CN101819149B - 高性能荧光光学传感器 - Google Patents
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Abstract
用于测定分析物的存在或浓度的光学传感器装置，包括波导(103)，放置在基底(100)的光源(101)之上并用内部挡板(104)分隔开，其中波导具有的厚度与光源的远场辐射点相对应，远场辐射点取决于光源和光探测器之间的遮光挡板。
Description
本申请是2002得12月11日提交的申请号为02824835.X、名称为‘高性能荧光光学传感器’专利申请的分案申请。
相关申请的交叉引用
根据35U.S.C.§119(e)条款，本申请要求对已于2001年12月11日申请的临时申请序列号60/338,647有优先权。
发明领域
本发明主要涉及传感器装置，用以探测来自指示剂的电磁辐射，所研究的分析物从指示剂中渗透过去，其中辐射特性作为分析物浓度的函数而变化。更具体地说，此发明涉及对这些传感器装置的设计和性能方面的改进。
技术背景
本文引用美国专利号5,517,313公开的内容，并在此作为参考，该专利描述的荧光传感装置包括：分层排列的包含分子的荧光指示剂矩阵(此后称为“荧光矩阵”)；高通滤波器以及光探测器。在此装置中，光源，最好是发光二极管(“LED”)，至少部分地位于指示剂材料内，这样，来自光源的入射光导致指示剂分子发出荧光。高通滤波器允许从指示剂分子发射出来的光到达光探测器，而滤掉来自光源的杂散入射光。分析物可以渗透荧光矩阵，与现存分析物数量成比例地改变指示剂材料的荧光性质。然后，用光探测器探测和测量荧光辐射，这样就提供了在所研究的环境中的现存分析物数量或浓度的度量。
在专利’313中公开的该类型传感器装置的一种有益的应用是把该装置植入体内，既可植入皮下，也可在静脉内或其他地方植入，以使得可以在任何想要的时刻即时测量分析物。例如，想要在病人失去知觉时测量其血 液中氧的浓度，或测量糖尿病人血液中葡萄糖的含量。
自从在专利’313中描述的装置发明以来，现今的发明家们已开发出许多改良设计，显著地提高了在专利`313中描述的该类型光学传感器装置的性能、可靠性及寿命。
具体说，这些传感器装置受到大小及重量的限制，尤其是在体内(in-vivo)或原位(in-situ)应用时，在使功率消耗和发热量最小化的同时，为了得到更可靠和精确的测量信号，重要的是使可用的指示剂矩阵的效率最大化。另外，传感器装置设计应该有可能使成本有效、可大批量生产的产品以合理价格销售。此外，期望装置的寿命可以最长化，尤其是对必须植入体内用于原位(in-situ)检测生物分析物的装置更是如此。
发明概述
按照本发明的一方面，提供一个用来测定分析物的存在或浓度的光学传感器装置，包括：基底；在基底上形成的遮光挡板层，并且其中至少有两个腔；光源装在其中一个腔内的基底表面上，通电后，主要发射预先选定的波长的光；光探测器装在与光源邻近的基底表面上另一个腔内，并用遮光挡板从中隔开，用来探测入射其上的光，并在此产生响应的电信号；波导形成在光源和光探测器之上，在装有光源的腔内充满了与波导有相同折射率的透明环氧材料(epoxy)，这样可认为光源安装在波导“内”；波导具有的平均厚度与光源的远场辐射点相对应，远场辐射点取决于光源相对于遮光挡板的位置、光源的固有辐射分布、或相对位置和固有辐射分布的结合；以及放置在波导外表面上的、分析物可渗透的指示剂矩阵，该荧光矩阵含有荧光指示剂分子，这些分子的荧光性由于所述荧光矩阵中有分析物存在而衰减或增强，预先选择好的波长以及荧光指示剂分子要这样来选择：使光源发出的波长在指示剂分子中激发荧光；其中光探测器对入射其上的荧光产生响应电信号，此荧光由所述荧光指示剂分子发射。光探测器腔充满了掺入颜料的材料，其作用类似滤波器，基本上阻止所述光探测器接收某些辐射波长，这些辐射波长不同于来自指示剂分子的需要的峰值辐射波长。光探测器腔和光源腔两者的填充材料可以是环氧材料或其它聚合材料。
根据本发明的另一方面，提供一种用于测定分析物的存在或浓度的光 学传感器装置，包括：基底；光源，通电时，用于发射主要为预先选择好波长的光，并装在所述基底的表面上；光探测器，用于探测入射其上的光并产生作为响应的电信号，装在邻近于所述光源的所述表面上，并用遮光挡板与光源隔开；波导，形成在所述光源和所述光探测器之上；可渗透分析物的指示剂矩阵，放置在所述波导的外表面上，所述指示剂矩阵含有发光的指示剂分子，该指示剂分子的光辐射会由于在所述矩阵中存在分析物而削弱或增强，选择所述指示剂分子以使得由所述光源发出的波长激发所述指示剂分子内的光辐射；以及透明填充材料，形成在腔内所述光源之上，所述光源位于该腔中，其中所述透明填充材料具有与所述波导大体相等的折射率，以便所述光源有效地装在所述波导内；其中所述光探测器响应入射其上的、由所述指示剂分子发出的光而产生电信号。
