CN103503043A - 用于从传感器阵列传送信息的系统 - Google Patents

用于从传感器阵列传送信息的系统 Download PDF

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CN103503043A
CN103503043A CN201180065839.8A CN201180065839A CN103503043A CN 103503043 A CN103503043 A CN 103503043A CN 201180065839 A CN201180065839 A CN 201180065839A CN 103503043 A CN103503043 A CN 103503043A
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CN103503043B (zh
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R·陈
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Roche Sequencing Solutions Inc
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Genia Technologies Inc
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    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3278—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction involving nanosized elements, e.g. nanogaps or nanoparticles
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Abstract

披露了一种用于从传感器阵列传送信息的系统。该系统包括传感器阵列，该传感器阵列包括多个传感器，其中，每一个传感器感测与该传感器通信的材料的物理属性。该系统进一步包括与每一个传感器相关联的信号处理电路，该信号处理电路在时间上对该传感器的输出进行积分，并将积分输出与阈值相比较。该系统进一步包括与信号处理电路耦合的通信网络，该通信网络输出指示对应于给定传感器的积分输出已达到阈值的信息。

Description

用于从传感器阵列传送信息的系统
对其他申请的交叉引用
本申请要求于2011年1月24日提交的、名称为“SYSTEM FORCOMMUNICATING INFORMATION FROMAN ARRAY OF SENSORS”的美国临时专利申请No.61／435,700(代理人案号No.GENIP009+)的优先权，该美国临时专利申请出于所有目的通过引用并入本文。
背景技术
近年来半导体产业内的微小型化中的进展已经使得生物技术专家能够开始将其传统上庞大的感测工具包装为越来越小的形状因子，包装到所谓的生物芯片上。将期望开发用于生物芯片的技术。
附图说明
在下面的详细描述及附图中披露了本发明的各个实施例。
图1是示出用于测量生物芯片中的单个细胞内的物理属性的传感器电路100的实施例的框图。
图2示出在恒定噪声基底的情况下，随着测量信号带宽减小，信噪比增大，从而改进了图1的传感器电路100的灵敏度。
图3是示出用于测量纳米孔阵列中的单个细胞内的物理属性(例如，电流)的传感器电路300的实施例的电路图。
图4是示出用于测量纳米孔阵列中的单个细胞内的物理属性的传感器电路400的第二实施例的电路图。
图5是示出电路300或电路400中的积分放大器的输出处的电压随时间变化的曲线图的图。
图6是示出生物芯片中的细胞阵列的实施例的框图。
具体实施方式
