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CN103392006A - 具有比色传感器的血液培养瓶的探测器装置 - Google Patents

具有比色传感器的血液培养瓶的探测器装置 Download PDF

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CN103392006A
CN103392006A CN2011800353652A CN201180035365A CN103392006A CN 103392006 A CN103392006 A CN 103392006A CN 2011800353652 A CN2011800353652 A CN 2011800353652A CN 201180035365 A CN201180035365 A CN 201180035365A CN 103392006 A CN103392006 A CN 103392006A
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布拉德福德·G·克莱
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Abstract

公开了一种血液培养瓶的探测装置，血液培养瓶包含比色传感器，比色传感器经受由于血液培养瓶内的样本媒介的pH或CO2的变化而引起的颜色变化。探测装置包括照明所述比色传感器的传感器LED、照明所述比色传感器的参考LED、用于选择性和交替地启动传感器LED和参考LED的控制电路、以及光电探测器。光电探测器测量在使用传感器LED和参考LED选择性和交替地照明比色传感器期间来自比色传感器的反射度，并产生强度信号。参考LED被选择成具有照明峰值波长，使得来自于参考LED照明的光电探测器的强度信号被比色传感器的颜色变化影响。

Description

具有比色传感器的血液培养瓶的探测器装置
相关申请的交叉引用
本申请要求2010年7月20日提交的标题为“DetectorArrangement forBlood Culture Bottles With Colorimetric Sensors”的美国临时专利申请号61/400,001的利益。
背景
用于培养血液以得知微生物的存在的瓶和用于以非侵入方式分析这样的瓶的相关仪器在本领域中是已知的，并在专利文献中被描述。参见美国专利5,858,769、5,795,773、4,945,060、5,094,955、5,164,796、5,217,876和5,856,175。上面列出的专利的瓶和仪器在商标BacT/ALERT下由本受让人成功地商业化。
在这些血液培养仪器中描述的瓶利用放置在瓶的底部中并与样本媒介接触的比色传感器来确定细菌生长的存在/不存在。一旦临床/工业样本被添加到存在于瓶中的液体生长媒介且孵育出现，在微生物的数量增加时二氧化碳的浓度就增加；二氧化碳是细菌生长的呼吸副产物。可选地，对与微生物的生长有关的媒介pH的改变也可由传感器监控。BacT/ALERT传感器和监测电子设备的基本操作在美国专利4,945,060中并且也在Thorpe等人的文章“BacT/Alert:an Automated Colorimetric Microbial DetectionSystem”中被描述，该文章在Clinical Microbiology的期刊（1990年7月,pp.1608-12）中被发表。‘060专利和Thorpe等人的文章通过引用并入本文。
在附图的图1中示出了‘060专利的基本比色传感系统。红色发光二极管（LED）（4）投光于BacT瓶（1）的底部上。比色传感器（2）放置在瓶（1）的底部上。LED光以相对于瓶（1）的底表面的45度角射在传感器上。大部分光穿透瓶的结构并射在比色传感器（2）上。部分光将以与瓶的底表面成45度角但在与入射光相反的方向（例如，反射角等于入射角）上从塑料瓶材料和传感器（2）反射。很多剩余的光从传感器的表面和内部散射。当分别地，在瓶中的CO2的百分比从0%改变到100%以及颜色从蓝色改变到黄色时，传感器（2）改变其颜色。硅光电探测器（5）“凝视”（即，连续地监控散射强度信号）传感器（2）中的区域，其中来自LED的光与传感器相互作用。由光电探测器探测的散射光的强度与瓶（1）内的CO2水平成比例。图1还示出包括电流源（6）、电流到电压转换器（7）和低通滤波器（8）的相关电子设备。
图2是由图1的光电探测器（5）接收的信号的曲线图。使用光纤探头代替图1中的光电探测器（5）来收集数据。光纤探头被按规定路线传送光光谱仪，其显示随强度（反射度单位）和波长而变化的散射光。每个曲线的形状是在特定CO2水平处LED强度分布与比色传感器（2）的反射率的卷积。
当用光纤探头代替图1的硅光电探测器（5）时，与图2所示的积分波长信号成比例的光电流由光电探测器产生。换句话说，硅光电探测器（5）将光谱响应积分成光电流。该光电流转而使用跨阻抗放大器转换成电压信号。
