CN101368926A - 含有可扩散的或不可滤出的氧化还原介质的小容积体外分析传感器 - Google Patents
含有可扩散的或不可滤出的氧化还原介质的小容积体外分析传感器 Download PDFInfo
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Abstract
描述了一种使用不可滤出的或可扩散的氧化还原介质的传感器。该传感器包括一个容纳样品使之与工作电极电解接触的样品室,并且至少在某些情况中,该传感器也含有不可滤出的或可扩散的第二种电子转移剂。该传感器和/或所用的方法因应分析物产生传感器信号,其能与介质引起的本底信号区分。本发明能用于使用如库仑分析法、电流分析法和电势分析法的技术测定生物流体如血液或血清中生物分子如葡萄糖或乳酸的浓度。能催化生物分子电氧化或电还原的酶一般用作第二种电子转移剂。
Description
本分案申请是基于申请号为99811815.X,申请日为1999年10月08日,发明名称同上的中国专利申请的分案申请。
发明领域
本发明涉及用于检测小体积样品中生物分析物的分析传感器。
发明背景
分析传感器在化学和医学中可用于测定生物分析物的存在和浓度。例如,监测糖尿病患者的葡萄糖和在重症护理期间监测乳酸需要这些传感器。
现有的技术测定相对较大样品体积的生物分析物,例如,通常需要3微升或更多的血液或其他生物流体。这些液体样品从患者中获得,例如,使用针头和注射器,或刺破一部分皮肤如指尖并“挤”该区域而获得有用的样品体积。这些方法对于患者是不便的,且常常是痛苦的,特别是当频繁需要样品时。已知有较少痛苦的获得样品的方法,如刺破臂或大腿,它们有较低的神经末梢密度。但是,刺破优选区域的身体一般只得到亚微升的血样,因为这些区域并不富含近表面毛细血管。
因此,十分希望发展一种相对无痛苦、易于使用的,能对小体积样品中分析物浓度进行精确且敏感的分析的血液分析传感器,并且是非常有用的。能电化学测定样品中分析物的传感器在本领域中已知。本领域所知的某些传感器至少使用两个电极,并可含有一种氧化还原介质以利于电化学反应。然而,电化学传感器测定小体积中分析物的应用给测定中引入了误差。一种类型的不准确性起因于可扩散的氧化还原介质的使用。因为在小容积传感器中电极如此靠近,所以可扩散的氧化还原介质可在工作电极与对电极之间穿梭,并增加至分析物测定信号。小容积传感器中不准确性的另一来源是测定小样品的体积或确定样品室是否充满的困难。因此,希望发展一种能降低由传感器和样品大小引起的误差的小容积电化学传感器。
发明概述
本发明的传感器提供一种检测并定量亚微升样品中分析物的方法。通常,本发明包括通过如库仑分析法、电流分析法和/或电势分析法分析小体积样品中的分析物的方法和传感器。本发明的传感器使用一种不可滤出的或可扩散的氧化还原介质。该传感器也包括一个容纳样品使之与工作电极电解接触的样品室。在许多情况中,该传感器也含有不可滤出的或可扩散的第二种电子转移剂。
在一个优选的实施方案中,工作电极面对一个对电极,在两个电极之间在样品室内形成一个测定区,其大小可含有不超过约1μL的样品,优选地不超过约0.5μL,更优选地不超过约0.25μL,最优选地不超过约0.1μL的样品。在样品室和测定区中任选地含有一种吸附剂,以减少充满样品室和测定区所需的样品体积。
在本发明的一个实施方案中,提供了一种生物传感器,其将库仑分析电化学传感与一种不可滤出的或可扩散的氧化还原介质相结合,以精确并有效地测定亚微升体积样品中的生物分析物。优选的传感器包括电极、电极上的不可滤出的或可扩散的氧化还原介质、用于容纳样品使之与电极电接触的样品室,和优选地,用于减小样品室容积的置于样品室内的吸附剂。含有任何吸附剂的样品室的大小适于一般不超过约1μL,优选地不超过约0.5μL,更优选地不超过约0.25μL,最优选地不超过约0.1μL的样品体积的分析。在某些情况中,该传感器也含有不可滤出的或可扩散的第二种电子转移剂。
本发明的一个实施方案包括一种测定样品中分析物浓度的方法,首先,使样品接触电化学传感器,然后测定分析物的浓度。电化学传感器包括一个由工作电极和对电极组成的面对面电极对和一个位于两个电极之间的样品室,包括一个测定区。测定区的大小可含有不超过约1μL的样品。
本发明也包括一种具有两个或更多面对面电极对的电化学传感器。每一电极对包括一个工作电极、一个对电极和位于两个电极之间的测定区,该测定区的大小可容纳不超过约1μL的样品。另外,该传感器也包括位于至少一个电极对的工作电极上的一种不可滤出的氧化还原介质,或位于样品室表面上或样品中的一种可扩散的氧化还原介质。
本发明的一个方面是一种测定样品中分析物浓度的方法,包括使该样品与电化学传感器接触,并用库仑法测定分析物的浓度。电化学传感器包括一个由工作电极和对电极组成的电极对。该传感器也包括一个容纳样品使之与工作电极电解接触的样品室。样品室内含有吸附剂,以减少充满样品室所需的样品体积,以使样品室的大小可含有不超过约1μL的样品。样品室也含有一种不可滤出的或可扩散的氧化还原介质,并任选地含有不可滤出的或可扩散的第二种电子转移剂。
传感器也可包含一个充满指示器,如一个指示电极或第二个电极对,它们能确定测定区或样品室何时充满。指示电极或第二种电极对也可用来提高分析物浓度测定的精确性。传感器也可包括一种加热元件,用于加热测定区或样品室,以提高分析物的氧化或还原速度。
传感器能为侧面填充或顶部填充构造。另外,在某些实施方案中,传感器可以是整合型样品获取和分析物测定装置的一部分。整合型样品获取和分析物测定装置可包括传感器和皮肤穿刺构件,使该装置能用来刺破使用者的皮肤,使流体样品如血液流出,然后能用传感器收集。至少在某些实施方案中,能在不移动整合型样品获取和分析物测定装置的情况下收集流体样品。
一种制成如上所述的传感器的方法包括在第一个基底(substrate)上形成至少一个工作电极,并在第二个基底上形成至少一个对电极或对/参比电极。在第一个或第二个基底上放置间隔层。该间隔层界定了一个沟槽,当传感器充满时样品能进入并容纳于该沟槽中。一种氧化还原介质和/或第二种电子转移剂被置于第一个或第二个基底上的当传感器充满时将暴露于该沟槽内的区域中。然后将第一个和第二个基底集合在一起,并用带有沟槽的间隔层隔开,使得可接近至少一个工作电极和至少一个对电极或对/参比电极。在某些实施方案中,第一个和第二个基底是单片或连续网状材料的一部分。
在附加的权利要求书中详细说明了表征本发明的这些及其他多种特征。为了更好地理解本发明、其优点和应用它获得的目标,应参考附图及其说明,其中说明并描述了本发明优选的实施方案。
附图简述
现在参照附图,其中参照数字和字母在几个视图中表示相应的结构:
图1是根据本发明原理的电化学传感器的第一个实施方案的示意图,其具有彼此面对的一个工作电极和一个对电极;
图2是根据本发明原理的电化学传感器的第二个实施方案的示意图,其在共面结构中具有一个工作电极和一个对电极;
图3是根据本发明原理的电化学传感器的第三个实施方案的示意图,其具有彼此面对的一个工作电极和一个对电极,并具有一个扩大的样品室;
图4是图1或图3的传感器之一部分的不按比例的侧剖面图,显示氧化还原介质、样品室和电极的相对位置;
图5是根据本发明原理的电化学传感器的第四个实施方案的俯视图,该传感器包括多个工作电极;
图6是根据本发明原理的分析物测定装置的一个实施方案的透视图,其具有一个样品获取装置和图4的传感器;
图7是用葡萄糖氧化酶作为第二种电子转移剂,用图1的传感器在电解质缓冲溶液(实心圆形)或血清溶液(空心圆形)中电氧化已知量的葡萄糖所需电荷的图;
图8是图7数据(只是缓冲溶液)的平均葡萄糖浓度的图,带有计算的校正曲线以拟合该平均值;对10-20mM浓度计算线性校正曲线,而对0-10mM浓度计算二阶多项式校正曲线;
图9是分析图7的葡萄糖量值的临床相关性的克拉克型临床栅格;
图10是用葡萄糖脱氢酶作为第二种电子转移剂,用图1的传感器在电解质缓冲溶液中电氧化已知量的葡萄糖所需电荷的图;
图11A、11B和11C是根据本发明的交叠工作电极和对电极的三种构造的俯视图;
图12A和12B是根据本发明用基层(base)材料凹槽构成的电极对的一个实施方案的横断面视图;
图13A和13B是在基层材料凹槽中形成的本发明的电极对的另一个实施方案的横断面视图;
图14A和14B是用基层材料凹槽和吸附剂构成的本发明的电极对的另一个实施方案的横断面视图;
图15是对于几种葡萄糖浓度,含有一种可扩散氧化还原介质的传感器随时间变化而释放的电荷的图;
图16是对于几种葡萄糖浓度,含有一种可扩散氧化还原介质的传感器所释放的电荷的图;
图17是含有不同量的可扩散氧化还原介质的传感器随时间变化而释放的电荷的图;
图18A显示在根据本发明的传感器的第五个实施方案中使用的具有工作电极的第一种膜的俯视图;
图18B显示将放置于图18A的第一种膜上的间隔层的俯视图;
图18C显示将放置于图18B的间隔层和图18A的第一种膜上,具有对电极的第二种膜的底视图(相对于图18A和18B翻转);
图19A显示在根据本发明的传感器的第六个实施方案中使用的具有工作电极的第一种膜的俯视图;
图19B显示将放置于图19A的第一种膜上的间隔层的俯视图;
图19C显示将放置于图19B的间隔层和图19A的第一种膜上,具有对电极的第二种膜的底视图(相对于图19A和19B翻转);
图20A显示在根据本发明的传感器的第七个实施方案中使用的具有工作电极的第一种膜的俯视图;
图20B显示将放置于图20A的第一种膜上的间隔层的俯视图;
图20C显示将放置于图20B的间隔层和图20A的第一种膜上,具有对电极的第二种膜的底视图(相对于图20A和20B翻转);
图21A显示在根据本发明的传感器的第八个实施方案中使用的具有工作电极的第一种膜的俯视图;
图21B显示将放置于图21A的第一种膜上的间隔层的俯视图;
图21C显示将放置于图21B的间隔层和图21A的第一种膜上,具有对电极的第二种膜的底视图(相对于图21A和21B翻转);
图22A显示在根据本发明的传感器的第九个实施方案中使用的具有工作电极的第一种膜的俯视图;
图22B显示将放置于图22A的第一种膜上的间隔层的俯视图;
图22C显示将放置于图22B的间隔层和图22A的第一种膜上,具有对电极的第二种膜的底视图(相对于图22A和22B翻转);
图23A显示在根据本发明的传感器的第十个实施方案中使用的具有工作电极的第一种膜的俯视图;
图23B显示将放置于图23A的第一种膜上的间隔层的俯视图;
图23C显示将放置于图23B的间隔层和图23A的第一种膜上,具有对电极的第二种膜的底视图(相对于图23A和23B翻转);
图24A显示在根据本发明的传感器的第十一个实施方案中使用的具有工作电极的第一种膜的俯视图;
图24B显示将放置于图24A的第一种膜上的间隔层的俯视图;
图24C显示将放置于图24B的间隔层和图24A的第一种膜上,具有对电极的第二种膜的底视图(相对于图24A和24B翻转);
图25显示根据本发明的电化学传感器的第十二个实施方案的俯视图;
图26显示一种整合型分析物获取和传感器装置的一个实施方案的透视图;
图27显示根据本发明的传感器的第十三个实施方案的横断面视图;
图28显示用本发明的传感器对采自患者上臂的血样中分析物浓度进行的测定与标准血试验法测定相比较的图;
图29显示用本发明的传感器对采自患者手指的血样中分析物浓度进行的测定与标准血试验法测定相比较的图;
图30显示用本发明的传感器对静脉样品中分析物浓度进行的测定与标准血试验法测定相比较的图;
图31A显示根据本发明的一片传感器组件的一个实施方案的俯视图;
图31B显示根据本发明的一片传感器组件的另一个实施方案的俯视图;
图32显示从仪表内部向置于该仪表中的本发明的传感器看去的横断面视图;
优选实施方案详述
当在此使用时,下列定义说明规定的术语:
“可空气氧化的介质”是一种可被空气氧化的氧化还原介质,优选地使得在空气中作为固体或作为液体贮存一定时间后,例如,一个月或更短,优选地一周或更短,更优选地一天或更短,至少90%的介质成为氧化态。
“电流分析法”包括稳态电流分析法、计时电流法和科特雷耳型测定。
“生物流体”是能检测其中的分析物的任何体液,例如血液、组织液、皮肤液、汗和泪。
本发明说明书中的术语“血液”包括全血及其无细胞成份,如血浆和血清。
“库仑分析法”是在分析物完全或几乎完全电解过程中,直接在电极上或通过一种或多种电子转移剂传递或预计传递的电荷的测定。电荷的测定方法包括,对分析物部分或几乎完全电解过程中传递的电荷的测定,或更常用的是,在电解过程中对衰减电流和实耗时间的多种测定。衰减电流是由电解引起的电解物种浓度的降低引起的。
“对电极”是指与工作电极配对的一个或多个电极,其中通过与通过工作电极的电流数值相同且符号相反的电化学电流。除非说明中指出“对电极”不包括参比电极或对/参比电极,否则术语“对电极”包括也起参比电极作用的对电极(即对/参比电极)。
“有效扩散系数”是表征物质如分析物、酶或氧化还原介质在电化学测定池电极之间的体积中运输的扩散系数。至少在某些情况中,测定池体积可被多于一种的介质(如样品液和聚合物膜)占据。物质通过每种介质的扩散可以不同的速率发生。有效扩散系数对应于通过这种多介质体积的扩散速率,并且一般不同于只充满样品液的测定池中物质的扩散系数。
“电化学传感器”是一种用来通过电化学氧化和还原反应检测分析物的存在和/或测定分析物浓度的装置。这些反应转化为可与分析物的量或浓度相关的电信号。
“电解”是化合物直接在电极处或通过一种或多种电子转移剂(例如氧化还原介质和/或酶)的电氧化或电还原。
术语“面对面电极”是指工作电极与对电极的一种构造,其中工作电极的工作表面与对电极的表面基本相对。至少在某些情况中,工作电极与对电极之间的距离短于工作电极的工作表面的宽度。
当一种化合物被截留于表面上或与之化学结合时,其“固定”于该表面。
“指示电极”包括一个或多个检测样品室和/或测定区部分或完全充满的电极。
“层”包括一个或多个层。
“测定区”在此定义为样品室的一个区域,其大小只可含有分析物测定过程中待检的样品部分。
