302也可以从样品收集单元302分离,并用于将样品从样品收集单元转移到如本发明所述装置的其它单元中。如图3B所示的样品尖端302包括在此描述的凸起部322,用于将尖端302与装置的机架和液体转移装置连接。样品尖端302还包含开口332,用于使液体或样品可以转移进出样品尖端。在一些实施方式中,样品尖端302与测试尖端301的形状相同。在其它实施方式中(例如如图3A和3B所示的实施方式),样品尖端302与测试尖端301的形状不同。
在一个实施方式中,尖端的一个功能是可以使样品和液体试剂与测定单元的捕获表面相接触。这种运动可以用各种方式进行,包括但不限于,毛细管作用、吸取和受控的泵吸。尖端的尺寸小使得可以对化学反应所需的温度进行迅速控制。热传递和/或保温可以简单地通过将尖端放在一个温度控制模块中来实施。
在一些实施方式中,尖端能容纳约1-40微升的液体。在另一个实施方式中,尖端能容纳约5-25微升的液体。在一个实施方式中,尖端容纳20微升液体。在一些实例中,尖端能容纳1微升或更少的液体。在其它实例中,尖端能容纳最多100微升。
如需要,在引入下一个测定组分之前,为了避免小量样品和/或试剂的污染,可以在吸附材料上(例如组合进一次性检测盒中)吸干尖端的末端。由于物理作用力,吸入尖端中的任何液体可以保持在任何需要的位置而液体流出的危险极小,即使是保持在直立方向。
测定单元(例如测定尖端)可以在使用前用测试捕获试剂包被,采用与测定中相似的流体力学技术(例如,受控的毛细或机械吸取)。
捕获表面(本发明中也可称为反应位点)可以由通过共价键或通过吸附结合在测定单元上的结合抗体或其它捕获试剂形成。然后,对表面进行干燥并且在用于测试之前保持干燥。在一个实施方式中,每个待测分析物都有一个反应位点。
在一个实施方式中,可以移动测定单元使试剂单元和/或样品收集单元进入流体连通,从而使试剂或样品能与反应位点相互作用,其中所结合的探针能检测体液样品中感兴趣的分析物。然后,反应位点提供指示感兴趣的分析物存在或浓度的信号,所述信号能被本发明所述的探测装置检测到。
在一些实施方式中,反应位点的位置和构造是测定装置的一个重要因素。大多数的,如果不是所有的,一次性免疫测定装置都将捕获表面设计成装置的一体化组成部分。
在一个实施方式中,模制的塑料测定单元可以是商品化的或者可以是用注模法制成精确的形状和大小。例如,基准尺寸可以是直径0.05-3毫米或可以是长度3-30毫米。这些单元可以用捕获试剂进行包被,采用的方法类似于用于包被微量滴定板的方法,但具有能够大批处理的优点:将它们放在一个大容器中,加入包被试剂,并且用滤筛、支架等进行处理,以回收各个单元并根据需要进行洗涤。
测定单元可以提供一个能够在其上固定化反应物的刚性支持物。还可以选择测定单元以提供适当的与光相互作用的特性。例如,测定单元可以由下列材料制成:例如功能化玻璃,Si,Ge,GaAs,GaP,SiO2,SiN4,改性硅,各种凝胶或聚合物(例如聚四氟乙烯、聚偏氟乙烯、聚苯乙烯、聚碳酸酯、聚丙烯、PMMA、ABS或其混合物)中的任何一种。在一个实施方式中,测定单元包含聚苯乙烯。可以依照本发明使用其它合适材料。透明的反应位点是有优越性的。此外,在有可透光的窗能让光线达到光学检测器的情形中,所述表面可以有利地是不透光的和/或优选是光散射的。
固定化在捕获表面上的反应物可以是用于检测体液样品中感兴趣的分析物的任何物质。例如,反应物包括但不限于,核酸探针、抗体、细胞膜受体、能与特定分析物反应的单克隆抗体和抗血清。可以使用各种商品化的反应物,例如许多特别针对特定分析物开发的多克隆和单克隆抗体。
一个本领域的技术人员将会意识到,有很多种方法将各种反应物固定化到发生反应的支持物上,固定化可以是共价的或非共价的、经由一个连接部分(linker moiety)的、或是将它们束缚在一个固定化的部分上。可以将核酸或诸如抗体等蛋白质分子连接到固体支持物上的结合部分的非限制性例子包括:链霉亲和素或抗生物素蛋白/生物素键、氨基甲酸酯键、酯键、酰胺、硫羟酸酯键、N-官能基-硫脲、官能基顺丁烯二酰亚胺、氨基、二硫化物、酰氨、腙键及其他。此外,可以用本领域已知的方法将甲硅烷基部分连接到直接连接在如玻璃等底物的核酸上。表面固定化可以经由聚L-赖氨酸链来实现,其为表面提供了一个电荷-电荷耦合。
在结合捕获表面的最后一个步骤之后,可以将测定单元进行干燥。例如,可以通过被动暴露于干燥空气或通过使用真空歧管和/或通过歧管应用洁净的干燥空气来实现干燥处理。
在很多实施方式中,测定单元被设计成能用大量、快速制造过程进行制造的单元。例如,尖端可以安装成大规模阵列,以便在尖端内或尖端上进行捕获表面的批量包被。在另一个实施例中,尖端可以放在传送带或旋转台上进行连续加工。在又一个实施例中,一个大阵列的尖端可以与真空和/或压力歧管相连接,以简化加工。
在一个实施方式中,测定单元可以可操作性地与液体转移装置相连接。液体转移装置可以在没有人工干预的自动控制下操作。在包含尖端的测定单元中,对一次性液体尖端的安装高度的控制依赖于尖端在液体分配器上的锥形干涉连接。液体转移装置可以与尖端接合。在一些实例中,尖端在待转移的液体中的浸没长度必须使没有受到控制的尖端外部与液体的接触最小化。为了将尖端连接或粘附到液体转移装置上,可以在与分配器的喷嘴接合的锥形连接器的底部模制一个坚固的限制器。气密性密封条可以通过处于锥形的半腰或喷嘴的平坦底部的O型环制成。通过分离尖端的密封功能和尖端的高度控制,二者可以分开调节。模块化的装置和液体转移装置使得平行进行多个测试成为可能。
装置的试剂单元可以存储进行用于检测特定感兴趣的分析物的特定化学反应所需的试剂。液体试剂可以分入小盒中,小盒可以用各种材料制成,包括但不限于如聚苯乙烯、聚乙烯或聚丙烯等塑料。在一些实施方式中,试剂单元是圆柱形杯。在图4A和4B中显示了包含杯的试剂单元401、402的两个实施例。需要时,单元401、402紧密安装在装置机架内的空腔中。单元401、402可以在开放表面上密封,以防止所携试剂411、412溢出。在一些实施方式中,密封件是镀铝塑料并且能通过热粘合封到杯上。单元可以是容纳试剂所需的任何形状。例如,在图4A中显示了圆柱形的试剂单元401,且试剂单元含有液体试剂411。在图4B中显示了不同形状的试剂单元402,也含有液体试剂412。示例性试剂单元401、402都在顶部表面包括有可任选的细微改变,使得单元401、402紧密的安装到在此描述的装置的机架中。
在本发明的许多实施方式中,试剂单元是模块化的。试剂单元可以设计成能用大量、快速制造过程进行制造的单元。例如,许多试剂单元可以在大规模加工过程中同时填充并密封。可以根据拟用装置进行的测定的类型,对试剂单元进行填充。例如,如果一个用户需要进行与另一个用户不同的测定,则可以根据每个用户的偏好来制造测定单元,而不需要制造整个装置。在另一个实施例中,试剂单元可以放在传送带或旋转台上进行连续加工。
在另一个实施方式中,试剂单元直接容纳在装置机架的腔体中。在该实施方式中,密封可以制作在围绕着单元的机架区域上。
本发明的试剂包括但不限于:洗涤缓冲液、酶底物、稀释缓冲液、共轭物、酶标共轭物、DNA扩增剂、样品稀释剂、洗涤溶液、包括添加剂如去垢剂、聚合物、螯合剂、白蛋白结合试剂、酶抑制剂、酶、抗凝血剂、红细胞凝集剂、抗体在内的样品预处理试剂、或在装置上进行测试所需的其他材料。酶标共轭物可以是酶标记的多克隆抗体或单克隆抗体,其中的酶在与合适的底物反应后要能够产生可检测信号。这些酶的非限制性的例子是碱性磷酸酶和辣根过氧化物酶。在一些实施方式中,试剂包含免疫测定试剂。通常,试剂,尤其是那些与液体混合时相对不稳定的试剂,被分别约束在装置内的限定区域(例如,试剂单元)内。
在一些实施方式中,试剂单元含有约5微升到约1毫升液体。在一些实施方式中,单元可以含有约20-200微升液体。在又一个实施方式中,试剂单元含有100微升液体。在一个实施方式中,试剂单元含有约40微升液体。试剂单元中液体的体积可以根据所进行的测定类型或所提供的体液样品而不同。在一个实施方式中,试剂的体积不必是预先确定的,但必须是大于已知的最小量。在一些实施方式中,试剂最初是干燥保存的,并在装置中一开始进行测试时溶解。
在一个实施方式中,试剂单元可以用虹吸管、漏斗、移液管、注射器、针或其组合进行填充。试剂单元可以通过填充通道和真空抽吸通道进行液体填充。试剂单元可以个别填充或作为大量制造过程的一部分进行填充。
在一个实施方式中,各试剂单元包含不同试剂作为使试剂彼此分离的手段。试剂单元还可以用于容纳洗涤溶液或底物。此外,试剂单元可用于容纳发光底物。在另一个实施方式中,在一个试剂单元中可以含有多种试剂。
在一些实例中,装置的设置使得能够在组装一次性装置前对测定单元和试剂单元进行预校准。
系统
在一个方面,本发明的系统包括一个包含测定单元和试剂单元的装置,其中的试剂单元包含试剂(液相和固相试剂)。在一些实施方式中,整个装置、测定单元、试剂单元、或其组合中的至少一个为一次性的。在本发明的一个系统中,用装置检验分析物是由一个仪器执行的。在大多数实施方式中,仪器、装置和方法提供一个自动化检测系统。自动化检测系统可以是基于已定义的协议或者是由用户提供给系统的协议来实现自动化的。
在一个方面,用于自动化检测体液样品中分析物的系统包含一个装置或检测盒以及一个用于检测指示该分析物存在与否的可检测信号的检测组合件或检测器。
在一个实施方式中,用户向装置施加一个样品(例如,检测的或未检测的血液样品)并且将装置插入仪器中。所有的后续步骤是自动化的,由装置(硬接线的)、用户、远程用户或系统、或根据标识符(例如装置上的条形码或RFID)对仪器操作的修改等来设定程序。
用本发明的系统可以执行的不同功能的例子包括但不限于:稀释样品,去除样品的组成部分(例如,红细胞(RBC)),使测定单元中的样品发生反应,向样品和测定单元中添加液体试剂,从样品和测定单元中洗掉试剂,和在装置使用过程中和使用后容纳液体。试剂可以是在试剂单元中或是在将要组装到装置上的试剂单元中进入装置的。
自动化系统可以通过酶联免疫吸附测定(ELISA)检测生物样品(例如血液)中的特定分析物。系统能够进行多重测试,尤其适于检测小量全血样品(例如20微升或更少)中的感兴趣的分析物。需要时,系统还可以用单个样品不同稀释度检测分析物,使得在同一装置上可以测试不同的灵敏度。所有的试剂、补给和废物可以容纳在系统的装置上。
使用时,将来自对象的样品被施用到组装好的装置上,并且将装置插入到仪器中。在一个实施方式中,仪器可以通过下列步骤的组合来开始加工样品:去除红细胞(血液样品)、稀释样品、和将样品移到测定单元中。在一个多重测定实施方式中,使用了多个测定单元,且依次或并行地将样品的一部分移入各测定单元中。然后可以通过次序受控的孵育和将试剂施用到捕获表面上来进行测定。
示例性的液体转移装置包含进行和/或读取测定所需的任何部件。部件的例子包括但不限于,将已知量的液体精确地从装置的孔或单元中吸取和射出的泵,改善系统内移动精度和准确性的至少一个平移平台,检测测定单元中分析物的检测器,提供用于进行测定孵育的受调控的温度环境的温度调节模块。在本发明的一个实施方式中,仪器控制装置的温度。在另一个实施方式中,温度在约30-40摄氏度的范围内。在一些实施方式中,系统的温度控制可包括主动冷却。在一些实例中,温度的范围是约0-100摄氏度。例如,对于核酸测定,温度可以最高达到100摄氏度。在一个实施方式中,温度范围为约15-50摄氏度。系统的温度控制单元可包含热电装置,例如珀耳帖装置。
本发明的检测盒、装置和系统可以提供现有POC系统或集成分析系统不具备的许多特性。例如,许多POC检测盒依赖于封闭的流体系统或环路方可有效地操作小量液体。本发明的检测盒和流体装置可以在检测盒单元之间有开放的液体流动。例如,试剂可以储存在一个单元中,样品储存在样品收集单元中,稀释剂储存在稀释剂单元中,而捕获表面可以是在测定单元中,其中在检测盒的一个状态中,没有任何一个单元与其他任何单元流体连通。使用如本发明的液体转移装置或系统,在某一状态中,各单元不必处于彼此流体连通中。各单元可以彼此相对移动,从而使一些单元进入流体连通状态。例如,液体转移装置可包含一个接合测定单元、并将该测定单元移动使之与试剂单元进入流体连通的头部。
本发明的装置和系统可以提供对来自对象的体液中存在的分析物进行高通量实时检测的有效方式。这些检测方法可以在许许多多情况下使用,包括鉴定和定量分析与特定生物学过程、生理状态、病症或病症阶段相关联的分析物。同样地,系统的使用范围很广,例如药物筛选、疾病诊断、系谱分类、亲子和法医鉴定、疾病发作和复发、对于基于人群的治疗的个体反应、以及治疗的监测。本装置和系统对于下列方面也很有用:推动疗法开发的临床前和临床阶段、改善患者的顺应性、监测与处方药有关的不良药物反应(ADR)、开发个性化药物、将血液测试从中心实验室外放到家庭或根据处方使用,用于制药公司在监管机构批准后监测治疗药物。本发明的装置和系统可提供一个针对个性化药物的灵活系统。采用同一系统,装置可以随协议或给系统的可编程处理器的指令改变或交换,以便进行所描述的各种测定。本发明的系统和装置以桌面或较小尺寸的自动化仪器的提供了许多实验室设备的特性。
在一些实施方式中,可以向患者提供用于检测各种分析物的多个装置。例如,对象可以在一周内的不同日子使用不同的流体装置。例如,在一些实施方式中,外部装置上将标识符与协议相关联的软件可以包括一个将当前日子与基于临床试验要使用流体装置的那个日子进行比较的进程。在另一个实施方式中,向患者提供能互换安装到装置机架上的不同试剂单元和测定单元。在又一个实施方式中,所述患者不需要每个测试日使用新装置,相反可以从诸如服务器等外部装置下载新的指令对系统进行编程或重新编程。例如,如果两个星期几是不相同的,则外部装置可以采用本发明的或本领域已知的任何方式将通知无线传递给对象,通知正确的装置和/或给系统的正确指令。这个例子只是说明性的,可以很方便地扩展为例如通知对象流体装置没有使用在正确的钟点。
