CN1294430C - 用于检测流体中分析物的方法 - Google Patents
用于检测流体中分析物的方法 Download PDFInfo
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- CN1294430C CN1294430C CNB038129574A CN03812957A CN1294430C CN 1294430 C CN1294430 C CN 1294430C CN B038129574 A CNB038129574 A CN B038129574A CN 03812957 A CN03812957 A CN 03812957A CN 1294430 C CN1294430 C CN 1294430C
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Abstract
一种用于检测流体中分析物的方法，该方法包括：使所述流体与一种全息元件接触，该全息元件包括介质和设置在所述介质整个体积中的全息照相，其中所述全息元件的光学特性随着在整个介质体积中发生的物理性质变化而变化，其中所述物理性质变化是由于所述介质与分析物间的相互作用而引起的，且其中所述相互作用和所述物理性质变化是可逆的；和检测所述光学特性的变化。
Description
技术领域
本发明涉及一种基于全息照相敏感元件的检测方法以及用于这类方法的装置。
背景技术
Spooncer等对于International Journal of Optoelectronics 7(3)：449-452(1992)的题为“A humidity sensor using awavelength-dependent holographic filter with fibre opticlinks”一篇短文中，描述了明胶基布拉格反射全息照相对环境湿度的响应。其结论是：对于提高和降低的湿度循环的光学响应存在着滞后现象，这种滞后现象会限制其作为传感器的工业应用。
WO-A-9526499公开了一种基于体积全息照相的全息传感器。这种传感器包括一种分析物敏感的基质，所述基质具有一种设置在其整个体积中的光学转换结构。由于这种转换结构的物理排列，使所述传感器产生的光学信号对于在所述分析物敏感基质中由于与分析物的相互作用或反应而发生的体积变化或结构重排是非常敏感的。例如一种包括明胶基全息介质的传感器可用来检测胰岛素。胰岛素对明胶介质起作用，会不可逆地破坏全息载体介质的完整性。
发明内容
按照本发明一个方面，一种连续检测流体中分析物的方法，该方法包括使所述流体与一种包括介质和设置在该介质整个体积中的全息照相的全息元件接触，其中该全息元件的光学特性随着在整个介质体积内发生的物理性质的变化而改变，其中所述物理性质变化是由于所述介质与分析物间相互作用而引起的，且其中所述相互作用和所述物理性质变化是可逆的；和检测所述光学特性的变化。
所述变化是由于所述介质与分析物间相互作用而引起的，其中所述相互作用和变化是可逆的。所述相互作用可以是化学或生化反应。由于可以发生相互作用和可逆相互作用，因此可以对分析物物种连续进行检测，优选实时进行。分析物浓度可以改变，但所述流体是稳态的。一种替代方案是所述流体可连续通过所述元件。
本发明可用来监测体内或体外的反应，例如在发酵罐中。它可用于动力学测量，且作为一种有效的控制系统。
本发明的另一方面，是一种用于检测流体中分析物的装置。所述装置包括一个含所述全息元件的传感器和允许所述流体进入与全息元件接触或通过所述全息元件的入口和出口。所述装置还包括一个用于非离子化辐射以照射所述全息元件的窗口。这样，就可以对所述元件中发生的反应进行观察。
具体实施方式
所述全息载体介质与分析物间的相互作用是可逆的，因此，可以实现对所述分析物的连续检测。当所述流体与全息元件接触时，所述分析物和载体介质发生相互作用，优选是通过化学或生化反应进行作用。如果所述流体通过所述元件，则所述相互作用可能是短暂的。