“不可扩散的”、“不可滤出的”或“不可释放的”化合物是在分析物测定期间基本上不能从工作电极的工作表面扩散出去的化合物。
“对/参比电极的电势”是当测定池中的溶液为pH7的0.1M NaCl溶液时,测定池的参比电极或对/参比电极的半电池电势。
“电势分析法”和“计时电势法”是指在一个或多个时间点进行电势测定。
“氧化还原介质”是在分析物和工作电极之间直接或通过第二种电子转移剂运送电子的电子转移剂。
除非说明中提出“参比电极”不包括对/参比电极,否则“参比电极”包括也起对电极作用的参比电极(即,对/参比电极)。
“第二种电子转移剂”是在氧化还原介质和分析物之间运送电子的分子。
“吸附剂”是毛细作用吸收、保留液体样品和/或被其湿润的材料,其一般不能防止分析物向电极的扩散。
“样品室表面”包括工作电极、对电极、对/参比电极、参比电极、指示电极、间隔区的表面,或围成样品室的其他任何表面。
“工作电极”是在或不在氧化还原介质的作用下分析物在该处电氧化或电还原的电极。
“工作表面”是覆盖不可滤出的氧化还原介质并暴露于样品的工作电极的部分,或者,如果氧化还原介质是可扩散的,“工作表面”是暴露于样品的工作电极的部分。
本发明的小容积体外分析传感器用来测定体积不超过约1μL,优选地不超过约0.5μL,更优选地不超过0.25μL,最优选地不超过0.1μL的样品部分中分析物的浓度。目标分析物一般存在于溶液或生物流体如血液或血清中。参照附图特别是图1-4,本发明的小容积体外电化学传感器20通常包括一个工作电极22、一个对(或对/参比)电极24和一个样品室26(见图4)。样品室26的构造使得当样品在样品室中时样品与工作电极22和对电极24均电解接触。这使电流可在电极之间流动,从而实现分析物的电解(电氧化或电还原)。
工作电极
工作电极22可由模制的碳纤维复合材料制成,或者可由惰性绝缘基层材料如聚酯构成,其上放置适当的导电层。操作中在传感器的电势范围内,导电层一般具有相对较低的电阻,并且一般是电化学惰性的。合适的导电层包括金、碳、铂、二氧化钌、钯,和导电的环氧类,如ECCOCOATCT5079-3填充碳的导电环氧涂层(可获自W.R.Grace公司,Woburn,Massachusetts),以及本领域技术人员所知的其他非腐蚀性材料。通过如蒸汽淀积或印刷的方法将电极(例如导电层)置于惰性材料的表面。
接头23可位于工作电极22末端,以使电极与外部电子设备(未显示)如电压电源或电流测定装置容易地连接。也可用其他已知的方法或结构(如接触垫)连接工作电极22与外部电子设备。
为防止在未覆盖介质的工作电极部分上发生电化学反应,当使用不可滤出的介质时,介电体40可置于电极上含氧化还原介质区域的上方、下方或周围,如图4所示。合适的介电材料包括蜡和绝缘的有机聚合物如聚乙烯。介电体40也可覆盖电极上的一部分氧化还原介质。覆盖的氧化还原介质部分将不接触样品,因此不是电极工作表面的一部分。
传感化学
除了工作电极22之外,为了分析分析物在样品室26中还应具有传感化学材料。该传感化学优选地包括一种氧化还原介质和第二种电子转移介质,尽管在某些情况中,可单独使用一种或另一种。氧化还原介质和第二种电子转移剂可能独立地是可扩散的或不可滤出的(即不可扩散的),使得其一或两者可以是可扩散的或不可滤出的。传感化学成份的放置可取决于它们是可扩散的还是不可滤出的。例如,不可滤出的和/或可扩散的成份一般在工作电极上形成一个传感层。此外,也可在加入样品之前将一种或多种可扩散的成份置于样品室的任一表面上。作为另一个实例,可在向传感器中加入样品之前将一种或多种可扩散的成份置于样品中。
如果氧化还原介质是不可滤出的,则不可滤出的氧化还原介质一般置于工作电极22上作为传感层32。在一个含有氧化还原介质和第二种电子转移剂的实施方案中,如果该氧化还原介质和第二种电子转移剂都是不可滤出的,则两种不可滤出的成份都置于工作电极22上作为传感层32。
例如,如果第二种电子转移剂是可扩散的而氧化还原介质是不可滤出的,则至少将该氧化还原介质置于工作电极22上作为传感层32。可扩散的第二种电子转移剂不需要置于工作电极的传感层上,但可置于样品室的任一表面上,包括氧化还原介质传感层内,或可置于样品中。如果氧化还原介质是可扩散的,则该氧化还原介质可置于样品室的任一表面上,或可置于样品中。
如果氧化还原介质和第二种电子转移剂都是可扩散的,则可扩散成份可独立地或共同地置于样品室的任一表面上,和/或置于样品中(即,每种可扩散成份不需要置于样品室的同一表面上或置于样品中)。
氧化还原介质,不论是可扩散的还是不可滤出的,均可调节工作电极22与分析物之间的电流,并能电化学分析可能不适于在电极上直接电化学反应的分子。该介质作为电极与分析物之间的电子转移剂起作用。
在一个实施方案中,氧化还原介质和第二种电子转移剂都是可扩散的,并置于样品室的同一表面如工作电极上。在这相同的装置中,两者都可置于例如对电极、对/参比电极、参比电极或指示电极上。在其他情况中,氧化还原介质和第二种电子转移剂都是可扩散的,并独立地置于样品室的表面上和/或样品中。例如,氧化还原介质可置于工作电极上,而第二种电子转移剂置于除工作电极之外的任一表面上,或置于样品中。类似地,相反情况也是一个合适的实施方案,其中第二种电子转移剂置于工作电极上,而氧化还原介质置于除工作电极之外的任一表面上,或置于样品中。作为另一个实例,氧化还原介质可置于对电极上,而第二种电子转移剂置于除对电极之外的任一表面上,或置于样品中。相反的情况也是合适的。
可扩散的氧化还原介质和/或第二种电子转移剂可快速扩散到样品中或可在一段时间内发生扩散。类似地,可扩散的氧化还原介质和/或第二种电子转移剂可作为固体首先从所处的表面上溶解,然后可扩散的氧化还原介质和/或第二种电子转移剂可快速地或经过一段时间扩散到样品中。如果氧化还原介质和/或第二种电子转移剂扩散需经历一段时间,使用者可能被要求在测定分析物浓度之前等待一段时间,以使氧化还原介质和/或第二种电子转移剂扩散。
本底信号
至少在某些情况中,可扩散的氧化还原介质甚至在无分析物时仍可在工作电极与对电极之间往复穿梭。这一般产生本底信号。对于库仑分析测定,该本底信号在此被称为“QBack”。该本底信号对应于不含分析物时电化学测定中传递的电荷。本底信号一般包括瞬时成份和稳态成份。例如,至少一部分瞬时成份由于特定氧化态的介质浓度梯度的建立而产生。例如,至少一部分稳态成份可由在工作电极和对电极或对/参比电极之间穿梭的氧化还原介质产生。穿梭是指氧化还原介质在工作电极处被电氧化(或电还原),然后在对电极或对/参比电极处被电还原(或电氧化),从而使该氧化还原介质可在工作电极处再次电氧化(或电还原),使得氧化还原介质在电氧化与电还原之间循环。
氧化还原介质穿梭的量,及本底信号的稳态成份随下列条件而不同,例如:氧化还原介质的有效扩散系数、样品粘度、样品温度、电化学测定池的尺寸、工作电极与对电极或对/参比电极之间的距离和工作电极与对电极或对/参比电极之间的角度。
在某些情况中,本底信号的稳态成份可包含与下列条件有关的噪音:(a)例如,样品温度、样品粘度或本底信号所依赖的其他任何参数在测定期间的变异性,(b)电化学测定池的缺陷,例如,工作电极与对电极或对/参比电极的不均匀的间距、电极几何形状的变化,或工作电极、对电极和/或对/参比电极的突起。
尽管本底信号的稳态成份可以是可重复的,但任何噪音固然是不可重复的。所以,噪音对准确性有不利影响。在某些情况中,本底信号和噪音是相关的。因此,降低本底信号能降低噪音和它引起的误差。例如,降低介质在工作电极与对电极或对/参比电极之间的穿梭可能将降低与可影响氧化还原介质扩散的样品温度和粘度改变有关的噪音。
因此,为了在降低本底信号时也降低噪音的情况中提高测定的准确性或降低测定误差,中等到近零水平的本底信号是希望的。至少在某些情况中,传感器构造为使本底信号至多5倍于一定量分析物电解产生的信号大小。优选地,本底信号至多为分析物电解所产生的信号的200%、100%、50%、25%、10%或5%。在电流分析法中,可通过测定氧化还原介质穿梭产生的电流与分析物电解产生的电流之比进行这种比较。在电势分析法中,可通过测定氧化还原介质穿梭的电势值和分析物电解产生的电势值进行这种比较。在库仑分析法中,可通过测定氧化还原介质穿梭在工作电极处转移的电荷和分析物电解在工作电极处转移的电荷进行这种比较。
本底信号的大小可与分析物的预定量相比。例如,样品中分析物的预定量可以是分析物的预期或平均摩尔量。分析物的预期或平均摩尔量可测定为例如,使用者或个体的平均值;群体的平均值;正常生理范围的最大、最小或平均值;群体的最大或最小生理值;使用者或个体的最大或最小生理值;使用者、个体或群体的正常生理范围值之外的平均、最大或最小偏差;群体平均值之上或之下的偏差;或使用者或个体的平均正常生理值之上或之下的平均、最大或最小偏差。群体可按例如健康状况、性别或年龄确定,如正常成人、儿童或新生儿群体。如果群体按健康状况确定,则群体可包括缺乏特定病症或具有特定病症如糖尿病的人群。适合平均值或预期值的参考区间,如《Tietz临床化学教科书》,附录(2175-2217页)(第二版,Carl A.Burtis和Edward R.Ashwood编,W.D.Saunders Co.,Philadelphia 1994)(在此引用作为参考)中所述的,可作为指标,但也可由医生通过身体检查或血液化学检验确定个体的平均值或预期值。例如,根据《Tietz临床化学教科书》,成人禁食后在全血中可含有浓度为65-95mg/dL的葡萄糖,在静脉全血中含有浓度为8.1-15.3mg/dL的L-乳酸。例如,成人的平均正常生理浓度可对应于80mg/dL的葡萄糖或12.7mg/dL的乳酸。其他实例包括患有幼年发作型糖尿病,但血糖控制较好,葡萄糖浓度为约50mg/dL~400mg/dL,因而平均摩尔量为225mg/dL的病人。在另一种情况中,非糖尿病成人可有约80mg/dL(禁食后)~140mg/dL(进食后)的葡萄糖浓度,从而有110mg/dL的平均摩尔量。
可测定的其他分析物包括,例如,乙酰胆碱、淀粉酶、胆红素、胆甾醇、绒毛膜促性腺激素、肌酸激酶(例如CK-MB)、肌酸、DNA、果糖胺、葡萄糖、谷氨酰胺、生长激素、激素、酮类、乳酸、过氧化物、前列腺特异的抗原、凝血酶原、RNA、甲状腺刺激激素和肌钙蛋白。也可测定药物如抗生素(例如庆大霉素、万古霉素等)、毛地黄毒苷、地高辛、滥用的药物、茶碱和华法令的浓度。在美国专利申请系列号09/138,888和09/145,776中公开并在美国临时申请系列号60/090,517、60/093,100和60/114,919中叙述了适于测定DNA和/或RNA浓度的试验,以此引用作为参考。
为了构建具有本底信号与分析物电解信号特定比值的传感器,可考虑并选择与氧化还原介质穿梭本底信号和/或分析电解产生的信号引起的电流和/或电荷有关的几个参数,以获得希望的比值。一般而言,对于库仑分析法测定的信号是电荷;而对于电流分析法测定的信号是进行测定时的电流。因为电流和电荷取决于几个参数,所以可用多种传感器构造和操作传感器的方法达到希望的氧化还原介质穿梭产生的本底信号与分析物电解产生的信号之比。
控制本底信号
一种控制本底信号的方法包括使用一种氧化还原介质,该介质可a)如用循环伏安法在pH7的0.1M NaCl中测定的,以相对于参比或对/参比电极的电位不高于约+100mV的半波电位氧化分析物,或b)如用循环伏安法在pH7的0.1M NaCl中测定的,以相对于参比或对/参比电极的电位不低于约-100mV的半波电位还原分析物。可选用合适的参比或对/参比电极(例如银/氯化银电极)。优选地,氧化还原介质可a)如用循环伏安法在pH7的0.1M NaCl中测定的,以相对于参比或对/参比电极电位不高于约+50mV、+25mV、0mV、-25mV、-50mV、-100mV或-150mV的半波电位氧化分析物,或b)如用循环伏安法在pH7的0.1M NaCl中测定的,以相对于参比或对/参比电极电位不低于约-50mV、-25mV、0mV、+25mV、+50mV、+100mV、+150mV或+200mV的半波电位还原分析物。此外,在对电极对氧化还原介质的还原中,在工作电极与对电极或对/参比电极之间施加不高于约+100mV、+50mV、+25mV、0mV、-25mV、-50mV、-100mV或-150mV的电势下操作传感器。对于氧化还原介质在对电极处的氧化,在工作电极与对电极或对/参比电极之间施加不低于约-100mV、-50mV、-25mV、0mV、+25mV、+50mV、+100mV、+150mV或+200mV的电势下操作传感器。
另一种方法包括控制施加的电势,使得对于电氧化测定,氧化还原介质在对电极或对/参比电极处不易还原,或对于电还原测定,氧化还原介质在对电极或/对/参比电极处不易氧化。其实现方法可以是,例如,在电氧化测定中使用含有可扩散的氧化还原介质的传感器,相对于参比或对/参比电极的电势与对电极(相对于参比电极)或对/参比电极的电势相比为负。选择工作电极(相对于参比或对/参比电极)的电势为相对于氧化还原介质为正,并可相对于对电极或对/参比电极为负,使得氧化还原介质在工作电极处氧化。例如,当一种可扩散的氧化还原介质在相对于参比或对/参比电极为-200mV的电势下介导分析物的电氧化,并且工作电极平衡时的电势相对于参比或对/参比电极为-150mV时,该氧化还原介质在工作电极处基本上被氧化,并将氧化分析物。进而,如果某些氧化的氧化还原介质到达对电极或对/参比电极处,该氧化还原介质不易在对电极或对/参比电极处还原,因为对电极或对/参比电极被充分平衡,相对于氧化还原介质电势为正(即150mV)。
在电还原测定中,使用一种含有可扩散的氧化还原介质的传感器,其相对于参比或对/参比电极的表观电位与对电极或对/参比电极的电势相比为正。相对于参比或对/参比电极的工作电极电势选择为相对于氧化还原介质为负,并可平衡为相对于对电极或对/参比电极为正的,使得氧化还原介质在工作电极处氧化。