例如,如图1所示的检测盒包括多种测定单元和试剂单元。测定单元可保护依据待测分析物的捕获表面。测定单元以即用即装的方式与装置的其他部分组装起来。在许多现有技术POC装置中,捕获表面与装置是一体的,而且如果捕获表面不正确或是形成不当,整个装置都作废。采用本发明的装置,捕获表面和/或测定单元可以是独立质量控制的且独立于试剂单元和装置机架来定制。
试剂单元可以用类似的即用即装的方式填充各种试剂。这就提供了装置可由客户定制的灵活性。此外,可以用不同量的试剂来填充试剂单元,而不影响装置的稳定性或装置中将要进行的化学反应。结合带液体转移装置的系统,本发明的装置和单元在进行测定的方法和协议方面提供了灵活性。例如,一批含有同样试剂的相似装置可以提供给一个患者群来进行临床试验。在临床试验的中途,用户意识到可以通过改变样品的稀释度以及提供给测定单元的试剂量来优化测定。如本发明所提供,可以通过仅仅改变给液体转移装置的可编程处理器的指令来改变或优化测定。例如,用于患者群的这批检测盒上载有过量的稀释剂。新的协议需要原协议4倍的稀释剂。根据本发明提供的方法和系统,可以在中央服务器更改协议,并且传递给所有的系统,通过不分明装置执行这些方法,而不必向患者群提供新的装置。换言之,本发明的POC装置和系统提供了许多通常带有过量的试剂以及过量的样品的标准实验室操作所具有的灵活性。
在一些实例中,其中检测盒的各单元是分离的,装置和系统提供了构建本发明所述系统的灵活性。例如,检测盒可以设计成用测定单元阵列和试剂单元阵列进行8个测定。由于本发明所述的检测盒的特征,同一机架或同一设计的机架可用于制造一个带有多达8个不同于先前检测盒的测定的检测盒。在许多现有的POC装置设计中难以达到这种灵活性,因为系统和液体通道是封闭的,所以装置不可以模块化或不像本发明一样易于组装。
目前,需要在各分析物存在的浓度范围差异比较大时能够检测一个以上分析物,例如,一个分析物的浓度范围是pg/ml,而另一个分析物的浓度范围是μg/ml。本发明的系统能够同时测定在同一样品中以宽浓度范围存在的各分析物。能够检测以宽浓度范围存在的不同分析物浓度的另一个优点是,可以将分析物的浓度比例与对患者施用的多个药物的安全性和效用联系起来。例如,意外的药物-药物相互作用是药物不良反应的常见原因。检测不同分析物的实时协同检测技术将有助于避免药物-药物不良相互作用所引起的潜在的灾难性后果。
能够监测一个对象在一段时间内的分析物浓度和/或PD或PK标记物浓度的变化速度,或进行浓度或PD或PK标记物的趋势分析,不论它们是药物还是其代谢物的浓度,能够有助于避免潜在的危险情况。例如,如果葡萄糖是感兴趣的分析物,在给定时间的样品中葡萄糖浓度以及在给定时间段内葡萄糖浓度的变化速度,对于预测和避免如低血糖事件非常有用。这样的趋势分析在药物给药方案方面提供广泛有利的信息。当涉及多个药物及其代谢物时,发现趋势并采取主动措施的能力通常是梦寐以求的。
因此,采用本流体装置和系统所产生的数据可用于进行对象中分析物浓度的趋势分析。
通常,同一检测盒中的8个测定可能需要不同的稀释作用或预处理。在两个测定之间,稀释的范围可以是相当大的。许多现有POC装置提供有限的稀释范围,因此POC装置只可能执行数量有限的测定。然而,由于能够对样品进行连续稀释,本发明的系统和/或检测盒能提供一个大的稀释范围。因此,可以在一个检测盒或多个检测盒上进行大量的潜在的测定,而不需要改造测定的检测器或读取仪器。
在一个实施例中,如本发明提供的系统用于进行多个(例如5个或更多)不同目标分析物检测试验。为了能将预期分析物的浓度落在本发明的和POC领域常用的免疫测定的检测范围内,样品必须稀释,例如3:1、8:1、10:1、100:1和2200:1来进行5个测定中的每一个测定。因为液体转移装置能够在装置内保持并移动液体,可以用本发明的系统来进行连续稀释,以达到这5个不同的稀释度,并且检测所有5个不同的目标分析物。如上所述,还能够调整执行测定的协议,而不需要对装置和系统进行改造。
在一个使用传统移液器的实验室背景中,通常要比POC设备使用更大体积的样品。例如,实验室可以分析从患者手臂抽取的毫升级体积的血液样品。在POC背景中,很多装置和用户要求过程是快速、简便和/或侵入性最小的,因此通常用POC装置分析的是小量样品(类似于微升级的体积),例如从手指穿刺取得的少量样品。由于样品的差异,在进行实验室背景得以实现的测定方面,现有POC装置失去了灵活性。例如,为了对样品进行多个测试,每一个测定需要有特定最小的体积,从而能够对分析物进行精确检测,因此对POC背景中的装置加上了一些限制。
在另一个实施例中,本发明的系统和/或液体转移装置提供了很大的灵活性。例如,液体转移装置可以自动化地移动测定单元、测定尖端、或将一个空的移液管从装置的一个单元移动到装置的一个分开的相互之间非流体连通的单元。在一些实例中,这可以避免在装置的单元之间的交叉污染。在其他实例中,这样可以根据协议或指令在本发明的装置中灵活移动数种液体使其相互接触。例如,在8个不同试剂单元中包含8种不同试剂的检测盒可以根据协议的指令以任何顺序或组合来编址并通过液体转移装置来接合。因此,在装置上进行的任何化学反应可以用许多不同的次序进行。不改变检测盒中试剂的体积或检测盒中试剂的类型,测定协议可以是不同的或在不需要第二检测盒或第二系统的情况下加以改变。
例如,用户订购的是一个有特定类型捕获表面和特定试剂的检测盒,用于进行检测样品中分析物(例如,C-反应蛋白(CRP))的测定。用户原计划的协议需要2个洗涤步骤和3个稀释步骤。在用户收到装置和系统之后,用户决定协议实际上应该有5个洗涤步骤和仅1个稀释步骤。本发明的装置和系统能够灵活改变协议而不需要改装装置或系统。在这个实施例中,只需要把一个新协议或一套新指令传送给系统或液体转移装置的可编程处理器。
在另一个实施例中,本发明的系统用于进行5个不同目标分析物的检测试验,其中每个试验需要在不同的温度进行孵育。在许多现有技术POC装置中,在不同温度孵育多个试验是一项困难的任务,因为这多个试验不是模块化的,且捕获表面不能相对于加热装置进行移动。在本发明的系统中,其中各测定单元被设计成用于进行化学反应,各测定单元可以放置在独立加热单元上。在一些实施方式中,系统包含多个加热单元。在一些实例中,系统包含至少与测定单元一样多的加热单元。因此,多个测定可以在多个温度下进行。
本发明的系统和装置还能提供许多现有技术的POC装置所不具备的各种质量控制措施。例如,因为装置的模块性,测定单元和试剂单元可以彼此分开、和/或与机架分开、和/或与系统或液体转移装置分开进行质量控制的。本文描述由本发明的系统和装置提供的质量控制的示例性方法和系统。
不管检测的是体液样品中的何种分析物,本发明的系统能进行各种测定。取决于装置身份的协议可以从储存响应的外部装置传递到阅读器组合件,使得阅读器组合件能在装置上执行特定的协议。在一些实施方式中,装置带有可被本发明的标识符检测器检测或读取的标识符(ID)。标识符检测器可以经由将标识符传送给外部设备的控制器与通信组合件相互通信。需要时,该外部设备基于标识符将一个存储在外部设备中的协议传送给通信组合件。即将在系统中运行的协议包含给系统控制器的执行协议的指令,包括但不限于待进行的特定试验和待执行的检测方法。一旦用系统执行了这项试验,即生成一个指示体液中分析物的信号并被系统的检测组合件检测到。被检测到的信号然后传送到通信组合件,在那里信号传输到外部设备进行加工,包括但不限于计算样品内分析物的浓度。
在一些实施方式中,标识符可以是众所周知的带有一系列黑白线条的条形码标识符,能被诸如条形码读取器等标识符检测器所读取。其他标识符可以是一系列的字母数字的值、色彩、凹凸块、或任何其他能定位在装置上并被标识符检测器检测到或读取的标识符。标识符检测器还可以是发光的LED,其发出的光与反射光的标识符相互作用并且被标识符检测器检测到,以确定装置的身份。在一些实施方式中,标识符可以包括存储或记忆装置,并且能将信息传送给识别检测器。在一些实施方式中,可以使用各种技术的组合。在一些实施方式中,使用诸如LED等光源对检测器进行校准。
在一个实施例中,体液样品可以提供给一个装置,而该装置能插入到系统中。在一些实施方式中,装置是部分地手动插入,然后读取组合件中的机械开关自动地将装置正确地放置到系统内。可以使用本领域已知的用于将盘或检测盒插入系统的任何其他机构。在一些实施方式中,可能需要手工插入。
在一些实施方式中,自动化地选择在系统上要进行的协议的方法包括:提供一个带有标识符检测器的装置和一个标识符;检测该标识符;将所述标识符传送给外部装置;以及从所述外部装置上与所述标识符相关联的多个协议中选择要在系统上运行的协议。
在一方面,揭示一个自动化检测体液样品中多个分析物的系统,包括:流体装置(比如本发明的),其包括有:用于容纳体液样品的样品收集单元;测定单元阵列,其中所述测定单元阵列的各测定单元设计成用于进行能产生指示所检测的多个分析物中各分析物的信号的化学反应;和试剂单元阵列,其中所述试剂单元阵列的各试剂单元含有试剂。该系统还包括有多个头的液体转移装置,其中这多个头中的各个头设计成用于接合各测定单元,并且其中所述液体转移装置包括可编程处理器,用于引导体液样品从样品收集单元和试剂从独立试剂单元转移到各测定单元的液体转移。例如,一个测定单元包含试剂并可用于与该试剂进行化学反应。
在一些实例中,处理器引导液体转移的配置可以在测定单元阵列中引起一定程度的体液样品的稀释作用,使指示被检测的多个分析物的信号落在可检测的范围内,从而使所述多个分析物可以用所述系统进行检测。在一个实施例中,体液样品包含至少2个分析物,其浓度相差至少2、5、10、15、50或100个数量级。在一个实施例中,体液样品是一滴血液。在一个实施方式中,样品中的至少两个分析物的浓度相差达10个数量级(例如,第一分析物为0.1pg/mL,第二分析物为500μg/mL)。在另一个实施例中,一些蛋白分析物的浓度大于100mg/mL,能将感兴趣的范围扩展到约12个数量级。
体液样品的稀释程度能使指示该至少两个分析物的信号落在可检测的范围内。在许多实例中,系统还包括检测器,例如光电倍增器(PMT)。例如,用光电倍增器,检测器的可检测范围可为每秒约10到1千万次计数。每计数对应于一个光子。在一些实例中,PMT不是100%有效的,观察到的计数率会略低于、但仍接近于每单位时间到达检测器的光子实际数量。在一些实例中,在约10个约一秒钟的时间间隔内检测计数,并对结果进行平均。在一些实施方式中,当使用PMT作为检测器时,测定的范围为每秒1000-1000000次计数。在一些实例中,低至每秒100次的计数率和高至每秒10000000次的计数率都可测。PMT的线性响应范围(例如,计数率与每单位时间的光子数量成正比的范围)可为约1000-3,000,000次/秒。在一个实施例中,测定的可检测信号在低端为约200-1000次/秒而在高端为10000-2000000次/秒。在一些蛋白生物标志的实例中,计数率与结合在捕获表面上的碱性磷酸酶成正比,并且也与分析物浓度成正比。其他示例性的检测器包括雪崩光电二极管、雪崩光电二极管阵列、CCD阵列和冷光源CCD阵列。许多其他检测器带有数字输出并通常与到达探测器的光子成正比。示例性检测器的可检测范围与所使用的探测器相适应。
液体转移装置的各个头可设计成附接在各个测定单元上。液体转移装置可以是移液管,例如空气置换移液管。液体转移装置可为自动化的。例如,液体转移装置还可包括与可编程处理器通信的电动机,并且电动机可以基于来自可编程处理器的协议来移动这多个头。如本发明所述,各测定单元可以是移液尖端,例如带有捕获表面或反应位点的移液尖端。
通常在POC装置中,例如本发明的系统和装置,必须估算稀释倍数并且尽量精确。例如,在非专业用户操作系统的情况下,需要有确保样品稀释的方法。
如本发明所述,液体转移装置可以影响样品的稀释度,来提供准确的测定结果。例如,可编程的液体转移装置可以是多头的,用于稀释或连续稀释样品并提供样品的混合作用和稀释剂。液体转移装置还可以在POC装置内提供液体的移动。
如本发明所述,本发明的系统和装置能够在POC环境中实现实验室环境才具有的许多灵活性特征。例如,可用桌面大小或较小的装置或系统来自动化地收集并操作样品。POC装置的一个普遍问题是在执行多个测定时实现不同的稀释度范围,其中各测定的灵敏度或特异性或有显著差异。例如,在样品中有2个分析物,但一个分析物在样品中的浓度高,且另一个分析物的浓度非常低。为了能检测两个分析物,本发明的装置和系统将样品稀释到显著不同的水平。例如,如果分析物为高浓度,将样品连续稀释到合适的检测范围并提供给捕获表面用于检测。在同一系统或装置中,有低浓度分析物的样品可以不需要被稀释。这样,本发明所提供的POC装置和系统的测定范围能比许多现有POC装置扩大。
液体转移装置可以是作为台式仪器的系统的一个组成部分。液体转移装置可包含多个头。本发明的液体转移装置可以具有用于检测样品中多个分析物所需的任何数量的头。在一个实施例中,液体转移装置有约8个头,这些头成一直线安装并且相互间分开一段距离。在一个实施方式中,各个头带有锥形喷嘴,所述喷嘴与各种尖端通过压力安装接合,比如本发明的测定单元或样品收集单元。尖端可以有一个特征,使得尖端被仪器自动地去除,并在使用后将尖端放置到所述装置的机架内。在一个实施方式中,测定尖端是清澈、透明的,并可类似于在其中进行测定的比色皿,能用诸如光电倍增管等光学检测器检测。
在一个实施例中,系统的可编程处理器可包含指令或命令,并能根据指令操作液体转移装置,通过将活塞收回(为了将液体吸入)或伸出(为了排出液体)进入一个封闭的空气空间来转移液体样品。移动的空气体积和移动的速度都能被精确控制,例如由可编程处理器控制。
