CN101091116A - 在生物传感器上产生参比区和样品区的方法及所得生物传感器 - Google Patents

在生物传感器上产生参比区和样品区的方法及所得生物传感器 Download PDF

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CN101091116A
CN101091116A CNA2005800451575A CN200580045157A CN101091116A CN 101091116 A CN101091116 A CN 101091116A CN A2005800451575 A CNA2005800451575 A CN A2005800451575A CN 200580045157 A CN200580045157 A CN 200580045157A CN 101091116 A CN101091116 A CN 101091116A
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biology sensor
reference region
printing
sample area
reagent
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CN101091116B (zh
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S·J·卡拉奇
A·G·弗鲁托斯
彭金林
G·A·皮切
M·B·韦布
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Corning Inc
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Abstract

本文描述了一种方法，可使用许多沉积技术中的任一种在单个生物传感器上形成参比区和样品区，在优选的实施方式中，生物传感器位于微量培养板的单个孔内。用于在生物传感器的表面上形成参比区和样品区的沉积技术包括：(1)将去活化试剂印刷/冲压到生物传感器的反应性表面上；(2)将靶分子(靶蛋白)印刷/冲压到生物传感器的反应性表面上；或(3)将反应性试剂印刷/或冲压到生物传感器的非反应性表面上。

Description

在生物传感器上产生参比区和样品区的方法及所得生物传感器
相关申请的交叉引用
本申请要求2004年12月29日提交的题为“在生物传感器上产生参比区和样品区的方法及所得生物传感器(Method for Creating a Reference Region anda Smaple region on a Biosensor and the Resulting Biosensor)”的美国专利申请第11/027,509号的优先权，其涉及2004年12月29日提交的题为“空间扫描光阅读器系统及其使用方法”(Spatially Scanned Optical Reader System And MethodFor Using Same)(律师案卷号SP04-149)的美国专利申请第11/027,547号，它们的内容通过引用包括在此。
发明背景
发明领域
本发明涉及一种其表面上既有参比区又有样品区的生物传感器，其中的参比区和样品区部分地通过使用沉积技术如印刷或冲压来形成。在一个实施方式中，所述生物传感器包含在微量培养板的孔中。
相关技术的描述
目前，生物传感器如表面等离子共振(surface plasmon resonance，SPR)传感器或共振波导光栅传感器使光学标记物独立检测(LID)技术能够被用来检测生物传感器表面上的生物分子结合事件。具体地说，SPR传感器和共振波导光栅传感器使得光学LID技术能够测定生物传感器折射率/光学响应的变化，进而检测生物传感器表面的生物分子结合事件。这些生物传感器与不同的光学LID技术一道已被用于研究许多生物分子结合事件，包括蛋白质-蛋白质相互作用和蛋白质-小分子相互作用。
