CN101910824A - 用于生物传感器的优化检测器读出 - Google Patents

用于生物传感器的优化检测器读出 Download PDF

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CN101910824A
CN101910824A CN2008801236974A CN200880123697A CN101910824A CN 101910824 A CN101910824 A CN 101910824A CN 2008801236974 A CN2008801236974 A CN 2008801236974A CN 200880123697 A CN200880123697 A CN 200880123697A CN 101910824 A CN101910824 A CN 101910824A
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CN101910824B (zh
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J·A·H·M·卡尔曼
B·米切尔斯
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Siemens Medical Diagnostic Solutions First Holdings Ltd
Siemens Medical Holland Ltd
Siemens Medical Systems Holland Ltd
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Koninklijke Philips Electronics NV
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Abstract

本发明提供了一种生物传感器系统，包括：光源；适于被所述光源照射的盒；适于检测源自所述盒的信号的光检测器；适于在至少两种不同状态之间改变对所述盒的照射的照射控制器件；用于生成具有第一频率的第一振荡的器件；以及用于生成具有第二频率的第二振荡的器件，其中，由所述第一振荡触发所述光检测器的帧率，并且由所述第二振荡触发所述照射控制器件。

Description

用于生物传感器的优化检测器读出
技术领域
本发明涉及一种生物传感器的光学检测器的改进读出的方法，并涉及一种用于所述方法的系统。
背景技术
近来，对生物传感器的需求一直在增加。通常，生物传感器能够检测分析物内的给定特异性分子，其中，所述分子的量通常很小。因此，如果分析物内存在要检测的分子，则使用仅结合到特异性结合位点或点的目标粒子，例如超顺磁性标记珠。一种用以检测结合到结合点的这些标记粒子的已知技术是FTIR。其中，光以全内反射角耦合到样品中。如果靠近样品表面不存在粒子，光被完全反射。不过，如果标记粒子结合到所述表面，破坏了全内反射的条件，一部分光被散射到样品中，由此表面反射的光量减小。通过利用光学检测器测量反射光的强度，可以估计结合到表面的粒子的量。
通常，将光电二极管用作光学检测器。然而，通过(CCD)相机或任何其他多像素系统进行检测要高效得多，这是由于相机能够并行检测很多结合位点或点。不过，使用相机的缺点在于，由于读出系统中的增益误差和偏移误差而很难精确测量结合点的强度。
发明内容
因此，本发明的目的在于提供一种用于生物传感器的改进的光学检测器读出。这一目的是利用权利要求的特征实现的。
本发明基于这样的想法，即：调制耦合到样品中的光的振幅并同时检测由样品表面反射的或源自样品的光。从而，可以精确地测量(一个或多个)结合点的相对变暗。
本发明提供了一种生物传感器系统，包括：光源；适于被所述光源照射的盒(cartridge)；适于检测源自所述盒的信号的光检测器；适于在至少两种不同状态之间改变对所述盒的照射的照射控制器件；用于生成具有第一频率的第一振荡的器件；以及用于生成具有第二频率的第二振荡的器件，其中，由所述第一振荡确定，例如触发所述光检测器的帧率，并且由所述第二振荡确定，例如触发所述照射控制器件。
由第一振荡触发检测器的帧率不表示同样由所述振荡确定检测器的积分时间。可以由检测器或其控制确定，或由所述第一振荡的波形确定积分时间。对于由第二振荡触发照射控制器件而言，也是同样的情况。
其中，所述第二频率优选地等于所述第一频率的一半。因此，盒经历两种不同的照射状态，例如，基本为暗的一种照射状态，和基本为亮的第二照射状态。由于由第一振荡触发光检测器，所以交替从暗状态和亮状态拍摄图像。这实现了改进的图像分析，这是由于所述暗状态包含了与噪声、背景、不均匀照射等有关的信息。