通过将待混合的组分吸入一个共用管中,然后反复地在尖端内将合并的液体的一大部分吸上吸下,实现样品(或试剂)与稀释剂(或其他试剂)的混合。可用相似的方式完成溶解进入管内的干试剂。可以通过将适当的液体吸入尖端中,并在那里保持一段预先确定的时间,来实现液体样品和具有其上结合了捕获试剂(例如抗体)的捕获表面的试剂一起孵育。可通过将液体排入本发明的装置内的储槽或吸垫上,来实现样品和试剂的除去。然后,可根据来自可编程处理器的指令或协议将另一种试剂吸入尖端中。
在如图11所显示的实施例中,原来尖端1101中的液体1111在排出时会在尖端1101中留下薄膜1113。因此,系统用下一个液体1112的前导(例如最上层)部分的作用从尖端1101上冲刷掉原来存在的液体1111。受到原来存在的液体1113污染的后续液体的这个部分被保持在尖端1101的顶部,它不会继续与捕获表面1102相互作用。捕获表面1102可以是在尖端1101的规定区域内,这样原有液体1111不与捕获表面1102反应,例如如图11所示,捕获表面1102占据尖端1101的圆柱部分的规定部分,并没有一直延伸到尖端的凸起部。在许多实例中,孵育时间短暂(例如10分钟),而液体污染区域的分隔是相对较大的(>1mm),所以在孵育过程中液体1113的污染部分的活性组分的扩散不会快到足以与捕获表面1102反应。对于许多高灵敏度测试,需要除去一个试剂,或洗涤捕获表面(例如,用测试信号发生因子标记的探测抗体)。在一个实施例中,本发明的液体转移装置可通过增加进一步的液体转移的去除和吸取循环来提供洗涤,例如使用洗涤试剂。在一个实施例中,4个洗涤步骤表明,与捕获表面相接触的未结合检测抗体减少了106倍以上。(非常不需要的)非特异性地结合到捕获表面上的任何检测抗体也可在该洗涤过程中被去除。
通过稀释样品,可以实现扩大试验的范围。在使用含有稀释剂的一次性检测盒的POC测定系统中,通常对稀释的程度有一个实用性限制。例如,如果通过刺破手指获得的少量血液样品(例如约20微升)要被稀释,放在管中的稀释剂的最大体积为250微升,稀释整个样品的实用性限制为约10倍。在一个本发明的实施例中,系统可以吸入较小体积的样品(例如约2微升),使得最大稀释倍数为约100倍。对许多测定,这样的稀释倍数是可以接受的,但对于诸如CRP等测定(如本发明的实施例所述)需要更加地稀释样品。基于分离的ELISA测定在捕获表面结合分析物的能力上有与生俱来的局限性(例如对于典型的蛋白分析物约几百纳克/毫升)。一些分析物在血液中以几百微克/毫升存在。即使稀释100倍,分析物浓度仍可能在校准范围之外。在本发明的系统、装置和液体转移装置的一个示例性实施方式中,可以通过向各测定单元或样品收集单元中进行多次稀释剂的液体转移,实现多重稀释。例如,如果如上文所述,样品中分析物的浓度非常高,可以将样品稀释多次,直到分析物的浓度落在可接受的检测范围内。本发明的系统和方法能准确测定或估算稀释作用,从而计算分析物的原始浓度。
在一个实施方式中,本发明的系统能移动液体样品和移动测定单元。系统包含加热模块和检测器。为了移动液体样品,系统可提供吸取式、注射式或移液式动作。在一个示例性实施方式中,用于移动液体样品的液体转移装置是移液管和移液端头系统。系统所需的移液装置数量可根据待测分析物的类型和所进行的试验数量进行调整。由移液系统执行的动作可以是自动化的或由用户手动操作。
图5显示了本发明的液体转移装置520和系统500的实施例。液体转移装置能用8个不同的头522同时移动8个不同或相同体积的液体。例如,检测盒(或在此所述的装置)510包含8个测定单元501。各个测定单元501是根据单元501中将要进行的试验类型来设计的。各测定单元501可能需要一定体积的样品。可用一个头522将正确量的样品分配到各测定单元501中。在这个实施例中,每个头522对应于一个设定了地址的测定单元501。
液体转移装置机构520还可用于从试剂单元分配试剂。不同类型的试剂包括共轭物溶液、洗涤溶液和底物溶液。在一个自动化系统中,可以移动一个安装了装置510的平台530,以相对于测定单元510和头522的定位并且根据完成如图5所示的测试所需的步骤来移动装置510。或者,可以相对于装置510的位置移动头522和尖端501或液体转移装置520。
在一些实施方式中,以干燥形式提供试剂,在试验过程中重新水化和/或溶解试剂。干燥形式包括冻干的物质和包被在表面上的膜。
系统可包含用于移动测定单元或尖端的固定器或衔接器。衔接器可包含真空组件或用于紧密配合测定单元尖端的凸起部的组件。例如,移动尖端的手段可以是以类似于移动液体转移装置端头的方式来移动的。还可根据衔接器或固定器的位置在平台上移动本发明的装置。
在一个实施方式中,用于移动尖端的仪器是与移动一定量样品的仪器一样的,例如本发明的液体转移装置。例如,利用收集尖端上的凸起部可以将样品收集尖端安装到移液端头上。然后可用收集尖端在整个装置和系统中分配液体。在分配液体之后,可丢弃收集尖端,并且利用测定单元上的凸起部将移液端头安装到测定单元上。然后可将测定单元尖端从一个试剂单元移动到另一个试剂单元,并且采用移液端头提供的吸取或移液式动作将试剂分配到测定单元中。移液端头还可通过吸取或注射式动作在收集尖端、测定单元或试剂单元中进行混合处理。
系统可包含加热模块,用于加热试验或测定单元和/或控制试验温度。热量可以用在测定反应的孵育步骤中来促进反应并缩短孵育步骤所需的持续时间。系统可包含用于接受本发明的测定单元的加热模块。加热模块可设计成接受来自于本发明装置的多个测定单元。例如,如果在装置上需要进行8个试验,加热模块可设计成接受8个测定单元。在一些实施方式中,使用移动测定单元的手段使用移动测定单元与加热模块进行热交换。可以用本领域已知的加热方式来进行加热。
在图6中显示了本发明的示例性系统600。系统600包括平动平台630,其上手动地或自动地或两者兼有地放有将装置610(或本实施例中的检测盒)。系统600还包括与装置610的测定单元611对齐的加热模块640。如图6所示,装置610包括一系列8个测定单元611和多个相对应的试剂单元612,并且加热模块640还包含一个区域641以便同时加热至少8个单元。根据所进行的试验的类型或所检测的分析物的类型,每个加热区域641能给每个测定单元611提供相同的或不同的温度。系统600还包含一个检测器(例如光电倍增管)650,用于检测来自测定单元611的代表样品中分析物检测的信号。
在一个实施方式中,提供了传感器,在对试验进行检测时,相对于检测器定位测定单元。
在一个实施方式中,检测器是装有检测组件的阅读器组合件,用于对装置上至少一个试验所产生的信号进行检测。根据所进行的试验的类型和所采用的检测机制,检测组件可以在装置的上方或相对于装置处于不同的取向。可以移动检测组件使其与测定单元彼此连通,或移动测定单元使其与检测组件彼此连通。
在许多实例中,提供了光学检测器,并用作检测装置。非限制性的例子包括光电二极管、光电倍增管(PMT)、光子计数检测器、雪崩光电二极管、或电荷耦合器件(CCD)。在一些实施方式中,可以使用插脚二极管。在一些实施方式中,插脚二极管可连接在放大器上,从而产生灵敏度比得上PMT的脚测装置。一些试验可以如本发明所述产生发光。在一些实施方式中,检测的是化学发光。在一些实施方式中,检测组件可包括连接到CCD检测器或PMT阵列上的多个光纤电缆束。光纤束可以由分散的光纤或融合在一起的许多小光纤形成一个实心束而构成的。这样的实心束是商品化的,并且可方便地与CCD检测器相接。
检测器还可包含光源、例如灯泡或发光二极管(LED)。为了检测结果,光源可以照亮试验。例如,试验可以是荧光测定或吸光度测定,如核酸测定中通常使用的。检测器还可包含向试验传送光源的光学器件,例如透镜或光纤。
在一些实施方式中,检测系统包含非光学检测器或传感器,用于检测对象的特定参数。这样的传感器包括温度、传导率、氧化的或还原的化合物的电势信号和电流信号,例如O2、H2O2和I2或可氧化/可还原的有机化合物。
在制造后,装置和系统可以一起或单独地运送给最终用户。本发明的装置或系统可与用户手册或使用说明书包装在一起。在一个实施方式中,本发明的系统对于在不同装置上进行的测试类型具有通用性。因为装置的部件是模块化的,在现场护理环境中,用户只需要一个系统和各种装置或测定单元或试剂单元来进行多个试验。在这个情境下,系统可以反复地用于多个装置,在装置和系统上都需要有传感器,来检测例如运送过程中的这种变化。在运送过程中,压力或温度的变化会影响本系统多个部件的性能,如此,在装置或系统上安装的传感器可以将这些变化传送给例如外部设备,这样可以在校准过程中或外部设备进行数据处理过程中进行调整。例如,如果在运输过程中流体装置的温度改变达到一定的水平,装在装置上的传感器能检测到这种变化,并且在用户将装置插入系统时,将这些信息传递给系统。系统中还可以有附加检测装置来执行这些任务,或这样的装置可以结合在另一个系统部件中。在一些实施方式中,信息可以是无线传送给系统或外部装置的,比如个人电脑或电视。同样地,系统内的传感器可以检测类似的变化。在一些实施方式中,在运输包装中也需要有一个传感器,或是替代系统部件中的或是额外增加一个。例如,能被感测到的会使试验检测盒或系统无效的不利条件包括暴露于高于最大可容忍的温度,或破坏检测盒的完整性发生潮气渗透。
在一个实施方式中,系统包含能向外部装置无线传送并从其接受信息的通讯组件。这样的无线通讯可以是蓝牙或RTM技术。可以使用各种通讯方法,例如用调制解调器的拨号有线连接,直接连接如T1、ISDN或电缆线等。在一些实施方式中,无线连接的建立,采用的示例性无线网络包括蜂窝式、卫星、或寻呼网络、GPRS、或局域数据传送系统如局部区域网络上的以太网或令牌网。在一些实施方式中,信息在传送到无线网络之前是经过加密处理的。在一些实施方式中,通讯组件包含用于传送和接受信息的无线红外通讯部件。系统包括集成的显卡来帮助显示信息。
在一些实施方式中,通信组件具有记忆或存储装置,例如局部RAM,其中可以存储收集的信息。如果由于如暂时不能无线连接网络而无法在给定时间内传送信息,就需要一个存储装置。信息可以与存储装置内的装置标识符相关联。在一些实施方式中,通信组件将在一定时间后重新尝试传送存储的信息。
在一些实施方式中,外部装置与阅读器组件内的通信组件进行通讯。外部装置可以无线地或物理性地与系统连通,但也可以与第三方通信,包括但不限于患者、医护人员、临床医生、实验室人员、或卫生保健业中的其他人员。
图7中显示了一个示例性的方法和系统。在图7的实施例中,患者将血液样品传递给本发明的装置,然后将装置插入一个阅读器中,其中阅读器是能读取血液样品中分析物的桌面系统。阅读器可以是本发明的系统。阅读器可为台式或桌面系统,并能读取多个本发明的不同装置。阅读器或系统能执行化学反应并检测或读取化学反应的结果。在图7的实施例中,阅读器是根据自外部装置(例如带有用户界面的服务器)发送的协议自动操作的。阅读器还能将化学反应的检测结果传送给服务器或用户界面。在一个示例性系统中,用户(例如,医护人员如内科医生或研究人员)能察看和分析结果,并决定或开发出用于自动化操作该系统的协议。结果可以本地存储(在阅读器上)或存储在服务器系统上。服务器还能存储患者的记录、患者日志和患者群数据库。
图8显示了构建用于评估对象病情的系统的操作流程。患者将个人数据和/或来自本发明的装置、阅读器和/或系统的测量数据输入或存在于所述服务器上的数据库。系统能在病人站显示器(patient station display)上显示个人数据。在一些实施方式中,病人站显示器是互动式的,病人能够修改输入的数据。同一个或不同的数据库包含来自病情相似的其他对象的数据。来自其他对象的数据可以是来自于公共或私人研究所的历史数据。来自其他对象的数据也可以是来自于临床研究的内部数据。
图8还显示了数据的流动,从包括来自对象的数据在内的阅读器收集数据传递给连接到公共网络上的服务器。服务器可对数据进行操作,或仅仅将数据提供给用户站。病人数据可以独立于存储在数据库中的与病情相关的数据输入到服务器中。图8还显示了用户终端显示器以及向医护人员或用户的信息流。例如,采用图8的示例性操作流程,在家的病人可以将体液样品输入本发明的检测盒中,并将其放入本发明的系统或阅读器中。病人能够从病人站显示器察看来自系统的数据、和/或修改或输入新的数据给操作流程。然后,来自病人的数据以加密的形式通过诸如因特网等公共网络传送给带有网络界面和处理器的服务器,其中服务器位于中央计算中枢或临床测试中心。服务器可以使用病情数据,处理并理解来自用户的数据,然后将结果经所述公共网络传给用户站。用户站可以在医务办公室或实验室,并具有能显示测定结果和患者数据处理给医务人员的用户站显示器。在这个实施例中,医护人员可以检索对病人在诸如家中等其他地方进行的检验所得到的样品测试的结果和分析,。在此描述了系统和系统部件的其他实施方式和实施例。
在一些实施方式中,外部装置可以是计算机系统、服务器、或能存储信息或处理信息的其他电子设备。在一些实施方式中,外部装置包括一个或一个以上计算机系统、服务器、或能存储信息或处理信息的其他电子设备。在一些实施方式中,外部装置包括患者信息数据库,例如但不限于,医疗记录或患者病史、临床试验记录、或临床前实验记录。外部装置能存储将在系统上运行的协议,当接收到指示哪个装置已经被插入系统的标识符时,能将这些协议传送给系统的通讯组件。在一些实施方式中,协议是依赖于装置的标识符的。在一些实施方式中,外部装置为每一个装置存储了一个以上的协议。在其他实施方式中,外部装置上的病人信息包括一个以上的协议。在一些实例中,外部服务器存储了数学算法,用以处理从通讯组件传来的光子计数,并且在一些实施方式中用以计算体液样品中分析物的浓度。
在一些实施方式中,外部装置包括一个或多个本领域所熟知且商品化的服务器。此类服务器能够提供负载平衡、任务管理、以及如果一个或多个服务器或外部设备的其他组件发生故障时的备份能力,以便改善服务器的可用性。如本领域所知,服务器也可以实现在存储和处理器单元的分布式网络上,其中本发明的数据处理在诸如计算机等工作站上进行,从而排除对服务器的需求。