为实现高灵敏度检测，关键是小心控制或剔除(reference out)可能导致测量的折射率/光学响应产生虚假改变的因素(例如，温度、溶剂效应、体积折射率变化和非特异结合)。在基于芯片的LID技术中，典型地使用两个生物传感器来实现上述作用，其中一个是实际生物传感器，另一个是毗邻生物传感器，用于剔除上述因素。两种示例性基于芯片的LID生物传感器包括Biacore的SPR平台和Dubendorfer的装置，Biacore的SPR平台中使用4个相邻流动通道中的一个作为参比，而Dubendorfer的装置则使用邻接传感器垫的独立垫作为参比。下面的文献详细描述了Biacore的SPR平台和Dubendorfer的装置：
·“改善的生物传感器分析”(Improving Biosensor Analysis)，Myska，J.Mol.Recognit，1999，12，279-284。
·“在Biacore S51中水动力访问检测点”(Hydrodynamic Addressing ofDetection Spots in Biacore S51)，Biacore Technology Note 15。
·J.Dubendorfer等，“集成光学免疫传感器的感应和参比垫”(Sensing andReference Pads for Integrated Optical Immunosensors)，Journal of BiomedicalOptics 1997，2(4)，391-400。
使用这些类型的参比方案的优点体现在Biacore S51中，这是目前市场上可获得的最新且最敏感的SPR平台。这种仪器因为其改进的参比作用而具有显著改善的灵敏度和性能，其基础在于使用所谓的水动力参比垫以尽可能减小单一通道内的噪音、温度效应、漂移、体积折射率效应。然而，基于芯片的LID技术要求使用流动细胞技术，因而这不易适用于微量培养板中。
为微量培养板设计的生物传感器非常吸引人，因为它们适用于高通量筛选应用。然而，目前使用的微量培养板是一个孔中包含样品生物传感器，而相邻孔中包含参比生物传感器。因为两个生物传感器间分开的距离较大，这就难以剔除温度效应。而且，使用两个相邻的生物传感器，则必须在样品孔和参比孔中使用两种不同的溶液，这会导致移液误差、稀释误差、和两种溶液间的体积折射率变化。其结果是，参比作用的有效性受损。为了解决上述问题，美国专利申请2003/0007896描述了几种不同的方法，其中为了剔除温度效应，使用的是同时测量单个生物传感器的光学响应以及不同的偏光。然而，这些方法不易实施，且无法考虑也无法校正体积折射率效应和非特异结合。
在另一种方法中，O’Brien等使用双元件SPR传感器，其中，通过使用激光消融联合表面化学的电化学制模来形成参比区。然而，由于该方法需要使用金属衬底，因而难以实施且应用性有限。关于双元件SPR传感器参比及该方法的详细描述参见O′Brien等题为“SPR生物传感器：同时去除热和体积组成效应”(SPR Biosensors：Simultaneously Removing Thermal and Bulk CompositionEffects)，Biosensors & Bioelectronics 1999，14，145-154。
由此可见，需要可用于微量培养板并且可用于检测生物分子结合事件，同时剔除温度效应、漂移、体积折射率效应和非特异结合的生物传感器。本发明满足了这种需要和其它需要。
发明概述
本发明包括一种方法，其中，可使用几种不同的沉积技术(例如，接触针印刷、非接触印刷、微触点印刷、网点印刷、丝网印刷、气溶胶印刷(aerosolprinting)、冲压(stamping)、喷雾)中的任一种在单个生物传感器上形成参比区和样品区，该生物传感器可位于微量培养板的单个孔内。用于在生物传感器表面上形成参比区和样品区的方法实施过程包括：(1)去活化试剂在生物传感器反应表面上的选择性沉积；(2)靶分子(例如蛋白质)在生物传感器反应表面上的选择性沉积；或(3)活化试剂在生物传感器非反应表面上的选择性沉积。表面具有参比区和样品区的生物传感器使得能够使用样品区来检测生物分子结合事件，并且使得能够使用参比区来剔除可不良影响生物分子结合事件的检测的虚假变化。