再另一种限制本底电流的方法包括当在对电极或对/参比电极上反应时用例如沉淀或聚合作用固定氧化还原介质。例如,该介质在氧化态时可以是阳离子,但在还原态时为中性且溶解度更低。在对/参比电极处的还原导致还原的中性介质在对/参比电极上的沉淀。
适用于控制本底信号的另一种传感器构造包括一种含有一定摩尔量的氧化还原介质的传感器,该介质在化学计量上等同于或低于分析物的预期或平均摩尔量。分析物的预期或平均摩尔量可如上所述测定。分析物的预期或平均摩尔量可测定为,例如,使用者或个体的平均值;群体的平均值;正常生理范围的最大、最小或平均值;群体的最大或最小生理值;使用者或个体的最大或最小生理值;使用者、个体或群体的正常生理范围值之外的平均、最大或最小偏差;群体平均值之上或之下的偏差;或使用者或个体的平均正常生理值之上或之下的平均、最大或最小偏差。例如,群体可按健康状况、性别或年龄确定,如正常成人、儿童或新生儿群体。如果群体按健康状况确定,则群体可包括缺乏特定病症或具有特定病症如糖尿病的人群。适于平均值或预期值的参考区间,如同上的《Tietz临床化学教科书》中所述的,可作为指标,但身体检查或血液化学检验也可确定平均值或预期值。例如,分析物的的生理平均摩尔量可取决于采取样品的人的健康状况或年龄。这种测定为医生所了解。
通过降低氧化还原介质相对于分析物浓度的浓度,可归因于分析物的信号相对于可归因于氧化还原介质穿梭的信号而言提高了。为实现该方法,氧化还原介质的摩尔量在化学计量基础上可不高于分析物的预期或平均摩尔量的50%、20%、10%或5%。
在这种传感器构造中使用的氧化还原介质的量应在范围内。测定该范围的上限可根据,例如,由氧化还原介质穿梭引起的可接受的最大信号;电化学测定池的设计,包括例如,测定池的尺寸和电极的位置;氧化还原介质的有效扩散系数;测定所需的时间长度。而且,由氧化还原介质穿梭引起的可接受的最大信号可随测定法而不同,这归因于一种或多种测定参数,例如,测定是定性的、半定量的还是定量的;分析物浓度的小差别是否作为改变治疗的基础;和分析物的预期浓度。
尽管使所用的氧化还原介质的量最小是有利的,但氧化还原介质的可接受的量的范围一般具有下限。可使用的氧化还原介质的最小量是在希望的测定时间内,如不超过约5分钟或不超过约1分钟内完成测定所需的氧化还原介质浓度。完成测定所需的时间取决于,例如,工作电极与对电极或对/参比电极之间的距离、氧化还原介质的有效扩散系数和分析物的浓度。例如在某些情况中,当不存在动力学限制时,即氧化还原介质的穿梭仅依赖于扩散时,氧化还原介质的最小浓度可用下列公式确定:
Cm=(d2CA)/Dmt
其中,Cm是所需介质的最小浓度;d是面对面排列的工作电极与对电极或对/参比电极之间的距离;CA是样品中的平均分析物浓度;Dm是样品中介质的有效扩散系数;t是希望的测定时间。
例如,当面对面电极对之间的距离为50μm,待测分析物是5mM葡萄糖,氧化还原介质的有效扩散系数是10-6cm2/sec,希望的响应时间不超过约1分钟时,最小氧化还原介质浓度为2.08mM。在这些条件下,本底信号将低于分析物电氧化产生的信号。
限制可扩散的氧化还原介质产生的本底电流的另一种传感器构造包括一个防止可扩散的介质向对电极流动的阻挡层。该阻挡层可以是,例如,氧化还原介质不能通过它扩散或氧化还原介质通过它缓慢扩散的薄膜。合适的薄膜的实例包括聚碳酸酯、聚乙烯醇和再生的纤维素或纤维素酯膜。另外,阻挡层也可包括带电的或极性颗粒、化合物或官能团,其防止或减少带电的氧化还原介质相对于电荷中性或弱荷电分析物流动的流动。如果氧化还原介质带正电,如以下所述的多种锇氧化还原介质,则阻挡层可以是带正电的或极性的薄膜,如甲基化的聚(1-乙烯基咪唑)。如果氧化还原介质带负电,则阻挡层可以是带负电的或极性的薄膜,如合适的极性基质的实例包括双极性膜—含有与阴离子聚合物交联的阳离子聚合物的膜,等等。在某些情况中,阻挡层使可扩散的氧化还原介质在对电极处的氧化或还原降低了至少25%、50%或90%。
限制本底电流的另一种传感器构造包括一种含有氧化还原介质的传感器,该介质在工作电极上比在对电极上更易氧化或还原。氧化还原介质在电极处的反应速率可以为电极材料的函数。例如,某些氧化还原介质在碳电极处可比在Ag/AgCl电极处反应更快。电极的适当选择可使一个电极处的反应速率明显低于另一个电极处的速率。在某些情况中,可扩散的氧化还原介质在对电极处的氧化或还原速率比在工作电极处降低至少25%、50%或90%。在某些情况中,氧化还原介质在对电极或对/参比电极处的反应速率受控于,例如,为需要超电势或比外加电势更高的电势的对电极或对/参比电极选择材料,以提高对电极或对/参比电极处的反应速率。
限制本底电流的另一种传感器构造包括适于降低氧化还原介质扩散的成份。例如,使用一种具有相对较低的扩散系数的氧化还原介质或提高测定区中样品的粘度能降低扩散。在另一个实施方案中,选用具有高分子量如大于5000道尔顿,优选地大于25000道尔顿,更优选地大于100000道尔顿的氧化还原介质可降低氧化还原介质的扩散。
氧化还原介质
尽管能用任何有机或有机金属氧化还原物质种类作为氧化还原介质,但一种合适的氧化还原介质是过渡金属化合物或络合物。适合的过渡金属化合物或络合物的实例包括锇、钌、铁和钴化合物或络合物。在这些络合物中,过渡金属与一个或多个配体配位结合。这些配体一般是单齿、二齿、三齿或四齿的。最优选的配体是杂环氮化合物,如吡啶和/或咪唑衍生物。多齿配体可包括多个吡啶和/或咪唑环。此外,也能使用金属茂衍生物,如二茂铁。
合适的氧化还原介质包括含有一个或多个配体的锇或钌过渡金属络合物,每个配体都有一个或多个含氮杂环。这些配体的实例包括吡啶和咪唑环和含有两个或多个吡啶和/或咪唑环的配体,如2,2’-联吡啶、2,2’:6’,2”-三联吡啶、1,10-菲咯啉和具有下列结构的配体:
及其衍生物,其中R1和R2各自独立是氢、羟基、烷基、烷氧基、链烯基、乙烯基、烯丙基、酰氨基、氨基、乙烯基酮类、酮基或含硫基团。
术语“烷基”包括含有1-6个碳原子的直链或支链饱和脂族烃链,例如,甲基、乙基、异丙基(1-甲基乙基)、丁基、叔丁基(1,1-二甲基乙基)等。优选地,烃链含有1至3个碳原子。
术语“烷氧基”包括通过一个氧原子与该结构的其余部分连接的上述烷基,例如,甲氧基、乙氧基、丙氧基、异丙氧基(1-甲基乙氧基)、丁氧基、叔丁氧基等。
术语“链烯基”包括含2至6个碳原子的不饱和脂族烃链,例如,乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-甲-1-丙烯基等。优选地,烃链含有2至3个碳原子。
术语“酰氨基”包括含有与羰基的碳原子键合的氮原子的基团,并包括具有下列通式的基团:
其中R3和R4各自独立地为氢、烷基、烷氧基或链烯基。
在此使用的术语“氨基”包括烷氨基,如甲氨基、二乙氨基、N,N-甲基乙氨基等;烷氧基烷氨基,如N-(乙氧基乙基)氨基、N,N-二(甲氧基乙基)氨基、N,N-(甲氧基乙基)(乙氧基乙基)氨基等;及含氮环,如哌啶子基、哌嗪基、吗啡基等。
术语“乙烯基酮”包括具有下列通式的基团:
其中R5、R6和R7各自独立地是氢、烷基、烷氧基或链烯基。
术语“酮”包括具有下列通式的基团:
其中R8是氢、烷基、烷氧基或链烯基。
术语“含硫基团”包括巯基、烷基巯基(如甲基巯基、乙基巯基等)、烷氧基烷基巯基(如甲氧基乙基巯基等)、烷基亚砜(如甲基亚砜和丙基亚砜等)、烷氧基烷基亚砜(如乙氧基乙基亚砜等)、烷基砜(如甲基砜、丙基砜等),及烷氧基烷基砜(如甲氧基乙基砜等)。优选地,含硫基团是巯基。
其他适合的氧化还原介质包括具有一个或多个配体的锇或钌过渡金属络合物,每个配体含有一个或多个含氮杂环,而每个含氮杂环含有选自氮、氧、硫和硒的第二个杂原子。
含有一个或多个含氮杂环且每个杂环含有第二个杂原子的配体的实例包括具有下列结构的配体:
其中Y1、Y2、Y3和Y4各自独立地是氧原子、硫原子、硒原子或具有通式NR9的取代氮原子,其中R9是氢、羟基、烷基、烷氧基、链烯基、酰氨基、氨基、乙烯基酮、酮基或含硫基团。术语“烷基”、“烷氧基”、“链烯基”、“酰氨基”、“氨基”、“乙烯基酮”、“酮基”和“含硫基团”如上定义。
这些配体的合适的衍生物包括,例如,向杂环的任何适当位点上添加烷基、烷氧基、链烯基、乙烯基酯和酰氨基官能团,这些位点包括,例如,吡啶环的4-位(即氮的对位)或咪唑环的氮原子之一。
可与锇阳离子络合的2,2’-联吡啶的合适的衍生物包括,例如,单-、二-和聚烷基-2,2’-联吡啶,如4,4’-二甲基-2,2’-联吡啶;单-、二-和聚烷氧基-2,2’-联吡啶,如4,4’-二甲氧基-2,2’-联吡啶和2,6’-二甲氧基-2,2’-联吡啶;单-、二-和聚乙酰氨基-2,2’-联吡啶,如4,4’-二(乙酰氨基)-2,2’-联吡啶;单-、二-、和聚烷基氨基烷氧基-2,2’-联吡啶,如4,4’-二(N,N-二甲基氨基乙氧基)-2,2’-联吡啶;和取代位的单-、二-和聚吡唑基-2,2’-联吡啶,如4,4’-二甲氧基-6-(N-吡唑基)-2,2’-联吡啶和4,4’-二甲氧基-6-(N-吡唑基甲基)-2,2’-联吡啶。
可与锇阳离子络合的1,10-菲咯啉的合适的衍生物包括,例如,单-、二-和聚烷基-1,10-菲咯啉,如4,7-二甲基-1,10-菲咯啉,和单-、二-、聚烷氧基-1,10-菲咯啉,如4,7-二甲氧基-1,10-菲咯啉和5-甲氧基-1,10-菲咯啉。
2,2’:6’,2”-三联吡啶的合适的衍生物包括,例如,单-、二-、三-和聚烷基-2,2’:6’,2”-三联吡啶,如4,4’,4”-三甲基-2,2’:6’,2”-三联吡啶、4,4’,4”-三乙基-2,2’:6’,2”-三联吡啶;单-、二-、三-和聚烷氧基-2,2’:6’,2”-三联吡啶,如4,4’,4”-三甲氧基-2,2’:6’,2”-三联吡啶和4’-甲氧基-2,2’:6’,2”-三联吡啶;单-、二-、三-和聚氨基-2,2’:6’,2”-三联吡啶,如4’-氨基-2,2’:6’,2”-三联吡啶;单-、二-、三-和聚烷基氨基-2,2’:6’,2”-三联吡啶,如4’-二甲基氨基-2,2’:6’,2”-三联吡啶;单-、二-、三-和聚烷硫基-2,2’:6’,2”-三联吡啶,如4’-甲硫基-2,2’:6’,2”-三联吡啶和4-甲硫基-4’-乙硫基-2,2’:6’,2”-三联吡啶。
吡啶的合适的衍生物包括,例如单-、二-、三-和多取代吡啶,如2,6-双(N-吡唑基)吡啶、2,6-双(3-甲基-N-吡唑基)吡啶、2,6-双(2-咪唑基)吡啶、2,6-双(1-甲基-2-咪唑基)吡啶、2,6-双(1-乙烯基-2-咪唑基)吡啶;单-、二-、三-和聚氨基吡啶,如4-氨基吡啶、4,4’-二氨基联吡啶、4,4’-二(二甲基氨基)联吡啶和4,4’,4”-三氨基三联吡啶。
其他合适的衍生物包括含有三个杂环的化合物。例如,一种合适的衍生物包括具有下列通式的化合物:
其中R10、R11、R12各自独立地是氢、羟基、烷基、烷氧基、链烯基、乙烯基、烯丙基、酰氨基、氨基、乙烯基酮、酮基或含硫基团。
术语“烷基”、“烷氧基”、“链烯基”、“酰氨基”、“氨基”、“乙烯基酮”、“酮基”和“含硫基团”定义同上。
其他合适的氧化还原介质衍生物包括具有下列通式的化合物:
其中R13是氢、羟基、烷基、烷氧基、链烯基、乙烯基、烯丙基、乙烯基酮、酮基、酰氨基、氨基或含硫基团;Y5和Y6各自独立地是氮原子或碳原子。
术语“烷基”、“烷氧基”、“链烯基”、“酰氨基”、“氨基”、“乙烯基酮”、“酮基”和“含硫基团”定义同上。
其他合适的衍生物包括具有下列通式的化合物:
其中R14如上所述,Y7和Y8各自独立地是硫原子或氧原子。
合适的氧化还原介质的实例也包括,例如,与下列配体络合的锇阳离子:(a)两个二齿配体,如2,2’-联吡啶、1,10-菲咯啉或其衍生物(两个配体不必相同),(b)一个三齿配体,如2,2’,2”-三联吡啶和2,6-二(咪唑-2-基)-吡啶,或(c)一个二齿配体和一个三齿配体。合适的锇过渡金属络合物包括,例如,[(bpy)2OsLX]+/2+、[(dimet)2OsLX]+/2+、[(dmo)2OsLX]+/2+、[terOsLX2]0/+、[trimetOsLX2]0/+和[(ter)(bpy)2LOs]2+/3+,其中bpy是2,2’-联吡啶,dimet是4,4’-二甲基-2,2’-联吡啶,dmo是4,4’-二甲氧基-2,2’-联吡啶,ter是2,2’:6’,2”-三联吡啶,trimet是4,4’,4”-三甲基-2,2’:6’,2”-三联吡啶,L是含氮杂环配体,X是卤素如氟、氯或溴。
氧化还原介质通常彼此并与电极快速交换电子,使得络合物能快速氧化和/或还原。通常,铁络合物比钌络合物更易氧化,而其比锇络合物更易氧化。另外,氧化还原电势通常随配位杂环的数量而增加;除了配位金属的氮在形式上是阴离子的情况外,六元杂环比五元环更能提高电势。只有当环中的氮通过单键与其相邻的两个碳原子结合时,才是如此。如果氮在形式上是阴离子,则通常在金属离子配位后氧化还原电势提高。
至少某些可扩散的氧化还原介质包含一个或多个吡啶或咪唑官能团。咪唑官能团也能包含其他取代基,并且可以是例如乙烯基咪唑如1-乙烯基咪唑或甲基咪唑如1-甲基咪唑。合适的可扩散介质的实例可包括[Os(dmo)2(1-乙烯基咪唑)X]X、[Os(dmo)2(1-乙烯基咪唑)X]X2、[Os(dmo)2(咪唑)X]X、[Os(dmo)2(咪唑)X]X2、[Os(dmo)2(1-甲基咪唑)X]X2和[Os(dmo)2(甲基咪唑)X]X2,其中dmo是4,4’-二甲氧基-2,2’-联吡啶,X是如上所述的卤素。
其他含锇氧化还原介质包括[Os((甲氧基)2菲咯啉)2(N-甲基咪唑)X]+/2+、[Os((乙酰氨基)2联吡啶)2(L)X]+/2+,其中L是为改进电势而选择的单齿含氮化合物(包括但不限于咪唑衍生物);和Os(三联吡啶)(L)2Cl,其中L是氨基吡啶,如二烷基氨基吡啶;N-取代的咪唑,如N-甲基咪唑;噁唑;噻唑;或烷氧基吡啶,如甲氧基吡啶。X是如上所述的卤素。