服务器包括数据库和系统进程。数据库可以驻留在服务器内,或驻留在能够被该服务器存取的另一个服务器系统上。由于数据库内的信息可能包含敏感信息,可以实现一个安全系统以防止未授权的用户进入数据库。
一些本发明的特性的一个优点是信息可以从外部装置不仅仅传送回阅读器组合件,而且还传送给其他部件或其他外部设备,非限制性的例子是PDA或手机。这样的通信可以通过本发明所揭示的无线网络来实现。在一些实施方式中,计算出的分析物浓度或其他病人信息可以传递给例如但不限于医务人员或病人。
因此,使用本装置和系统产生的数据可用于完成对象中分析物浓度的趋势分析。
本发明的另一个优点在于试验结果基本上能够立刻传达给任何能从结果中受益的第三方。例如,一旦外部设备上确定了分析物的浓度,就将它传送给病人或可能需要采取进一步行动的医务人员。向第三方的通信步骤可以如本发明所述以无线方式进行,并且通过将数据传送给第三方的手持设备,实际上能够在任何时间任何地点将试验结果通报给第三方。因此,在时间敏感性场景中,如果需要紧急医疗措施,可以在任何地方立即联络病人
在将流体装置插入系统之后,通过基于与该流体装置相关联的标识符来检测装置,系统允许从外部装置下载并运行流体装置特异性的协议。在一些实施方式中,外部装置能存储与系统相关联的、或与特定患者或患者群相关的多个协议。例如,当标识符传送到外部装置时,外部装置上的软件可以获取标识符。一旦获取,诸如数据库等外部装置上的软件能用该标识符来识别存储在数据库内的与该标识符相关联的协议。例如,如果只有一个协议与标识符相关联,数据库可以选择该协议,然后外部装置上的软件能将该协议传送给系统的通信组件。使用与装置特异性地相关联的协议的能力,使得本发明装置的任何部件能够在单个系统中使用,从而事实上能在单个系统中检测任何感兴趣的分析物。
在一些实施方式中,多个协议可以与单个标识符相关联。例如,如果有益的是从同一患者身身每周一次检测一种分析物,而每周2次检测另一种分析物,则外部装置上与标识符相关联的各协议也可各自与一周的不同日子相关联,这样当检测到该标识符时,外部装置上的软件可以选择与一周中这个日子相关联的特定协议。
在一些实施方式中,可以向病人提供多个装置,用于检测多种分析物。例如,对象可在一周的不同日子使用不同的装置。在一些实施方式中,装置上将标识符和协议联系起来的软件,可以包括一个例如基于临床测试将当前日子与一周中使用这个装置的日子进行比较的进程。例如,如果这两个一周中的日子不是相同的,外部设备可以通过本发明的或本领域已知的任何方式向对象以无线方式发送通知,通知他们系统中的装置不正确并通知其那一天所应该使用的正确装置。该实施例只是说明性的,并切能够扩展为例如通知对象装置没有在正确的钟点使用。
系统还可使用网络方法评估对象病情。传达信息的系统可以包括或不包括用于读取对象数据的阅读器。例如,如果生物标志数据是从微流体现场护理装置获得的,赋予不同生物标志的值可以由装置本身读取或由分开的装置读取。阅读器的另一个示例是扫描对象数据的条形码系统,所述对象数据为已经输入电子医疗记录或内科医生图表中的对象数据。阅读器的另一个示例包含一个电子病人记录数据库,从中可以经由通信网络直接获取对象数据。这样,可以实时显示特定药物的功效,从而证明疗法的效果。
不顺从包括临床试验在内的医学治疗,会严重破坏治疗或试验的功效。同样地,在一些实施方式中,使用本发明的系统来监测病人的顺从性,并且将这些非顺从性通知病人或其他医务人员。例如,服用药物制剂作为医学治疗计划一部分的病人,可以提取体液样品,进行如本发明所述的测定,但是,例如系统检测到的代谢物浓度相对于已知图谱处于较高水平,则表明已经服用了多个剂量的药物制剂。可以通过本发明的任何无线方式将这样的非顺从性经通知病人或医务人员,包括但不限于通过如PDA或手机等手持设备通知。此类已知图谱可定位或存储在本发明的外部装置上。
在一个实施方式中,可用系统来识别从治疗中受益或受害的患者亚群。这样,本来会被从市场清除出去的具有不同毒性的药物,可以保留下来只分配给能从中受益的病人。
方法
本发明的装置和方法提供一种实时检测来自对象的体液中存在的分析物的有效手段。检测方法可在各种情况下使用,包括对与特定生物过程、生理状态、病症、病症阶段或治疗阶段相关联的分析物进行鉴别和定量。同样地,装置和方法可以广泛应用于如药物筛选、疾病诊断、系谱分类、亲子和法医鉴定、疾病发作和复发、对于基于人群的治疗的个体响应、以及疗法的监测。本发明的装置和方法对于下列方面也特别有用:推动疗法的临床前和临床阶段、改善患者的顺从性、监测与处方药有关的ADR、个性化药物、将血液测试从中心实验室外放到患者的住所。可根据处方使用装置,制药公司用于在监管机构批准后监测治疗药物,或付款人用于将血液测试从中央实验室外包出去。
因此,在一个实施方式中,本发明提供一种检测体液样品中分析物的方法,包括:向本发明的装置或系统提供血液样品,使样品在装置的至少一个测定单元中发生反应,以及检测血液样品中分析物产生的可检测信号。
图1显示了本发明的装置的一个示例性的实施方式,包括至少一个测定单元和至少一个试剂单元。测定单元(例如设计成图1中的样品尖端和校准尖端)可含有捕获表面,试剂单元可含有诸如共轭物、洗涤剂或底物等。图1中所例证的装置还可包含全血样品收集尖端、血浆样品收集尖端、血液输入孔、磁珠孔或血浆分离孔、尖端擦除或吸水垫、稀释孔、稀释的血浆样品孔或血浆稀释剂孔、收集尖端的丢弃区。
在一个实施方式中,方法包括进行酶联免疫吸附测定(ELISA)。在如本段所描述的一个实施例中,将样品提供给本发明装置的样品收集单元。然后将装置插入系统中,其中系统检测所插入的检测盒或装置的类型。然后系统与外部装置相互通讯,接受一套指令或协议,使系统进行所需的检测盒测定。协议可以传送给系统的液体转移装置的可编程处理器。在一个实施例中,液体转移装置接合检测盒的一个样品尖端,从样品收集单元中取得一定量的样品,并将它移动到预处理单元,在那里去除血红细胞。然后根据协议通过液体转移装置将样品的血浆吸入到血浆尖端或任何测试尖端中。然后含有血浆的尖端可吸取稀释剂,根据待进行的测定的需要来稀释样品。通过使用样品连续稀释,可以进行许多不同的稀释作用。例如,每一测定尖端或测定单元可含有不同稀释度的样品。在用液体转移装置将样品吸入测定单元后,将测定单元与样品一起孵育,使存在的任何目标分析物皆连接到捕获表面上。如本实施例所述的孵育可以在系统或室温下孵育任何时间长度,例如10分钟,或可在本发明的系统的加热装置上进行。测定单元可以接合一个设定地址的试剂单元,该试剂单元含有与每个带有用于测试的捕获表面的测定单元中将要进行的测试相对应的试剂。在这个实施例中,第一试剂是ELISA的检测溶液,例如,包含诸如标记有与捕获表面不同的抗蛋白抗体等探测抗体。然后将检测溶液从测定单元中吸出,然后将洗涤溶液吸入测定单元中,去除任何多余的检测溶液。可以使用多个洗涤步骤。最后加入的试剂是酶底物,酶底物会使结合的检测溶液化学发光。然后将酶底物从测定单元中排出,用系统的检测器读取测试的结果。在所述的每一步,可以如本发明所述根据需要进行孵育。在这个实施例中,在将试剂盒放入系统之后,整个过程都是自动化的,并且根据给可编程系统的协议和一套指令来执行。
一个示例性的方法进行至将血液样品送入血液输入孔。再由收集尖端吸取样品,并插入到血浆分离孔中。或者,血液可以直接放到含有血液分离剂的孔中。例如,可以用如本发明所述的各种方式进行血浆分离。在这个实施例中,采用可磁化珠和抗体来进行血浆分离,去除血液的非血浆组分。然后,为了不让全血收集尖端污染样品,使用血浆收集尖端运送血浆。在这个实施例中,血浆收集尖端能吸取预定量的稀释剂,并稀释血浆样品。然后,将稀释的血浆样品分配到测定单元(样品尖端)中,使之结合到捕获表面上。可以孵育测定单元,使捕获反应得以进行。然后可用测定单元收集测定单元中与反应结合的共轭物。共轭物可包含能用诸如光学检测器等检测器来检测感兴趣的分析物的实体。一旦共轭物已经加入到测定单元中,可以对反应进行孵育。在一个采用图1示例性装置的示例性方法中,随后测定单元(样品尖端)可以接触含有共轭物洗涤液的试剂单元,去除会干扰任何分析物检测的任何过量的共轭物。在洗掉过量共轭物后,可以向测定单元中加入底物进行检测。此外,在图1和本方法的实施例中,可以用校准尖端测定单元来进行除了收集和分配样品之外的在本段描述的所有方法。使用校准测定单元进行的检测和测定可用于校准样品的分析物的检测和测定。下文中描述与本实施例中所用相似的其他过程和方法。
任何可能含有感兴趣的分析物的体液,可以使用本发明的系统或装置。例如,图1的实施例中的输入孔或样品收集单元可收集或容纳任何类型的常用体液,包括但不限于血液、血清、唾液、尿液、胃液和消化液、眼泪、粪便、精液、阴道液、从组织样品提取的源于肿瘤组织液的间质液、以及脑脊髓液。在一个实施方式中,体液样品为血液,并且通过刺破手指获取。在一个实施方式中,体液样品为血浆样品。
体液可以取自病人,然后用各种方式提供给装置,包括但不限于:切口、注射、或移液管吸取。在一个实施方式中,用柳叶刀切开皮肤,用例如重力、毛细作用、吸力或真空力等递送样品。柳叶刀可以是在装置机内的、或者是阅读器组件的一个部分、或是独立部件。需要时,可以用各种机械的、电的、电机的、或任何其它已知激活机制或这些方式的任意组合来启动柳叶刀。在另一个不需要激活机制的实施方式中,患者可以简单地向装置提供体液,例如对唾液样品而言。可以将收集的液体放在装置的收集孔或单元中。在一些实施方式中,装置内有用户启动的柳叶刀和样品收集毛细管。
本发明所述的方法或装置使用的体液体积通常少于约500微升,还可为约1-100微升之间。需要时,可以采用本流体装置,用1-50微升、1-40微升、1-30微升、1-10微升或甚至1-3微升样品来检测分析物。在一个实施方式中,样品为20微升。
在一个实施方式中,使用本发明装置、系统或方法来检测分析物所用的体液体积为一滴液体。例如,从刺破的手指取得的一滴血液能够提供待分析的体液样品给本发明的装置、系统或方法。
在一些实施方式中,体液样品不再进一步加工而直接用于检测体液样品中存在的分析物。然而,需要时,可以在用装置进行分析前,对体液样品进行预处理。预处理的选择取决于所用体液的类型和/或所研究分析物的特性。例如,当体液样品中分析物处于低水平时,可以通过任何富集分析物的常规方式来对样品进行浓缩。浓缩分析物的方法包括但不限于干燥、蒸发、离心、沉降、沉淀和扩增。当分析物为核酸时,可以根据制造商提供的使用说明用各种裂解酶或化学溶液或是用核酸结合树脂来提取。当分析物为细胞上或细胞内存在的分子时,可以用裂解试剂进行提取,包括但不限于抗凝血剂如EDTA或肝素、变性去垢剂如SDS、或非变性去垢剂如Thesit、脱氧化钠、Triton X-100和吐温-20
在一个实施方式中,对象用注射器收集体液样品。样品通过毛细管进入到注射器内。在一个检测血液样品中分析物的实施方式中,对象进行手指穿刺,并用玻璃毛细管的末端外缘接触血液,使得血液被毛细作用吸取并充满毛细管一定体积。在一些实例中,样品体积是已知的。在一些实施方式中,样品体积在约5-20微升的范围内或在如本发明所述的其他体积范围内。
在另一个实施方式中,提供一种从血液样品获取基本不含红细胞的血浆样品的方法和系统。当进行测定时,分析物通常含在血浆中,而红细胞会干扰反应。
通常,当检测血液样品时,感兴趣的分析物在血清或血浆中。出于临床目的,多个血液测试最终报告的浓度通常需要与稀释的样品中血清或血浆的浓度有关。在许多情况下,血清或血浆是实验室选择的测试介质。在进行测试前可能需要2个操作,即稀释和去除红细胞。红细胞所占的样品体积比例(血细胞比容变化为约20-60%)在血液样品中差异显著。此外,在由非专业人士操作测定系统的现场护理环境中,获取的样品的体积可能并不是所要求的体积。如果没有意识到体积变化,这就会导致报告的分析物浓度产生偏差。
在一个相关但分开的实施方式中,本发明提供一种从血液样品中回收血浆的方法,包括:在样品收集单元中将血液样品在可磁化颗粒存在下混合,其中可磁化颗粒包含有用于与血液样品中非血浆组分结合的抗体捕获表面,以及在血浆收集区域上方对混合的血液样品施加一个磁场,使血液样品非血浆组分悬浮于血浆收集区域顶部,从而从血液样品中回收血浆。
为了处理血液样品,本发明的装置或系统可包括磁性试剂或物体,这种磁性试剂或物体能结合到红细胞上并实现从血浆中磁性去除红细胞。试剂可以用冻干形式提供,还可以是液态分散体的形式。由可磁化颗粒(例如,尺寸约1微米)组成的试剂可包被针对红细胞抗原或一些连接分子的抗体。在一些实施方式中,试剂还包含未结合到红细胞表面抗原的抗体,所述抗体可以是未标记的或标记有连接部分(例如生物素、地高辛或荧光素)的。在一个分析血液样品的实施方式中,稀释的样品中的红细胞在溶液相抗体的帮助下与可磁化颗粒共凝集。或者,可以使用识别红细胞表面糖类的凝集素作为共凝集试剂。有时候,使用红细胞凝集试剂的组合。或者,本发明的装置可包含诸如玻璃纤维垫等血液过滤器,帮助从样品中分离红细胞。
当血液与磁性试剂混合时,会发生共凝集,其中大量的(如果不是全部的)红细胞与可磁化颗粒形成混合凝集物。通过用本发明的尖端或收集尖端或类似移液管的尖端进行反复吸取,来进行试剂的溶解和混合。当可磁化聚集物形成后,通过使用磁体可以从血浆中分离磁性聚集物,作法是允许血浆离开尖端时而将所述磁性聚集物保持定位。在一个实施方式中,血浆通过重力作用从垂直方向离开尖端,而磁体将磁性聚集物保持定位。在另一个实施方式中,血浆通过真空或压力方式离开尖端,而聚集物被留在了尖端内。血浆可以放入孔中、另一个收集尖端或本发明的测定单元中。