附图简要说明
结合附图，参考以下详细说明可更全面地理解本发明，其中：
图1是一示意图，有助于描述根据本发明在单个生物传感器上形成参比区和样品区的三种不同的方法；
图2-5显示了为评价本发明第一种方法的可行性而进行的实验结果的图表和照片；
图6-7显示了为评价本发明第二种方法的可行性而进行的实验结果的图表和照片；
图8显示了为评价本发明第二种方法的可行性而进行的实验结果的图表和照片。
附图详述
图1是一示意图，用于描述在位于微量培养板108单个孔106底部的单个生物传感器100上形成参比区102和样品区104的三种不同的方法。然而，在描述本发明详细内容之前，应理解，优选的生物传感器100是可用于实施LID技术的传感器，如SPR传感器100和共振波导光栅传感器100。以下文献详细描述了本发明中可使用的这些示例性生物传感器100的结构和功能：
·欧洲专利申请0 202 021 A2，题为“光学分析：方法与设备“(Optical Assay：Method and Apparatus)。
·美国专利4,815,843，题为“选择性检测物质和/或检测气态、液态、固态和多孔样品折射率变化的光学传感器”(Optical Sensor for Selective Detectionof Substances and/or for the Detection of Refractive Index Changes in Gaseous，Liquid，Solid and Porous Samples)。
这些文献的内容通过引用包括在此。
图1显示了采用特定沉积技术以便在位于微量培养板108单个孔106内的单个生物传感器100上形成参比区102和样品区104的方法的三个例子。在第一种方法中，用反应性试剂112(例如，聚(乙烯-alt-马来酸酐)(EMA))涂覆(步骤1a)生物传感器100的表面110。(反应性试剂112的例子包括但不限于：具有酸酐基团、活性酯、马来酰亚胺基团、环氧化物、醛、异氰酸酯、异硫氰酸酯、磺酰氯、碳酸酯、亚胺酰酯、或烷基卤的试剂)。然后，通过将阻断剂/去活化试剂116沉积在其上，特异性地去活化(步骤1b)表面110上的预定区域。例如，当表面110涂覆有胺反应性涂层如EMA时，可使用许多含胺反应试剂来阻断/去活化表面，例如乙醇胺(EA)、乙二胺(EDA)、三羟甲基氨基乙烷(tris)、O，O’-二(2-氨基丙基)聚乙二醇1900(PEG1900DA)或其它聚乙二醇胺或二胺。或者，可使用不含胺的反应试剂来水解反应性基团。在随后的固定化步骤(步骤1c)中，将靶分子118(例如，蛋白质118)加入到孔106中。靶分子仅结合未用去活化试剂116处理的传感器区域。靶分子可以是蛋白质、肽、合成或天然膜、小分子、合成或天然DNA或RNA、细胞、细菌、病毒。这是在单个生物传感器100上形成参比区102和样品区104的一种方法。
在第二种方法中，用反应性试剂112涂覆(步骤2a)生物传感器100的表面110。然后，将靶分子118直接印刷(步骤2b)到表面110上涂覆有反应性试剂112的预定区域中。随后，使整个孔106接触(步骤2c)去活化试剂116，以去活化/阻断表面110上未印刷区域，用作参比区102。这是可用于在单个生物传感器100上形成参比区102和样品区104的另一种方法。
在第三种方法中，用具有可转化为反应性基团的官能团(例如羧酸基团)的物质涂覆(步骤3a)生物传感器100的表面110。在步骤3b中，通过将活化反应试剂如1-[3-(二甲基氨基)丙基]]-3-乙基盐酸盐(EDC)/N-羟基琥珀酰亚胺(NHS)沉积在其上来使预定的表面区域有反应活性。然后，整个孔106接触包含靶分子118的溶液，使靶分子118结合(步骤3c)表面110上通过印刷活化试剂112而活化的区域。表面110上不具有附连的靶分子118的区域可用作参比区102。这是用于在单个生物传感器100上形成参比区102和样品区104的另一种方法。