虽然图1的BacT/ALERT传感系统是鲁棒性的并在血液培养系统中成功地使用了很多年，但它有几个待改进的方面。首先，如果血液培养瓶（1）在小室中移动（例如，在z轴上移位，使得它从光电探测器的位置移远），系统（如它当前被实现的）将这个移动探测为强度的减小。然而，强度的这个减小被仪器解释为瓶中的CO2水平的减小，其可能实际上不出现。因为这个效应与当二氧化碳含量增加（意味着细菌生长）时瓶的反射率增加的效应相反，所以系统将平移的瓶视为没有生长（即，假阴性条件）是有可能的。
同样，当仪器在临床实验室中老化时，光学系统可收集随时间而变化的尘土或光学材料经历减小的透射率。例如，当塑料老化时，它们的透射率可能由于光、微粒增加（尘土）或清洗剂的重复使用的效应而减小。这些效应将不影响读数，但将表现为系统的响应中的漂移。周期性校准检查可补偿该漂移。因此，对在光学系统中有透射的实时监测器和调节或补偿这些错误源中的一些的能力有长期以来感到的但未被满足的需要，特别是瓶未完全安装在容器中且不在标称或原始位置处（有远离光学探测器装置的某种Z轴移位）的情况。
所关注的其它现有技术包括下面的美国专利：7,193,717、5,482,842、5,480,804、5,064,282、5,013,155、6,096,2726、6,665,061、4,248,536以及1994年11月24日公布的所公布的PCT申请WO94/26874。
概述
公开了包含比色传感器的血液培养瓶的改进的探测装置。
探测装置包括光电探测器、传感器LED和参考LED、以及用于选择性地和交替地启动传感器LED和参考LED以照明比色传感器的控制电路。传感器LED像图1的LED一样起作用，并用于确定比色传感器的颜色变化。光电探测器通过监测强度变化来监测在被传感器LED照明时来自传感器的反射度。参考LED被选择为其所具有的波长使得来自于参考LED的照明的光电探测器的强度读数不被比色传感器的颜色变化影响。因此，参考LED可用作参考，在由参考LED照明期间的光电探测器读数不被瓶内的CO2浓度的变化影响。已发现，在近红外中的波长（在750和950nm之间的LED的峰值λ）适合于参考LED。
参考LED对指示瓶和探测器子组件之间的距离是否改变、周围光照条件是否改变、或在传感器LED、瓶和光电探测器之间的物理光路内的任何事物是否改变是有用的。因为参考LED中的变化不取决于比色传感器的状态，参考LED可提供关于光学系统中的与微生物生长无关的变化的信息，使得来自系统的这样的非生长相关的变化可与生长相关的变化区别开。这个特征帮助减小系统中的假阳性率，并提高感测准确度和可靠性。
在使用中，传感器LED和参考LED例如以时分复用方式交替和重复地照明。来自这样的连续照明的光电探测器信号被馈送到计算机。当参考LED照明时，计算机监测光电探测器信号中的变化；这些变化将指示瓶位置或光学系统中的变化。例如由于探测系统中的瓶位置从原始或标称位置偏移，计算机可根据传感器LED和参考LED信号之间的所得到的校准关系来补偿传感器LED信号。
附图的简要说明
图1是如在美国专利4,945,060中描述的血液收集瓶的已知传感器和探测器装置的图示。
图2是作为波长和CO2浓度的函数的代替图1的光电传感器的光谱仪上的比色传感器的反射度的曲线图。
图3是根据本公开的血液收集瓶的传感器和探测器装置。
图4是在存在于瓶内的0-100%CO2范围内对于比色传感器的传感器LED和参考LED照明的来自图3的光电探测器的强度信号的曲线图。
图5是随从标称或原始位置的瓶位移而变化的传感器LED和参考LED的光电探测器强度信号的曲线，其中瓶在接近图3的探测系统的其设计位置上。
图6是在瓶内的微生物生长的条件期间随时间变化的传感器LED和参考LED的光电探测器强度信号的曲线图。
图7是操作图3的传感器装置的电子设备的方框图。
图8是图3的参考和传感器LED的占空比的曲线，其示出操作的时分复用方法。代表占空比的脉冲的宽度并不按比例绘制；在一个可能的实施方式中，占空因数是33%：在1/3的时间参考LED照明，在1/3的时间传感器LED照明，以及在1/3的时间这两个LED都不照明以使“暗”测量能够进行。
详细描述
本发明涉及次级LED作为光源使用来补偿对光学系统的非乳状液传感器（LES）变化。图3示出了光学配置的方框图。该配置用于测试具有包含在瓶1内的比色LES2的瓶1。该配置包括传感器LED4、IR参考LED10和产生强度信号的光电探测器5。这两个LED4和10都如图3所示相对于瓶的底表面成45度角。借助于选择性地和交替地启动传感器LED和参考LED的控制电路（图7的42）来连续地测量瓶底和LES2的反射率。例如，传感或红色LED4被开启，且反射信号由光电探测器5测量。传感LED4接着熄灭。参考LED10接着照明，且同一光电探测器5测量反射光。然后它熄灭，且该过程重复。该方法也称为时分复用方案，其在图8中示出并将在下面被更详细地描述。
如上所述，LED4和10被定向成相对于瓶的底部成45度角。这使得从瓶的底表面的反射并不很强地耦合到光电探测器5中。入射角=反射角，使得射到瓶底部的光将以45度角离开，且将不强烈地影响光电探测器读数（因为来自LES的散射光是唯一所关注的）。LED具有15-17度的空间发射角；即，LED发射由在半最大功率处的峰值发射和全幅角定义的圆锥体中的光；圆锥体的角在15-24度的范围内。