在图9A-9E中显示了本发明的血浆分离方法的一个实施例。在图9A中,全血样品901已经被吸入了本发明的样品尖端910中,例如,量为约20微升。然后将全血样品901放到实施例装置的分离孔920(例如,一个含有磁珠或磁性颗粒的孔)中。图9B显示了在分离孔里的全血样品902中悬浮和混合磁性试剂(例如,磁珠颗粒和游离结合分子)。图9C显示了能用于防止尖端910的损失的10微升气塞930。混合的全血样品和磁性试剂902一起孵育数秒(例如60-180秒),使凝集反应发生。
图9D显示了施加一个磁场940给全血细胞和磁性试剂混合物902。可以通过与系统结合的磁性线圈942或本领域已知的任何磁装置施加磁场940。磁场940吸引已经附接到磁性试剂上的任何颗粒。这样一来,没有附接到磁性试剂上的血浆903能与全血样品中的非血浆组分分离开来。
图9E显示将通过在此所述的磁性试剂分离了的血浆样品903分配进入本发明的装置的孔或单元950中。血浆样品903还可分配进入收集尖端或测定单元,以及本领域技术人员所熟知的任何其他类型的测定装置。在图9E中,显示磁场940与分配血浆样品903的尖端910一起移动。在这个实施例中,从20微升全血样品中去除5-8微升血浆。1-99%的全血样品可以是用本发明的方法分离的血浆。在一个实施方式中,25-60%体积的全血样品为可被分离的血浆。
可以完成所述方法的其他示例性步骤。为了将血浆样品移动到另一个孔或单元中,毛细管血浆收集尖端(可以用机器人系统或本发明的任何其他系统进行操作)通过毛细作用和吸力收集血浆样品。另一个步骤包括将血浆样品分配给稀释剂,然后用稀释剂来稀释样品。接着用收集尖端收集预定量的稀释血浆样品。然后混合稀释的血浆样品,并分配到装置的一个孔或单元中,或分配到本发明的装置的一个或多个测定单元中。样品还可分配进入本领域技术人员所熟知的任何其他类型的装置里,例如微量滴定板。
除了本发明所公开的装置和系统,图9A-9E显示的实施例过程可使用其他装置和系统。例如,液体转移尖端可含有凝集的物质,且血浆可以放入微量滴定板中。可以使用本领域技术人员所熟知的其他装置和系统,进行本发明所的血浆分离实施例。
体液样品还可用各种其他方式进行稀释,例如使用能进行稀释作用的样品收集装置。样品收集装置的机架可以包括一个管子。在管子中,两个可移动的密封件可以容纳一定体积的稀释剂。在一个优选实施方式中,稀释剂的体积是预先确定的,例如在约50微升到1毫升的范围内,优选在约100微升到500微升的范围内。
在一个方面,提供一种自动化检测体液样品中多个分析物的方法,包括:向流体装置提供体液样品,其中流体装置包括:用于容纳体液样品的样品收集单元;测定单元阵列,其中所述测定单元阵列的各测定单元设计成用于进行产生指示被检测的所述多个分析物中各分析物的信号的化学反应;和试剂单元阵列,其中所述试剂单元阵列的各试剂单元含有试剂。该方法还可包括用液体转移装置接合各测定单元。其后,可以用液体转移装置将体液样品从样品收集单元转移到各测定单元,并且将试剂从各试剂单元转移到各测定单元,从而试剂与体液样品发生反应,产生指示被检测的多个分析物中各分析物的信号。在一些实施方式中,液体转移装置包括多个头,其中多个头中的各个头用于接合各测定单元;且其中所述液体转移装置带有可编程处理器,该处理器用于引导体液样品从样品收集单元和试剂从试剂单元转移进入测定单元的液体转移。
在一些实例中,例如通过用户、对象或制造商将指令提供给可编程处理器。指令可由外部装置提供,例如个人电子设备或服务器。这些指令可以引导体液样品转移给测定单元的步骤。例如,转移体液样品的步骤可以在测定单元中启动一定程度的体液样品稀释作用,使指示被检测的多个分析物中各分析物的信号落在可检测的范围内。在一些实施例中,如本发明所述,这种程度的体液样品的稀释将指示至少2个独立分析物的信号落在可检测的范围内。
可以使用模式识别技术来确定用本发明的方法检测的一个分析物或多个分析物是落在一定范围内还是落在一定范围之外。例如,在可报告范围之外的可检测信号可被弃去。该一定范围可以是在校准流体装置的试剂和测定单元的过程中确定的。例如,当按即用即装的方式组装装置时,确定这个范围。
在一些实例中,当用较低稀释系数或稀释度检测到的分析物的可检测信号超过了较高稀释系数的信号,则较低稀释的结果作为无效的结果被弃去。在多数实例中,样品中分析物的浓度以及源于不同稀释度的样品的信号随着稀释度变大而降低。如果发生了这样的情况,可以确认测试结果。本发明的系统、装置和方法提供了质量控制规则的灵活性,这是许多POC装置无法提供的。本发明系统、装置和方法提供了许多在实验室环境中所期待的质量控制特征。
在一个实施方式中,按照一个既满足高灵敏度又满足低灵敏度测定的比例来稀释样品。例如,样品与稀释剂的稀释比例可在约1:10000-1:1的范围内。装置可以将样品稀释到分开的位置或程度。装置还可对样品进行连续稀释。在另一些实例中,装置或系统内的连续稀释可以将样品稀释直至10,000,000,000:1。
在实施方式中,通过吸取式、注射式或移液式作用将含有要检测的分析物的样品从第一位置移动到第二位置。通过毛细作用或减少气压,将样品吸入到反应尖端中。在一些实施方式中,样品可以移动到多个位置,包括本发明的装置的测定单元阵列和本发明装置的机架的不同孔中。如本发明所述,移动样品的过程可以由本发明的系统自动化进行。
带有样品的测定单元和/或收集尖端也可从第一位置移动到第二位置。移动测定单元或收集尖端的过程可以是自动化的,并按用户定义的协议来执行。
在一个实施方式中,移动测定单元来从本发明的试剂单元收集试剂。在许多实施方式中,测定单元的移动是自动化的。吸取式、注射式或移液式作用可用于将试剂从试剂单元收集到测定单元中。
一旦将样品添加到包含捕获表面的测定单元中,可将整个单元孵育一段时间,使样品和测定单元的捕获表面进行反应。孵育反应所需的时间通常取决于所进行测定的类型。这个过程可以是由本发明的装置自动化进行的。在一个实施方式中,孵育时间为30秒到60分钟之间。在另一个实施方式中,孵育时间为10分钟。
测定单元还可在升高的温度下进行孵育。在一个实施方式中,测定单元在约20-70摄氏度的温度范围内进行孵育。可将测定单元插入到加热模块上,提高测定单元和/或测定单元内容物的温度。
在本发明方法的一个实施方式中,在将样品加入单元后,向测定单元中加入共轭物。共轭物可含有用于对被测定单元内的捕获表面所捕获的分析物进行标记的分子。在下文中描述了共轭物和捕获表面的实施例。共轭物可以通过吸取式、注射式或移液式作用分配到测定单元中,一旦共轭物已经分配到一个测定单元中,可以对测定单元进行孵育,使共轭物在测定单元中与分析物发生反应。孵育时间可由测定的类型或待测的分析物来确定。孵育温度可以是适合反应的任何温度。
在一个方面,提供一种校准用于自动化检测体液样品中分析物的装置的方法。装置包括可编址的测定单元阵列,所述测定单元用于进行产生指示分析物存在与否的可检测信号的化学反应;和可编的试剂单元阵列,每个试剂单元被编址为对应于所述装置中一个或多个可编址的测定单元,从而在将诸阵列组装到装置上之前可以根据相对应的测定单元对试剂单元进行校准。在将它们组装到装置上之前,通过校准测定单元和试剂单元,对装置进行校准。然后用校准过的部件组装装置,使装置以及使用装置的方法和系统成为模块化部件。
在将测定单元和试剂单元组装到本发明的装置上之前,通过测定如共轭物等测定试剂的性能,预先进行校准。校准信息和算法可以存储在与测定系统无线连接的服务器上。校准可以提前进行,或通过在分离的位置上在复本系统中进行的测定以回溯方式进行,或通过运用测定系统在使用时所获得的信息进行。
在一个方面,在装置或系统中使用对照物质,来测定或验证体液样品的稀释程度。例如,诸如ELISA等基于固相的试验的另一个问题是,试验使用固相试剂,难以在不破坏其功能的情况下进行质量控制。本发明的系统和方法提供了一种方法,来确定使用带有自动化混合和/或稀释的一次性装置的POC系统内达到的稀释作用。
在一个实施方式中,本发明方法提供回溯式分析,例如在报告结果前通过实时使用服务器分析数据。例如,可以进行测定,且平行地进行一个对照测定。对照测定提供对样品预期稀释的测量。在一些实施例中,对照测定可以验证样品的稀释作用,因此,系统内进行的一个或多个测定的样品的稀释可以被认为是准确的。
测量液体样品体积的方法包括:将液体样品中已知量的对照分析物与试剂反应,产生指示对照分析物的可检测信号;以及将所述可检测信号强度与所述可检测信号的预期强度相比较,其中所述信号的预期强度指示所述液体样品的预期体积,其中所述比较提供了被检测的所述液体样品的体积的一种测定值。在一些实例中,在所述液体样品中不存在可检测量的对照分析物。
在一个实施方式中,方法还可包括当样品体积的测定值在液体样品的预期体积约50%之内时,验证所述液体样品的体积。
例如,使用本发明的装置或系统的方法还包括:使含有目标分析物的体液样品与试剂反应,产生指示目标分析物的可检测信号;以及采用指示目标分析物的所述可检测信号的强度和所述液体样品的体积测定值,来测量体液样品中目标分析物的量。液体样品和体液样品可以是同样的样品。在一些实施方式中,对照分析物不与体液中的目标分析物反应,所以不会对目标分析物的检测造成干扰。
在一些实例中,液体样品和体液样品是不同液体样品。例如,对照液体如水,和血液样品。或在另一个实施例中,是唾液样品和血液样品。
对照分析物可以是但不限于荧光素标记白蛋白、荧光素标记IgG、抗-荧光素、抗-地高辛、地高辛标记的白蛋白、地高辛标记的IgG、生物素化蛋白、非人IgG。其他示例性的对照分析物对本领域的技术人员而言是显而易见的。在一个实施方式中,对照分析物在人体液样品中不存在。
在本发明的用于检测样品中多个分析物的POC系统中,系统可具有稀释和混合液体的能力。在许多实例中,自动化系统或用户可使用对照测试来测量实际上达到的稀释并将其用作系统校准的稀释系数。例如,对照分析物不会在感兴趣的样品中发现,并且干燥地进入试剂单元中。干燥的对照分析物的量可为已知的,并与试剂单元中的样品相混合。可以测量分析物的浓度来指示样品的体积以及对样品进行的任何稀释作用。
免疫测定的对照分析物的例子包括但不限于:荧光素标记的蛋白、生物素化的蛋白、荧光素标记的、AxlexaTM标记的、若丹明标记的、得克萨斯红标记的免疫球蛋白。例如,标记可以通过在每一个蛋白质分子连上至少两个半抗原来实现。在一些实施方式中,在每个蛋白分子上连上1-20个半抗原。在另一个实施方式中,在每个蛋白分子上连上4-10个半抗原。很多蛋白质带有大量的可以连接半抗原的游离氨基基团。在许多实例中,半抗原修饰的蛋白是稳定的和可溶的。同样,诸如荧光素和得克萨斯红等半抗原足够大和坚固,可用于制造高亲和力的抗体(例如,半抗原大到足以填充抗体结合位点)。在一些实施方式中,使用试剂将半抗原连接到蛋白上,比如异硫氯酸荧光素、和荧光素羧酸NHS酯,以产生对照分析物,在对照分析物中能被测定系统识别的部分是半抗原。
在一些实施方式中,方法使用干燥的对照分析物。在一些实施例中,干燥的对照分析物避免了对样品的稀释,并使对照分析物更加稳定。干燥的对照分析物可以经过配制,使它在与液体样品接触后快速并完全溶解。在一些实施方式中,对照分析物可为对抗体高亲和力的分析物。在一些实例中,对照分析物可为不与任何内源样品组分交叉反应的分析物。此外,例如,分析物可以是不昂贵的和/或易于制造的。在一些实施方式中,对照分析物在本发明的装置或系统的使用期限内是稳定的。用于产生共价键连接半抗原的分析物的示例性载体包括但不限于以下蛋白质:例如白蛋白、IgG和酪蛋白。用于产生与半抗原共价连接的新分析物的示例性的聚合物载体包括但不限于:右旋糖苷、聚乙烯吡咯烷酮。用于配制并稳定化对照分析物的示例性的赋形剂包括但不限于:蔗糖、盐类和缓冲液(例如磷酸钠和三羟甲基氨基甲烷盐酸盐)。
如本发明所述的对照分析物和方法可以多种方式使用,包括如本发明实施例所述的方式。例如,方法能测量样品的体积。在一些实施方式中,方法测量样品的稀释或稀释系数或稀释度。在一些实例中,方法提供样品中对照分析物的浓度。在检测多个分析物的系统或装置中,使用对照分析物用本发明的方法进行的测定值,来验证或描述目标分析物的测量。例如,可以使用带有多个头的液体转移装置将液体分配到多个测定单元中,包括对照单元在内。在一些实例中,假设分配到多个单元中的液体量,在各个单元之间是相同的或相似的。在一些实施方式中,使用对照分析物的本发明所述的方法,可以验证在装置或系统内已经收集或使用了正确量的样品。在另一个实施方式中,方法验证已经向样品提供了正确量的稀释剂。而且,也可验证稀释系数和稀释度。在又一个实施方式中,用对照分析物的方法验证已经向多个单元分配了正确量的稀释样品。
图10显示了包含已知量的对照分析物的本发明的对照测试的示例性方法。在安装到检测盒之前,用包含已知量对照分析物1002的溶液1001充填单元1010。溶液的液体可以除去,并对单元1010进行干燥,使对照分析物1002留在单元1010中。然后可将单元1010插入到装置中并运送供使用。当使用单元1010并接收样品或稀释剂1003时,传送的可以是预期体积的样品1003,并在单元1010中与干燥的对照分析物1002混合,产生预期浓度的对照溶液1004。可任选地稀释对照溶液1004。在一个实施方式中,可以在装置中用与目标分析物相同的方式检测对照分析物1002。测量对照溶液1004中对照分析物的浓度。可使用这个浓度测定值来计算产生对照溶液1004所加入的样品1003的体积。以这种方式,用户可以将测得的样品1003的体积与样品1003的预期体积进行比较。
在一个实施例中,可从血液样品中去除红细胞。然而,如果留有一些红细胞,或红细胞没有从血液样品中被除去,用对照分析物的方法可以用来修正血液样品中红细胞的影响。因为血细胞比容可能差异显著(例如样品总体积的20-60%),固定或预期体积(v)的血液中分析物的量可能随血细胞比容而变(H在这里以十进制小数表示)。例如,血浆中浓度为C的分析物的量为C*v*(1-H)。因此,血细胞比容为0.3的样品的量,是血细胞比容为0.5的样品的1.4倍。在一个示例性的实施方式中,可将未稀释的血液分配进所述装置中,并且可将红细胞去除。然后可以测定血浆部分中对照分析物的浓度,来估算样品血浆的体积和确定血细胞比容。