应指出，存在许多可用于上述方法的不同沉积技术。例如，沉积技术可包括：接触针印刷、非接触印刷(喷墨打印、气溶胶印刷)、毛细管印刷、微触点印刷、凹版移印(pad printing)、网点印刷、丝网印刷、微量移液(micropipetting)和喷雾。
还应理解，本领域技术人员能够采用任何一种上述方法在表面100上印刷多个不同的点，以在微量培养板108同一个孔106中形成参比区102、阳性/阴性对照和/或多个不同的靶分子1-2(例如)。这种情况的一个例子如图1底部所示。
以下是为评价本发明三种不同方法各自可行性而进行的多个实验的描述。
参考与本发明第一种方法相关的实验，采用荧光分析和康宁LID分析来评价在生物传感器100上形成参比(非结合)区102和样品(结合)区104的可行性。康宁LID分析是指采用共振波导光栅传感器进行的分析。在第一组实验中，将三种溶解在硼酸盐缓冲液(100mM，pH9)中的不同的去活化试剂116(乙醇胺(EA)、乙二胺(EDA)和O，O’-二(2-氨基丙基)聚乙二醇1900(PEG1900DA))印刷到三个不同的孔中涂覆有反应性试剂112(聚(乙烯-alt-马来酸酐(EMA))的玻片上。采用配备有10号衬套针的Cartesian自动针式印刷机来进行印刷，印刷5×7独立点阵列(间隔300um)以形成印刷(参比)区102。各点印刷得足够近，以至于融合在一起而形成矩形区域。然后用生物素-peo-胺溶液118孵育各孔，用于评价印刷过程的有效性。据预计，生物素118仅结合孔的非印刷(样品)区域104。然后，使各孔接触cy3-抗生物素蛋白链菌素的溶液，荧光扫描仪下成像。
图2总结了这些实验的结果。由图可见，在对应于印刷有去活化试剂116的各孔内的圆形区域中未观察到荧光信号。这个结果表明，所有三种阻断剂116(包括EA、PEG1900DA和EDA)可有效灭活反应性试剂112(EMA)，因而阻止生物素118与cy3-抗生物素蛋白链菌素的结合。图表显示，印刷(参比)区102相对于未印刷(样品)区104的荧光强度降低＞98％。荧光图像的检查还表明，去活化试剂116未显著扩散到印刷(参比)区102外部。
进行另一组实验来研究去活化试剂116浓度对性能的影响。使用太浓的去活化试剂116可导致未印刷(样品)区104的交叉污染。图3显示了在印刷有各种浓度EA116的玻片上进行cy3-抗生物素蛋白链菌素结合试验后获得的5幅荧光图像。由图像1-2可见，使用较高浓度的EA116时，存在显著铺展/交叉污染。并且，由图像3-4可见，使用较低浓度的EA116时，EA116限制在印刷区域并仍可有效灭活表面，一如该区域中观察到低荧光信号强度所证明。最后的图像5是没有印刷EA116的图像。
进行又一组实验来证明：(i)在孔106内使用印刷的去活化试剂116不会负面影响后续靶分子118在未印刷(反应性)区域112上的固定，和(ii)使用印刷的去活化试剂116与大量溶液中使用去活化试剂一样起作用。在这些实验中，首先用反应性试剂112(EMA)涂覆康宁LID微量培养板108(含Ta2O5波导薄层)中的几个孔106。然后，将去活化试剂(PEG1900DA)116印刷到康宁LID微量培养板108各孔106的预定区域上。作为对照，其它孔106用相同的阻断剂116溶液孵育或保持未处理。然后，使所有的孔106接触生物素-peo-胺118溶液，再与cy3-抗生物素蛋白链菌素孵育。
图4显示了这些荧光成像实验的结果。对于抗生物素蛋白链菌素与生物素118的特异性结合，一半区域被去活化试剂(PEG1900DA)116阻断的孔106相对于不包含去活化试剂116的孔106观察到相当的cy3荧光信号。这说明印刷区域之外的区域不存在阻断剂116的扩散。印刷沉积相对于体积溶液沉积去活化(阻断)试剂116有效性的比较表明两种方法同样有效，一如两种处理低荧光信号水平所证明的那样。