可以利用非离子化辐射对所述相互作用进行遥控检测。所述全息介质与分析物物种间的相互作用程度反映为所述物理性质的变化程度，而所述物理性质的变化程度是作为光学特性的变化进行检测的，优选为非离子化辐射波长的迁移。
可以变化的所述全息元件的性质可以是其电荷密度、体积、形状、密度、粘度、强度、硬度、电荷、疏水性、膨胀性、完整性、交联密度或其它物理性质。所述或各种物理性质的变化反过来会引起全息元件光学特性的变化，例如极化率、反射率、折射率或吸光率的变化。
所述全息照相可设置在部分或全部所述载体介质体积主体之上或其中。一种非离子化辐射光源，例如可见光，可用来观察所述全息元件的所述或各种光学特性的变化。
在全息元件上或其中可负载一种以上全息照相。可以提供装置来检测由于所述或各种光学特性变化而引起的从所述或各种全息照相发出的辐射变化。可以对所述全息元件确定尺寸和进行排列，从而能够检测两种独立的事件/物种并同时或不同时以两种不同方式影响辐射。所述全息元件可以以阵列的形式提供。
存在有不同类型的全息照相。其中一种或多种可在所述全息载体介质上或其中制得。下述将描述一些不同类型的全息照相。
一种具有“相位(phase)”全息照相特性的全息元件，可包括折射率的3-D分布(调制)，其中所述分布是原始干涉图案的物理记录。一种具有“振幅”全息照相特性的全息元件，包括辐射折射物质的3-D分布(调制)，其中所述分布是原始干涉图案的物理记录。所述调制的峰指的是条纹(fringe)。全息照相可能具有“相位”和/或“振幅”全息照相的特性。
由于所述载体介质部分或整个体积中负载的分布峰间的间距变化而对折射率分布的调节，使所述辐射可能会经历相位迁移。条纹间隔(fringe separation)的变化，可由在固定角度的入射/衍射峰(布拉格)波长变化、由在固定角度的单色光强度变化或由在单色峰强度时角度变化进行测量。
全息照相还可进一步分为4种不同的类型，这些类型可以共存于同一载体介质中。它们是透射、反射、边缘照亮(edge-lit)和表面全息照相。还存在易消散波全息照相。
“透射”全息照相，其中出射光线经由与入射光线进入表面相对的表面离开全息载体介质。条纹通常以相当大角度向所述表面倾斜，例如典型为约90°。
“反射”全息照相，其中光线经由入射光线进入的同一表面离开。条纹通常基本平行于所述全息载体介质的表面。
“边缘照亮”全息照相，其中光线经由与入射光线进入表面基本成90°的表面离开该全息照相基底或全息载体介质的体相(例如玻璃板)。条纹通常与表面成一定角度，典型为约45°。
“表面”全息照相，其中介质表面与合适的空间振幅和规则间隔的图案等高从而能够衍射和/或反射光线。这种全息照相由于从其表面上每个点到达到一个共同点时在衍射和/或反射光线之间产生路程差，从而具有另一类“相位”全息照相的特性。如果这类表面限定在透明介质上，则透过所述介质的光线在通过所述表面时会经历周期性相位变化，这归因于所述介质体相的折射率引起的光程变化。
所述全息载体介质是这样一种介质，其中可以进行全息照相，而且能够表现出下述的一种或多种感光机理的特性。这种载体介质优选包括一种天然或改性的具有粘弹性的基质，它会由于与分析物物种的相互作用而变化。
例如所述基质是由(甲基)丙烯酰胺和/或(甲基)丙烯酸酯衍生的共聚单体的共聚物形成的。特别地，单体HEMA(甲基丙烯酸羟乙酯)是易于聚合和交联的。聚HEMA由于其可膨胀、亲水且广泛生物相容而是一种通用的载体材料。
全息载体介质的其它实例有明胶、K-carageenan、琼脂、琼脂糖、聚乙烯醇(PVA)、溶胶-凝胶(一般分类)、水凝胶(一般分类)和丙烯酸酯。其它材料是多糖、蛋白质和含蛋白质的材料、寡核苷酸、RNA、DNA、纤维素、纤维素醋酸酯、硅氧烷、聚酰胺、聚酰亚胺和聚丙烯酰胺。明胶是一种用于负载感光物种如卤化银颗粒的标准基质材料。明胶也可在凝胶束上的羧基间通过铬III离子光致交联。这些材料也可以两种或多种组合使用。