在一些实施方式中,需要从反应位点洗掉未结合的共轭物,来防止未结合的共轭物产生不正确的检测结果。许多免疫测定的限制性步骤是洗涤步骤。最小残留和高灵敏度之间的妥协,取决于洗涤去除未结合的共轭物。由于难以从孔中去除洗涤液体(例如用自动化方式),在微量滴定板的形式下洗涤步骤受到严重的局限。在处理液体的方式上,本发明的测定单元装置和系统具有很多的优点。一个优点是能改善测试的信噪比。
如果共轭物粘到装置的测定单元的边缘,会难以去除共轭物,例如如果没有过量的洗涤溶液。
洗涤共轭物可以通过从上方给洗涤溶液施压或将洗涤溶液吸起并且排出液体,类似于装载样品。可以按需要反复多次洗涤。
当在试验中使用洗涤缓冲液时,装置可以在试剂单元中存储洗涤缓冲液,并使测定单元与洗涤液进入流体连通。在一个实施方式中,洗涤试剂能够通过洗涤从测定单元中去除约99%、99.9%或99.999%的未结合试剂。一般而言,优选能大大减少不需要的背景信号的高效率洗涤。洗涤效率一般定义为来自给定试验的信号和由没有洗涤步骤的试验产生的信号总量之间的比率,并可由常规实验方便地测得。通常优选增加洗涤溶液的体积和孵育的时间,但不牺牲来自给定试验的信号。在一些实施方式中,用约50μL到5000μL洗涤缓冲液进行洗涤约10到300秒,优选为约50μL到500μL洗涤缓冲液。
另外,优选重复使用若干个少量的洗涤溶液循环,其间间隔一段不使用洗涤溶液的时间。这个顺序产生扩散洗涤,一段时间后标记的抗体从测定单元受保护的部件扩散进入到大量洗涤溶液中,所比如从标记的抗体松散地结合的边缘和表面,当从反应位点移走洗涤溶液时可以去除这些抗体。
在许多实施方式中,最后一步是分配酶的底物,通过光的或电的方式来检测共轭物。底物的例子在下文中描述。
例如,本发明装置的试剂单元中的试剂可以是免疫测定用的酶底物。在另一个实施方式中,在捕获位点的反应发生之后,可以重复从试剂单元转移底物试剂的步骤。例如,将酶底物转移到反应位点并进行孵育。测定了产生的试验信号后,去除用过的底物,用新鲜底物进行替换,并且重新测定试验信号。可以用本发明所述的系统在第一次和第二次施用底物后检测指示所测分析物的信号。第二底物通常与原始底物相同。在一个实施方式中,第二底物是从本发明装置的第二试剂单元转移到反应位点的。在另一个实施方式中,第二底物是从与原始底物同一个试剂单元转移到反应位点的。转移第二底物即产生第二反应,第二反应能产生指示分析物的第二信号。可以比较原始信号的强度和第二信号的第二强度,计算分析物指示信号的最终强度,以及试验是否正确进行。
在一个实施方式中,多个信号的强度用于试验的质量控制。例如,如果信号相差20%、30%、40%、50%、60%、70%、80%、90%、100%或更多,试验结果可被抛弃。
在一个实施方式中,本发明的方法包括重新装载样品和/或检测剂-共轭物(酶标抗体)和/或酶底物和样品,来矫正或确认试验信号或用作内部对照。例如,可以重新使用测定尖端或单元用于验证功能和/或添加另一个样品或对照材料以获得第二信号。
在一些实例中,向酶单元中重新装载底物的方法是通过本发明的系统自动化地将液体样品和试剂转入测定单元中而实现的。一些试验不要求系统立即或按时传送结果,因此,对照方法提供了可能提高结果可靠性的机会。在重复加入酶底物后观察到的响应,能够用来验证初始响应或计算回收峰值(spike recovery)。
实验表明,通过向测定单元中添加第二酶底物,可以保持结果的再现性。在一些实施方式中,对照方法提供了采用测定单元给出了显著低于预期的响应时的副本分析。
采用本发明的任何对照方法,可以从执行对照方法解释或假定许多可能的误差。示例性的试验误差包括但不限于测定单元或装置制造不当,样品和/或一种或多种试剂的吸取不当,在检测中测定单元没有相对于光电倍增器正确放置,装置或系统中缺失测定单元。
在一些实施方式中,本发明提供一种使用流体装置或系统获得用于评估药物制剂对测试动物的效用和/或毒性的药理学数据的方法。
在药物制剂的临床前试验中使用实验动物时,通常需要杀死实验对象来取得足够的血液进行检测感兴趣的分析物的测试。这牵涉到财政和伦理问题,因此,优选能从测试动物提取一定量的血而不用杀死测试动物。此外,也可以对同一测试动物在几个不同的时间点进行测试,从而能更有效的评估一个药物在单个动物上的作用。平均而言,例如,一个小鼠的血液总量为每100克体重6-8mL血液。本发明的好处在于只需要非常小体积的血液就能在小鼠或其他小型实验动物上进行临床前测试。在一些实施方式中,提取了约1微升到50微升。在一个实施方式中,提取了约1微升到10微升。在优选实施方式中,提取了约5微升血液。
另一个使测试动物活着的优点在临床前时间过程研究中是明显的。例如,当使用多个小鼠监测随着时间推移在测试对象体液中的分析物水平,在测试引入了使用多个对象的额外变数。然而,当使用单个测试动物作为其自己在一段时间内的对照时,可以完成更为精确和有利的临床前试验。
在一些实施方式中,提供一种采用本发明装置或系统自动化监测患者对药物治疗顺应性的方法。该方法包括使体液样品与测定试剂在装置中反应,产生指示样品中分析物存在的可检测信号;用所述装置检测所述信号;将所述信号与所述医学治疗相关联的已知图谱比较,确定所述患者是否顺应所述药物治疗;以及将所述顺应性或非顺应性通报给患者。
在另一个实施方式中,本发明的系统和方法提供一种发现新的生物标志和/或将这些标志的趋势与疾病和治疗结果相关联进行验证的手段。
在另一个实施方式中,本发明的系统和方法可以识别生物标志水平的趋势和在一段时间内日常的患者日志信息,这种信息可用于针对特定的患者将药品剂量调节到最佳水平(例如,适应的剂量范围修正)。
在一些实施方式中,非顺应性包括服用非正确剂量的药品,包括但不限于多剂量或无剂量;或可包括不正确地混用药品。在优选实施方式中,在信号与已知图谱进行比较后,实际上即时通报患者。
临床试验的患者或对象可能忘记提取用于本发明所述分析的体液样品。在一些实施方式中,采用本发明的装置提醒患者测试体液样品的方法,包括提供在所述装置上运行的协议,所述协议位于外部装置上、与所述患者相关联,且包含测试所述体液样品的时间和日期;如果样品还未测试,则通报患者在所述日期和时间测试所述体液。在一些实施方式中,可以无线方式通报患者。通过在显示器上提示并获得患者的响应(例如,通过触摸屏幕),可以改善治疗方案的顺应性。
获得药物处方时,可用任何常见方式向患者提供装置,例如在药房。同样地,当开始临床测试时,可以向临床测试对象提供这样的装置。可以在此时将患者或对象的联系信息输入外部装置,并在一个数据库中与患者或对象相关联,联系信息包括但不限于移动电话、电子邮件地址、文字短信地址、或无线通信的其它方式。外部装置上的软件包括当从检测装置产生的信号还未传送到外部装置时(例如在给定时间)能够作出检测的脚本或其它程序,然后该外部装置发送一个通知患者提取体液样品的警报。
在一个实施方式中,系统直接提供给消费者,用在生活方式和/或运动管理中。可以输入相关的生活方式和锻炼数据,并且测量指示肌肉损伤、无氧代谢(例如,乳酸)的参数。在一些实施方式中,系统可以足够小到便于携带。
在另一个实施方式中,系统特别适于检测诸如大鼠和小鼠等常用于临床前工作的小动物血液中标志的检测。这些动物只有少量体积的血液,要求非常小量样品的试验系统特别有用,尤其是在需要从一个动物迅速连续提取多个样品进行纵向研究时。当需要平行检测数个分析物时,这些考虑是特别重要的。
在一个实施方式中,系统包括一种为了以安全方式运送而将多个复合试验所需的数个零件进行包装的便利方式。例如,试验零件卡配(click fit)到机架上。
试验
可以在本发明的流体装置上执行各种试验来检测样品中感兴趣的分析物。本领域存在多种多样的标记,能用于进行本发明的试验。在一些实施方式中,标记可以通过分光光谱、光化学、生物化学、电化学、免疫化学或其它化学方式检测。例如,有用的核酸标记包括放射性同位素32P、35S、荧光染料、电子致密试剂、酶。多种适于标记生物组分的标记是已知的,并且在科学文献和专利文献中都详尽报道,并且通常都可以应用于本发明进行生物组分的标记。合适的标记包括放射性核苷酸、酶、底物、辅助因子、抑制因子、荧光部分、化学发光部分、生物发光标记、或比色标记。决定试验特异性的试剂可任选地包括例如单克隆抗体、多克隆抗体、蛋白质、核酸探针或其它聚合物如亲和基质、碳水化合物或脂类。可以通过各种已知方法中的任一种进行检测,包括分光光度或光学示踪放射性的、荧光的、或发光的标志,或根据大小、电荷和亲和力追踪分子的其它方法。可检测部分可以是有可检测的物理或化学特性的任何材料。这样的可检测标记在凝胶电泳、柱层析、固体基质、光谱技术等领域已成熟开发,并且通常用于这些方法的标记可以应用于本发明中。因此,标记包括但不限于可以用光谱、光化学、生物化学、免疫化学、基于核酸探针、电、光、热和其它化学方式检测的任何成分。
在一些实施方式中,根据本领域熟知的方法,将标记直接或间接地连接到如产物、底物或酶等待测分子上。如上所述,根据所需的灵敏度、化合物结合的方便性、稳定性的需求、可用的仪器和处置规定来选择标记,使用了很多种标记。非放射性的标记通常用间接方式连接。通常,分析物特异性受体是连接到信号发生部分上的。有时,分析物受体是连接到接头分子(如生物素或抗生物素蛋白)上,而测定试剂组包括结合到接头上并结合到分析物上的结合部分(例如生物素化的试剂或抗生物素蛋白)。分析物结合到反应位点上的特异性受体。标记的试剂可以形成一个分析物位于中间的三明治型复合物。试剂也可以与分析物竞争反应位点上的受体,或结合到反应位点上未被分析物占据的空受体上。标记可以是本来就可检测的或者是结合到信号系统上,例如可检测的酶、荧光化合物、化学发光化合物、或化学发光实体如带有发光底物的酶。可以使用许多配体或配体抗体。当配体具有天然配体抗体时,例如生物素、甲状腺素、地高辛和氢化可的松,它可以与标记的配体抗体协同使用。或者,任何半抗原或抗原化合物可以与抗体联合使用。
在一些实施方式中,标记也可以是直接连接到信号产生化合物上,例如通过连接酶或荧光团。作为标记的感兴趣的酶主要是水解酶,尤其是磷酸酶、酯酶和糖苷酶、或氧化还原酶,尤其是过氧化物酶。荧光化合物包括荧光素及其衍生物、若丹明及其衍生物、丹酰基团和7-羟基香豆素、化学发光化合物包括二氧杂环丁烷、吖啶酯、虫荧光素和2,3-二氢二氮杂萘二酮,例如发光氨。
检测标记的方法是本领域技术人员所熟知的。因此,例如,当标记是放射性的,检测方式包括闪烁计数或放射自显影的照相胶片。当标记是荧光的,检测荧光可以通过用合适波长的光激发荧光物,并且检测获得的荧光,可通过例如显微镜、目测、经由照相胶片、使用电子探测器例如数码相机、电荷藕合器件(CCD)或光电倍增器和光电器、或其它探测装置。同样地,通过提供酶的合适底物并且检测获得的反应产物,来检测酶标记。最后,通过观察与标记相关的颜色,通常可以容易地检测简单的比色标记。例如,结合金通常表现为粉红色,而各种的结合珠呈现珠子的颜色。
在一些实施方式中,可以通过发光源提供可检测信号。术语“发光”通常用于指因除了温度上升之外的任何原因从物质上发射光。一般而言,原子或分子从一个激发态移动到一个能量较低的状态(通常为基态)时发射出电磁能量(如光)的光子。如果激发原因是光子,发光过程称为光致发光。如果激发原因是电子,发光过程称为电致发光。更具体地,电致发光缘于直接注入或去除电子形成电子空穴对、然后重新组合该电子空穴对发射出光子。由化学反应产生的发光通常称为化学发光。由活生物体产生的发光通常称为生物发光。如果光致发光是自旋允许跃迁(如单重态-单重态跃迁、三重态-三重态跃迁)的结果,光致发光过程通常称为荧光。典型地,在去除激发原因之后荧光发射不会持续,因为短寿命的激发态会通过这样的自旋允许跃迁很快释放。如果光致发光是自旋禁阻跃迁(如三重态-单重态跃迁)的结果,光致发光过程通常称为磷光。典型地,在去除激发原因之后磷光发射会长时间持续,因为长寿命的激发态只能通过这样的自旋禁阻跃迁来释放。发光标记可具有上述特性中的任何一种。
合适的化学发光源包括能被化学反应电激发、然后发射出能作为可检测信号或提供给荧光接受器能量的光的化合物。已经发现多种化合物家族能在各种条件下提供化学发光。一族化合物是2,3-二氢-1,4-酞嗪二酮类。常用的化合物是发光氨,一个5-氨基化合物。该家族的其他成员包括5-氨基-6,7,8-三甲氧基-和二甲氨基[ca]苯(dimethylamino[ca]benz)同系物。这些化学物可以用碱性过氧化氢或次氯酸钙和碱反应,产生冷光。另一个化合物家族是2,4,5-三苯基咪唑类,其母体的通用名为洛粉碱。化学发光同系物包括对二甲基氨基-和-甲氧基取代基。化学发光也可以用草酸盐/酯(通常是乙二酰活性酯,例如对硝基苯基)和诸如过氧化氢等过氧化物在碱性条件下反应获得。其他已知的有用化学发光化合物包括N-烷基-吖啶酯和二氧杂环丁烷类。或者,可以用虫荧光素与虫荧光素酶或光泽精联用,提供生物发光。
本发明所用术语“分析物”包括但不限于药物、前药、药物制剂、药物代谢物、诸如表达的蛋白和细胞标志等生物标志、抗体、血清蛋白、胆固醇和其他代谢物、多糖、核酸、生物分析物、生物标志、基因、蛋白质、或激素、或上述物质的组合。分析物可以是多肽、糖蛋白、多糖、脂类和核酸的组合。
尤其感兴趣的生物标志与特定疾病或疾病的特定阶段相关。此类分析物包括但不限于与下列疾病相关的分析物:自身免疫性疾病、肥胖、高血压、糖尿病、神经和/或肌肉退行性疾病、心脏病、内分泌紊乱、代谢紊乱、炎症、心血管病、脓血症、血管生成、癌症、阿尔兹海默氏症、运动并发症及其组合。