根据本发明的另一方面，提供一种用于测定分析物的存在或浓度的光学传感器装置，包括：基底；光源，通电时，用于发射主要为预先选择好波长的光，并装在所述基底的表面上；光探测器，用于探测入射其上的光并产生作为响应的电信号，装在邻近于所述光源的所述表面上，并用遮光挡板与光源隔开，该遮光挡板限定至少二个腔，所述光源与光探测器在装到所述基底上时分别位于这二个腔中；波导，形成在所述光源、所述光探测器和所述腔之上；可渗透分析物的指示剂矩阵，放置在所述波导的外表面上，所述指示剂矩阵含有发光的指示剂分子，该指示剂分子的光辐射会由于在所述矩阵中存在分析物而削弱或增强，选择所述指示剂分子以使得由所述光源发出的波长激发所述指示剂分子内的光辐射；以及掺入颜料的填充材料，形成在所述腔内的光探测器之上，所述光探测器位于该腔中，其中所述掺入颜料的填充材料起滤波器的作用，用来阻止由所述光源发射的主要的波长照射到所述光探测器上；其中所述光探测器响应入射其上的、由所述指示剂分子发出的光而产生电信号。
附图简述
参考下面对优选实施例结合附图的详细描述，将会更充分地理解此发明。附图仅作为例证，因而不是对本发明的限定，其中：
图1A是根据本发明的一个实施例的光学传感器装置的俯视图；
图1B是图1A中的光学传感器装置的侧视图；
图2A是图1A-1B中的光学传感器装置的侧视图，例示了激发视场和指示剂的响应视场；
图2B是图2A的端视图；
图3A和3B是侧视图，分别说明从光学传感器的光源发射光噪声的问题和本发明实现的解决方案；
图4是侧视图，依照本发明另一个实施例例示出用于的光学传感器的波导具有弯曲表面；
图5A-5D是侧视图，依照本发明例示了传感器装置的波导厚度最优化；和
图6是一曲线图，显示了依照本发明的，适用于光学传感器装置的LED光源的光辐射分布。
发明详述
图1A和1B显示了依照本发明的光学传感器装置的实施例。该装置包括：光源，例如LED 101；及光探测器，例如光电二极管102，光源和光探测器装在基底100上。光源和光探测器由波导103封装，波导的外表面提供了荧光指示剂矩阵105，其中含有分析物-指示剂分子。矩阵105以下列多种方式之一放置在波导103外表面上，诸如沉积、涂敷、粘合等等，。光源101和光探测器102用内部档板104a分开，它是基底100的档板层部分104的一部分。档板部分104既可和基底100分开形成，或者也可以利用随后对腔的蚀刻或掩膜，来与基底的形成过程集成在一起。
档板层104能在基底100的基底层110上形成，来限定若干装在基底上并在其中放置光源和光探测器的腔的界限。在腔上形成波导层103以前，将光源腔充满透明的环氧或其它聚合材料106，这些材料最好与波导103具有大体相同的折射率，填充材料106可以和用于波导103的材料相同，但不是必须相同。
光探测器腔充满掺入颜料的环氧或聚合材料107，该材料起到滤波器的作用，用以阻挡来自光源101的直接或反射光照射到光探测器102上。选择材料107的颜色，使得与指示剂分子的峰值辐射相对应。
或者，光探测器腔充满掺入颜料的材料，而后光源腔的填充与波导层的形成可一起进行，这样就将光源嵌入在整体的波导层中。
另外，也可将光源腔充满掺入颜料的材料，而不是充满透明材料，选择的材料颜色可以大体上阻挡除了所需峰值波长辐射以外的光源所有波长的辐射。
如图2A和2B所示，按照本发明，光学传感器装置的结构基于实现以下目的：基本上只用光源101直接照射波导103的具有荧光指示剂矩阵105的几乎整个外表面；以及基本上只在光探测器102表面上直接收集来自指示剂矩阵105发出的响应辐射。内部档板104阻止光源101的杂散光照射光探测器102。LED光源的光辐射分布几何图形显示在图6中。
先前的传感器结构的一个问题是由于用作光源的标准LED所发出的光波长不纯，包括很多波长较长的光辐射，这可以降低所得到的测量信号的品质。例如，标准蓝光LED提供波长为460nm的辐射，但是由于各种因素，包括在生产过程中涉及的因素，有很多的(例如，大约占总辐射量的0.1％或更多)光辐射扩展到光谱的红光区域(例如，600nm以上)。作用类似滤波器的红色掺杂环氧材料107可以阻挡蓝光波长光入射到光探测器103上，但不能够滤掉这种来自LED光源的称为“红色末端”(red tail)的辐射。
在用氧传感器装置的情形下，用联苯基菲咯啉钌作为指示剂矩阵，这种指示剂的峰值辐射是613nm。因此，LED的“红色末端”辐射污染了来自指示剂的信号。这种“红色末端”辐射导致信号基线(signal baseline)提升并因此抑制了来自指示剂的荧光辐射中有用、可读的调制。这些显示在图3A中。