本发明可以以多种方式来实现，包括被实现为：过程；设备；系统；物质组成；计算机可读存储介质上体现的计算机程序产品；和／或处理器，诸如被配置为执行存储在耦合至处理器的存储器上和／或由该存储器提供的指令的处理器。在该说明书中，这些实施方式或者本发明可采用的任何其他形式可以被称为技术。一般地，在本发明的范围内，所披露的过程的步骤的顺序可以被更改。除非另有声明，可以将被描述为被配置为执行任务的诸如处理器或存储器之类的部件实现为被临时配置为在给定的时间处执行该任务的一般部件或被制造为执行该任务的具体部件。如本文所使用的那样，术语“处理器”涉及被配置为处理诸如计算机程序指令之类的数据的一个或多个器件、电路和／或处理核心。
在各个实施例中，在多种系统或形式中实现本文所描述的技术。在一些实施例中，以硬件方式将技术实现为专用集成电路(ASIC)或现场可编程门阵列(FPGA)。在一些实施例中，使用处理器(例如，诸如ARM核心之类的嵌入式处理器)，其中该处理器被提供或加载有用于执行本文描述的技术的指令。在一些实施例中，将技术实现为在计算机可读存储介质中体现且包括计算机指令的计算机程序产品。
下文中，连同示出本发明原理的附图一起，提供本发明的一个或多个实施例的详细描述。与这些实施例结合描述本发明，但本发明并不限于任何实施例。本发明的范围仅由权利要求限定，且本发明包含多种替换、修改及等同物。为了提供对本发明的透彻理解，在下面的描述中阐述多个具体细节。这些细节是为了示例的目的而提供的，并且可以在没有这些具体细节中的一些或全部的情况下根据权利要求来实施本发明。为了清楚的目的，并未详细地描述本发明相关技术领域中已知的技术材料，以便不会不必要地使本发明模糊。
近年来半导体产业内的微小型化中的进展已经使得生物技术专家能够开始将其传统上庞大的感测工具包装为越来越小的形状因子，包装到所谓的生物芯片上。这些芯片本质上是可执行数百或数千个同时生物化学反应的小型化实验室。生物芯片使得研究人员能够出于从疾病诊断到生物恐怖剂(bioterrorismagent)的探测的多种目的而迅速地筛查大量的生物分析物。
典型地，生物芯片包括大的细胞阵列。例如，用于核苷酸测序的生物芯片可以在阵列中包含数千或数百万个单个细胞。每个细胞包括由构成低聚纳米孔和单链DNA的单体以及被绑定至该单链DNA的任何物组成的分子配合物。纳米孔是可被用作单分子探测器的电绝缘膜中的小孔。可以使用诸如α-溶血素或MspA之类的生物材料来形成纳米孔。可以使用诸如半导体材料之类的固态材料来形成纳米孔。当跨越包含纳米孔的分子配合物施加较小电压时，可以测量通过分子配合物的离子电流，以提供关于经过分子配合物的分子的结构的信息。在阵列的单个细胞中，可以将电路用于控制跨越包含纳米孔的脂双层施加的电刺激，并用于探测穿过纳米孔的分子的电图案或签名。这些图案或签名标识出所关注的事件，诸如对分子配合物的增加或减少或者对分子配合物的构象变化。为了降低阵列的成本，其中的高度灵敏的传感器内的物理上小的单个细胞是期望的。
图1是示出用于测量生物芯片中的单个细胞内的物理属性的传感器电路100的实施例的框图。如图1中所示，由探测器102探测物理属性(例如电流、电压或电荷)，作为探测信号104。如下文中进一步描述的那样，传感器电路100可以用于在不采样的情况下测量探测信号104的均值。
在一些实施例中，发起标记106重置积分放大器108，并开始在时间上对探测信号104的连续积分。使用比较器112将积分输出110与跳闸阈值114进行比较。当积分输出110达到跳闸阈值114时，可以使用跳闸标记116作为对积分放大器108的反馈信号，以终止对探测信号104的积分。例如，当跳闸标记116为“开启”或被断言时，终止积分。发起标记106的断言和跳闸标记116的断言之间的持续时间与探测信号104的均值(例如，电流的均值)成比例。相应地，可以将跳闸标记116(仅1个信息比特)的“开启”和“关闭”从细胞发送至外部处理器，以计算探测信号104的均值。可替换地，可以将“开启／关闭”信息从细胞发送至外部存储器，以用于延迟处理。例如，可以将发起标记106和跳闸标记116分别被断言的时钟周期记录在外部存储器中。然后，可以使用两个被断言的标记之间的时钟周期的数目来在稍后的时间处确定探测信号104的均值。