进行了采用康宁LID微量培养板108的其它实验以体现采用本发明孔内参比的优点。在这些实验中，将去活化试剂(PEG1900DA)116印刷到LID微量培养板108的一些EMA涂覆孔106。然后通过将孔106与生物素-peo-胺的溶液孵育，使生物素固化化到表面上。随后，将微量培养板108安装到康宁LID设备中，监测抗生物素蛋白链菌素(100nM在PBS中)的结合随时间的变化。在试验期间，LID设备连续扫描各孔106底部/生物传感器100，以监测参比(未结合)区102和样品(结合)区104中的信号。关于LID设备更详细的内容，参见同时提交的题为“空间扫描光学阅读器系统及其使用方法”(Spatially ScannedOptical Reader System and Method for Using Same)(律师案卷号SP04-149)的上述美国专利申请序列第11/027,547号。
图5A显示了试验过程期间一个孔106内参比区102和样品区104的响应。在该图表中，痕迹“差值组_B6”是由样品痕迹“信号组_B6”减去参比痕迹“参比组_B6”得到的参比校正数据。由图可见，在第一个～10分钟内，两通道内都存在信号随时间的系统性降低(即漂移)。然而，这种漂移在参比校正痕迹“差值组_B6”中实质上被消除了。具体地，未校正痕迹“信号组_B6”中的漂移率约为-2.5pm/分钟，参比痕迹“参比组_B6”中的漂移率约为～0pm/分钟。
图5B显示了相同试验的第一个10分钟的图表，其中采用了孔内(孔B6信号区和参比区)或孔间参比(孔B6信号区减去相邻孔B5参比区)。数据清楚表明，孔内参比技术能非常有效得消除生物传感器100的环境漂移。
图5C显示了总的波长位移(结合抗生物素蛋白链菌素之后)与传感器100上的位置关系的曲线。由图可见，传感器100上参比(阻断)区102和样品(未阻断)区104之间存在清楚明显的转变，表明印刷过程可以受控的方式进行。
以下是关于本发明第二种方法的实验的描述。同样，在本发明第二种方法中，通过将靶分子118直接印刷到反应性表面100上，然后通过用去活化试剂116处理来灭活表面100的其余部分，在单个生物传感器100内形成参比区102和感应区104。该方法的优点是与采用体积溶液(＞～10ul)的固定化作用相比，显著降低了所消耗的蛋白质体积(＜～1nl)。
为了证明该方法的可行性，将BSA-生物素118(50ug/ml，100mM硼酸盐pH9)印刷到康宁LID微量培养板108的一些孔106中。然后，用乙醇胺116(200mM在硼酸盐缓冲液中，pH9)处理每个孔106，再用cy3-抗生物素蛋白链菌素(100nM在PBS中)孵育。图6是荧光图像，其中，在印刷BSA-生物素118的样品区104中观察到强荧光信号，在参比区102中观察到非常弱的信号(＜感测区信号的3％)。这些结果表明，(i)印刷方法可有效固定BSA-生物素118；(ii)印刷区之外没有发生BSA-生物素118的扩散；(iii)印刷的BSA-生物素118维持了其结合抗生物素蛋白链菌素的能力。图7显示了采用康宁LID平台进行的类似实验的结果。～240pm的结合信号水平表明，大量蛋白质118结合在了表面上。与上述荧光实验的结果相一致，在生物传感器100的参比部分102中没有观察到抗生物素蛋白链菌素的结合。
以下是关于本发明第三种方法的实验的描述。同样，在本发明第三种方法中，通过将活化试剂112(例如1-[3-(二甲基氨基)丙基])-3-乙基碳二亚胺盐酸盐(EDC，Aldrich)和N-羟基琥珀酸亚胺(NHS，Aldrich))印刷到非反应性表面(例如具有羧酸基团的表面)，形成用于附着靶分子118的反应性结合表面104，在单个生物传感器100内形成参比区102和感应区104。
为了证明这个概念，将包含EDC(1mM)和NHS(1mM)的水溶液印刷到微量培养板108孔106中水解EMA表面上。然后将整个孔106用生物素-胺118孵育，并进行cy3-抗生物素蛋白链菌素荧光结合试验。图8显示了图表和照片，其中，仅对应于印刷区的区域中观察到荧光信号，证明可选择性地控制靶分子附着而未印刷区域可用作参比区102。
下面将描述根据本发明，采用印刷/冲压技术来形成LID生物传感器100的孔内参比的一些其它特征和优点。
1)相同孔内形成的参比区可显著降低或消除温度、体积折射率效应和非特异结合导致的偏差。采用孔内参比剔除这些因素比采用相邻孔作为参比更加有效。