如图所示，蓝光波长光辐射301(需要的)伴随着额外的、不需要的红光波长辐射302，先前的波导结构能把这些红光波长辐射反射到光探测器102的探测表面上。按照本发明的直接照射结构，大多数来自LED光源的不需要的红光波长辐射302，不从波导表面反射回光探测器，而是直接从波导穿出，这样，基本上只有响应由蓝光波长光波301激发的红光波长荧光辐射303，照射在光探测器102的光探测表面上。根据实验测量，其基线噪音比用先前几何结构生产的波导减少40倍以上(例如，从23mV减少到不足0.5mV)。此外，如上面讨论过的那样，用掺蓝填充材料填充光源腔能有 助于减少来自光源的“红色末端”辐射。
按照此发明，光学传感器装置的最简单和最有效的结构是波导有一平坦的表面，如图1A-1B和图2A-2B所示。也可能有一弯曲表面，如图4所示。此外，可能有其他几何形状的表面，如象锯齿形、三角形或倒置的表面式样，这是为了增加表面面积，因而增加了可用的与分析物相互作用的指示剂数量。
在先前的设计中，设想过波导的弧形弯曲可起到把信号光聚焦在光探测器上的作用。恰巧相反，按照本发明的设计，内部反射或聚焦并不是有意义的现象。如图4所示，弧形的焦点402与探测器102无关，事实上完全聚焦在整个传感器装置之外。
实验观察和测量已确认，绝大多数的指示剂光，只是指示剂对来自光源的直接照明的响应产物，而不是内部反射光的产物。
图5A-5D列示出若干不同波导厚度的优化，其根据在于发现反射系数未对信号强度起主要贡献。如图所示，已经制造出来不同厚度的波导，其中厚度的特点在于与下述距离成比例：即从LED光源到LED光源的远场辐射点X与波导表面的相交处的距离。对于每个厚度，在LED固定的电流和放大器增益时，测量其信号强度，如图所示：对厚度为X/3的波导，产生大约5mV的信号；厚度为2X/3时，产生约20mV的信号；厚度为X时，产生约50mV的信号；以及厚度为4X/3时，产生约40mV的信号。从这些结果可以看出，当波导厚度设定为X时，换句话说，在LED光源的远场辐射点与波导的角的顶点一致时，得到了峰值信号强度。只要光源和挡板之间的相对位置适当，只要选择具有特定的固有辐射分布几何形状的光源，或是这些因素的结合，就可以实现峰值信号强度。
为了增加波导的表面积，把表面做成不平坦的，其厚度X等于从波导的下表面量起的表面式样的平均高度。
按照此发明，光学传感器装置也可设定为二重或多重探测器，用若干个光探测器装在LED的各边，不同的指示剂矩阵放置在各个相应的光探测器上，这样，LED的相同激发波长可在各个指示剂矩阵中激发出不同的荧光波长。或者，可用多个LED，其中各个LED发射出不同的激发波长导致不同的荧光波长响应。
此外，虽然按照本发明的一个优选实施例中描述过折射率匹配问题，依旧可能为各种光源填充材料、波导材料和光探测器填充材料选择不同的折射率。众所周知，光自然地从折射率较低的媒体传播到折射率较高的媒体。
因此由于希望激发光从光源传播到放置在波导表面的指示剂矩阵，并希望荧光辐射从指示剂矩阵传播到光探测器，因此本发明的替换实施例会陆续为光源填充材料、波导材料和光探测器填充材料提供更高的折射率。发明现已描述，对本领域的技术人员应当理解，在不违背本发明的精神和范围的情况下，本发明可以有多种变化。例如，尽管为了例证的目的，本发明的描述涉及荧光传感器装置，但本发明的原理可以应用于使用光学传感器装置探测荧光以外的现象。任何或所有这样的修改，都包括在下面的权利要求书中。
Claims (4)
1.一种用于测定分析物的存在或浓度的光学传感器装置，包括：
基底；
光源，通电时，用于发射主要为预先选择好波长的光，并装在所述基底的表面上；
光探测器，用于探测入射其上的光并产生作为响应的电信号，装在邻近于所述光源的所述表面上，并用遮光挡板与所述光源隔开；
波导，形成在所述光源和所述光探测器之上；
可渗透分析物的指示剂矩阵，放置在所述波导的外表面上，所述指示剂矩阵含有发光的指示剂分子，该指示剂分子的光辐射会由于在所述矩阵中存在分析物而削弱或增强，选择所述指示剂分子以使得由所述光源发出的波长激发所述指示剂分子内的光辐射；以及
透明填充材料，形成在腔内所述光源之上，所述光源位于该腔中，其中所述透明填充材料具有与所述波导大体相等的折射率，以便所述光源有效地装在所述波导内；
其中所述光探测器响应入射其上的、由所述指示剂分子发出的光而产生电信号。
2.如权利要求1中所述的光学传感器装置，其中所述填充材料是聚合材料。
3.一种用于测定分析物的存在或浓度的光学传感器装置，包括：
基底；