然而，除1∶1之外的暗帧与亮帧的其他频率比也是可能的。具体而言，这取决于干扰，即噪声的带宽。1∶1的比率既能最大降低带宽又能获得最大数量的亮帧。不过，只要必需抑制缓慢变化的暗电流，这个比例可以是例如1∶10。在那种情况下，大部分的帧是亮的，从而能够从结合点自身收集到更多信息。
具体而言，光检测器可以包括视频或CCD相机。在那种情况下，或者可以使用相机的(电子)快门来在两个值之间调制光振幅，而不是调制光源自身。不过，这样不会在相机传感器受抑制之前诱发背景光。
不过，也想到了其他检测器，例如分立的光电二极管或任何适当的多像素系统。
系统还可以包括用于分析视频或CCD相机输出的视频处理软件以及用于将由盒反射或源自盒的光投射到光检测器或相机上的光学装置。
本发明还涉及一种检测生物传感器盒的结合点处相对变暗的方法。所述方法包括如下步骤：在第一照射下拍摄所述结合点及其周围的第一图像，并分析所述第一图像中所述结合点处的强度I1(A)及其周围处的强度I1(B)。然后，在第二照射下拍摄所述结合点及其周围的第二图像，并分析所述第二图像中所述结合点处的强度I2(A)及其周围处的强度I2(B)。最后，计算所述结合点的相对变暗。其中，所述第二照射具有比所述第一照射更高的强度。任选地，该方法还包括识别结合点的步骤。
优选地，通过D＝(I2(A)-I1(A))/(I2(B)-I1(B))计算所述结合点的相对变暗D。不过，其他计算相对变暗的方法也是可能的。例如，可以逐个像素地执行分析第一和第二图像的强度的步骤。
当然，生物传感器系统或检测方法都不限于逐帧的照射调制。可以对帧的不同部分进行不同的照射。例如，可以想到检测器渐进地扫描像素或类似例如图像的水平条的区域。
可以将所述方法实施于不同的已知技术以执行生物感测。例如，可以通过受抑全内反射(FTIR)测量靠近传感器表面的标记粒子的量。不过，根据本发明的方法不限于任何特定的感测技术或传感器。传感器能够是用以检测在传感器表面上或附近粒子的存在的任何适当传感器，例如，通过成像技术、荧光技术、化学发光技术、吸收技术、散射技术、倏逝场技术、表面等离子体谐振、Raman等进行所述检测。
参考下文描述的(一个或多个)实施例，本发明的这些和其他方面将显而易见并得到阐述。
附图说明
图1示意性示出了由FTIR获得的相机图片；
图2示出了对于两个不同增益的相机响应；
图3示意性示出了根据本发明的FTIR系统的实施例；
图4a绘示出示出了照射光强度与时间的关系的图表；
图4b绘示出示出了区域A的光强度与时间的关系的图表；
图4c绘示出示出了区域B的光强度与时间的关系的图表。
具体实施方式
图1示意性示出了由FTIR获得的相机图片。这幅图片是(主要)通过对盒的FTIR表面进行均匀照射并经由光学系统将反射光投射到(CCD)相机上获得的。其中，可以在具有特定背景照射或噪声水平的区域B中识别六个结合位点或点A1、A2。结合位点的亮度取决于结合到这些位点的标记粒子的量：结合了越多的标记粒子，在相应区域就散射越多的光，从而引起反射光的减少。于是，暗的结合位点表示大量的结合标记粒子。结合点与周围区域相比的相对变暗D是对结合数量的度量，因此是对样品流体内特异性分子的量的度量。
然而，因为读出系统中增益误差和偏移误差的原因，不能精确地测量所述相对变暗。这是由光学光路中的未知光学增益、照射等级、相机中的增益参数(曝光时间、快门、有源像素等)引起的。其他负面效应是杂散背景光和相机中的暗电流。
在典型的FTIR几何结构中，在较大的光学基线信号上检测来自标记粒子或标记珠的小信号变化。所述光学基线信号源自于来自结合表面的表面的大反射。由于这一大的光学基线信号，源自传感器、信号处理和光学光路中温度效应(漂移)的增益变化将引起被检测信号中大的变化，这限制了生物传感器的可实现精确度和检测限制。这在对低目标浓度进行较长时间测量期间，尤其是一个问题。
此外，对于高灵敏度应用而言，对检测电子线路的动态范围的要求是相当严格的。此外，来自环境和光照的杂散光源可能会干扰测量。
相机响应是每个像素的输出与所施加光强度的关系，由于制造公差的原因，所述相机响应在像素之间可能有变化。此外，增益取决于类似曝光时间、快门设置、选定像素(黑白或彩色)的很多参数，并非是明确的。图2示出了由于不同增益的原因，典型像素的两种不同响应。动态范围通常由分辨率确定，例如为8比特。
图3示意性示出了根据本发明的FTIR系统的实施例。由光源2照射FTIR盒1。该光源例如可以是激光器或LED。入射光2a满足全内反射条件，并且在盒1的传感器表面被反射。在相机3处检测反射光3a，所述相机3例如可以是CCD相机。入射光2a在盒1内生成倏逝波。如果靠近盒的表面存在光学不均匀性，例如，标记粒子，所述波的一部分被散射。因此，在相机3处检测的反射光3a的强度被改变。