同样感兴趣的生物标志在一种或多种身体组织中以差异性丰度存在,包括心、肝、前列腺、肺、肾、骨髓、血液、皮肤、膀胱、脑、肌肉、神经和受到各种疾病影响的选定组织,比如各种癌症(恶性的或非转移性的)、自身免疫性疾病、炎性或退行性疾病。
感兴趣的还有能指示微生物、病毒或衣原体的分析物。示例性的微生物包括但不限于细菌、病毒、真菌和原生生物。能用本发明方法检测的分析物还包括血液中原来就有的病原体,选自以下但不非限制性组:上皮葡萄球菌、大肠杆菌、甲氧苯青霉素抗性的金黃色葡萄球菌(MSRA)、金黄色葡萄球菌、人葡萄球菌、粪肠球菌、绿脓杆菌、头状葡萄球菌、沃氏葡萄球菌、克雷伯氏肺炎杆菌、流感嗜血杆菌、模仿葡萄球菌、肺炎链球菌和白色念珠菌。
能被本发明方法检测的分析物还包括选自下列的各种性传播疾病:淋病(奈瑟淋病)、梅毒(梅毒螺旋体)、衣原体(Clamyda tracomitis)、非淋菌性尿道炎(解脲支原体)、酵母感染(白色念珠菌)、软性下疳(杜克雷嗜血杆菌)、滴虫病(阴道鞭毛滴虫)、生殖器疱疹(I和II型HSV)、HIV I、HIV II和甲、乙、丙、庚型肝炎,以及由TVV引起的肝炎。
能被本发明方法检测的其他分析物包括多种呼吸道病原体,包括但不限于,绿脓杆菌、甲氧苯青霉素抗性的金黃色葡萄球菌(MSRA)、克雷伯氏肺炎杆菌、流感嗜血杆菌、金黄色葡萄球菌、嗜麦芽寡养单胞菌、副流感嗜血杆菌、大肠杆菌、粪肠球菌、粘质沙雷氏菌、副溶血嗜血杆菌、阴沟肠球菌、白色念珠菌、粘膜炎莫拉氏菌、肺炎链球菌、弗氏拧檬酸杆菌、粪肠球菌、产酸克雷伯氏菌、荧光假单胞菌、脑膜炎奈瑟菌、产脓链球菌、卡氏肺孢子菌、克雷伯氏肺炎杆菌、嗜肺军团菌、肺炎微浆菌和结核杆菌。
下面列出了本发明的其他示例性标志:茶碱、CRP、CKMB、PSA、肌球素、CA125、黄体酮、TxB2、6-酮-前列腺素Flα、和茶碱、雌二醇、黄体生成素、甘油三酯、类胰蛋白酶、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、胆固醇、IGFR。
示例性的肝标志包括但不限于:LDH、(LD5)、(ALT)、精氨酸酶1(肝型)、甲胎蛋白(AFP)、碱性磷酸酶、丙氨酸氨基转移酶、乳酸脱氢酶和胆红素。
示例性的肾标志包括但不限于:TNF-α受体、胱抑素C、脂笼蛋白型前列腺素D合成酶(LPGDS)、肝细胞生长因子受体、多囊蛋白2、多囊蛋白1、纤囊素、尿调素、丙氨酸、氨基肽酶、N-乙酰-β-D-氨基葡萄糖苷酶、白蛋白和视黄醇结合蛋白(RBP)。
示例性的心脏标志包括但不限于:肌钙蛋白I(TnI)、肌钙蛋白T(TnT)、CK、CKMB、肌球素、脂肪酸结合蛋白(FABP)、CRP、D-二聚体、S-100蛋白、BNP、NT-proBNP、PAPP-A、髓过氧化酶(MPO)、糖原磷酸化酶同工酶BB(GPBB)、凝血酶激活的纤溶抑制因子(TAFI)、纤维蛋白原、缺血修饰白蛋白(IMA)、心肌营养素-1和MLC-I(肌球蛋白轻链-I)。
示例性的胰腺标志包括但不限于淀粉酶、胰腺炎相关蛋白(PAP-1)和再生基因蛋白(REG)。
示例性的肌肉组织标志包括但不限于肌肉生长抑制素。
示例性的血液标志包括但不限于红细胞生成素(EPO)。
示例性的骨标志包括但不限于,骨I型胶原交联氨基末端肽(NTx)、骨胶原羧基端交联末端肽、赖氨酰吡啶啉(脱氧吡啶啉)、吡啶啉、抗酒石酸酸性磷酸酶、I型前胶原C前肽、I型前胶原N前肽、骨钙素(骨谷氨酸蛋白)、碱性磷酸酶、组织蛋白酶K、COMP(软骨寡聚基质蛋白)、骨素、护骨素(OPG)、RANKL、sRANK、TRAP 5(TRACP 5)、成骨细胞特异性因子1(OSF-1,多效生长因子)、可溶性细胞黏附分子、sTfR、sCD4、sCD8、sCD44和成骨细胞特异性因子(OSF-2,骨膜素)。
在一些实施方式中,本发明的标志是疾病特异性的。示例性的癌症标志包括但不限于,PSA(总前列腺特异性抗原)、肌氨酸酐、前列腺酸性磷酸酶、PSA复合物、前列腺特异性基因-1、CA 12-5、癌胚抗原(CEA)、甲胎蛋白(AFP)、hCG(人绒毛膜促性腺激素)、抑制素、卵巢CAA C1824、CA 27.29、CA 15-3、乳房CAA C1924、Her-2、胰腺、CA 19-9、癌胚抗原、胰腺CAA、神经元特异性烯醇化酶、血管生长抑素DcR3(可溶性诱饵受体3)、内皮抑素、Ep-CAM(MK-1)、游离的免疫球蛋白轻链κ、游离的免疫球蛋白轻链λ、赫斯达汀(Herstatin)、嗜铬粒蛋白A、肾上腺髓质素、整合素、表皮生长因子受体、表皮生长因子受体-酪氨酸激酶、肾上腺髓质素前体氨基端20肽、血管内皮生长因子、血管内皮生长因子受体、干细胞因子受体、c-kit/KDR、KDR和中期因子。
示例性的传染病病症包括但不限于:病毒血症、菌血症、脓血症。示例性的标志包括但不限于:PMN弹性蛋白酶、PMN弹性蛋白酶/α1-PI复合物、表面活性蛋白-D(SP-D)、HBV核心抗原、HBV表面抗原、HBV核心抗体、HIV抗体、抑制性T细胞抗原、T细胞抗原比例、辅助性T细胞抗原、HCV抗体、热原、p24抗原、胞壁酰二肽。
示例性的糖尿病标志包括但不限于,C-肽、血红蛋白A1c、糖化白蛋白、晚期糖基化终产物(AGE)、1,5-脱水山梨醇、抑胃肽、葡萄糖、血红蛋白、ANGPTL3和4。
示例性的炎症标志包括但不限于类风湿因子(RF)、抗核抗体(ANA)、C-反应蛋白(CRP)、克拉拉细胞蛋白(子宫珠蛋白)。
示例性变态反应标志包括但不限于总IgE和特异性IgE。
示例性的自闭症标志包括但不限于血浆铜蓝蛋白、金属硫蛋白、锌、铜、B6、B12、谷胱甘肽、碱性磷酸酶和脱辅基-碱性磷酸酶(apo-alkaline phosphatase)的活化。
示例性的凝血功能紊乱的标志包括但不限于b-血小板球蛋白、血小板因子4、血管假性血友病因子。
在一些实施方式中,标志可以是治疗特异性的。COX抑制剂包括但不限于TxB2(Cox-1)、6-酮-前列腺素Flα(Cox 2)、11-去氢血栓素-la(Cox-1)。
本发明的其它标志包括但不限于,瘦素、瘦素受体、和前降钙素原、脑S100蛋白、P物质、8-异前列腺素F2a。
示例性的衰老标志包括但不限于,神经元特异性烯醇酶、GFAP和S100B。
营养状态的示例性标志包括但不限于,前白蛋白、白蛋白、视黄醇结合蛋白(RBP)、转铁蛋白、酰化刺激蛋白(ASP)、脂联素、刺鼠色蛋白相关蛋白(AgRP)、血管生成素样蛋白4(ANGPTL4,FIAF)、C-肽、AFABP(脂肪细胞脂肪酸结合蛋白,FABP4)、酰化刺激蛋白(ASP)、EFABP(表皮脂肪酸结合蛋白,FABP5)、肠高血糖素、胰高血糖素、胰高血糖素样肽-1、胰高血糖素样肽-2、生长激素释放肽、胰岛素、瘦素、瘦素受体、PYY、抵抗素样分子(RELM)、抵抗素、和sTfR(可溶性转铁蛋白受体)。
脂类代谢的示例性标志包括但不限于,载脂蛋白(数种),Apo-Al、Apo-B、Apo-C-CII、Apo-D、Apo-E。
示例性的凝血状态标志包括但不限于,因子I:纤维蛋白原,因子II:凝血素,因子III:组织因子,因子IV:钙,因子V:促凝血球蛋白原,因子VI,因子VII:血清凝血酶原转变加速因子前体,因子VIII:抗溶血因子,因子IX:克里斯馬斯因子,因子X:斯图亚特因子,因子XI:血浆凝血激酶前质,因子XII:哈格曼因子,因子XIII:纤维蛋白稳定因子、前激肽释放酶、高分子量激肽原、蛋白C、蛋白S、D-二聚体、组织型血纤维蛋白溶酶原激活因子、血纤维蛋白溶酶原、a2-纤溶酶原抑制物、血纤维蛋白溶酶原激活因子抑制剂1(PAH)。
示例性单克隆抗体包括EGFR、ErbB2和IGF1R的单克隆抗体。
示例性的酪氨酸激酶抑制剂包括但不限于,Abl、Kit、PDGFR、Src、ErbB2、ErbB 4、EGFR、EphB、VEGFR1-4、PDGFRb、FLt3、FGFR、PKC、Met、Tie2、RAF和TrkA。
示例性的丝氨酸/苏氨酸激酶抑制剂包括但不限于,AKT、极光激酶A/B/B、CDK、CDK(pan)、CDK1-2、VEGFR2、PDGFRb、CDK4/6、MEK1-2、mTOR和PKC-β。
GPCR靶包括但不限于,组胺受体、五羟色胺受体、血管紧缩素受体、肾上腺素受体、毒蕈碱型乙酰胆碱受体、GnRH受体、多巴胺受体、前列腺素受体和ADP受体。
在另一个实施方式中,提供一种监测一个以上用于评估治疗剂的功效和/或毒性的药理学参数的方法。例如,治疗剂可以包括具有治疗效用和/或潜力的任何物质。这些物质包括但不限于生物或化学化合物,比如简单的或复合的有机或无机分子、肽类、蛋白质类(如抗体)或多聚核苷酸类(如反义核酸)。一大批化合物可以合成,例如多聚体,例如多肽和多聚核苷酸,以及基于各种核心结构的合成有机化合物,并且这些也可以包含在治疗剂内。此外,各种天然来源可以提供化合物进行筛选,例如植物或动物提取物等等。应该理解,尽管没有总是明确指出试剂是单独使用的或与另一个试剂联用的,而这另一个试剂是与本发明筛选识别的试剂具有相同或不同的生物学活性。试剂和方法还可用于与其他治疗联用。例如,小分子药物通常用质谱进行检测,质谱可能不精确。ELISA(基于抗体)测定可以更为精确和准确。
本发明的生理参数包括但不限于下列参数,例如温度、心率/脉搏、血压和呼吸速度。药效参数包括诸如蛋白质、核酸、细胞和细胞标志等生物标志的浓度。生物标志可以指示疾病或药物作用的结果。本发明的药物动力学(PK)参数包括但不限于药物和药物代谢物浓度。为了药品的适当安全性和功效,非常需要对样品体积的PK参数进行实时鉴定和定量。如果药物和代谢物的浓度落在了所需范围之外,和/或由于药物的非预期的反应产生了非预期的代谢物,则需要立即行动来确保患者的安全。同样地,如果在治疗方案中药效(PD)参数落到了预期的范围之外,也需要采取立即行动。
能够监测单个对象在一段时间内的分析物浓度或PD或PK参数的变化速率,或对浓度、PD或PK参数进行趋势分析,不论参数是药物或它们代谢物的浓度,都能够帮助避免潜在的危险情况。例如,如果葡萄糖是感兴趣的分析物,在给定时间在样品中的葡萄糖浓度以及在一段给定时间内葡萄糖浓度的变化率,在预测和避免诸如低血糖等事件中将会是非常有用的。这样的趋势分析在药物给药方案中具有广泛的益处。当涉及多个药物和它们的代谢物时,通常需要能对趋势作图并进行主动测定。
在一些实施方式中,本发明提供帮助临床医生提供个性化医学治疗的商业方法。商业方法可包括通过监测生物标志随时间变化的趋势,在处方后对药物治疗进行监测。该商业方法包括从接受药物治疗的个体收集至少一个药理学参数,所述收集步骤通过将体液样品交给流体装置中所含的反应物来进行,提供给所述个体是为了产生指示所述至少一个药理参数的可检测信号;在所述个体的计算机医疗记录的帮助下交叉参照所述个体的至少一个药理学参数,由此帮助所述临床医生提供个性化医学治疗。
本发明的装置、系统和方法可以对患者的药理学参数进行自动化定量,并自动化地将参数与包括被监测的参数历史的患者医疗记录、或与另一个对象组的医疗记录进行比较。用外部装置实时监测分析物,该外部装置存储数据并进行各种类型的数据处理或算法,例如,提供典型患者看护帮助的装置,包括例如将当前患者数据与过去患者数据进行比较。所以,本发明还提供了能有效进行至少一部分目前由医务人员进行的患者监测的商业方法。
实施例1
在本实施例中,采用本发明的装置、方法和系统进行人VEGFR2的测定。本实施例显示了能在现场护理进行的一种测定。根据测定,本实施例中即VEGFR2测定,可以将测定单元的捕获表面包被在测定单元上。通过吸入和气压排出,使测定单元(用与图3A的实施例相似的注模聚苯乙烯制成)的内表面与一连串的包被试剂相接触。向测定单元中吸入20微升每一种包被试剂,并且在室温孵育10分钟。以连续使用的方式,本实施例中所用的包被试剂是:溶于碳酸盐-碳酸氢盐缓冲液(pH9)中的中性链亲和素(Neutravidin,20μg/mL)、溶于Tris缓冲盐水(pH8)中的生物素化的“捕获抗体”(针对VEGFR2的单克隆抗体,20μg/mL)、和溶于Tris缓冲盐水中的含有3%牛血清白蛋白的“固定”试剂。在这一系列的包被作用后,将测定单元暴露于干燥空气中进行干燥,并且干燥保存。
然后将用于分析的样品分入测定单元中,用含有牛血清白蛋白和等压蔗糖的50mMTris缓冲液(pH8)溶液稀释20分钟。在含有共轭物的试剂单元中,向测定单元提供溶于(毕尔斯戴博公司(Biostab)出品的)稳定剂中的含有250ng/mL(牛肠)碱性磷酸酶标记的针对VEGFR2的单克隆抗体(与捕获表面的抗体的特定表位相结合)的溶液10分钟。当共轭物与结合在捕获表面上的分析物复合物结合之后,用试剂单元中的溶液(测定设计公司(AssayDesigns)的商品化的洗涤缓冲液)洗涤测定单元。洗涤测定单元5次。然后移动测定单元,收集并混合不同试剂单元中的另一个试剂,碱性磷酸酶的商品化的发光底物(KPLPhosphaglo出品)溶液,并且孵育10分钟。然后用本发明的检测器组件检测在测定单元中进行测定反应。
图12显示了用本实施例的方法得到的VEGFR2测定响应。X轴是VEGFR2浓度(pg/mL),y轴是相对发光(计数)。该曲线用于校准模块化测定单元和试剂单元。
实施例2
用本发明的测定单元和试剂单元进行人P1GF的测定,用商品化的仪器读取。平行地,用同样的试剂在原型阅读器中在一次性检测盒内进行试验(如下所述)。分析物浓度分别为0、4、80和400pg/mL。用如图13所示的检测来校准进行人P1GF测定所需的测定单元和试剂单元。
实施例3
磁珠是邦氏实验室公司(Bangs Laboratories)的直径1.3μm的BioMag磁性颗粒。磁珠(由厂商)用抗兔IgG包被。磁珠以14mg/mL分散在含有3%牛血清白蛋白和>=1.15mg/mL的兔抗人红血细胞IgG(赛达兰公司CedarLane出品)的Tris缓冲蔗糖(或Tris缓冲盐水)中。等分试样(10μL该分散体)分配到锥形管中,并且冻干(在液氮中冷冻且在-70℃冻干约24小时),然后插入到检测盒机架的槽中。兔抗体与红细胞和抗兔IgG包被的磁珠都结合,并形成共凝集的磁珠和红细胞。