所述聚合物的组成可以进行优化以获得适合用于制备反射全息照相的高质量薄膜。这种薄膜应该能够用于制备一种其中能够形成全息条纹的均匀基质。
可利用本发明确定和量化的分析物实例包括：气体和液体如离子、代谢物、抗原/抗体、葡萄糖、氧、二氧化碳、脲、离子(包括质子，用于pH检测)、醇、硫化物和乳酸类。所列举的分析物仅是作为例子给出的。很显然，可能存在其它分析物物种，并可使用本发明的合适全息传感器来进行确定。
本发明可用来检测体液中的分析物，例如尿、血液或眼睛流体。一种特别感兴趣的分析物是葡萄糖，已知其在眼睛中的水平与其在血液中的水平是相互关联的。因此，可通过本发明监测眼睛流体如眼泪中的水平来间接监测葡萄糖的血液水平。
有多种可用来改变物理性质并从而改变光学特性的基本方法。可利用这些方法的一种或多种的组合来影响全息照相和/或全息载体介质中的变化，从而引起所述全息元件的物理性质变化。如果有变化发生，同时所述全息照相正在被入射宽带、非离子化电磁辐射所重放，则光学性质会发生变化，例如可能观察到颜色或强度变化。
可以改变的物理性质是调制复合折射指数。这可通过化学调节全息元件而改变，从而改变一种或多种光学性能。例如通过在条纹之间的位置裂开，酶最初可提高复合折射指数调制的深度。优选地，所述传感器包括一种全息元件，它包括一种含调制折射指数空间分布的介质，它可通过添加分析物物种而进行调节，从而根据调制折射指数的所述空间分布变化调节入射辐射的光谱和/或方向性质。
也可以制备所述全息元件，使其对于与分析物的相互作用响应为温度变化。例如所述全息元件的一个或多个尺寸随着温度变化而改变。这将导致一种或多种光学性质发生变化。
可以变化的物理性质优选是所述载体介质的尺寸或体积。这可通过向所述载体基质中引入一类基团而实现，这种基团在与分析物相互作用时发生可逆变化，并能引起所述载体介质膨胀或收缩。所述载体介质可包括聚合物或共聚物基质，所述基团例如以互相贯穿的网络形式固定或存在于其上或其中。这类基团的一个实例是分析物物种的特定结合共轭物。可以使用特征聚合物或合成或生物受体。
其它变化是在所述载体介质的活性水、溶剂或负荷量的变化。在这种情况下，全息载体介质优选为凝胶形式。
能与元件中至少两种官能团进行反应的分析物分子可以在载体基质的不同部分之间形成可逆交联，从而改变所述载体基质的粘弹性性能。其结果是，如果存在于含溶剂的环境中，则所述载体基质变化，所述载体基质收缩，和条纹间隔减小。特异性可通过保证在所述凝胶基质内提供特定结合位置而提供。
确定这类体系响应的一个参数是交联程度。由于单体聚合反应的交联点数目不应过大，以致使聚合物与分析物结合基团间的配合物的形成相对较低，这是由于该聚合物薄膜可能变得过于坚硬。这可能抑制载体介质的膨胀。
利用葡萄糖传感器的实例，为了连续检测葡萄糖，一种水凝胶基全息照相可具有一种含侧链葡萄糖基团和外源凝集素优选伴刀豆球蛋白A(con A)的载体介质。所述外源凝集素结合到侧链葡萄糖基团上，并在所述聚合物结构中充当交联剂。在可自由扩散的葡萄糖的存在下，当溶液中葡萄糖从外源凝集素上的结合位置取代聚合物上附着的葡萄糖时，交联程度将会降低，从而导致所述聚合物发生膨胀。使用反射全息照相，可以观察到含侧链葡萄糖基团和con A的水凝胶薄膜中的体积变化。水凝胶的体积变化将会改变全息照相结构的条纹间隔，并可能接着发生光谱反射响应的峰波长的迁移。
水基体系在这类全息传感器中是优选的，这是由于它们能保护所述外源凝集素不与有机溶剂接触。合适的葡萄糖成分的实例是高分子量葡聚糖和单体烯丙基葡糖苷和甲基丙烯酸2-葡糖基氧乙基酯(GEMA)。葡聚糖不具有固有的可聚合官能度，在丙烯酰胺基单体的聚合过程中可能被捕获；烯丙基葡糖苷和GEMA既可单独聚合，也可与共聚单体一起聚合。所述聚合物优选制成玻璃载体上的薄膜。
全息葡萄糖传感器可使用任意其它允许载体介质在与葡萄糖结合后物理性质发生可逆变化的合适葡萄糖受体构造。例如所述载体介质可包括侧链硼酸根基团，例如苯基硼酸酯。葡萄糖中的两个相邻二醇基团在可逆缩合反应中与硼酸根基团结合。这样，在全息元件中，葡萄糖与侧链硼酸根基团反应由于葡萄糖和与其相联的水合外壳的尺寸而引起载体介质膨胀。这种膨胀可观察为反射率最大值朝向更长的波长迁移。