根据本发明，由照射光控制器件4控制光源2。具体而言，能够由控制器件4控制由光源2发射的光的强度。
系统还包括振荡器6，其生成第一频率的第一振荡，所述第一频率例如是30Hz。由所述第一振荡确定相机3的帧率。除法器5将第一频率除以一因子，优选地为2，以生成具有第二频率的第二振荡。在第一频率为30Hz且因子为2的示例性情况下，，第二频率将为15Hz。所述第二振荡触发照射光控制器件4。
于是，利用第二频率，例如15Hz改变照射的强度，而相机的帧率等于第一频率，例如30Hz。因此，以交替的方式拍摄反射光3a的亮图片和暗图片。然后由软件7，例如LabView或任何其他适当软件，来分析这些亮图片和暗图片。
或者，可以使用相机3的(电子)快门在两个值之间调制光振幅，而不是调制光源2自身。如上所述，这不会考虑到背景光的降低。
图4a绘示出示出了照射光2a的变化强度与时间的关系的图表。如上所述，具有低强度IL(可以为零)的暗帧紧跟在具有高强度IH的亮帧之后。因此，相机3拍摄的图片中区域B(参考图1)的背景强度将以图4c所示的相应模式变化：如果利用低强度照射盒，背景强度BL也将是低的。如果利用高强度照射盒，背景强度BH也将增大。
对于结合点A(参考图1)的强度而言，也是同样的情况。图4b中示出了特异性结合点或位点的交替强度AL和AH。当然，从图1中显而易见的是，这些强度的绝对值将取决于特异性结合点。虽然如此，对于所有结合点而言，强度随时间变化的模式是类似的。
将所述亮帧和暗帧传输到视频处理软件7，这使得接口连接稳定而鲁棒，这是由于相机和软件是照射序列的“从属设备”，而不需要接口控制环路等。
根据可以容易地计算出结合点的相对平均变暗D。在测定开始时，盒是“白色的”，因此在t＝0时(即测定开始时)平均强度满足方程
Figure BPA00001174933700052
结果，结合点的相对变暗D减小到
Figure BPA00001174933700053
其中，BL和BH是整个背景区域B上的平均光值。
不过，这种方法不会给出结合点内结合分布的信息，因为针对每个结合点仅计算平均相对变暗。因此，建议利用改进的处理来计算每个像素的相对变暗。
在必须要评估结合点内的结合分布时，需要有针对增益和偏移进行矫正的图像。因此，对于图像中的每个像素P，根据
Figure BPA00001174933700061
参照白色区域计算相对变暗DP。与上述方法相反，
Figure BPA00001174933700062
这是因为实际像素值可能偏离平均值。
显然，结合点A的平均相对变暗为：
Figure BPA00001174933700063
与利用上述方法获得的值相比，对于不均匀偏移光而言，这是更为精确的。
本发明的系统提供了几个优势：不需要正向感测或监测二极管，对于FTIR通常是需要的。所获得的结果独立于增益。抑制了杂散背景光和相机暗电流。并且与系统软件的接口连接容易而鲁棒。
当然，尽管参考FTIR传感器进行的描述，但是本发明中描述的方法不限于FTIR。所述传感器能够是用以基于任何粒子属性检测在传感器表面上或传感器表面附近粒子的存在的任何适当传感器，例如，通过反射或透射成像技术、荧光技术、化学发光技术、吸收技术、散射技术、倏逝场技术、表面等离子体谐振、Raman等进行检测。
可以在几种类型的生物化学测定中采用根据本发明的方法，这样的生物化学测定例如为结合/拆分测定、夹层测定、竞争测定、移位测定、酶测定等。本发明的方法适于传感器复用(即，并行采用不同传感器和传感器表面)、标记复用(即，并行采用不同类型的标记)以及室复用(即，并行采用不同反应室)。可以将本发明中描述的方法用作针对小的样品体积的快速、鲁棒并且易于使用的护理点生物传感器。反应室可以是与紧凑型读取器结合使用的一次性用品，其包括一个或多个磁场生成器件以及一个或多个检测器件。而且，本发明的方法可被用于自动化高通量测试中。在这种情况下，反应室例如是适合于自动化仪器的孔板或试管(cuvette)。
尽管已经在附图和上述说明中详细图示出和描述了本发明，但是应当将这样的图示和描述看作是示范性或示例性的，而不是限定性的；本发明不限于所公开的实施例。通过研究附图、说明书和权利要求书，本领域技术人员能够在实践所要求保护的本发明时能够理解并实施针对所公开的实施例的其他变型。在权利要求中，“包括”一词不排除其他元件或步骤，并且不定冠词“一”、“一个”不排除多个。单个处理器或其他单元可以实现权利要求中列举的若干项的功能。在互不相同的从属权利要求中列举某些措施不表示不能有利地采用这些措施的组合。权利要求中的附图标记不应被理解为对范围进行限制。