在一些实施例中，可以通过在多个积分周期上对探测信号104进行积分来获得更加精确的结果。例如，可以在多个积分周期上对探测信号104的所确定的均值进一步平均。在一些实施例中，发起标记106至少部分地基于跳闸标记116。例如，可以响应于跳闸标记116被断言而重新断言发起标记106。在该示例中，可以将跳闸标记116用作用于重新初始化积分放大器108的反馈信号，使得一旦前一个积分周期被终止，探测信号104的另一个积分周期就可以开始。在跳闸标记116被断言之后立即重新断言发起标记106减少了探测器102生成未被积分且因此未被测量的信号时的时间的部分。在信号可用的近似整个时间上进行积分。由此，捕获了信号的大部分信息，从而最小化了获得测量信号的平均值的时间。
在特定积分周期期间，散粒噪声可能破坏跳闸标记116。相应地，一些实施例可以包括用于进行下述操作的逻辑：确定跳闸标记116是否已被散粒噪声在跳闸标记116被存储或用于任何计算之前的特定积分周期中破坏。
通过在不采样的情况下对探测信号102进行连续积分来最大化传感器电路100的灵敏度。这用来限制测量信号的带宽。继续参考图1，跳闸阈值114和积分系数A设置了测量信号的带宽。随着积分系数A减小或者随着跳闸阈值114增大，测量信号带宽减小。图2示出在恒定噪声基底的情况下，随着测量信号带宽减小，信噪比增大，从而改进了传感器电路100的灵敏度。在一些实施例中，可以通过改变跳闸阈值114来动态地调整测量信号带宽。
图3是示出用于测量纳米孔阵列中的单个细胞内的物理属性(例如，电压)的传感器电路300的实施例的电路图。图4是示出用于测量纳米孔阵列中的单个细胞内的物理属性的传感器电路400的第二实施例的电路图。
参考图3和4，S1控制电路包括比较器和其他逻辑，例如用于切换的逻辑。电路300(或电路400)的包含差分对的其他部件实现与图1中的积分放大器类似的积分放大器。电路300(或电路400)的输入连接至纳米孔系统局部电极。
图5是示出电路300(或电路400)中的310(或410)处的电压随时间变化的曲线图的图。在图5中，ttrip指示流经纳米孔的平均电流。减小噪声带宽减少了与ttrip相关联的噪声。相应地，平均电流测量将具有更高的信噪比(SNR)且更加精确。
积分放大器生成包含分子配合物的所关注的事件的期望带宽内的信号。积分放大器被配置为仅放大所关注的带宽中的信号并拒绝该带宽外的信号。由于有用信号的带宽比探测信号小得多，因此放大所有信号就大部分放大了噪声，从而导致较差的SNR。可以通过针对电路300和400中的Cl和IO选择合适的值来限制所关注的带宽。在一些实施例中，Cl和IO被选择为将所关注的带宽限制在0.3Hz和300Hz之间。在一些实施例中，可以通过改变Cl的值来动态地调整所关注的带宽。
在一些实施例中，将用于每一个细胞的跳闸标记116与由生物芯片内的所有细胞共享的全局时钟进一步同步。例如，与全局时钟同步的跳闸标记116可以由脉冲生成电路生成。在同步之后，跳闸标记116为与全局时钟同相的单个脉冲。
图6是示出生物芯片中的细胞阵列的实施例的框图。每个细胞可以包含如上所述的用于测量细胞内的物理属性的传感器电路100。如图6中所示，细胞阵列具有m列乘n行的单个细胞。给定列中的所有细胞共享相同列线302，并且给定行中的所有细胞共享相同行线304。当用于特定细胞的跳闸标记116被断言时，该细胞断言其特定列线302和行线304。为了减少生物芯片的管脚计数，可以使用列复用器306来输出用于指示哪个列线302已被断言的列号(0-2m-1)。相似地，可以使用行复用器308来输出用于指示哪个行线304已被断言的行号(0-2n-1)。例如，如果第二列和第二行中的细胞的跳闸标记116被断言，则输出的列和行号为(1,1)。只要一次仅一个细胞断言其跳闸标记116，所报告的列和行号就足以唯一地标识在特定时刻处哪个特定细胞被断言。
上述技术具有相对于其他方法的多个优点。积分放大器需要极小的管芯面积，且允许每一阵列部位具有其自身专用的测量电路。该特征去除了将敏感的模拟信号路由至阵列外围的必要且避免了对复用的需要，从而减小了噪声。积分放大器不需要前置放大器、采样和保持、或抗混叠滤波器，从而进一步减小了管芯面积和潜在的误差源。由于仅需要单个标记来表示测量的完成，因此该积分方法是一种从每个阵列部位传送数据的高效方式。测量是连续地进行的(除重置积分电容器所需的短暂时间外)，因此，数据几乎是在100％的时间内收集的。此外，每一个细胞及其关联的测量电路自主地操作，允许每个细胞追踪测量分子的状态。如上所述，该积分方法还具有固有信号平均和噪声优势。