对各种LED颜色执行测试，且发现近红外LED（从750到950nm的峰值波长）反射率被LES颜色变化轻微地影响。当CO2水平从0%改变到100%时，光的所有其它波长具有反射率的负或正变化。这个效应在超出大约750nm（近红外LED）的波长处最小化，如表1中所示的。
Figure BDA00002750281000051
表1-使用用于感测（红色）LED和参考（IR）LED的CO2锥形瓶的光电探测器输出（伏特）
图4示出表1的图形等效形式。参考传感器的光电探测器读数被绘制为线20，而传感器LED的光电探测器读数被绘制为线22。当瓶中的二氧化碳水平从0%CO2增加到100%CO2时，在曲线上看到红色LED信号22中的极大增加（它从大约0.6伏特改变到几乎2伏特）。同时，参考LED信号20从2.32伏特改变到2.29伏特（30mV的变化），所以它在LES改变颜色的过程中非常稳定。
为了研究随瓶相对于光学系统的位置而变化的光信号中的变化，由附接到BacT/ALERT瓶的数字测微计组成的校准/测试固定装置被构造。瓶首先放置在BacT/ALERT搁架组件中的标称（原始）位置上，使得它尽可能接近光学系统。反射度的读数被获取，接着瓶通过调节测微计被移位。测微计提供对z轴移位的精确的小调节（即，它将瓶移动得距光学系统更远），使得移位的效应可被量化。随位移而变化的光信号中的标准化变化在图5中示意性示出，再次，参考LED的照明的光电探测器信号被绘制为线20，而传感器LED的光电探测器信号被绘制为线22。看到移位引起光电探测器所接收的信号中的线性位移。虽然传感器LED信号22和参考LED信号20具有不同的变化斜率，但其每个都是线性的，所以例如由于瓶从原始或标称位置的移位，可产生一种关系用于根据参考LED探测器输出中的变化来补偿信号LED中的变化。对图5中的曲线计算方程；下面在表2中列出方程连同拟合参数（R2）的品质因数。
表2
探测器_输出（信号）=0.2652-0.2554x R2=0.9963
探测器_输出（参考）=0.5621-0.2384x R2=0.9999
其中x=线性移位距离（以英寸为单位）
因此，通过映射参考LED的输出的强度的变化，移位值可被确定。将该值应用于信号LED的输出，强度减小的量可被量化和补偿。
通过将酿酒酵母的接种体注入到血液培养瓶中并当酵母在瓶中生长时使用传感器LED和参考LED光学器件监控比色传感器，来执行图3的探测器装置的能力的进一步测试。图6示出酵母生长的生长曲线——滞后、指数和静止生长阶段被示出。在生长（以及LES传感器的响应中的变化）期间，看到参考LED信号20未改变，而传感器LED信号22由于作为微生物生长的结果的CO2浓度的变化而改变。曲线20的平坦性验证了在参考LED的照明期间光电探测器读数对LES颜色变化的不敏感性。它进一步验证了监测光学系统中的变化同时不被细菌生长影响的能力。
图7是图3的实施方式的电子设备30的方框图。电子设备30包括由传感器LED4、参考LED10和光电探测器5组成的“光学套件”32。光电探测器的输出在A/D转换器34中转换成数字信号，并被馈送到数据采集系统36。数据采集系统将信号发送到包括控制电路和LED驱动器的LED控制板42，LED驱动器通过导体44和46发送信号以使LED4和10以时分复用方式照明。来自数据采集系统的光电探测器信号被发送到计算机38，计算机38可以是包含图3和7的光学套件32的仪器的部分（附带的电子设备例如滤波器和电流到电压转换器在附图中被省略，但可存在于电子设备中）。
存储器40存储校准常数和从例如图5曲线得到的和上面在表2中解释的在参考和信号LED输出之间的关系。例如，存储器40存储随瓶离原始位置的距离而变化的传感器LED的强度信号之间的校准关系（图5中的曲线22）；计算机38根据传感器LED和参考LED的校准关系来补偿由于瓶位于远离原始位置的一段距离处而引起的来自传感器LED的强度信号的下降。
图8是图3的参考LED10和传感器LED4的占空比的曲线，其示出操作的时分复用方法。传感器LED的开启和关闭状态在线50上示出；参考LED的开启和关闭状态在线42中示出。表示占空比的脉冲的宽度不一定按比例绘制，且可改变。在一个可能的实施方式中，占空因数是33%：在1/3的时3参考LED照明，在1/3的时间传感器LED照明，以及在1/3的时间3这两个LED都不照明以使“暗”测量能够进行。
使用图3的装置，补偿光学系统中的尘土、漂移、变化、以及在光束路径中的光学材料的老化也是可能的。因为这些出现在延长的时间（被预期是在数月的持续时间中）内，它们将非常缓慢地改变。补偿通过保存来自初始校准的数据点（例如，从图5得到）来实现，并比较IR LED10的发射水平的光电探测器信号与初始值，以补偿光学系统中的恶化机制。这个变化也适用于传感器LED4。对于较短时间段漂移事件，监测在细菌的生长周期内应非常稳定的IR LED10中的变化；例如使用所存储的校准关系，IR LED性能中的任何变化相应地引起传感器LED光电探测器读数中的调节。
所附权利要求是所公开的发明的进一步陈述。