2)孔内参比区因不再需要使用独立参比(对照)孔而降低了反应试剂的消耗。
3)印刷/冲压技术可根据微量培养板的制造规模来调节。
4)与采用体积溶液反应的蛋白质固化相比，印刷/冲压靶蛋白可降低蛋白质用量约～100-10,000倍。
5)事实上，可将印刷/冲压技术应用于任何类型的基板，用于在生物传感器上制备表面。
6)也可包含第二种检测方法如质谱法以提供生物分子结合的更详细信息。
虽然附图和上文所述发明详述中阐述了本发明的一些实施方式，但应理解，本发明并不限于所述实施方式，而是能够进行各种重排、改进和替换，而不背离所附权利要求书所提出和限定的本发明的精神。

Claims (40)

1.一种生物传感器，其表面包含部分地采用沉积技术形成的参比区和样品区。
2.如权利要求1所述的生物传感器，其特征在于，通过进行以下步骤在所述表面上形成参比区和样品区：
用反应性试剂涂覆所述表面；
将去活化试剂沉积到所述涂覆表面的预定区域以形成参比区；和
使所述表面接触靶分子，其中，所述靶分子结合于未用去活化试剂处理的所述涂覆表面的预定区域，形成样品区。
3.如权利要求1所述的生物传感器，其特征在于，通过进行以下步骤在所述表面上形成参比区和样品区：
用反应性试剂涂覆所述表面；
将靶分子沉积到所述涂覆表面的预定区域以形成样品区；和
使所述涂覆表面接触去活化试剂以使一部分的其上仍然显露反应性试剂的所述涂覆表面灭活，形成参比区。
4.如权利要求1所述的生物传感器，其特征在于，通过进行以下步骤在所述表面上形成参比区和样品区：
将活化试剂沉积到所述表面的预定区域并使靶分子附着于至少一部分的其上显露活化试剂的所述涂覆表面，以形成样品区；和
使用没有活化试剂的区域作为参比区。
5.如权利要求1所述的生物传感器，其特征在于，所述表面包括一个以上的参比区和/或一个以上的样品区。
6.如权利要求1所述的生物传感器，其特征在于，包括参比区和样品区的所述表面使得能够利用样品区来检测生物分子结合事件，并且使得能够利用参比区来剔除对生物分子结合事件的检测造成不良影响的效应。
7.如权利要求1所述的生物传感器，其特征在于，包括参比区和样品区的所述表面使得能够利用质谱仪来同时检测两区域以获得关于生物结合事件的进一步信息。
8.如权利要求1所述的生物传感器，其特征在于，通过沉积抵抗靶分子非特异结合的分子来形成所述参比区。
9.如权利要求1所述的生物传感器，其特征在于，所述表面位于微量培养板孔的底部。
10.如权利要求1所述的生物传感器，其特征在于，所述表面是玻片。
11.如权利要求1所述的生物传感器，其特征在于，所述生物传感器是表面等离子共振传感器。
12.如权利要求1所述的生物传感器，其特征在于，所述生物传感器是共振波导光栅传感器。
13.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是接触针印刷。
14.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是非接触印刷如喷墨打印或气溶胶印刷。
15.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是毛细管印刷。
16.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是微触点印刷。
17.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是凹版移印。
18.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是网点印刷。
19.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是丝网印刷。
20.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是微量移液。
21.如权利要求1所述的生物传感器，其特征在于，所述沉积技术是喷雾。
22.一种微量培养板，其包括：
包含许多形成在其中的孔的框架，每个孔包含一生物传感器，所述生物传感器的表面具有部分地采用沉积技术形成的参比区和样品区。
