CN1302375A - 用于生物聚合物阵列成象和分析的方法及装置 - Google Patents
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Abstract
使用全内反射荧光进行生物聚合物阵列成象。光束(2)以一定角度导入固体支持体(1),在固体支持体内引起全内反射。一部分光从内玻片表面不反射,而以渐消散的波从玻片中穿出。它将激发与支持体表面结合的生物聚合物分子结合的荧光团。这样引起的荧光导入光敏元件(7),提供位于支持体表面上的荧光分子的数据。所述荧光信号的检测迅速,每个荧光通道约需10秒。
Description
本发明涉及分子生物学、分子诊断学和激光光学等领域。更具体地说涉及一种利用全内反射荧光的方法，在二维阵列上对荧光标记的生物聚合物分子进行平行测定和分析的方法，以及一种荧光检测装置。
在二维结构固体透明支持体(玻片)上的预制的短生物聚合物(核酸，缩氨酸等)的化学健结合过程中，所述的阵列结构可用于诊断目的，例如，当将样靶核酸加(杂化)到固定的核苷酸聚合物中时。靶样品在杂化之前用荧光团进行标记，但是标记的结合在扫描前迅速发生。至于核酸阵列的分析和成象，可使用基于不同物理原理的装置，主要涉及两类：一是检测器，二是基于同焦显微镜的扫描仪。
与本发明所描述的装置最密切的类型，基于全内反射的荧光检测器，是基于由Vysis公司(Downers Grove,IL,USA)制造的、称为GenoSensorTM的CCD摄像机装置。
基于CCD摄像机的装置GenoSensorTM功能如下。通过光透射DNA阵列(图1)引起的激发，检测与结合在玻片支持体上的DNA探针杂化的荧光标记的靶分子。光由氙灯产生，并通过滤光镜选择必要的光谱带。由荧光团发出的光通过发射滤光片并经过光学系统的引导，到达高分辨率的冷却的CCD摄像机上。所得信号在计算机内进行处理。
核酸阵列是与固体透明支持体结合的高密度、二维结构的核酸分子。由于较低的灵敏度、选择性(由于用于激发的谱带必须从整个光谱中过滤出来，因此使用透射光进行荧光团的激发效率低)和较低的检测速度(扫描总是要耗时的)，阵列上进行生物反应的结果评定存在问题。当存在整列引物延伸反应(APEX)的情况下，在反应中同时使用四种不同的的寡聚核苷酸或终止剂，每个携带不同荧光团，就需要能在四个光谱区域中运行的检测器，进行核酸阵列成象。所述检测器必须是能对每一个荧光团最大限度地激发和信号捕获，并能得到综合反应结果的装置。
作为上述提到问题的解决方案，本发明提出了一种包括全内发射荧光(图2)，进行生物聚合物阵列成象(类似于靶DNA的测序)的方法，以及能够在四个不同的光谱带内迅速并精确地评估核酸阵列上的反应结果的荧光检测器装置。
本发明的目的在于，提供一种用于分析生物聚合物阵列或“芯片”上进行的生物反应的装置和方法。核酸阵列主要用在两个方面。首先，在仅基于杂化分析的情况下，待分析的荧光标记靶将与固定在阵列上的遗传物质杂化。在扩增过程中将标记结合。由于双链核酸中的氮基间形成氢键的能量受到限制，该基于杂化反应机理的类型就不特别具有选择性，也不能清楚地分辨信号和噪音。
另一个可能在于固定的寡聚核苷酸探针和靶核酸的杂化中添加酶反应。例子是聚合酶介导的延伸反应(polymerase-mediated extension)，在此每个固定的寡聚核苷酸变成加长了一个荧光标记核苷酸。DNA聚合酶增加了一个有关靶DNA的遗传信息的核苷酸。
阵列的DNA扩展反应用荧光团标记的二脱氧核苷酸作为DNA聚合酶的基质。同时使用四种不同标记的二脱氧核苷酸，但仅有一种与探针结合，其对应于靶核酸的初级结构。
所述酶机理方法优于仅基于杂化的反应之处在于：
1．如果固定探针和靶之间的杂化不好，则聚合酶既不识别结构也不进行反应。
2．如果杂化很好，酶在探针上与二脱氧核苷酸结合，形成稳定的共价键。这能使阵列在反应后得以洗涤，以除去非特定结合的生物物质。因此做到实质性地提高信噪比，使系统能够检测杂合突变。
本发明所描述的方法用于生物聚合物阵列分析。一束已知波长的光(激光)以一定的角度射入支持体(玻片)的边缘，该角度将引起光束的全内反射。该支持体成为波导(图2)。一部分光不会从玻片的内表面反射，但是将作为容易消散的波从玻片中穿出。其强度将呈指数下降，但在1/4波长的距离上保持足够强度。该距离足以激发与玻片紧接的探针中所含的荧光团。由于在聚合酶延伸的情况下有四种不同的核苷酸/标记，使用四种不同波长的激光束来达到最大限度地激发荧光标记。发射的光将通过各自的发射滤光镜聚集以去除背景光，并通过光学系统(物镜)聚焦进入CCD摄像机。由于使用的摄像机已冷却，所以成象时间短，对于每个核苷酸/荧光通道约需10秒种。
本发明将依照附图进行描述，在此：
图1是通过横向光对位于生物聚合物阵列表面上荧光团进行激发；
图2是根据本发明的方法通过全内反射荧光进行所述激发；
图3是本发明方法的应用，在此引起全内反射的激光束通过柱面透镜聚焦，这样其直径小于支持体的厚度；
图4是本发明方法的应用，在此使用棱镜将激光束引导进入支持体。在棱镜和支持体之间存在透明液体，其折射率与棱镜和支持体的折射率接近。
图5是本发明装置，荧光检测器的主要设计图。
图2到图4表示本发明用于生物聚合物阵列成象的方法。荧光标记的生物聚合物分子固定到带有平行壁(1)的薄支持体上。为了最大限度地激发荧光分子，使用激光束(2)。该激光通过一个呈扇形的比边缘(1)薄的柱面镜(3)聚焦，在此光束以使支持体变为全内反射的波导的角度入射到边缘(1)上。
由激光束得到的荧光光学地进入光敏元件，该光敏元件可提供固定在支持体(1)上的荧光分子的图象。通过由上面所述原理获得的荧光投影到光敏元件上，该光敏元件能够获得如图5所示的固定在支持体(1)上并由激光束激发的荧光分子的图象。激光束通过侧表面射向支持体。使用数字控制的CCD摄像机作为光敏元件。激光束通过透明平板或六面体(4)散射，同时用光楔调整。这些元件的组合修正来自反射镜(6)的激光进入支持体(1)的角度。