连续检测氧可通过向全息载体介质中引入与氧可逆结合的基团而实现。合适基团的实例是过渡金属如钴、镍、铱或钌的配合物，例如配合物Ir(PPh3)2(CO)Cl(“Vaska’s配合物”)、四氰合钴酸盐和卟啉环配合物，特别是血红素蛋白质血红蛋白和肌红蛋白。这些基团可以固定到载体介质的聚合物基质上。一旦与氧结合，这些基团就会产生构象迁移，从而导致全息照相膨胀。这种膨胀经光学检测为波长迁移。
对于大环基团如可与一些离子物质可逆结合的冠醚也会发生类似的构象迁移。已知冠醚可与第I族和第II族金属离子可逆结合。因此，可以将专门针对离子分析物的冠醚固定在载体介质中用来连续监测分析物的存在。
下述实例结合附图描述本发明。
实例1：检测葡萄糖
通过添加NaOH水溶液，将由0.36g丙烯酰胺、0.42g甲基丙烯酰胺、0.35g N，N-二甲基丙烯酰胺、1ml水、40μl的5％DMPA、0.03g亚甲基二丙烯酰胺和0.1g乙烯基苯基硼酸组成的单体混合物调节到pH为9，随后进行聚合。使用溶于5％乙酸中的0.2M AgNO3向所得到的聚合物中添加银。然后在20％甲醇中记录全息照相，并在标准显影剂中进行显影；这类显影剂详细记载在Graham Saxby的PracticalHolography中(Prentice Hall出版)。
葡萄糖的检测是在0.1M磷酸盐缓冲液存在下利用0.1M NaCl溶液于不同pH值下进行的。在搅拌作用下，将全息照相放入到1ml缓冲液中，将20ml溶于水中的葡萄糖(已经放置24小时)添加到缓冲液中，使葡萄糖的浓度为2mM。
对于一定范围的pH值，按30秒间隔读取读数。在所有测试的pH值(包括生理学pH值)下，这种体系都是可逆的。
例如在pH为8.1时，添加葡萄糖导致聚合物膨胀，最明显的膨胀发生在添加葡萄糖5分钟内。这种膨胀观察为反射波长缩短，如图1所示。在用缓冲液清洗两次后，所述全息照相收缩，回复到其原始构象；波长返回到其原始数值，如图2所示。
实例2：使用“Vaska’s配合物”检测氧
通过从氯仿溶液(2ml的5mg/ml溶液)中蒸发，将“Vaska’s配合物”固定到空白HEMA全息照相上。然后用存在于氮饱和的缓冲液(50mmol磷酸盐缓冲液，pH为7.0)中的氧喷射所述全息照相。
用氧喷射后，发生少量可逆膨胀，从而导致波长相对于参比提高约10nm。这种波长迁移如图3所示。在停止喷射后，部分结合的氧分子进行可逆反应，全息介质略有收缩。这一点观察为波长略微缩短。
实例3：使用氧结合蛋白质检测氧
通过干燥将血红蛋白固定到HEMA聚合物上而制备全息传感器，然后添加1.5％酸化的戊二醛并持续3分钟。类似地制备包括固定的肌红蛋白的全息传感器。
全息照相用氧喷射约5分钟。从图4可以看出，包括血红蛋白和肌红蛋白的全息照相都显示出对于氧浓度变化的响应。
实例4：检测pH
使用包括聚合物含量为8％甲基丙烯酸(MAA)的全息照相监测在MRS培养基流体中培养的乳酸菌酪蛋白的pH值。随着所述乳酸菌生长并产生乳酸，所述全息照相针对pH的下降快速收缩。这可观察为在发酵过程中全息照相的反射峰波长缩短，如图5所示。
将全息照相反射峰波长与pH探针确定的pH进行比较，可建立起精确的关联关系，相对pH探针全息照相具有更少的“散射”。
类似地，采用包括4％DMAEM(甲基丙烯酸二甲基氨基乙酯)-HEMA的全息照相连续监测大肠杆菌培养基，它在膨胀时也产生酸。所述全息照相的反射峰波长与pH密切相关。
图6给出了四种不同全息传感器的pH灵敏度，其中每个传感器均包括由HEMA和pH-敏感共聚单体形成的共聚物。在此实例中，所用的pH-敏感共聚单体是乙烯基咪唑、二乙基氨基甲基丙烯酸酯、甲基丙烯酸和三氟丙烯酸。所述pH灵敏度明显不同，这表明为了在特定pH范围内达到更大的灵敏度，可以对聚合物组成进行优化。