不含锇的可扩散氧化还原介质包括,例如,吩噁嗪,如7-二甲基氨基-1,2-苯并吩噁嗪(麦尔多拉蓝)、1,2-苯并吩噁嗪和尼罗蓝;3-β-萘酰(亮甲酚蓝);四甲基苯二胺(TMPD);二氯靛酚(DCIP);N-甲基二甲基苯基吡唑酮鎓盐,如吩嗪硫酸二甲酯(PMS)、N-甲基吩嗪硫酸二甲酯和甲氧基吩嗪硫酸二甲酯;四唑盐,如四唑蓝或硝基四唑蓝;和吩噻嗪,如甲苯胺蓝O。
其他氧化还原种的实例包括稳定的醌和在其氧化态中含有醌型结构的物种,如尼罗蓝和靛酚。合适的醌的实例包括,例如,萘醌、苯酚合苯醌、苯醌、环烷醌(naphthenequinone)等的衍生物。萘醌衍生物的实例包括胡桃醌(即,5-羟基-1,4-萘醌)及其衍生物,例如,2,3-二氯-5,8-二羟基-1,4-萘醌、2,3-二甲基-5,8-二羟基-1,4-萘醌、2-氯-5,8-二羟基-1,4-萘醌、2,3-甲氧基-5-羟基-1,4-萘醌等。其他实例包括氨基萘醌,例如,吗啉代萘醌,如2-氯-3-吗啉代-1,4-萘醌;哌啶子基萘醌,如2-甲基-3-哌啶子基-1,4-萘醌;哌嗪萘醌如2-乙氧基-3-哌嗪-1,4-萘醌;等等。
合适的苯酚合苯醌衍生物包括,例如,coerulignone(即3,3’,5,5’-四甲氧基联苯酚合苯醌)及其衍生物,如3,3’,5,5’-四甲基联苯酚合苯醌、3,3’,5,5’-四羟基联苯酚合苯醌等。
合适的苯醌衍生物包括,例如,辅酶Q0(即2,3-二甲氧基-5-甲基-1,4-苯醌)及其衍生物,如2,3,5-三甲基-1,4-苯醌、2,3-二甲基-5-甲氧基-1,4-苯醌、2,3-二甲基-5-羟基-1,4-苯醌等。
其他合适的醌衍生物包括,例如,二氢苊醌和泛醌,如辅酶Q,包括Q1、Q2、Q6、Q7、Q9和Q10。
其他合适的不含锇可扩散氧化还原介质包括,例如,泰勒蓝(即1,9-二甲基亚甲蓝)、N,N’-二乙基噻花青碘和硫堇。
在另一种方法中,传感层32含有一种不可滤出的(即不可释放的)氧化还原介质,并置于工作电极22的一部分上。不可滤出的氧化还原介质可以是,例如,氧化还原聚合物(即含有一个或多个氧化还原物种的聚合物)。优选地,在测定过程中只有很少的或没有不可滤出的氧化还原介质从工作电极22向样品中滤出。测定过程一般短于约5分钟。该实施方案的氧化还原介质可结合或以其他方式固定于工作电极22上,而防止该介质向样品中的滤出。可用已知方法将氧化还原介质结合或以其他方式固定于工作电极上,例如,与带相反电荷的聚电解质形成多离子桥、氧化还原介质与工作电极上的聚合物的共价结合、氧化还原介质在对该氧化还原介质有高亲和力的基质中的截留,或氧化还原介质与工作电极上结合的化合物的生物结合。在一个实施方案中,可用一种阳离子交换膜截留阴离子氧化还原化合物。类似地,在另一个实施方案中,可用一种阴离子交换膜截留阳离子氧化还原化合物。在关于生物偶联的另一个实施方案中,生物素结合的氧化还原介质能与靠近或固定于工作电极上的基质中的抗生物素蛋白或抗生蛋白链菌素结合。另一个实施方案包括地高辛或洋地黄毒苷氧化还原介质与靠近或固定于工作电极上的基质中的抗地高辛反应。
优选的不可滤出的氧化还原介质是氧化还原聚合物,如聚合过渡金属化合物或络合物。用来形成氧化还原聚合物的聚合物一般含有含氮杂环,如吡啶、咪唑或其衍生物,以作为配体与氧化还原种结合。与氧化还原种如上述过渡金属络合物络合的合适的聚合物包括,例如,聚(1-乙烯基咪唑)的聚合物和共聚物(称为“PVI”)和聚(4-乙烯基吡啶)的聚合物和共聚物(称为“PVP”),以及通过添加侧含氮杂环如吡啶和咪唑修饰的聚(丙烯酸)或聚丙烯酰胺的聚合物和共聚物。聚(丙烯酸)的修饰可通过至少一部分羧酸功能基与氨基烷基吡啶或氨基烷基咪唑如4-乙基氨基吡啶反应形成酰胺来进行。合适的PVI、PVP和聚(丙烯酸)的共聚物取代基包括丙烯腈、丙烯酰胺、丙烯酰肼和取代的或季铵化的1-乙烯基咪唑。共聚物可以是随机的或嵌段共聚物。
不可滤出的氧化还原聚合物的过渡金属络合物一般与聚合物的含氮杂环(例如咪唑和/或吡啶环)共价或配位结合。过渡金属络合物可含有乙烯基官能团,络合物可通过该官能团共聚合。合适的乙烯基官能团包括,例如,乙烯杂环、酰胺、腈、羧酸、磺酸或其他极性乙烯化合物。这类氧化还原聚合物的一个实例是用来提高氧化还原聚合物在水中溶胀的聚(乙烯基二茂铁)或聚(乙烯基二茂铁)的衍生物。
另一类氧化还原聚合物含有一种通过形成多离子桥而离子结合的氧化还原种。这类介质一般包括与带相反电荷的氧化还原种偶联的带电聚合物。这类氧化还原聚合物的实例包括与多种带正电的氧化还原种如锇或钌聚吡啶基阳离子偶联的带负电的聚合物如(DuPont)。离子结合的介质的另一个实例是与带负电的氧化还原种如铁氰化物或亚铁氰化物偶联的带正电的聚合物如季铵化聚(4-乙烯基吡啶)或聚(1-乙烯基咪唑)。优选的离子结合氧化还原种是在带相反电荷的聚合物中结合的带多价电荷的,通常是多阴离子的,氧化还原种。
另一种合适的氧化还原聚合物包括与聚合物配位结合的氧化还原种。例如,该介质可通过锇、钌或钴2,2’-联吡啶络合物与聚(1-乙烯基咪唑)或聚(4-乙烯基吡啶)配位或通过4-乙烯基-2,2’-联吡啶锇、钌或钴络合物与1-乙烯基咪唑或4-乙烯基吡啶共聚合而形成。
一般而言,锇或钌过渡金属络合物与不可滤出的氧化还原聚合物的咪唑和/或吡啶基之比为1:20~1:1,优选地1:15~1:2,更优选地1:10~1:4。氧化还原电势通常至少部分地取决于聚合物,氧化还原电势的顺序为聚(丙烯酸)<PVI<PVP。
可用多种方法将氧化还原聚合物固定于电极表面。一种方法是吸附固定。该方法特别可用于相对高分子量的氧化还原聚合物。例如,通过交联可提高聚合物的分子量。氧化还原聚合物的聚合物可含有如酰肼、胺、醇、杂环氮、乙烯基、烯丙基和羧酸基的官能团,它们能用交联剂交联。这些官能团可位于聚合物或一种或多种共聚物上。另外,也可通过如季铵化的反应添加官能团。一个实例是用溴乙胺基对PVP的季铵化。
合适的交联剂包括,例如,含有两个或更多环氧化物(例如聚(乙二醇)二环氧甘油醚(PEGDGE))、醛、氮丙啶、烷基卤和叠氮基官能团或其组合的分子。当聚合物含有多个丙烯酸功能基时,它可与二硫酚或聚硫醇交联;当含有多个硫醇功能基时,能与二丙烯酸酯或聚丙烯酸酯交联。交联剂的其他实例包括为与胺或其他氮化合物缩合而可活化羧酸或其他酸官能团的化合物。这些交联剂包括碳二亚胺或含有活性N-羟基琥珀酰亚胺或imidate官能团的化合物。交联剂的其他实例是醌(例如,四氯苯醌和四氰醌二甲烷)和氰尿酰氯。也可使用其他交联剂。在某些实施方案中,不需要另外的交联剂。交联与交联剂的其他叙述和实例见美国专利号5,262,035;5,262,305;5,320,725;5,264,104;5,264,105;5,356,786和5,593,852,在此引用作为参考。
在另一个实施方案中,通过电极表面的官能作用,然后将氧化还原聚合物与官能团在电极表面上通常共价地化学键合,来固定氧化还原聚合物。这类固定的一个实例由聚(4-乙烯基吡啶)开始。聚合物的吡啶环与可还原/可氧化的物种如[Os(bpy)2Cl]+/2+部分络合,其中bpy是2,2’-联吡啶。吡啶环的一部分通过与2-溴乙胺反应季铵化。然后用双环氧化合物如聚(乙二醇)二环氧甘油醚交联该聚合物。
为了氧化还原聚合物结合可通过例如重氮盐的电还原修饰碳表面。一个例子是,对氨基苯甲酸重氮化后形成的重氮盐的还原修饰含有苯基羧酸官能团的碳表面。这些官能团能被碳二亚胺如1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺盐酸(EDC)活化。活化的官能团与胺官能化的氧化还原对如上述季铵化的含锇氧化还原聚合物或2-氨基乙基二茂铁结合,形成氧化还原对。
类似地,金与其他金属表面也能用例如胺如胱胺,或用羧酸如硫辛酸官能化。氧化还原对如[Os(bpy)2(吡啶-4-羧酸)Cl]0/+可被1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺盐酸(EDC)活化,形成反应性邻酰基异脲,其可与金结合的胺反应形成酰胺。硫辛酸的羧酸官能团能用EDC活化,以结合聚合物或蛋白胺形成酰胺。
当所用的酶为PQQ葡萄糖脱氢酶或葡萄糖氧化酶时,优选的不可滤出的氧化还原介质具有相对于标准甘汞电极(SCE)约-300mV到约+400mV的氧化还原电势。最优选的不可滤出的氧化还原介质含有锇氧化还原中心,有相对于SCE低于+100mV的氧化还原电势,更优选地氧化还原电势相对于SCE低于0mV,最优选地相对于SCE接近-150mV。
至少在某些情况中,传感器的氧化还原介质是可空气氧化的。即,氧化还原介质可被空气氧化,优选地,使得在向传感器中加入样品之前至少90%的介质为氧化态。可空气氧化的氧化还原介质包括与两个单-、二-或聚烷氧基-2,2’-联吡啶或单-、二-或聚烷氧基-1,10-菲咯啉配体络合的锇阳离子,这两个配体不必相同,并进一步与含有吡啶和咪唑官能团的聚合物或其他配体络合。特别是,与聚(4-乙烯基吡啶)或聚(1-乙烯基咪唑)络合的Os[4,4’-二甲氧基-2,2’-联吡啶]2Cl+/+2在空气中可达约90%或更高的氧化。当氧化还原介质为固体时,如当以干燥状态包被于传感器上或贮存时,可发生氧化还原介质的空气氧化。此外,当氧化还原介质在溶液中时,例如在将溶液加于传感器上干燥之前,也可发生氧化还原介质的空气氧化。氧化还原介质在溶液中空气氧化时,含有该氧化还原介质的溶液可在生产过程中使用该溶液之前贮存足以空气氧化该介质的一段时间。
第二种电子转移剂
在本发明的一个优选的实施方案中,传感器包含一种氧化还原介质和能向该氧化还原介质和分析物中或从中向外转移电子的第二种电子转移剂。第二种电子转移剂可以是可扩散的或可以是不可滤出的(例如,在氧化还原聚合物中截留或与之配位、共价或离子结合)。合适的第二种电子转移剂的一个实例是可催化分析物反应的酶。例如,当分析物是葡萄糖时使用葡萄糖氧化酶或葡萄糖脱氢酶,如吡咯并喹啉醌葡萄糖脱氢酶(PQQ)。当分析物是乳酸时,乳酸氧化酶起这一作用。对于其他分析物可使用其他酶。这些酶通过经氧化还原介质在分析物与电极之间转移电子催化分析物的电解。在某些实施方案中,第二种电子转移剂是不可滤出的,更优选地固定于工作电极上,以防止该剂向样品中的不希望的滤出。实现方法是,例如,将不可滤出的第二种电子转移剂与不可滤出的氧化还原介质交联,由此在工作电极上产生含有不可滤出成份的传感层。在其他实施方案中,第二种电子转移剂是可扩散的(并可置于样品室的任一表面上或置于样品中)。
对电极
如图1-4所示的对电极24可用类似于工作电极22的方法构建。对电极24也可以是对/参比电极。此外,可提供一个分开的参比电极与样品室接触。适用于对/参比电极或参比电极的材料包括在印制于绝缘基层材料上的Ag/AgCl或Ag/AgBr或银金属基底上的氯化银。可以用与构造工作电极22相同的材料和方法制造对电极,但也可使用不同的材料和方法。在电极上可有一个接头25,以便于连接外部电子仪器(未显示),如库仑计、恒电位仪或其他测量装置。
电极构造
在本发明的一个实施方案中,工作电极22和对电极24彼此相对且面对面放置,形成如图1和图3所示的面对面电极对。在这种优选的结构中,样品室26一般位于两个电极之间。对于这种面对面电极结构,优选地电极分开不超过约0.2mm的距离(即,至少工作电极的一部分与对电极的一部分分开不超过200μm),优选地不超过100μm,最优选地不超过50μm。
电极不需要彼此完全相对;它们可略微偏移。而且,两个电极不需要为相同大小。优选地,对电极24至少如工作电极22的工作表面一样大。对电极22也能形成如梳形的齿尖。对电极和工作电极的其他结构也属于本发明的范围之内。但是,对于这种具体实施方案,工作电极的至少一部分与对电极的某一部分之间分开的距离优选地不超过上文所述的限度。
如上所述,图11A、11B、11C显示面对面电极22、24对的不同实施方案。两个电极22、24的重叠区21一般对应于将在其中测定样品的测定区。电极22、24的每一个为导电表面,并作为电容器极板。电极22、24之间的测定区作为极板之间的介电层。因此,在两个电极22、24之间存在电容。这种电容是交叠电极22、24的大小、电极22、24的间距和电极22、24之间物质的介电常数的函数。因此,如果交叠电极22、24的区域21的大小和电极之间物质(如空气或吸附剂)的介电常数已知,则能计算电极之间的距离,而确定测定区的容积。
图11A显示本发明的一个实施方案,其中电极22、24面对面排列。为了在类似构造的具有这种特定传感器结构的分析传感器之间有均匀的电容,定位(即,两个电极相对于另一个的定位)应是均匀的。如果任一个电极的位置在x-y平面上偏离在图11A所示的位置,重叠区的大小因而电容的大小将改变。相同原则适用于测定区的容积。
图11B和11C显示具有面对面排列的电极22、24的本发明的其他实施方案。在这些特别排列中,任一个电极的位置可在x-y平面上相对于另一个电极移动至少某一最小距离,而不发生测定区电容和容积的改变。在这些电极排列中,每个电极22、24分别包含一个臂122、124,该臂与另一个电极的相应的臂交叠。两个臂122、124彼此不平行(如图11A所示);相反,臂122、124以大于0的交角123放置。另外,两个臂122、124延伸到重叠区21之外(即,每个臂具有对应于臂222、224各自长度与重叠区21的宽度121之差的超出长度)。使用这些电极排列,在电极22、24的定位中可有一定程度的允许的不精确性,这不改变电极排列的电容。通过改变臂122、124交错的角度123和臂122、124相对于重叠区21的宽度121的超出长度,能为电极排列设计希望程度的允许的不精确性。一般而言,臂122、124越接近于垂直(即角度123为90°),允许的不精确性越大。同样,臂122、124各自(可以有相同的长度或不同的长度)相对于重叠区21宽度超出的长度越大,允许的不精确性越大。相反,允许的不精确性越大,电极的大小越大(对于特定电极的宽度、厚度和与另一电极的交角123)。因此,一个电极相对另一电极偏移的最小距离应与对电极所需材料的量相平衡。交角123一般为5-90度,优选地30-90度,更优选地60-90度。臂122、124的超出长度(对应于臂长222、224与重叠区21的宽度121的差)与重叠区21的宽度之比一般为0.1:1-50:1,优选地1:1-15:1,更优选地4:1-10:1。