如图4所示，使用棱镜(8)将光束通过边缘表面导入支持体(1)。为减少光从棱镜(8)进入支持体(1)的转换过程中的反射损失，而使用透明液体(9)，例如在显微镜中使用的浸油，其折射率与棱镜(8)和支持体(1)的折射率接近。
尽管本发明结合具体的优选实施例进行了描述，可以理解的是本发明不限于所描述的主题，而相反的是，本发明还要包括包含所加专利权利要求书精神和范围的各种改进和等效的装置。
Claims (11)
1．一种生物高分子阵列成象和分析方法，特征在于一定波长的光束以在支持体内引起全内反射的角度射入阵列支持体，该支持体成为波导，并且一部分光作为渐消散的波穿过支持体的表面，并激发迅速设置到表面的与分子结合的荧光团。
2．如权利要求1的所述的方法，特征在于所述光束为激光束。
3．为权利要求1和2所述方法提供的荧光检测器，包括数控CCD摄像机(7)，带通滤光镜和散射柱面镜(3)，以增宽照明区域。
4．根据权利要求3所述的荧光检测器，特征在于生物高分子阵列支持体中的区域的增宽，通过激光束的扫描移动完成，其中所述的扫描通过透明平板或六面体(4)完成，旋转该平板或六面体可改变激光束进入支持体(1)的入射角度。
5．根据权利要求3或4的荧光检测器，特征在于使用调整元件来获得支持体(1)上较均匀的光分布。
6．根据权利要求5所述的荧光检测器，特征在于调整元件是一个能围绕它的轴旋转的光楔(5)，其中光楔的轴位于激光束的光轴附近。
7．根据权利要求3至6中任一个的荧光检测器，特征在于为得到支持体较均匀的激光束分布，支持体(1)的激光束入射边缘或侧表面是磨砂的，以得到光的色散。
8．根据权利要求3至7中任一个的荧光检测器，特征在于为得到支持体上较高强度的激光束，支持体(1)的激光束入射边缘或侧表面是抛光的。
9．根据权利要求3至8中任一个的荧光检测器，特征在于使用位于支持体(1)上的衍射光栅，使得激光束射入支持体(1)。
10．根据权利要求3至9中任一个的荧光检测器，特征在于使用光学棱镜(8)使激光束经过支持体(1)的侧表面导入支持体。
11．根据权利要求3至10中任一个的荧光检测器，特征在于在支持体(1)和棱镜(8)之间放置透明液体(9)，例如浸油，其反射率与棱镜(8)和支持体(1)的反射率接近。
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| DE10326223B4 (de) * | 2003-06-11 | 2008-07-31 | Technische Universität Dresden | Verfahren zur Strukturierung dünner Schichten mittels optischer Lithographie und Anordnung zur Durchführung der optischen Lithographie |
| CN102097458B (zh) | 2004-06-04 | 2013-10-30 | 伊利诺伊大学评议会 | 用于制造并组装可印刷半导体元件的方法和设备 |
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| US3939350A (en) * | 1974-04-29 | 1976-02-17 | Board Of Trustees Of The Leland Stanford Junior University | Fluorescent immunoassay employing total reflection for activation |
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| DE3481644D1 (de) * | 1984-12-10 | 1990-04-19 | Prutec Ltd | Verfahren zum optischen nachweis von parametern von substanzen in einem fluessigen analyt. |
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| US5633724A (en) * | 1995-08-29 | 1997-05-27 | Hewlett-Packard Company | Evanescent scanning of biochemical array |
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1999
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- 2000-04-20 AT AT00925106T patent/ATE430306T1/de not_active IP Right Cessation
- 2000-12-20 US US09/741,960 patent/US20010003043A1/en not_active Abandoned
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| EP1088214B1 (en) | 2009-04-29 |
| EP1088214A1 (en) | 2001-04-04 |
| AU4394400A (en) | 2000-11-02 |
| CA2335438A1 (en) | 2000-10-26 |
| JP2002542479A (ja) | 2002-12-10 |
| ATE430306T1 (de) | 2009-05-15 |
| DE60042100D1 (de) | 2009-06-10 |
| US20010003043A1 (en) | 2001-06-07 |
| WO2000063677A1 (en) | 2000-10-26 |
| EE9900072A (et) | 2000-12-15 |
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