光源，通电时，用于发射主要为预先选择好波长的光，并装在所述基底的表面上；
光探测器，用于探测入射其上的光并产生作为响应的电信号，装在邻近于所述光源的所述表面上，并用遮光挡板与所述光源隔开，该遮光挡板限定至少二个腔，所述光源与光探测器在装到所述基底上时分别位于这二个腔中；
波导，形成在所述光源、所述光探测器和所述腔之上；
可渗透分析物的指示剂矩阵，放置在所述波导的外表面上，所述指示剂矩阵含有发光的指示剂分子，该指示剂分子的光辐射会由于在所述矩阵中存在分析物而削弱或增强，选择所述指示剂分子以使得由所述光源发出的波长激发所述指示剂分子内的光辐射；以及
掺入颜料的填充材料，形成在所述腔内的光探测器之上，所述光探测器位于该腔中，其中所述掺入颜料的填充材料起滤波器的作用，用来阻止由所述光源发射的主要的波长照射到所述光探测器上；
其中所述光探测器响应入射其上的、由所述指示剂分子发出的光而产生电信号。
4.如权利要求3中所述的光学传感器装置，其中所述掺入颜料的填充材料的折射率高于所述波导的折射率。
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| KR102306147B1 (ko) * | 2020-05-29 | 2021-09-29 | 주식회사 수젠텍 | 검체 내 분석물을 검출하기 위한 디바이스 |
| CN111755557A (zh) * | 2020-06-18 | 2020-10-09 | 深圳市兴邦维科科技有限公司 | 一种接近传感器整合型封装结构 |
| AT524748B1 (de) * | 2021-02-19 | 2023-03-15 | Johannes Krottmaier Dr | Optische Einheit für die Messung von Fluoreszenzlicht |
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- 2002-12-11 CN CN2010101550227A patent/CN101819149B/zh not_active Expired - Fee Related
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Also Published As
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|---|---|
| TW200303984A (en) | 2003-09-16 |
| US7190445B2 (en) | 2007-03-13 |
| US20030156290A1 (en) | 2003-08-21 |
| BR0214824A (pt) | 2004-09-14 |
| EP1454129A1 (en) | 2004-09-08 |
| JP4430396B2 (ja) | 2010-03-10 |
| AU2002359673B2 (en) | 2009-01-08 |
| CN101819149A (zh) | 2010-09-01 |
| CN1602420A (zh) | 2005-03-30 |
| CA2469870C (en) | 2011-07-26 |
| AU2002359673A1 (en) | 2003-06-23 |
| US6940590B2 (en) | 2005-09-06 |
| CA2469870A1 (en) | 2003-06-19 |
| CN1602420B (zh) | 2010-05-26 |
| TWI293363B (en) | 2008-02-11 |
| WO2003050519A1 (en) | 2003-06-19 |
| MXPA04005608A (es) | 2004-12-06 |
| US20050237518A1 (en) | 2005-10-27 |
| DE60232912D1 (de) | 2009-08-20 |
| HK1148067A1 (en) | 2011-08-26 |
| EP1454129B1 (en) | 2009-07-08 |
| HK1064442A1 (en) | 2005-01-28 |
| EP1454129A4 (en) | 2006-08-02 |
| JP2005513426A (ja) | 2005-05-12 |
| ATE436011T1 (de) | 2009-07-15 |
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