在本发明的另一个实施方案中,两个电极22、24如图2所示共面。在这种情况中,样品室26与两个电极接触,并通过绝缘惰性基质30结合于电极的对侧。惰性基质的合适的材料包括绝缘材料如聚酯。
本发明的传感器的其他结构也是可能的。例如,两个电极可在平面上形成,彼此形成一个角度。一种这样的结构在形成直角的表面上具有电极。另一种可能的结构在曲面如管的内表面上具有电极。工作电极和对电极可排列为使其从管的对侧彼此面对。这是面对面电极对的另一个实例。此外,电极可在管壁上彼此靠近地放置(例如,一个位于另一个顶部或并排)。
在所有结构中,两个电极必须构造为使其彼此不直接电接触,以防止电化学传感器的短路。当面对面电极分开平均不超过约100μm时这可能难以避免。
当电极如图1和图3所示彼此面对时,能用间隔层28使电极分开。间隔层一般用隋性绝缘材料制成,如为其化学惰性所选的压敏粘合剂、聚酯、MylarTM、KevlarTM或其他任何强力薄聚合物膜或薄聚合物膜如TeflonTM膜。除了防止电极之间接触之外,间隔层28通常作为样品室26边界的一部分,如图1-4所示。其他间隔层包括粘合层和双面粘合带(例如,在膜的对侧有粘合剂的底膜)。
样品室
样品室26一般由电极22、24、惰性基质30和间隔层28围成,如图1-4所示。该样品室中含有一个测定区,它是在分析物测定过程中只含有待测样品部分的样品室区域。在图1和图2所示的本发明的实施方案中,样品室26是两个电极22、24和/或隋性基质30之间的空间。在该实施方案中,样品室具有优选地不超过约1μl,更优选地不超过约0.5μl,最优选地不超过约0.25μl的容积。在图1和图2所示的本发明的实施方案中,测定区具有与样品室容积大致相等的容积。在一个优选的实施方案中,测定区包括样品室的80%,在更优选的实施方案中为90%,在最优选的实施方案中为约100%。
在图3所示的本发明的另一个实施方案中,样品室26包括比接近电极22、24的区域更大的空间。这种构造使得能够提供与一个或多个样品室接触的多个电极,如图5所示。在该实施方案中,样品室26的大小优选地可含有不超过约1μl,优选地不超过约0.5μl,最优选地不超过约0.25μl的容积。测定区(即含有待测样品体积的区域)的大小通常可含有不超过约1μl,优选地不超过约0.5μl,更优选地不超过约0.25μl,最优选地不超过约0.1μl的体积。该实施方案的一个特别有用的构造将工作电极22与对电极24彼此面对面放置,如图3所示。在该实施方案中,相当于含有待测样品部分的区域的测定区是由工作电极的工作表面界定并位于两个面对面电极之间的样品室26的一部分。
在上述两个实施方案中,样品室和测定区的厚度一般对应于间隔层28的厚度(例如,图1和图3中电极之间的距离,或图2中电极与隋性基质之间的距离)。间隔层可以是例如粘合剂或双面粘合带或薄膜。优选地,该厚度较小,以促进分析物的快速电解,因为对于特定的样品体积更多的样品将与电极表面接触。另外,薄样品室有助于减少分析物测定过程中分析物从样品室的其他部分向测定区中扩散的误差,因为扩散时间长于测定时间。样品室的厚度一般不超过约0.2mm。优选地,样品室的厚度不超过约0.1mm,更优选地,样品室的厚度约为0.05mm或更低。
样品室可用其他方法制成。典型方法包括压花、刻痕或以其他方式在基底中形成凹槽,在其中形成工作电极22或对电极24。图12A和12B显示这种结构的一个实施方案。首先,在惰性绝缘基层材料102上形成导电层100。如上所述,导电层100可包括金、碳、铂、二氧化钌、钯或其他非腐蚀性材料。惰性绝缘基层材料102能用聚酯、其他聚合物或其他绝缘的可变形材料制成。然后在绝缘基层材料102的区域中形成凹槽104,使得导电层100的至少一部分包含于凹槽104中。凹槽104可用多种技术形成,包括刻痕、变形或以其他方式在基层材料102上冲击。形成凹槽的另一种典型方法包括压花基层材料102。例如,基层材料102可与有凸起部分如穿孔膜或槽的压花辊或印模接触,形成凹槽104。在某些实施方案中,可加热基层材料102以软化该材料。
凹槽104可以是圆形、椭圆形、矩形或其他任何规则或不规则的形状。此外,凹槽104也可形成为沿基层材料102的一部分延伸的沟槽。导电层100可沿整个沟槽或沟槽的一部分延伸。例如,通过将传感层32仅沉积于沟槽特定区域内导电层100的部分上,可将测定区局限于该沟槽内的特定区域。此外,也可通过将第二个电极107仅置于第一个电极105的希望的区域之上限定测定区。
导电层100的至少一部分(在某些情况中是全部)位于凹槽104中。导电层100的这一部分可作为第一个电极105(对电极或工作电极)。如果导电层100形成工作电极,则可通过在凹槽104中沉积不可滤出的氧化还原介质和/或第二种电子转移剂在导电层100的部分之上形成传感层32,如图12B所示。若使用一种可扩散的氧化还原介质或第二种电子转移剂,则可将可扩散的材料置于样品室的任一表面上或样品中。
然后通过将第二个导电层沉积于第二个基层材料106上形成第二个电极107。然后将第二个电极107以面对面排列置于第一个电极105之上。尽管未加说明,但如果氧化还原介质是不可滤出的,则应当理解,如果第一个电极105用作对电极,则传感层32将沉积于用作工作电极的第二个电极107上。然而,如果氧化还原介质是可扩散的,氧化还原介质可置于样品室任一表面上或可置于样品中。
在一个实施方案中,第二种基层材料106位于第一种基层材料102和/或未凹陷的导电层100的一部分上,使得第二个电极107延伸到凹槽中。在另一个实施方案中,在第一个和第二个基层材料102、106之间有一个间隔层(未显示)。在该实施方案中,第二个电极107可以或可不延伸到凹槽中。在任何情况中,第一个和第二个电极105、107都不能接触,否则两个电极将短路。
凹槽104的深度和凹槽104中导电层100、传感层32和第二个电极107的部分的体积决定了测定区的容积。因此,测定区容积的预测取决于凹槽104形成的均匀程度。
如图14A所示,除了导电层100之外,也可在形成凹槽104之前,将以下详述的吸附层103沉积于基层材料102上。如图14B所示,可用导电层100和基层材料102刻痕、压花或变形吸附剂103。此外,也可在刻痕、压花或变形导电层100和基层材料102形成凹槽104之后沉积吸附剂103。
在制成分析传感器的另一个示范方法中,如图13A和13B所示,在第一种基层材料112中形成凹槽114。可通过刻痕、压花、蚀刻(例如,用光刻法或激光去除基层材料的部分),或以其他方式变形或除去基层材料112的一部分来形成凹槽。然后在凹槽114中形成第一个导电层110。可使用上述任何导电材料。优选的材料是导电墨水,如可从Ercon,Inc.(Wareham,MA)获得的导电碳墨。导电墨水一般含有溶解或分散于溶剂或分散剂中的金属或碳。当除去溶剂或分散剂时,金属或碳形成导电层110,其能用作第一个电极115。如上所述,第二个电极117能在第二种基层材料116上形成,并位于凹槽114之上。在含有不可滤出的氧化还原介质的实施方案中,如图13B所示,在第一个电极115上形成传感层32,以构成工作电极。在含有不可滤出的氧化还原介质的其他实施方案中,可在第二个电极117上形成传感层32,构成工作电极。此外,若使用可扩散的氧化还原介质,则工作电极不需要包括置于其上的传感层。实际上,因为氧化还原介质可置于样品中,所以不需要传感层,对于可扩散的第二种电子转移剂—如果存在的话—同样如此。任何可扩散的成份可独立地置于样品室的任一表面上或置于样品中。此外,吸附剂(未显示)可形成于凹槽内,例如在第一个电极115上。
在导电墨水中也可包含粘合剂,如聚氨酯树脂、纤维素衍生物、高弹体(例如,硅氧烷、聚合二烃或丙烯腈-丁二烯-苯乙烯(ABS)树脂)、高度氟化的聚合物等。熟化粘合剂可提高导电层110的电导率,但熟化不是必需的。熟化粘合剂的方法可取决于所使用的特定粘合剂的性质。某些粘合剂通过加热和/或紫外线熟化。
这些结构使得能形成这样的电化学传感器,其中测定区的容积至少部分取决于凹槽104的准确度和可重复性。能用压花、激光蚀刻、光蚀刻及其他方法制成可重复的规格为200μm或更小的凹槽104。
吸附剂
在将样品置于样品室之前,样品室可以是空的。此外,样品室也可包含吸附剂34以在测定过程中吸附并容纳液体样品。合适的吸附剂包括聚酯、尼龙、纤维素和纤维素衍生物如硝基纤维素。吸附剂有利于通过毛细作用对小体积样品的吸收,这可补充或优选地代替样品室的毛细管作用。另外,一部分或全部样品室壁可用表面活性剂如Zonyl FSO覆盖。
在某些实施方案中,用其中溶解或分散有吸附剂的液体或浆液沉积吸附剂。然后可通过加热或蒸发法除去液体或浆液中的溶剂或分散剂。合适的吸附剂包括,例如,溶解或分散于适当溶剂或分散剂如水中的纤维素或尼龙粉。特定溶剂或分散剂也应与工作电极22的材料相容(例如,溶剂或分散剂不应溶解电极)。
吸附剂的最重要的功能之一是减少充满传感器的样品室和相应测定区所需的液体体积。测定区中样品的实际体积部分取决于吸附剂内空隙空间的大小。合适的吸附剂一般包括约5%~约50%的空隙空间。优选地,吸附剂包括约10%~约25%的空隙空间。
用吸附剂代替液体是有利的。通过加入吸附剂,充满样品室26只需要较少的样品。这减少了测定所需样品的体积,也缩短了电解样品所需的时间。
吸附剂34可包括一个接头33,其由与吸附剂相同的材料制成,并从传感器或从传感器的开口伸出,使得样品可接触接头33,被接头吸收,并通过吸附剂34的毛细作用输送到样品室26中。这提供了一种优选的将样品导入样品室26中的方法。例如,传感器可与用刺血针刺破采血的动物(包括人)的区域接触。血液与接头33接触,并通过吸附剂34的毛细作用吸入样品室26中。当样品极少,如用刺血针刺破不富含近表面毛细血管的动物身体一部分并提供1μL或更少的血样体积时,样品向传感器的直接转移特别重要。
可用除吸附剂毛细作用之外的方法向样品室或测定区中输送样品。这些输送方法的实例包括对样品施加压力以将其压入样品室中,用泵或其他真空产生方法在样品室中产生真空而将样品吸入样品室中,由样品与薄样品室壁的界面张力引起的毛细管作用,以及吸附剂的毛细作用。
传感器也能与流动样品流一起使用。在这种构造中,使样品流流经样品室。定时停止样品流,并用电化学方法如库仑法测定分析物的浓度。测定后重新开始流动,从而从传感器中除去样品。此外,样品也可以极低的速率流经样品室,使得所有分析物在输送中电解,产生只取决于分析物浓度和流速的电流。
也可用其他填充材料填充测定区并降低样品体积。例如,可在测定区中放置玻璃珠占据空间。优选地,这些填充材料是亲水的,使得体液能容易地流入测定区中。在某些情况中,如具有大表面积的玻璃珠,这些填充材料也可由于其大表面积和亲水性而将体液吸入测定区中。
全部传感器组件紧固地结合在一起,以确保样品与电极接触,且样品室和测定区保持相同的容积。在样品的库仑分析中这是一个重要的考虑因素,其中需要测定明确的样品体积。图1和图2中显示了一种将传感器结合在一起的方法。两个极板38位于传感器的相对端。这些极板一般由绝缘材料如塑料制成。这些极板设计为使其能与两个极板之间的传感器固定在一起。合适的固定装置包括粘合剂、夹子、螺帽和螺栓、螺钉等。
备择的传感器设计
图18A-18C显示形成薄膜传感器的一种备择传感器设计。该传感器包括第一个基底500,在其上形成工作电极502。工作电极502包括一个用来连接外部电子仪器的接触区503。间隔层504(图18B)如粘合层或双面粘合带界定了沟槽506,产生传感器的样品室。如图18C(相对于图18A和18B翻转,以显示电极上侧)所示在第二个基底508上形成两个对(或对/参比)电极510、512。如下所述,这种多对电极排列可具有充满指示功能。每个对电极510、512具有用来接触外部电子仪器的接触区511、513。将第二个基底508翻转并置于第一个基底500之上,之间为间隔层504,使得工作电极502和两个对电极510、512在沟槽506的区域中面对。
在某些情况中,最靠近沟槽506的入口514的对电极510在样品室内具有至少两倍于另一个对电极512的表面积,并可至少大5或10倍。如上所述在第一个或第二个基底500、508上对应于沟槽506的区域中可含有不可滤出的或可扩散的氧化还原介质和/或第二种电子转移剂。
能形成工作电极和对电极,覆盖全部沟槽区(除了两个对电极之间的小空间之外)。在该实施方案中,样品室和测定区同样有效并有相同的容积。在其他实施方案中,测定区占有例如样品室容积的80%或90%。应当理解,用一个对电极或三个或更多的对电极能构成类似的传感器。也应当理解,在传感器上也可有多个工作电极。
对于图18A-18C所示的传感器排列描述了制造薄膜传感器的方法的一个实例,能用该方法制造多种其他的传感器排列,包括前面所述。提供了基底如塑料基底。基底可以是单片或卷材上的连续的辊。能用该基底制造单个传感器或制造多传感器。多传感器能在基底1000上形成工作电极1010和对电极1020。在某些实施方案中,能刻痕和折叠基底,使工作电极1010和对电极1020靠近形成传感器。在某些实施方案中,如图31A所示,各工作电极1010(在个别章节中,对电极1020)能在基底1000上彼此紧接地形成,以减少废料,如图31A所示。在其他实施方案中,各工作电极1010(在个别章节中,对电极1020)能空间分隔,如图31B所示。对多电极的制造叙述了该方法的其余部分,但能容易地改变而形成单个传感器。
碳或其他电极材料(例如金属如金或铂)在基底上形成,为每个传感器提供工作电极。能用多种方法沉积碳或其他电极材料,包括印染碳或金属墨水、蒸气淀积和其他方法。
任选地,能紧靠工作电极形成绝缘材料如绝缘墨水,提供沿样品流体运动路径的平面。绝缘材料适用于产生平滑表面,以利于通过毛细管作用填充,和/或适用于降低气泡在工作电极附近被截留的可能性。这种绝缘材料可以是有色或无色的,并可通过印花或其他技术在基底上形成。绝缘材料可在形成工作电极之前或之后沉积。