虽然为了清楚理解的目的较为详细地描述了上述实施例，但是本发明并不限于所提供的细节。存在多种替换方式来实现本发明。所披露的实施例是示意性的而非限制性的。
权利要求如下：

Claims (52)

1.一种用于从传感器阵列传送信息的系统，包括：
包括多个传感器的传感器阵列，其中，每一个传感器感测与该传感器通信的材料的物理属性；
与每一个传感器相关联的信号处理电路，其在时间上对该传感器的输出进行积分，并将积分输出与阈值相比较；以及
与信号处理电路耦合的通信网络，其输出指示对应于给定传感器的积分输出已达到阈值的信息。
2.根据权利要求1所述的系统，其中，在时间上对该传感器的输出进行积分包括：基于发起标记来发起积分；以及基于指示对应于该传感器的积分输出已达到阈值的信息来终止积分。
3.根据权利要求2所述的系统，其中，通信网络进一步输出发起标记的状态。
4.根据权利要求2所述的系统，其中，积分的发起和终止之间的时间段与物理属性的均值相对应。
5.根据权利要求2所述的系统，其中，通过下述操作来重复在时间上对该传感器的输出进行积分：至少部分地基于指示对应于该传感器的积分输出已达到阈值的信息来导出发起标记。
6.根据权利要求5所述的系统，其中，响应于指示对应于该传感器的积分输出已达到阈值的信息来重新断言发起标记。
7.根据权利要求1所述的系统，其中，至少部分地基于调整与信号处理电路相关联的系数来调整积分输出的带宽。
8.根据权利要求1所述的系统，其中，至少部分地基于调整阈值来调整积分输出的带宽。
9.根据权利要求1所述的系统，其中，至少部分地基于调整与信号处理电路相关联的电容来调整积分输出的带宽。
10.根据权利要求1所述的系统，其中，至少部分地基于减小积分输出的带宽来增大积分输出的信噪比。
11.根据权利要求1所述的系统，其中，传感器阵列包括纳米孔阵列。
12.根据权利要求1所述的系统，其中，物理属性包括下述各项之一：电流、电压或电荷。
13.根据权利要求1所述的系统，其中，所述信息对应于物理属性的均值。
14.根据权利要求1所述的系统，其中，所述信息包括1比特标记。
15.根据权利要求14所述的系统，其中，将用于给定传感器的1比特标记与由多个传感器共享的全局时钟进行同步。
16.根据权利要求15所述的系统，其中，该1比特标记由脉冲生成电路生成。
17.根据权利要求14所述的系统，其中，传感器阵列包括第一多个行的传感器和第二多个列的传感器，以及其中，用于每一行的传感器的1比特标记共享行信号线，以及其中，用于每一列的传感器的1比特标记共享列信号线，以及其中，每个行信号线在共享该行信号线的至少一个1比特标记被断言的情况下被断言，以及其中，每个列信号线在共享该列信号的至少一个1比特标记被断言的情况下被断言。
18.根据权利要求17所述的系统，进一步包括：行复用器，响应于被断言的行信号线输出行号，该行号对应于被断言的行信号线。
19.根据权利要求17所述的系统，进一步包括：列复用器，响应于被断言的列信号线输出列号，该列号对应于被断言的列信号线。
20.根据权利要求1所述的系统，进一步包括：被配置为确定信息是否被散粒噪声破坏的逻辑。
21.一种用于从传感器阵列传送信息的方法，包括：
感测与传感器阵列中的每个传感器通信的材料的物理属性；
在时间上对每个传感器的输出进行积分，并将积分输出与阈值相比较；以及
输出指示对应于给定传感器的积分输出已达到阈值的信息。
22.一种用于探测分子配合物的电属性的系统，包括：
与分子配合物电耦合的电极，分子配合物输出受分子配合物的电属性影响的电信号，其中，分子配合物的电属性对该电信号的影响由期望带宽表征；以及
积分放大器电路，其被配置为：
从该电极接收电信号；以及
选择性地对预定带宽内的电信号的部分进行放大并在时间上对其进行积分，其中，预定带宽是至少部分地基于期望带宽来选择的。
23.根据权利要求22所述的系统，其中，期望带宽包括分子配合物的所关注的事件的带宽。