Claims (10)

1.一种血液培养瓶的探测装置，所述血液培养瓶包含比色传感器，所述比色传感器经受由于所述血液培养瓶内的样本媒介的pH或CO2的变化而引起的颜色变化，所述探测装置包括：
传感器LED，其照明所述比色传感器；
参考LED，其照明所述比色传感器；
控制电路，其用于选择性和交替地启动所述传感器LED和所述参考LED；以及
光电探测器，所述光电探测器测量在使用所述传感器LED和所述参考LED选择性和交替地照明所述比色传感器期间来自所述比色传感器的反射度并产生强度信号；
其中所述参考LED被选择成具有照明峰值波长，使得来自于所述参考LED照明的所述光电探测器的所述强度信号实质上不被所述比色传感器的颜色变化影响。
2.如权利要求1所述的探测装置，其中所述参考LED具有在750和900nm之间的照明峰值波长。
3.如权利要求1或2所述的探测装置，还包括接收所述强度信号的计算机，所述计算机包括存储器，该存储器存储随所述瓶离相对于所述探测装置的原始位置的距离而变化的所述参考LED的强度信号之间的校准关系。
4.如权利要求4所述的探测装置，其中所述存储器还存储随所述瓶离所述原始位置的距离而变化的所述传感器LED的强度信号之间的校准关系，且其中所述计算机根据所述传感器LED和所述参考LED的校准关系来补偿由于所述瓶位于远离所述原始位置一段距离处而引起的来自所述传感器LED的强度信号的下降。
5.一种用于探测包含在血液培养瓶中的比色传感器的方法，所述比色传感器经受由于所述血液培养瓶内的样本媒介的pH或CO2的变化而引起的颜色变化，所述方法包括下列步骤：
使用传感器LED和参考LED交替和重复地照明所述比色传感器；
使用光电探测器测量由于通过所述传感器LED和所述参考LED照明所述比色传感器而引起的来自所述比色传感器的反射度，所述光电探测器响应地产生强度信号；
其中所述参考LED被选择成具有照明峰值波长，使得来自于所述参考LED照明的所述光电探测器的所述强度信号实质上不被所述比色传感器的颜色变化影响。
6.如权利要求5所述的方法，其中所述参考LED具有在750和900nm之间的照明峰值波长。
7.如权利要求5或6所述的方法，还包括以下步骤：将随所述瓶离相对于所述传感器LED、所述参考LED和所述光电探测器的原始位置的距离而变化的所述参考LED的强度信号之间的校准关系存储在计算机存储器中。
8.如权利要求5、6或7所述的方法，还包括以下步骤：将随所述瓶离相对于所述传感器LED、所述参考LED和所述光电探测器的原始位置的距离而变化的所述传感器LED的强度信号之间的校准关系存储在计算机存储器中。
9.如权利要求8所述的方法，还包括以下步骤：根据所述传感器LED和所述参考LED的校准关系，来补偿由于所述瓶位于远离所述原始位置一段距离处而引起的来自所述传感器LED的强度信号的下降。
10.如权利要求9所述的方法，其中所述补偿步骤包括以下步骤：使用所述参考LED的校准关系来确定所述瓶的位移值，并使用所述传感器LED的校准关系来按照所述位移值调节来自所述光电探测器的所述强度信号从而校正所述瓶的位移。
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AU2011279815A1 (en) 2013-01-31
US20160356797A1 (en) 2016-12-08
US10247740B2 (en) 2019-04-02
CN105462826B (zh) 2018-01-12

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