一个或多个对电极可在基底上形成。对电极通过在基底上沉积碳或其他电极材料而形成。在一个实施方案中,对电极的材料是Ag/AgCl墨水。可用多种方法包括印刷或蒸汽淀积法沉积对电极的材料。在某些实施方案中,对电极由不同材料构成,和/或一个电极是对电极或对/参比电极,而一个电极是参比或对/参比电极。在一个实施方案中,在聚合物片或卷材的第一半上形成工作电极,而在聚合物片或卷材的另一半上形成对电极,使得能折叠片或卷材而以面对面排列叠置工作与对电极。
可邻近对电极和/或在其之间沉积第二种绝缘材料,以提供沿样品流体运动路径的平面。在将是样品室一部分的对电极之间的区域中这是特别希望的,以使样品室表面成为平面。绝缘材料适用于产生平滑表面,以利于通过毛细管作用填充,和/或适用于降低气泡在工作电极附近被截留的可能性。这种绝缘材料可以是有色或无色的,并可通过印刷或其他技术在基底上形成。绝缘材料可在形成对电极之前或之后沉积。
至少在基底/工作电极和基底/对电极之一上形成粘性间隔层。粘性间隔层可以是单层粘合剂或双面粘合带(例如含有置于相对面上的粘合剂的聚合物底膜)为形成沟槽,可切开(如冲切)任选地具有一个或多个隔离衬垫的间隔层,以在将间隔层置于基底上之前除去对应于沟槽的粘合剂部分。此外,也可按照确定沟槽区域的样式在基底上印刷或以其他方式放置粘合剂。间隔层的厚度一般决定工作与对电极之间的间距。当传感器之间的间距的一致性必需时(例如,对于库仑测定),间隔层厚度的一致性是重要的。优选地,在单个传感器中和/或在一批中的各个传感器之间厚度变化不超过±5%。
不可滤出的或可扩散的氧化还原介质和/或第二种电子转移剂置于基底上至少样品室区域中。如果这两种成份之一或两者都是不可滤出的,则该一种或多种成份必须置于工作电极上。如果这两种成份之一或两者都是可扩散的,则该成份可置于沟槽区中基底的任一表面上。氧化还原介质和/或第二种电子转移剂能在间隔层安置之前或之后独立地或一起置于基底上。可用多种方法放置氧化还原介质和/或第二种电子转移剂,包括,例如,筛网印花、喷墨印刷、喷射、涂抹、沿相对和/或相邻电极的行或列制成条纹等。其他成份可分开或与氧化还原介质和/或第二种电子转移剂如表面活性剂、聚合物、聚合物膜、防腐剂、粘合剂、缓冲液和交联剂一起放置。
安放间隔层、氧化还原介质和第二种电子转移剂之后,可折叠基底形成传感器。用间隔层的粘合剂将基底的表面结合在一起。待表面结合后,能用多种方法切开传感器,包括,例如,冲切、纵切或用其他方式切去多余的基底并分离各传感器。在某些实施方案中,可使用这些方法的组合。例如,某些部件可冲切,而传感器的其余部分可纵切。另外,可首先从基底上切下传感器组件(例如,图18A和18C中所示的组件),然后用间隔层粘合剂粘合两个组件将其结合形成传感器。
图18A-18C中显示的传感器实施方案是顶部填充传感器的一个实例。图19A-19C显示另一种传感器结构。这是一种侧面填充传感器。图19A显示具有工作电极522的第一个基底520。图19B显示限定沟槽526的间隔层524。图19C(相对于图19A和19B翻转以显示电极)显示具有三个对(或对/参比)电极530、532、534的第二个基底528。
该传感器能如上所述制造。对电极的对称放置使传感器能从左侧或右侧填充而便于左手和右手之人。然而应当理解,能用一个、二个或四个或更多的对电极和/或两个或更多的工作电极构成类似的传感器排列。扇形区536、538可通过例如冲切形成,并且至少在某些情况中,可精确控制以产生可重复的沟槽长度。作为另一种排列,传感器侧面可以是直线,使得可用如gang arbor blade系统以平行方向切开基底而使传感器与基底的其余部分和/或其他传感器断开。如图19A、19B和19C所示,传感器的边缘能确定样品室和/或测定区的边缘。通过精确控制切口之间的距离,通常能减少样品室容积的变化。在某些情况中,这些切口优选地彼此平行,因为平行的切口可能最易于重复形成。
图20A、20B和20C显示侧面填充的传感器排列的另一个实例。图20A显示具有工作电极542的第一个基底540。图20B显示限定了沟槽546的间隔层544。图20C(相对于图20A和20B翻转)显示具有三个对(或对/参比)电极550、552、554的第二个基底548。
图21A、21B和21C显示顶部填充的传感器排列的另一个实例。图21A显示具有工作电极562的第一个基底560。图21B显示限定了沟槽566的间隔层564。图21C(相对于图21A和21B翻转)显示具有两个对(或对/参比)电极570、572的第二个薄膜基底568。穿过第二个基底有一个通风孔574(在图21C中以阴影区表示)。在所示实施方案中,只穿过具有对电极和任选地间隔层564的基底568形成通风孔574。在该实施方案中,例如,可通过冲切基底的一部分形成通风孔。这种冲切可切掉至少一个对电极的一部分,但应有足够数量的对电极与沟槽中的样品接触并与传感器另一端的接触区电连接。在另一个实施方案中,可穿过所有层或穿过第一个基底而不是第二个基底形成通风孔574。
图22A、22B和22C显示具有不同形状的另一个实施方案。该传感器包括具有至少一个工作电极580的第一个基底579,如图22A所示。该传感器也包括在间隔层581中形成沟槽582的间隔层581,如图22B所示。该传感器还包括具有两个对电极584、585的第二个基底583,如图22C所示(相对于图22A和22B翻转)。通风孔586一般穿过所有层切成,并从传感器的一侧伸出。在某些实施方案中,将传感器的通风孔和前部587同时切割为在传感器的通风孔和前部587之间有可重复的距离,而使沟槽582和工作电极580有可重复的长度。图22A、22B和22C也显示任何传感器排列能用的另一个特征。凹穴588可在沟槽582的注入口处形成,以利于流体向传感器中吸引。在该构造中,液体没有平面,而是有助于沟槽(即样品室)的毛细作用或毛细管作用填充的锯齿面。这种构造也可降低传感器的使用者在收集样品过程中阻塞沟槽的可能性。侧面对准皮肤按压传感器的尖端可阻塞平面传感器。
图23A、23B和23C显示侧面填充的传感器排列的另一个实例。图23A显示具有工作电极642的第一个基底640。图23B显示限定了沟槽646的间隔层644。图23C(相对于图23A和23B翻转)显示具有三个对(或对/参比)电极650、652、654的第二个基底648。该传感器可通过对基底制造直切口形成。如图31A所示,这些传感器能彼此相邻地制成,这可产生较少的废料。沟槽646的长度一般由沿传感器侧面656、658的两个平行切口限定。另一个任选的加工优点,特别是在传感器彼此相邻时,是能通过沿相邻传感器的行或列添加氧化还原介质和/或第二种转移剂的连续流而将这些成份置于沟槽中。与其他技术如将这些成份单个置于单个沟槽中相比,这可产生更高的效率和较低的氧化还原介质和/或第二种电子转移剂的浪费。
图24A、24B和24C显示另一种传感器构造。该传感器包括具有至少一个工作电极602的第一个基底600,如图24A所示。该传感器也包括在间隔层604中形成沟槽606的间隔层604,如图24B所示。该传感器还包括具有两个对(或对/参比)电极610、612的第二个基底608,如图24C所示(相对于图24A和24B翻转)。该传感器也可包括,例如,一个指示器,如槽614或传感器主体的延伸部分616,它能为使用者指明哪一侧应与样品相邻放置。当传感器读数只有在样品从特定一侧进入时才正确时,这是特别重要的。
图24B也显示可在任何传感器构造中使用的另一个任选的部件。在该图例中,样品室606不是由直线构成的,而是在样品室中有一个膨胀区618。这可有较大的样品室而不必形成较大的开口。该膨胀区能为任何形状,包括圆形、正方形、矩形及其他规则和不规则的形状。
图25是装配的传感器的一个实例,显示侧面填充传感器620的另一种传感器排列。该传感器包括传感器主体624的延伸部分622,其为使用者指明样品室626的开口位于何处。
图32显示一个任选的部件,它是从仪表内部看去的传感器的侧面视图。图32显示从传感器1100的其余部分(即,在图32中部分1140相对于基底1120和1130凹进)延伸到仪表中的第一个基底1120和第二个基底1130。图18A-18C和24A-24C显示这一构造的实例。一般而言,传感器1100与仪表1110相连,后者包括接触传感器1100的电极接触区(例如,图18A和18C中的区域503、511和513)的接触垫(未显示)。具有接触区的传感器1100的末端能滑入仪表1110中。仪表1110的接触垫接触传感器的正确接触区而使工作电极和对电极与仪表正确连接一般是重要的。在某些情况中,传感器构造为使第一个基底1120上的工作电极的接触区具有宽度w1,其不同于带有对电极的第二个基底1130的接触区的宽度w2。图18A-18C和24A-24C中显示具有这种结构的电极构造的实例。为了确保传感器1100正确插入仪表1110中,仪表1110可包括可防止或阻止传感器以不正确方向插入的凸起区域1140。例如,第二个基底1130的接触区的宽度w2可宽于第一个基底1120的接触区的宽度w1,如图32所示。在这种情况中,凸起区域1140的位置使传感器1100滑入仪表中而使第一个基底1120紧接凸面1140从中突出的表面1150,但可防止或阻止第二个基底1130紧接凸面1140从中突出的表面1150。也能用除凸面之外的物体指导使用者将传感器正确置入仪表中。
整合型样品获取和分析物测定装置
在本领域中已知多种方法可获取小样品和/或将其从体内输送到传感器中。例如这包括美国专利号5,746,217、5,820,570、5857983和5879311,在此引用作为参考。本发明的传感器可适用这些样品获取和/或输送方法的任一种。
在本发明的一个优选的实施方案中,根据本发明的原则构建的分析物测定装置52包括如上所述的传感器20,其连接一个样品获取装置50,形成整合型取样与测定装置。图6所示的样品获取装置50包括,例如,皮肤穿刺组件54,如刺血针,其连接一个弹性可弯曲簧片56(或其他类似的装置,如弹簧),其可将刺血针注射到患者皮肤中获得血流。
然后释放弹性簧片56,缩回皮肤穿刺组件54。然后可利用例如吸附剂34的毛细作用将组件54刺破的皮肤区域流出的血液输送到传感器20中进行分析物的分析。然后可将分析物测定装置52置于读数器中(未显示),它将库仑计或其他电化学分析装置与电极接头23、25连接,以通过电分析方法测定分析物的浓度。优选地,当与库仑计或其他电化学分析装置连接时,分析物测定装置封装于读数器中。
在一个优选的实施方案中,整合型样品获取和分析物测定装置包括一个固定刺血针与测定簧片的穿刺装置。该穿刺装置优选地需要激活击发。由于需要使用者在使用前旋紧该装置,所以无意触发刺血针的危险减为最小。
优选地,当以足够的压力对皮肤紧压穿刺装置时,穿刺装置自动触发。本领域中已知,当在皮肤上产生孔的部位周围施加压力时,可压出较多的体液样品如血液或组织液。例如,见上述颁给Integ和Amira的美国专利,以及Becton Dickenson所售穿刺装置的尖端设计。所有这些穿刺装置都有一个环绕切割部位的突出环,用来产生将样品压出伤口的压力。然而,所有这些装置都需要使用者对创伤部位施加足够的压力才能压出样品,并且所有穿刺装置都由使用者用按扭触发。适当压力触发器的设计为本领域技术人员所周知。
优选地,穿刺装置也可允许使用者调节刺血针刺入皮肤的深度。这些装置已可从如Boehringer Mannheim和Palco的公司商品获得。该部件使使用者能根据身体上的不同部位和不同使用者之间皮肤厚度、皮肤耐久性和疼痛敏感性的不同调节穿刺装置。
在一个更优选的实施方案中,穿刺装置和检测读数器与单个装置整合。为了操作该装置,使用者只需将含有测定簧片和穿刺装置的一次性筒插入整合型装置中,旋紧穿刺装置,对皮肤按压将其激发,并读取测定结果。这种整合型穿刺装置和检测读数器为使用者简化了检测步骤并使体液的处理减至最少。
图26显示整合型样品获取和传感器装置700的另一个实例。该整合型样品获取和传感器装置700包括一个机箱702、一个皮肤穿刺组件(例如刺血针)704、一个穿刺/收集孔706、一个可任意移除的传感器708、一个传感器导杆710和一个皮肤穿刺组件的回缩机件714。该装置700能设计为重复使用(例如,使皮肤穿刺组件704和传感器708成为可移除的)或一次性使用。
机箱702可由多种材料包括金属和塑料制成。机箱702可包括一个合页716或其他构造(例如粘合剂或联锁部分)将机箱的各部分结合在一起。
机箱702中具有穿刺/收集孔706,使皮肤穿刺组件704通过孔706伸出,并刺入使用者的皮肤,由此获得血流(或其他体液)。传感器708也可延伸到孔706的边缘或之外,通过传感器尖端的开口(未显示)收集血液(或其他体液)。这可使使用者在不移动装置700的情况下穿刺皮肤收集流体样品。此外,皮肤穿刺组件704和传感器708可具有不同的开孔。传感器导杆可构造于机箱702中或添加于机箱中,以在传感器插入并通过机箱时将传感器708导入位置,和/或在机箱中和在样品收集过程中支持传感器。
皮肤穿刺组件704可包括一个启动器(未显示),其包括一个可旋紧和释放皮肤穿刺组件704的机件,或者皮肤穿刺组件可外部启动。例如,传感器读数器(未显示)或其他装置可与样品获取和传感器装置、传感器读数器或包括可旋紧和域释放皮肤穿刺组件704的机件在内的其他装置连接。
装置700的回缩机件714可以是,例如,在穿入使用者皮肤后可使皮肤穿刺组件704缩回机箱中的弹簧或弹性金属簧片。这可允许无阻碍地收集样品,和/或防止再次穿刺使用者或其他人的皮肤,从而降低或防止了体液转移或其他有害试剂转移引起的污染或感染。此外,皮肤穿刺组件的回缩也可用外部装置或仪器实现。
操作的一个实例包括旋紧皮肤穿刺组件704,然后释放皮肤穿刺组件704,使其穿过穿刺/收集孔706伸出机箱702外,并刺入使用者的皮肤中。皮肤穿刺组件704在伸出机箱之外时任选地将传感器推离正轨。用回缩机件714将皮肤穿刺组件704缩回机箱702内。皮肤穿刺组件回缩后,传感器通过传感器708上的开口从刺破的皮肤中收集样品流体。