下述实例5-7用3环糊精(CD)衍生物制备传感器来描述本发明。
实例5
环己三烯并直链淀粉(cyclohexaamylose)“α-CD”
将1gα-CD(干燥的)溶解在5ml干燥DMF和3ml干燥三乙胺中。烧瓶然后在冰浴中冷却。然后在10分钟内将2.7ml甲基丙烯酰氯以100μl的增量缓慢添加到搅拌混合物中。所述烧瓶用CaCl2干燥管塞住，并在室温下搅拌过夜。所述混合物然后用100ml甲苯进行摇动，溶剂通过布氏漏斗/水泵过滤除去。沉淀物然后用100cc丙酮进行摇动，并再次过滤，用50cc丙酮进行最后清洗并干燥。
甲基丙烯酸化的产物然后贮存在标有α-CD-M的黑色瓶中。
然后制备一种“精确”聚合物，如下所述：
将60mgα-CD-M溶解在150μl甲醇中。
然后依次添加下述成分，每种成分在添加下一种成分前溶解。
5mg DMPA
125μl HEMA
10μl EDMA。
然后将所述溶液涂到显微镜载玻片上，并如前文所述在UV光下进行聚合。(一种替代方案是，如果DMPA被AIBN取代，则所述聚合可在约60℃以加热方式进行数小时)。
然后如前文所述用扩散方法，在所述载玻片中制备全息照相栅。
实例6
环庚三烯并直链淀粉(cycloheptaamylose)或β-CD
将1g β-CD(干燥的)溶解在5ml干燥DMF和3ml干燥三乙胺中。烧瓶然后在冰浴中冷却。
然后将2.5ml甲基丙烯酰氯在10分钟内以100μl的增量缓慢添加到搅拌混合物中。
所述烧瓶采用CaCl2干燥管塞住，并在室温下搅拌过夜。
所述混合物然后用100ml甲苯进行摇动，溶剂通过布氏漏斗/水泵过滤除去。沉淀物然后用100cc丙酮进行摇动，并再次过滤，用60cc丙酮进行最后清洗并干燥。
甲基丙烯酸化的产物然后贮存在标有β-CD-M的黑色瓶中。
然后制备一种“精确”聚合物，如下所述：
将60mg β-CD-M溶解在150μl甲醇中。
然后依次添加下述成分，每种成分在添加下一种成分前溶解。
5mg DMPA
125μl HEMA
10μl EDMA。
然后将所述溶液涂到显微镜载玻片上，并如前文所述在UV光下进行聚合。(一种替代方案是，如果DMPA被AIBN取代，则所述聚合可在约60℃以加热方式进行数小时)。
然后如前文所述用扩散方法，在所述载玻片中制备全息照相栅。
实例7
羟丙基环辛四烯并直链淀粉或HPγ-CD
将1g HPγ-CD(干燥的)溶解在5ml干燥DMF和3ml干燥三乙胺中。
烧瓶然后在冰浴中冷却。
然后将2.5ml甲基丙烯酰氯在10分钟内以100μl的增量缓慢添加到搅拌混合物中。
所述烧瓶采用CaCl2干燥管塞住，并在室温下搅拌过夜。
所述混合物然后用100ml甲苯进行摇动，溶剂通过布氏漏斗/水泵过滤除去。沉淀物然后用100cc丙酮进行摇动，并再次过滤，用50cc丙酮进行最后清洗并干燥。
甲基丙烯酸化的产物然后贮存在标有HPγ-CD-M的黑色瓶中。
然后制备一种“精确”聚合物，如下所述：
将60mg HPγ-CD-M溶解在150μl甲醇中。
然后依次添加下述成分，每种成分在添加下一种成分前溶解。
5mg DMPA
125μl HEMA
10μl EDMA。
然后将所述溶液涂到显微镜载玻片上，并如前文所述在UV光下进行聚合。(一种替代方案是，如果DMPA被AIBN取代，则所述聚合可在约60℃以加热方式进行数小时)。
然后如前文所述用扩散方法，在所述载玻片中制备全息照相栅。
由图7和8可以看出CD空穴尺寸受分析物分子尺寸的影响。
实例8
此实例描述使用醇传感器全息照相连续监测由发面酵母产生的醇。
使用醇传感器全息照相在24小时内对葡萄汁中由发面酵母产生的醇进行监测。
将在白色葡萄汁中生长的指数生长期发面酵母细胞旋出，重新悬浮在20％甘油中并冷冻。细胞密度以活菌计数为8×106ml-1。
将0.5ml种子培养物添加到比色杯中的2.5ml白色葡萄汁中，并在30℃培养24小时。在此期间产生的醇(乙醇)通过使用聚HEMA醇传感器全息照相进行监测，将每个时间间隔的反射峰波长与使用乙醇和葡萄汁得到的校准值进行比较(图9)。在24小时培养期间产生的乙醇如图10所示。