Claims (11)

1.一种生物传感器系统，包括：光源；适于被所述光源照射的盒；适于检测源自所述盒的信号的光检测器；适于在至少两种不同状态之间改变对所述盒的照射的照射控制器件；用于生成具有第一频率的第一振荡的器件；以及用于生成具有第二频率的第二振荡的器件，其中由所述第一振荡确定所述光检测器的帧率，并且由所述第二振荡确定所述照射控制器件。
2.根据权利要求1所述的系统，其中，用于生成所述第二振荡的所述器件包括用于将所述第一频率除以一因子的器件。
3.根据权利要求1所述的系统，其中，所述第二频率等于所述第一频率的一半。
4.根据权利要求1所述的系统，其中，一种照射状态基本为暗的，且第二照射状态基本为亮的。
5.根据权利要求1所述的系统，其中，所述光检测器包括视频或CCD相机。
6.根据权利要求5所述的系统，还包括用于分析所述视频或CCD相机的输出的视频处理软件。
7.根据权利要求1所述的系统，还包括用于将来自所述盒的光投射到所述光检测器上的光学装置。
8.一种检测生物传感器盒的结合点处相对变暗的方法，所述方法包括如下步骤：
a)在第一照射下拍摄所述结合点及其周围的第一图像；
b)分析所述第一图像中所述结合点处的强度I1(A)及其周围处的强度I1(B)；
c)在第二照射下拍摄所述结合点及其周围的第二图像；
d)分析所述第二图像中所述结合点处的强度I2(A)及其周围处的强度I2(B)；以及
e)计算所述结合点的相对变暗；
其中，所述第二照射具有比所述第一照射更高的强度。
9.根据权利要求8所述的方法，其中，通过D＝(I2(A)-I1(A))/(I2(B)-I1(B))计算所述结合点的相对变暗D。
10.根据权利要求8所述的方法，还包括识别所述结合点的步骤。
11.根据权利要求8所述的方法，其中，逐个像素地执行步骤b)、d)和e)。
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