如果使用传感器读数器,则传感器读数器也可构造为与传感器的接触端连接。传感器读数器可包括一个恒电位仪或其他组件来为传感器的电极提供电势和域电流。传感器读数器也可包括一个处理器(例如,微处理器或硬件),用于由传感器信号测定分析物浓度。传感器读数器可包括一个显示器或连接显示器与传感器的端口。显示器可显示传感器信号和/或由传感器信号确定的结果,包括例如,分析物浓度、分析物浓度改变速度和/或分析物浓度超出阈值(例如,表明血糖过低或过高)。该传感器读数器可与整合型样品获取和传感器装置一起使用,或者传感器读数器可只与传感器一起使用,传感器的接触区可与传感器读数器的接触区连接。
传感器的操作
本发明的一种电化学传感器可在施加或不施加电势的情况下操作。在一个实施方案中,电化学反应自然发生,且不需要在工作电极与对电极之间施加电势。
在另一个实施方案中,在工作电极与对电极之间施加电势。但电势不需要保持恒定。所需电势的量值取决于氧化还原介质。电极本身平衡时,或通过施加外部偏离平衡时,和分析物电解时的电势一般为,使得电化学反应趋于或接近完成,但优选地不能氧化足以导致明显的干扰物如尿酸盐、抗坏血酸和乙酰氨基苯酚的电化学反应,其可影响所测定的信号。对于不可滤出的氧化还原介质,电势一般为相对于标准甘汞电极(SCE)约-350mV~约+400mV。优选地,氧化还原介质的电势低于+100mV,更优选地电势低于0mV,最优选地电势为相对于SCE约-150mV。
当施加外部电势时,可在向样品室中加入样品之前或之后施加。如果测定区只包括样品室的一部分,则优选地在样品在样品室中静止后施加电势,以防止当样品室充满时通过测定区的样品的电解。此外,如果测定区包括样品室的大部分或全部,则任选地可在样品室充满之前或期间施加电势,而不影响测定的准确性。当施加电势且样品在测定区中时,电流将在工作电极与对电极之间流动。该电流至少部分地是样品中分析物电解的结果。这种电化学反应借助于氧化还原介质和任选的第二种电子转移剂发生。对于多种生物分子B,该过程可用下列反应方程式表示:
nA(red)---→nA(ox)+ne- (2)
在适当酶的存在下生物化学物B被氧化还原介质物种A氧化为C。然后氧化还原介质A在电极处氧化。电极收集电子,并测定产生的电流。测定的电流也可包括导致测定的本底电荷的本底电流,其至少部分上是由于可扩散的氧化还原介质在工作电极与对电极之间的穿梭。能如上所述最小化或解决该本底电流。
一个实例是,本发明的一种传感器基于葡萄糖分子与两个[Os(dmo-phen)2(NMI)Cl]2+阳离子的反应,其中dmo-phen是4,8-二甲氧基菲咯啉,NMI是N-甲基咪唑,在葡萄糖氧化酶的存在下产生两个[Os(dmo-phen)2(NMI)Cl]+阳离子、两个质子和葡萄糖的氧化产物,例如,葡糖酸内酯或另一种酮。通过将[Os(dmo-phen)2(NMI)Cl]+阳离子电氧化为[Os(dmo-phen)2(NMI)Cl]2+阳离子并测定传递的总电荷来测定存在的葡萄糖的量。
本领域的技术人员应当认识到,有许多不同的反应可产生相同的结果;即分析物通过氧化还原介质参与的反应途径的电解。方程式(1)和(2)是这种反应的非限制性实例。
库仑法
在本发明的一个优选的实施方案中,用库仑法测定分析物的浓度。这种测定技术利用在测定过程中以一定间隔获得的电流量值来测定分析物的浓度。随时间积分这些电流量值而获得传递到或离开电极的电荷的量Q。然后以下列方程式(当氧化还原介质是不可滤出的时)用Q计算分析物的浓度(CA):
CA=Q/nFV (3a)
其中n为电解分析物所需的电子当量数,F是法拉第常数(每当量约96500库仑),V是测定区中的样品体积。当使用可扩散的介质时,能由下列方程式获得分析物浓度:
CA=(Qtot-Qback)/nFV (3b)
其中Qtot是测定过程中转移的总电荷,Qback是不由分析物引起的转移的电荷量,例如,可扩散介质在工作电极与对电极之间穿梭转移的电荷。至少在某些情况中,传感器构造为使本底电荷至多5倍于一定量分析物电解产生的电荷的大小。优选地,本底信号至多为分析物电解产生的电荷的200%、100%、50%、25%、10%或5%。
测定本底信号与分析物电解所产生信号之比的方法的一个实例对于面对面电极对而言描述如下。如果施加的电势不能使氧化还原介质无法穿梭,则氧化还原介质穿梭产生的电荷可用下列公式表示:
Qback=(A F DM CM/d)(t nM)
其中A是工作电极的面积;F是法拉第常数(96500库仑/当量);DM是氧化还原介质的有效扩散系数;CM是测定区中氧化还原介质的浓度;d是面对面电极的间距;t是测定时间长度;nM是氧化还原介质获得或丢失的电子数。
另外,当分析物在测定过程中电氧化完成约90%时,分析物例如葡萄糖的电荷可用下列公式表示:
QG=A d(0.90)CG nG F
其中A是工作电极的面积;d是面对面电极的间距;CG是葡萄糖的浓度;n是电解分析物所需的电子数(例如每个葡萄糖分子2个电子);F是法拉第常数。当CG为5mM(或5×10-6mol/cm3),t为60秒,nG为2,nM为1时,氧化还原介质产生的电荷与分析物电解所产生电荷之比可用下列公式表示:
QBack/QG=(DMCM/d2)(t nM/(0.9nG CG))=(DMCM/d2)×(6.7×106)例如,如果QBack/QG的比值为5,则(DMCM)/d2为7.5×10-7mol/(cm3sec)。同样例如,如果QBack/QG的比值为1,则(DMCM)/d2为1.5×10-7mol/(cm3sec)。另一个例子是,如果比值为0.1,则(DMCM)/d2为1.5×10-8mol/(cm3sec)。因此,根据希望的比值,可通过选择DM、CM和d构造传感器使之具有希望的比值。例如,可降低氧化还原介质的浓度(即可降低CM)。另外,例如,通过在可扩散介质向对电极的流动中放置阻挡层(即降低氧化还原介质的有效扩散系数—DM)可降低氧化还原介质的扩散。其他传感器构造也适用于控制本底信号与分析物产生的信号之比,并将在下面描述。
能以多种方法解决本底电荷Qback。例如,通过只使用有限量的可扩散氧化还原介质,通过在对电极之上加一个限制氧化还原介质向对电极扩散的膜,或通过在工作电极与对电极之间产生相对较小的电势差,能使Qback变小。适于减少Qback的传感器构造和方法的其他实例包括已描述的,如在工作电极处氧化还原介质反应速率明显快于对电极处;在工作电极上固定氧化还原介质;氧化还原介质在对电极或对/参比电极处反应后,固定于对电极或对/参比电极上;或减缓氧化还原介质扩散的传感器。
此外,可单个或分批校准传感器,确定校正曲线或Qback的值。另一个选项包括第二个电极对,其缺少分析物电解所需的成份,如第二种电子转移剂,而使第二个电极对产生的完整信号对应于Qback。
对于库仑测定,至少20%的分析物电解。优选地至少50%,更优选地至少80%,再更优选地至少90%的分析物电解。在本发明的一个实施方案中,分析物完全或几乎完全电解。然后能由电化学反应中得到的电流量值计算电荷,并用方程式(3a)或(3b)确定分析物的浓度。当电流达到稳态值时,一般指示电化学反应的完成。这表明所有或几乎所有分析物已被电解。对于这种测定,一般至少90%的分析物被电解,优选地至少95%的分析物电解,更优选地至少99%的分析物电解。
对于库仑法,一般希望分析物快速电解。电化学反应的速度取决于几个因素,包括在电极之间施加的电势和反应(1)和(2)的动力学。(其他重要因素包括测定区的大小和测定区中吸附剂的存在。)通常,电势越大,通过细胞的电流越大(可达输送最高限值),因此一般反应发生得越快。然而,如果电势太大,其他电化学反应可在测定中产生明显误差。一般选择电极之间的电势及特异的氧化还原介质和任选的第二种电子转移剂,使分析物在不到5分钟内几乎完全电解,这取决于样品中预期的分析物浓度。优选地,分析物在约2分钟内,更优选地在约1分钟内几乎完全电解。
在本发明的另一个实施方案中,分析物只部分电解。在部分反应期间测定电流,然后用本领域技术人员所知的数学方法外推,确定分析物完全或几乎完全电解的电流曲线。如果分析物完全或几乎完全电解,该曲线的积分可得到传递的电荷量,并用方程式(3a)或(3b)计算分析物的浓度。
尽管库仑法具有需要已知待测样品体积的缺点,但库仑法是一种优选的分析少量样品的技术,因为它具有下列优点,例如:对测定无温度依赖性,对测定无酶活性依赖性,对测定无氧化还原介质活性依赖性,在样品中分析物损耗的测定中无误差。如以上所述,库仑法是一种测定在分析物完全或几乎完全电解过程中传递或预计传递的电荷量的方法。一种电量分析技术包括在工作电极上电解分析物,并在电解过程中两次或多次测定在工作电极和对电极之间产生的电流。当电流达到稳态时电解完全。然后通过对时间积分测定的电流并考虑任何本底信号计算用于电解样品的电荷。因为电荷直接与样品中分析物的量有关,所以测定无温度依赖性。另外,酶活性不影响测定的值,而只影响获得量值所需的时间(即,活性较低的酶需要较长的时间实现样品的完全电解),使得酶随时间的衰减不会使分析物浓度测定不准确。最后,电解对样品中分析物的消耗不是误差的原因,而是该技术的目的。(然而,如果根据众所周知的电化学原理由部分电解曲线外推电解曲线,则分析物不需要完全电解)
非库仑测定
尽管库仑测定是有用的,但本领域技术人员应认识到,本发明的传感器也可利用电势分析、电流分析、伏安法及其他电化学技术测定样品中分析物的浓度。这些非库仑分析法获得的量值不象电量测定一样可能是温度依赖的。
另外,这些非库仑分析电化学技术获得的量值可对传感器中的活性酶的量敏感。如果酶经过一定时间灭活或衰变,则可影响得到的量值。这可限制这些传感器的保存期,除非酶非常稳定。
最后,如果在测定过程中大部分分析物和/或氧化还原介质电解,则可不利地影响非库仑分析电化学技术如稳态电流分析法获得的量值。精确的稳态量值可能是不可获得的,除非有足够的分析物和/或氧化还原介质,使得在测定过程中只有相对少部分的分析物和/或氧化还原介质电解。这在不超过1μl的样品容量中可能有前途。
在某些情况中利用非库仑测定如电流分析法或电势分析技术可能是希望的。例如,库仑法需要已知待测样品的体积。而且,如果测定区的一个或多个维数的制造公差具有明显变化,则小容积传感器(即不超过1微升)测定区中的样品体积可能难以精确再现。
如对于库仑测定所述,在薄层电化学测定池中对不超过1μl的样品的电流测定或电势测定中,氧化还原介质在电极之间穿梭产生的本底信号可能是测定误差的来源。通常希望在测定期间介质在一对电极之间穿梭不超过10次,优选地不超过1次,更优选地平均不超过0.1次。为了降低本底信号引起的误差,可使用类似于,在某些情况中相同于,库仑测定所用的方法和传感器构造。实例包括上述所有方法和结构,如在施加的相对较低的电势下进行电化学测定,在施加的负电势下电氧化分析物,或在施加的正电势下电还原分析物,使用氧化还原介质反应相对较慢的对电极(特别是与氧化还原介质在工作电极处的反应相比),和/或使用在对电极处经历不可逆反应的氧化还原介质。以下讨论了其他实例。
如对于库仑测定所述,优选地设计并操作传感器,使得本底信号至多5倍于分析物电解所产生的信号大小。优选地,本底信号至多为一定量分析物电解产生的信号的200%、100%、50%、25%、10%或5%。以上在题目为“本底信号”的章节中叙述了与本底信号相比的分析物的量。对于电流分析法,一定量的分析物电解产生的信号是进行测定时的电流。对于电势分析法,一定量的分析物电解产生的信号是进行测定时的电势。
在特定的一组操作条件下,例如,温度、测定池的几何形状和电极大小,本底电流的数值Iback用下列表达式得出:
iback=K CM DM/d
其中:K是比例常数;CM是测定区中的介质浓度;DM是在正常操作条件下测定区中介质的有效扩散系数;d是电极之间的距离。
对于非库仑测定希望降低本底电流。上述传感器构造和方法通常是有用的,包括,例如,相对于分析物的浓度,使用低浓度的氧化还原介质和域第二种电子转移剂(例如酶),和/或使用具有相对较低有效扩散常数的较大氧化还原介质。上述其他有用的方法包括降低氧化还原介质扩散的方法,例如,为可扩散的介质的流动放置阻挡层(例如带电的或极性阻挡层),或使用具有相对较低有效扩散常数的氧化还原介质。
在某些情况中,有效扩散系数不超过约1×10-6cm2/sec,不超过约1×10-7cm2/sec,或不超过约1×10-8cm2/sec。而且在某些情况中,CMDM的乘积(氧化还原介质的浓度乘有效扩散系数)不超过约1×10-12mol/cm·sec,不超过约1×10-13mol/cm·sec,或不超过约1×10-14mol/cm·sec。
以下提供了进行60秒的葡萄糖电流测定的具体实例,测定期间10%的葡萄糖在1微升测定池中电解,面对面电极的间距为d=0.01cm。如果在下列条件下进行测定:葡萄糖浓度CG=5mM(或5×10-6mol/cm3),面积A=0.1cm2,来自于氧化还原介质的电子数nM=1,来自于葡萄糖的电子数nG=2,则如下确定氧化还原介质和葡萄糖所产生的本底电流。
iback=A F nM DMCM/d
=(0.1)(96500)(1)DM CM/(0.01)
=9.65×105CM DM
iG=nG A d(0.1)F CG/t
=(2)(0.01)(0.1)(96500)(5×10-6)/60=1.61μamps
因此,如果iback/iG=5,则CM DM的值等于8.34×10-12mol/cm2·sec。另一个实例是,如果iback/iG=0.5,则CM DM的值等于8.34×10-13mol/cm2·sec。另外,如果iback/iG=0.05,则CM DM的值等于8.34×10-14mol/cm2·sec。
在某些电流分析或电势分析实施方案中,通过将工作电极与对电极或对/参比电极分开,使测定过程中氧化还原介质扩散的距离不大于例如电极之间的距离,从而降低氧化还原介质循环。氧化还原介质能扩散等于(DMt)1/2的距离,其中DM是电极之间介质的有效扩散系数,t是时间。对于30秒的测定时间和有效扩散系数为10-5~10-4cm2/sec的氧化还原介质,电极应分开至少100μm,优选地至少200μm,更优选地至少400μm。