23.如权利要求22所述的微量培养板，其特征在于，通过进行以下步骤在所述表面上形成参比区和样品区：
用反应性试剂涂覆所述表面；
将去活化试剂沉积到所述涂覆表面的预定区域以形成参比区；和
使所述表面接触靶分子，其中，所述靶分子结合于未用去活化试剂处理的所述涂覆表面的预定区域，形成样品区。
24.如权利要求22所述的微量培养板，其特征在于，通过进行以下步骤在所述表面上形成参比区和样品区：
用反应性试剂涂覆所述表面；
将靶分子沉积到所述涂覆表面的预定区域以形成样品区；和
使所述涂覆表面接触去活化试剂以使其上仍然显露反应性试剂的所述涂覆表面中的一部分灭活，形成参比区。
25.如权利要求22所述的微量培养板，其特征在于，通过进行以下步骤在所述表面上形成参比区和样品区：
将活化试剂沉积到所述表面的预定区域并使靶分子附着于至少一部分的其上显露活化试剂的所述涂覆表面，以形成样品区；和
使用没有活化试剂的区域作为参比区。
26.如权利要求22所述的微量培养板，其特征在于，所述表面包括在每个孔内的一个以上的参比区和/或一个以上的样品区。
27.如权利要求22所述的微量培养板，其特征在于，包括参比区和样品区的所述表面使得能够利用样品区来检测生物分子结合事件，并且使得能够利用参比区来剔除对生物分子结合事件的检测造成不良影响的虚假变化。
28.如权利要求22所述的微量培养板，其特征在于，所述生物传感器是表面等离子共振传感器。
29.如权利要求22所述的微量培养板，其特征在于，所述生物传感器是共振波导光栅传感器。
30.如权利要求22所述的微量培养板，其特征在于，所述沉积技术包括以下一种：接触针印刷、非接触印刷(喷墨印刷、气溶胶印刷)、毛细管印刷、微触点印刷、凹版移印、网点印刷、丝网印刷、微量移液和喷雾。
31.一种在生物传感器上制备模式表面的方法，其包括以下步骤：
采用沉积技术在所述生物传感器的表面上形成参比区和样品区。
32.如权利要求31所述的方法，其特征在于，通过进行以下步骤在所述生物传感器的表面上形成参比区和样品区：
用反应性试剂涂覆所述表面；
将去活化试剂沉积到所述涂覆表面的预定区域以形成参比区；和
使所述表面接触靶分子，其中，所述靶分子结合于未用去活化试剂处理的所述涂覆表面的预定区域，形成样品区。
33.如权利要求31所述的方法，其特征在于，通过进行以下步骤在所述生物传感器的表面上形成参比区和样品区：
用反应性试剂涂覆所述表面；
将靶分子沉积到所述涂覆表面的预定区域以形成样品区；和
使所述涂覆表面接触去活化试剂以灭活一部分的其上仍然显露反应性试剂的所述涂覆表面，形成参比区。
34.如权利要求31所述的方法，其特征在于，通过进行以下步骤在所述生物传感器的表面上形成参比区和样品区：
将活化试剂沉积到所述表面的预定区域并使靶分子附着于至少一部分接触活化试剂的所述涂覆表面，以形成样品区；和
使用没有活化试剂的区域作为参比区。
35.如权利要求31所述的方法，其特征在于，所述生物传感器具有一个以上的参比区和/或一个以上的样品区。
36.如权利要求31所述的方法，其特征在于，具有参比区和样品区的所述生物传感器使得能够利用样品区来检测生物分子结合事件，并且使得能够利用参比区来剔除对生物分子结合事件的检测造成不良影响的虚假变化。
37.如权利要求31所述的方法，其特征在于，所述生物传感器位于微量培养板孔的底部。
38.如权利要求31所述的方法，其特征在于，所述生物传感器是表面等离子共振传感器。
39.如权利要求31所述的方法，其特征在于，所述生物传感器是共振波导光栅传感器。
40.如权利要求31所述的方法，其特征在于，所述沉积技术包括以下一种：接触针印刷、非接触印刷(喷墨印刷、气溶胶印刷)、毛细管印刷、微触点印刷、凹版移印、网点印刷、丝网印刷、微量移液和喷雾。
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WO2006072042A3 (en) 2006-08-24
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