加入20μL全血重新悬浮冻干的磁珠小球,然后在锥形管内吸-排分散至少8次(约1.5分钟)。
通过将尖端放入一个水平取向的强磁场中,分离血液。典型地,从20μL血样中回收8μL基本不含红细胞、看不到溶血的血浆(70%产率)。与不接受磁场分离的血浆相比,C蛋白、VEGF、P1GF、胰岛素、GIP和GIP-1等分析物的回收率接近100%。
实施例4
可以在本发明的系统中进行分析物的待分析样品的连续稀释。C-反应蛋白(CRP)是一个急性期标志。正常水平是在上限的ng/ml水平到下限的μg/ml水平的范围内。在任何急性疾病过程中,人肝脏产生CRP,血液中的水平升高至数百微克/毫升。由于待测分析物的变动范围大(>105倍),用现有技术POC分析系统检测CRP存在问题。
开发出本发明的系统,本发明系统包括液体转移装置和具有测定单元和试剂单元阵列的检测盒或装置。将有单克隆抗-CRP抗体结合在其内表面上的测定尖端安到检测盒上,同时还有检测抗体溶液(碱性磷酸酶标记的单克隆抗-CRP抗体,与尖端中的抗体具有不同的表位特异性)、洗涤溶液和KPL公司出品的化学发光碱性磷酸酶底物。
为了测定CRP,对预先稀释的CRP溶液不再进一步稀释,装载到检测盒上。用系统处理检测盒。将CRP溶液(10μL)、探测抗体(12μL)依次吸入到尖端中,34℃孵育10分钟,然后弃去。通过四次吸入20μL洗涤液清洗尖端,然后将15μL底物吸入到尖端中。37℃处理10分钟后,用仪器测量5秒钟的光发射。如图14所示,CRP浓度对测定信号(光子计数)作图,数据符合其下所示的5项多项式函数,形成如图14所示的校准函数。
实施例5
在本发明的系统和装置中,用含有高度浓缩的分析物的样品的连续稀释进行实验,以获得明确的测定响应。在检测盒中装载20μL的CRP溶液,用仪器进行连续稀释(分别为1:50、250、750和1500倍稀释)。然后向实施例4那样处理稀释后的溶液。当稀释后的CRP浓度超出测定的校准范围(300ng/mL)时,看到的是下降的响应(示于下方,数据来自两台仪器)。
可以用Scathard结合等温线的变型(S/Smax=C/(C+C0.5)作为图15所示响应的模型。该变型假定,测定响应与检测抗体的浓度成线性正比关系,就像本实施例的情况(结果未显示)一样。稀释的样品中的任何CRP遗留物在转入到下一个试剂(检测抗体)中时,都会迅速地与试剂发生反应,使之无法再与结合在固相抗体上的抗原相结合。有效浓度的下降与CRP遗留物成正比下降,并且可以用系数(D-C*f)/D解决。
因此,S=Smax*(C/(C+C0.5))*(D-C*f)/D,其中S是测定信号,Smax为信号最大值(对应于无遗留物的情况),C为分析物的浓度,C0.5为最大信号(无遗留物)一半时的浓度,D为检测抗体的浓度,f是遗留物分数。
用于拟合数据的值,来源于通过将数据与模型之拟合的最小平方差的最小化技术对下列四个参数的优化。可以从图15看出,获得了极佳的拟合,且参数Smax、C0.5和D的值(参见表2)接近于根据达到的最大信号、测得的C0.5和已知的检测抗体的浓度能够估算出来的值。该模型估算的遗留物限度为0.034%(十进制3.83E-04)。
表1:描述两相CRP测定响应的模型的最佳拟合参数
参数 | 值 | 单位 |
Smax | 7.24E+05 | 计数 |
C0.5 | 5.02E+01 | ng/mL |
D | 5.72E+00 | ng/mL |
f | 3.83E-04 |
随后根据每个测定尖端中达到最终浓度所用的稀释情况查看数据,对于每一个稀释水平,响应拟合相同的响应,如图16所示,表明稀释是准确的和精确的。
在此描述的模型能用来计算任何给定稀释的响应并建立算法,以确保在任何尖端中的分析物浓度都在可以校准的范围内。图17显示了代表数据的图形,其中,针对稀释度1:1(实线)、5:1(划线)和25:1(点线),用归一化的测定响应(B/Bmax)对归一化的浓度(C/C0.5)的对数作图。图18和19显示了在不同的归一化浓度时与图17相似的实施例。可以用简单的模式识别算法来鉴别对于高浓度样品有效的数据。例如,对于大多数剂量-响应而言,信号随着稀释而降低。当任何稀释度的信号等于或超过下一个更高稀释度的信号时,较低稀释度的结果被弃去。在另一个实施例中,使用如实施例4所示的校准函数推导出的浓度,应当在系统不精确度的范围之内对应于已知稀释度。如果为低稀释度计算出的浓度低于对应于较高稀释度计算得到的浓度,则较低稀释度的结果被弃去。
当测定的剂量-响应接近最高值时,浓度对信号的斜率(ΔC/ΔS)增大。对于信号的相对偏差(ΔS/S)基本恒定的试验(例如所述系统的一些实施例)而言,这就等于在较高浓度下计算得到的浓度结果产生了较大的偏差。在本发明中,稀释或连续稀释能够提供一种浓度精确性,就如同免疫测定在显著地高于(例如>10倍)空白(无分析物)的信号、但又不接近于最大信号(例如<0.3*最大信号)的信号水平上所实现的那样。连续稀释能够使测试信号落在这个范围之内。
通过从不同的稀释度对分析物浓度进行几次估算,可以得到一个平均值。也可以通过对一个稀释水平进行重复测定来获得平均值。在一些实例中,本发明的方法、系统和装置提供的连续稀释方法,通常能够消除由于稀释作用的非线性所导致的误差,因为有了(例如)样品的矩阵效应。
实施例6
荧光素是一种广为人知的化学品,已知有对该分子有特异性的高亲和力抗体。通过将若干个荧光素部分连接到诸如白蛋白等蛋白质上,就创造了一种能用ELISA检测的人造分析物。这个实施例是建立在微量滴定板上的,以便显示这种测定的可行性,并且可以很方便的转化成本发明的装置或系统。
在384孔微量滴定板的孔上连接抗荧光素单克隆抗体,形成捕获表面。通过向孔中添加一系列的溶液,然后在必要时在每个阶段于室温下孵育10分钟,来完成测定。向孔中加入30μL已知浓度的商品化的比例为每个分子合5个荧光素的荧光素标记牛白蛋白(样品)制剂。在机械移除样品后,加入30μL浓度为100ng/mL的碱性磷酸酶标记的抗-荧光素(检测抗体)。在移除检测抗体后,各个孔用40μL洗涤溶液(“洗涤缓冲液”目录号#80-1351[测定设计公司(Assay Designs),地址:密歇根周安阿伯市],使用前1:20稀释)清洗3次。然后加入PhosphaGLOTM(40μL)底物,在M5分光照度计中读取测定响应0.5秒钟。测定响应显示在图20中。
荧光素标记白蛋白(5μL,各种浓度,最高80ng/mL)溶解在含有3mg/mL牛白蛋白的Tris-缓冲盐水(缓冲液)中,放入聚丙烯管中,并且通过暴露于低湿度空气中过夜进行干燥。确认是否已经完全干燥,方法是通过在干燥前后称量多个管子的重量,验证合适的重量损失,并且实现几乎恒定的最终重量。通过加入5μL水、20μL人血清和180μL缓冲液并且混合,对分析物进行回收。通过将分析物溶液的5μL等分试样与20μL血清和180μL缓冲液混合,来进行对照实验。
用在此描述的试验对分析物回收液进行检测。如下所示,测定信号(和分析物)的回收在所有的浓度都基本上是定量的。需要能有较好的回收率(>90%),而且是精确的(回收的CV<2%)。在某些实例中,因分析物的浓度低而试剂过量时,试验的剂量-响应在感兴趣的范围内是线性的。例如,当捕获表面具有足够的抗原结合能力以致于即使分析物在最高浓度时,在结合反应的终点也只有中等比例(例如,<30%)的位点被占据,就可以获得线性的试验剂量-响应。在本发明中,ng/mL级的分析物以及孵育时间较短(例如<30分钟)的测定,可以通过前述的对捕获表面的包被来达到这样的条件。在另一个实施例中,检测抗体的浓度足够高以致于在检测抗体的孵育过程中浓度并没有明显的耗尽(例如,在最高抗原水平下,<30%的试剂结合到表面上),可以使用浓度为约5-100ng/mL的尽测抗体来满足这样的条件。在又一个实施例中,可以通过形成小于尽测抗体线性响应范围的信号(例如采用高达约400万光子/秒的PMT),来获得线性的试验剂量-响应。如本发明所述,系统和方法可以落在这个范围内。在又一个实施例中,可以通过形成高得足以精确测定的水平的信号(例如,光子计数度高于约每秒1000次),来获得线性试验剂量-响应。
测试尖端(如本发明所述)通过连续吸入下列试剂进行包被:20μL溶于pH 9的碳酸盐缓冲液中的5μg/mL的兔抗抗-荧光素(分子探针公司(Molecular Probes)A#6413),20μL溶于pH 8的Tris缓冲盐水中的3%牛白蛋白,和20μL的2.5μg/mL荧光素标记的牛白蛋白(西格玛-奥德里奇公司(Sigma-Aldrich)A9771),每次加入后孵育10分钟再将液体排出。然后通过向尖端中吸入溶于pH 8的Tris缓冲盐水的牛白蛋白洗涤3次,再用溶于pH 8的Tris缓冲盐水中的3%牛白蛋白孵育。然后如在此所述对尖端进行干燥。用这些尖端对含有羊抗抗-荧光素的测试样品进行测定,方法是依次用下列试剂的20μL等分试样进行孵育:溶于含3%的BSA的pH 8Tris缓冲盐水中的羊抗抗-荧光素(样品),100ng/mL碱性磷酸酶标记的兔抗羊荧光素的StabilzymeTM(商品化的溶剂)溶液,用洗涤缓冲液洗涤4次,PhosphaGLOTM碱性磷酸酶化学发光底物,每次在室温下孵育10分钟。对试验进行评估,方法是通过将每个尖端放在与微量滴定板平台相配的客户改良的框架中,用采用分子设备公司(MolecularDevices)的M5照度计中的光电倍增管的仪器测定约10秒钟内产生的光子,结果显示在图21中。在本实施例中,图21显示了如图20所示相类似的线性响应。
表2:候选对照分析物的试验配置
实施例7
本实施例显示了用本发明的测试尖端按照以下方式进行CRP免疫测定时其响应的可预测性:最初添加试剂,除出反应产物,洗涤尖端,然后重新引入一些或所有的测试组分。试验的顺序是将尖端在原型仪器中在34℃依次用下列试剂孵育10分钟:(1)样品(CRP 0.3、3、30、150和300μg/mL),用仪器稀释500然后2000倍;(2)碱性磷酸酶标记的兔抗羊IgG["Dab"](5ng/mL),然后洗涤3次;(3)PhosphaGLOTM碱性磷酸酶化学发光底物["底物"]。在第3步后,用能读取10秒钟内光子产生率的若干个仪器来完成实验。最终的(尖端内)CRP浓度为0.15、0.6、1.5、6、15、60、75、300和600ng/mL,而且发光水平从2000到600000个/0.5秒范围内。在一些实验中,在测定步骤3后,弃去反应产物,并且重复步骤3(菱形和实线)、步骤2+3(方形和划线)或步骤1+2+3(三角形和点线),结果如图21所示作为经过再加工的测定信号对原始测定信号的图。
经过再加工的测定信号与原始测定信号线性相关(成正比)。第二底物的添加给出了比原始信号更高的信号,而其中同时引入Dab和底物的再加工试验,或者是样品、Dab和底物全都重新引入的再加工试验,给出了比原始信号低的信号。在采用本方法的一个实施例中,按试验顺序对所有步骤进行审查,进行质量监控,以期了解这些步骤是否根据试验步骤的第一和后续反复之间的预期关系依次进行、不出所料。
例如,如在此所述,如果一个试验步骤未能正常进行,那么或者是将试验结果作为不正确内容而弃去,或者用后面的重复得到的结果作为正确的试验响应。
在本发明的系统中进行了C反应蛋白的免疫测定。6个等价的测定尖端依次用样品(200ng/mL CRP)、碱性磷酸酶标记的兔抗羊IgG抗体进行孵育且随后洗涤、用PhosphaGLOTM碱性磷酸酶化学发光底物一起孵育。孵育是在34℃进行10分钟。用3个仪器进行实验,这些仪器还能读取10秒钟内光子的产生率。检测到每0.5秒的读取时间内平均约40000次计数(光子)。在本实施例中,在仪器3中尖端1和2的发光水平给出了如表3所示的明显不同的结果。然后用仪器洗涤尖端,并且引入新的PhosphaGLOTM底物(吸取2)。表中的结果用每个尖端的发光率对每个仪器上6个尖端的平均值的比例。在第二次吸取后,在仪器3中尖端1和2给出了与其他4个尖端相符合的结果,说明无论是什么导致了尖端1和2信号变低,问题都已经得到了矫正。
表3:从故障吸头恢复合适的信号
Claims (7)
1.一种从血液样品中回收血浆的方法,包括:
a在仪器中放置检测盒,其中,所述检测盒包括:含样品的至少一个样品容器;多个试剂单元;多个测定单元;至少一个移液管尖端和至少一个除余垫,前述所有都按二维模式排布并且并不一起在单个行中;
其中,所述检测盒被配置成包含在至少两个分析物的检测中所使用的所有的试剂和补给;
b在样品收集单元中将血液样品在可磁化颗粒存在下混合,其中,所述可磁化颗粒包括用于结合血液样品中的非血浆部分的抗体捕获表面;
c在血浆收集区域上方向混合后的血液样品施加一个磁场,使血液样品的非血浆部分的悬浮在血浆收集区域的顶部;以及
d在测定单元接收所述血液样品的至少一部分,并用所述部分来进行化学反应,其中所述各测定单元包含测定尖端,所述测定尖端包含在尖端的第一端的第一开口和在尖端的第二端的第二开口,其中所述第一开口具有大于第二开口的直径。
2.如权利要求1所述的方法,其特征在于,所述样品收集单元是毛细管。
3.如权利要求1所述的方法,其特征在于,所述血液样品小于20微升。
4.如权利要求1所述的方法,其特征在于,所回收的血浆小于10微升。
5.如权利要求1所述的方法,其特征在于,所述血液样品未经稀释。
6.如权利要求1所述的方法,其特征在于,所述混合在存在未结合到固体表面的抗体的情况下进行。
7.如权利要求1所述的方法,其特征在于,所述混合包括通过注射作用进行混合。
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