24.根据权利要求22所述的系统，其中，所关注的事件包括对分子配合物的增加或减少。
25.根据权利要求22所述的系统，其中，所关注的事件包括分子配合物的构象变化。
26.根据权利要求22所述的系统，其中，分子配合物由构成低聚纳米孔和单链DNA的单体以及被绑定至该单链DNA的任何物组成。
27.根据权利要求22所述的系统，其中，电属性包括下述各项之一：电流、电压、电荷、或电容。
28.根据权利要求22所述的系统，其中，积分放大器电路进一步被配置为：
将选择性地放大和积分的电信号与阈值相比较；以及
输出选择性地放大和积分的电信号已达到阈值的指示。
29.根据权利要求28所述的系统，其中，至少部分地基于调整阈值来调整预定带宽。
30.根据权利要求28所述的系统，其中，所述指示对应于电属性的均值。
31.根据权利要求28所述的系统，其中，所述指示包括1比特标记。
32.根据权利要求28所述的系统，其中，积分放大器电路被配置为：
基于发起标记来发起积分；以及
基于所述指示来终止积分。
33.根据权利要求32所述的系统，其中，积分的发起和终止之间的时间段与电属性的均值相对应。
34.根据权利要求32所述的系统，其中，通过下述操作来重复在时间上的积分：至少部分地基于所述指示来导出发起标记。
35.根据权利要求34所述的系统，其中，响应于所述指示来重新断言发起标记。
36.根据权利要求22所述的系统，其中，至少部分地基于调整与积分放大器电路相关联的电容值来调整预定带宽。
37.根据权利要求22所述的系统，其中，至少部分地基于调整跨越与该分子配合物相关联的纳米孔施加的偏置电压来调整预定带宽。
38.根据权利要求22所述的系统，其中，积分放大器电路进一步包括对电信号进行滤波的噪声滤波器。
39.一种用于探测分子配合物的电属性的方法，包括：
将电极与分子配合物电耦合，分子配合物输出受分子配合物的电属性影响的电信号，其中，分子配合物的电属性对电信号的影响由期望带宽表征；
从该电极接收电信号；以及
选择性地对预定带宽内的电信号的部分进行放大并在时间上对其进行积分，其中，预定带宽是至少部分地基于期望带宽来选择的。
40.根据权利要求39所述的方法，其中，期望带宽包括分子配合物的所关注的事件的带宽。
41.根据权利要求39所述的方法，其中，电属性包括下述各项之一：电流、电压、电荷、或电容。
42.根据权利要求39所述的方法，进一步包括：
将选择性地放大和积分的电信号与阈值相比较；以及
输出选择性地放大和积分的电信号已达到阈值的指示。
43.根据权利要求42所述的方法，进一步包括：至少部分地基于调整阈值来调整预定带宽。
44.根据权利要求42所述的方法，其中，所述指示对应于电属性的均值。
45.根据权利要求42所述的方法，其中，所述指示包括1比特标记。
46.根据权利要求42所述的方法，进一步包括：
基于发起标记来发起积分；以及
基于所述指示来终止积分。
47.根据权利要求46所述的方法，其中，积分的发起和终止之间的时间段与电属性的均值相对应。
48.根据权利要求46所述的方法，其中，通过下述操作来重复在时间上的积分：至少部分地基于所述指示来导出发起标记。
49.根据权利要求48所述的方法，其中，响应于所述指示来重新断言发起标记。
50.根据权利要求39所述的方法，其中，至少部分地基于调整与积分放大器电路相关联的电容值来调整预定带宽。
51.根据权利要求39所述的方法，其中，至少部分地基于调整跨越与该分子配合物相关联的纳米孔施加的偏压来调整预定带宽。
52.根据权利要求39所述的方法，进一步包括：对电信号进行噪声滤波。
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CN108088985B (zh) * 2016-11-23 2019-12-03 立锜科技股份有限公司 生物检测装置以及生物检测方法
CN113631925A (zh) * 2019-03-19 2021-11-09 牛津纳米孔科技公司 电流测量设备、分子实体感测设备、测量电流的方法、感测分子实体的方法

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