Claims (10)
1.一种用于检测流体中分析物的方法，该方法包括：
使所述流体与全息元件接触，该全息元件包括介质和设置在所述介质整个体积中的全息照相，其中所述全息元件的光学特性随着在整个介质体积中发生的物理性质变化而变化，其中所述物理性质变化是由于所述介质与分析物间的相互作用而引起的，且其中所述相互作用和所述物理性质变化是可逆的；和
检测所述光学特性的变化。
2.权利要求1的方法，其中所述物理性质是所述介质的尺寸。
3.权利要求1或2的方法，其中所述光学特性是所述全息元件的反射率、折射率或吸光率。
4.权利要求1或2的方法，其中所述光学特性的变化作为颜色变化进行检测。
5.权利要求1或2的方法，其中所述光学特性的变化作为强度变化进行检测。
6.权利要求1或2的方法，其中所述分析物是葡萄糖或乳酸。
7.权利要求1或2的方法，其中所述分析物是CO2或氧。
8.权利要求1或2的方法，其中所述接触包括使所述流体连续通过所述元件。
9.权利要求1或2的方法，其中所述流体是眼睛的流体。
10.一种用于检测流体中分析物的装置，该装置包括一个具有入口、出口的流体管道和一个所述流体能够流过的全息元件，其中所述装置还包括一个窗口，从而非离子化辐射可照射所述全息元件，其中所述全息元件包括介质和设置在所述介质整个体积中的全息照相，其中所述全息元件的光学特性随着在整个介质体积中发生的物理性质变化而变化，其中所述物理性质变化是由于所述介质与分析物间的相互作用而引起的，且其中所述相互作用和所述物理性质变化是可逆的。
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- 2003-04-04 KR KR1020047015876A patent/KR100971043B1/ko not_active IP Right Cessation
- 2003-04-04 EP EP03722730A patent/EP1493049A1/en not_active Withdrawn
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- 2003-04-04 CN CNB038129574A patent/CN1294430C/zh not_active Expired - Fee Related
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|---|---|
| AU2003229893A1 (en) | 2003-10-27 |
| US20060166350A1 (en) | 2006-07-27 |
| JP4163629B2 (ja) | 2008-10-08 |
| GB0207944D0 (en) | 2002-05-15 |
| AU2003229893B8 (en) | 2006-04-27 |
| US7402441B2 (en) | 2008-07-22 |
| CA2481632A1 (en) | 2003-10-23 |
| KR100971043B1 (ko) | 2010-07-16 |
| AU2003229893B2 (en) | 2005-12-22 |
| EP1493049A1 (en) | 2005-01-05 |
| WO2003087899A1 (en) | 2003-10-23 |
| KR20050013535A (ko) | 2005-02-04 |
| JP2005522703A (ja) | 2005-07-28 |
| HK1081662A1 (en) | 2006-05-19 |
| CN1659458A (zh) | 2005-08-24 |
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