分开工作电极与对电极的一种方法是在电极之间使用一个较厚的间隔层。图27显示了一种备择方法。在该实施方案中,工作电极740置于第一个基底742上,对电极744置于第二个基底746上(备择地,电极也可置于同一基底上)。工作电极742和对电极744偏移,使两个电极之间的有效距离d大于间隔层748的厚度w。在一个实施方案中,电极的间距d选择为25-1000μm、50-500μm或100-250μm。
另外,对于稳态电流分析法和电势分析法,在测定期间,如30秒、1分钟、5分钟或10分钟内,可通过限制电解速度,使速度低到足以防止分析物浓度降低超过约20%、10%或5%或更低,来控制本底信号。在某些情况中,为了控制电解速度,可降低第二种电子转移剂的浓度或活性,和/或可降低工作电极的面积。
例如,第二种电子转移剂可以是酶,而酶活性可能是电解速度的限制因素。例如,如果分析物浓度为5mM葡萄糖(即5×10-9mol/μl葡萄糖),并且在30秒测定过程中将有不超过10%的葡萄糖(5×10-10摩尔)被电氧化,则对1μl而言电流应不超过3.3×10-6安培。酶的一个单位是于pH7.4和37℃下在HEPES缓冲液中在60秒钟内催化1μmol底物电解的酶量。因此,对于葡萄糖能产生每1cm3(即1mL)可达3.3×10-3安培的电流。因此,在通过控制酶量限制电解程度的传感器中使用的最大酶量应为1单位/cm3或更低。
也可利用相对较小的工作电极面积限制电解速度。当工作电极面积足够小时(例如,不超过约0.01cm2,不超过约0.0025cm2,或不超过约0.001cm2),在施加的恒定电势下,分析物向电极的径向扩散可产生稳态电流,这代表分析物的浓度。对于盘状电极,可用半径不超过60μm、不超过30μm或不超过20μm的电极达到适当的表面积。分析物的径向扩散包括分析物从所有方向而不是从垂直于电极表面的方向运送,因此能减少或防止电极表面附近分析物的消耗。平面上的小电极允许径向扩散。在具有较大表面积电极的传感器中,分析物向电极的运送模式可以是半无限线性扩散而不是径向扩散。因此,分析物向电极的运送受垂直于电极表面的方向的扩散所控制。因此,降低的输送速度一般不能克服靠近电极表面的分析物的损耗,并且在施加的恒定电势下,电流按照t-1/2随时间t降低。
对于Yarnitzky和Heller,物理化学杂志(J.Phys.Chem.)102:10057-61(1998)提出的类型的电势分析法,其中电势随分析物浓度线性变化,分析物和/或特定氧化态的氧化还原介质的浓度在测定期间变化不应超过约20%。如果浓度变化超过20%,则分析物向氧化还原介质的扩散应受例如控制样品室和/或测定区的温度和/或容积的影响。
尽管本说明书中已叙述了分析物的电解,但本领域的技术人员应当认识到,相同的装置和技术也将适用于介质平均氧化态的测定,如科特雷耳型反应。
可空气氧化的氧化还原介质
在含有氧化还原介质的传感器中,测定误差的潜在来源是未知混合氧化态的氧化还原介质(即,不能以已知氧化态再现的介质)的存在。当氧化还原介质在工作电极处电氧化或电还原时,传递的电荷受其初始氧化态的影响。参考标题为“传感器操作”的章节中的上述方程式(1)和(2),由于氧化还原介质的部分A—即在加入样品前为还原形式的部分—的电氧化,无法归因于生物化学剂B氧化的电流将流动。因此,在向传感器中加入样品前知晓分析物的氧化态是重要的。此外,在样品加入传感器之前,希望所有或几乎所有氧化还原介质具有相同的氧化状态或程度。
每种氧化还原介质都具有还原形式或状态和氧化形式或状态。优选地在加入样品之前还原形式的氧化还原介质的量显著低于样品中预期的分析物的量,以避免对测定电流的明显的本底影响。在本发明的该实施方案中,在加入分析物之前还原形式的氧化还原介质的摩尔量以化学计量计对于预期的分析物浓度优选地不超过分析物摩尔量的约10%,更优选地不超过约5%,最优选地不超过约1%。(根据适用的氧化还原反应的化学计算法,比较分析物和氧化还原介质的相对摩尔量。例如,如果电解一摩尔的分析物需要两摩尔的氧化还原介质,则加入分析物之前还原形式的氧化还原介质的摩尔量对于预期的分析物浓度优选地不超过分析物摩尔量的20%,更优选地不超过约10%,最优选不超过约2%。)以下叙述了控制还原介质的量的方法。
在本发明的另一方面,在向传感器中加入样品之前,氧化的氧化还原介质的量与还原的氧化还原介质的量之比优选地在类似构造的传感器之间相对恒定。使该比值相对恒定的任何偏差都可增加用多种类似构造的传感器对相同样品获得的结果的离散。对于本发明的该方面,在向传感器中加入样品之前,还原形式的氧化还原介质的百分数在类似构造的传感器之间变化不超过约20%,优选地不超过约10%。
在向传感器中加入样品之前控制还原的氧化还原介质的量的一种方法是添加一种氧化剂来氧化还原形式的介质。最方便的一种氧化剂是O2。氧通常易于获得而行使这种氧化功能。能通过使传感器暴露于空气而提供氧。另外,大多数聚合物和液体可从空气中吸收O2,除非采取特殊的预防措施。一般而言,在贮存或暴露于空气一定时间后,如一个月或更短,优选地一周或更短,更优选地一天或更短,至少90%的可空气氧化(即可O2氧化的)的固态介质呈氧化态。空气氧化可在固态时发生,或当溶液在沉积于传感器上之前贮存足以空气氧化该介质的一定时间后发生。对于溶液中的可空气氧化的氧化还原介质,氧化还原介质完成至少80%,优选地至少90%的氧化所需的时间希望地至少10倍于预期的测定时间,并且也短于溶液的贮存期。优选地,至少80%,更优选地至少90%的氧化还原介质在不到1周,优选地不到1天,更优选地不到8小时,再更优选地不到1小时内被空气氧化。
尽管希望使一批中生产的传感器的介质为相同的氧化状态或程度,但介质完全氧化为更高价的状态是不必要的。另外,希望溶解的氧化还原介质的空气氧化不要太快,以免测定期间的空气氧化可干扰测定或产生误差。
以上已叙述了可空气氧化(即可O2氧化)并具有电子转移能力的合适的介质。有用介质的一个特定家族是与多电子含氮杂环结合的锇络合物或多电子含氮杂环与卤化物的组合物。多电子含氮杂环包括但不限于含有供电子取代基如烷基、烷氧基、氨基、烷氨基、酰氨基和巯基的咪唑衍生物和吡啶或菲咯啉衍生物。优选地,锇络合物含有不超过一个的与金属配位的卤化物,使得介质总体上带正电,因而是水溶性的。一个实例是与单-、二-和聚烷氧基-2,2’-联吡啶络合的锇。其他实例包括单-、二-和聚烷氧基-1,10-菲咯啉,其中烷氧基具有足以保持水中溶解度的碳氧比,它们是可空气氧化的。这些锇络合物一般含有两个取代的联吡啶或取代的菲咯啉配体,这两个配体不必相同。这些锇络合物进一步与含有一个或多个含氮杂环(如吡啶或咪唑)的单体或聚合配体络合。优选的聚合配体包括聚(4-乙烯基吡啶)和,更优选地,聚(1-乙烯基咪唑)或其共聚物。与聚(1-乙烯基咪唑)或聚(4-乙烯基吡啶)络合的[Os[4,4’-二甲氧基-2,2’-联吡啶]2Cl]+/+2显示特别可用作Os+2阳离子,其可被O2氧化为Os+3。对于[Os(4,7-二甲氧基-1,10-菲咯啉)2Cl]+/+2和其他单-、二-和聚烷氧基联吡啶和菲咯啉与相同聚合物的络合物预期有类似的结果。可用其他卤素基团如溴代替氯。如上所述,对于包含下列结构的络合物预期也有类似的结果:
如果氧化还原介质的空气氧化快得使大部分分析物还原的氧化还原介质在分析物测定期间被O2氧化,则发生与可空气氧化的介质有关的问题。这将导致不准确的测定,因为由于介质将被空气氧化而不是在电极处电氧化,所以分析物的量将被低估。优选地氧化还原介质与O2的反应进行得比介质的电氧化更慢,因为如果介质的空气氧化加快,则溶解的空气和空气的内扩散可影响测定结果。
因为测定一般需要约10分钟或更短,优选地5分钟或更短,最优选地约1分钟或更短,故优选地尽管介质在贮存中可被空气氧化,但在测定期间不被溶解氧氧化。因此,当溶解于血浆或血清中时在1分钟优选地甚至在10分钟后仍未空气氧化的介质是优选的。一般而言,在测定期间少于5%优选地少于1%的还原介质应被空气氧化。
介质空气氧化的反应速度能通过选择适当的络合聚合物来控制。例如,与聚(1-乙烯基咪唑)配位偶联的[Os(4,4’-二甲氧基-2,2’-联吡啶)2Cl]+/+2的氧化反应比与聚(4-乙烯基吡啶)偶联的相同Os络合物更快。适当聚合物的选择将取决于预期的分析物浓度和在电极之间施加的电势,这两者都决定了电化学反应的速度。
因此,在本发明的一个实施方案中,优选的氧化还原介质具有下列特征:1)该介质不与样品中或传感器中除分析物之外的任何分子反应(任选地,通过第二种电子转移剂);2)在向传感器中加入样品前,几乎全部氧化还原介质都被氧化剂如O2氧化;3)氧化剂对氧化还原介质的氧化慢于电极对介质的电氧化。
此外,如果氧化还原介质将在分析物存在下氧化并在电极处电还原,则需要还原剂而不是氧化剂。适当选择还原剂和介质的相同考虑因素如上所述适用于氧化剂。
在本发明的电化学传感器中使用稳定的可空气氧化的氧化还原介质在贮存与包装期间具有另一个优点。包含可空气氧化的氧化还原介质的本发明的传感器能包装于含分子氧的空气中,并贮存较长时间,例如长于1个月,而使至少80%,优选地至少90%的氧化还原物种保持氧化态。可空气氧化的介质在光学传感器中的应用
本发明的可空气氧化的氧化还原物种能在其他类型的传感器中使用。由于络合的Os+2和Os+3物种的吸收光谱、发光和/或荧光特征的差异,上述锇络合物适用于光学传感器。氧化还原物种的吸收、发射、透射、发光和/或荧光测定将与样品中分析物的量相关联(在分析物与氧化还原物种直接或通过第二种电子转移剂如酶反应后)。在这种构造中,氧化还原介质的摩尔量以化学计量计应大于预计将充满传感器测定区的分析物的摩尔量。
包括光导光纤传感器在内的标准光学传感器和测定技术能适于使用可空气氧化的介质。例如,本发明的光学传感器可包括光透射或光反射支架,其上覆盖有可空气氧化的氧化还原物种和优选地分析物反应性酶,形成薄膜。支承薄膜构成测定区的一个边界,样品置于其中。测定区的其他边界取决于测定池的构造。待含分析物的样品充满测定区后,分析物优选地通过与分析物反应性酶反应对可空气氧化的介质的还原导致介质氧化态的转变,这可根据介质在一种或多种波长的光下光透射、吸收或反射光谱或发光和/或荧光的改变来检测。
多电极传感器和校准
可由于多种原因使用多电极传感器。例如,多电极传感器可用于使用单一样品检测多种分析物。图5显示的多电极传感器的一个实施方案含有一个或多个样品室,该室又可含有一个或多个工作电极22,每个工作电极22界定了不同的测定区。如果氧化还原介质是不可滤出的,则一个或多个工作电极含有适当的化学试剂如适当的酶用于检测第一种分析物,而其余的一个或多个工作电极含有适当的化学试剂用于检测第二种分析物。这些化学试剂(例如氧化还原介质和/或第二种电子转移剂)能在工作电极上沉积为传感层,或者,若使用可扩散的试剂,则它们能沉积于样品室的任一表面上或置于样品中。例如,一个多电极传感器可包括1)一个或多个工作电极,其在传感层中含有葡萄糖氧化酶用来测定葡萄糖浓度,和2)一个或多个工作电极,其在传感层中含有乳酸氧化酶用来测定乳酸浓度。
多电极传感器也可用来提高所得读数的精度。可平均得自(全部或检测相同分析物的)每个工作电极的量值,获得更精确的读数。在某些情况中,如果数值与平均值的差超过阈限,则可舍弃该量值。例如,该阈限可根据统计学参数如平均量值的标准差来确定。然后可忽略舍弃的数值重新计算平均值。而且,如果假定特定电极有问题,可在后面的检测中忽略产生弃值的电极的读数。此外,只有在根据其他电极的读数舍弃预定量的读数后才可舍弃特定的电极。
除了使用多电极传感器提高精度外,也可对每一电极进行多次测定,并将其平均以提高精度。该技术也可用于单电极传感器来提高精度。
当使用大量生产的传感器时,由于传感器测定区容积的变化,可发生测定误差。测定区三个维度中的两个—长度和宽度—通常相对较大,约为1-5mm。能以2%或更低的变度容易地产生这种尺寸的电极。但是,亚微升测定区容积需要第三个维度比长度或宽度小一或两个数量级。如上所述,样品室的厚度一般为约50-约200μm。厚度的制造偏差可为约20-50μm。因此,希望提供一种方法以适合测定区内样品体积的这种不确定性。
在图5所示的本发明的一个实施方案中,基层材料48上具有多个工作电极42、44、46。这些电极被另一种基底(未显示)覆盖,该基底具有置于其上的对电极(未显示),产生多个面对面电极对。特定传感器中电极对之间工作电极与对电极间距的变异明显降低,因为工作电极和对电极均位于一种基底上,在每一电极对之间有相同的间隔层28(见图3)。
在此展示了能用于精确测定电极对测定区容积,并也可用于降低噪音的多电极传感器的一个实例。在该实例中,一种工作电极42含有一种不可滤出的氧化还原介质和不可滤出的第二种电子转移剂(如酶)。工作电极42与相应的对电极之间可放置吸附剂。另一种工作电极44包括不可滤出的氧化还原介质,但在电极上无第二种电子转移剂。此外,这第二种电极对可在工作电极44与相应的对电极之间含有吸附剂。任选的第三种工作电极46不含氧化还原介质并且无第二种电子转移剂与电极结合,在工作电极46与相应的对电极之间也无吸附剂。能用可扩散的氧化还原介质和/或可扩散的第二种电子转移剂构造类似的结构,尽管可扩散的成份不只限于置于工作电极上。在某些情况中,电极对之间的距离足以使得氧化还原介质和/或酶在测定期间和/或从向样品室中加入相同样品到测定结束为止的时间内基本上不在电极对之间扩散。
通过同时电解靠近电极42和44的测定区中的样品,能测定在加入样品之前不均一氧化态的氧化还原介质引起的传感器误差。在电极42处,分析物电解产生样品信号。在电极44处,由于不存在第二种电子转移剂(假定第二种电子转移剂是必需的)故分析物不电解。然而,由于在加入样品之前为混合氧化态的氧化还原介质(即一些氧化还原中心为还原态,一些为氧化态)的电解,和/或可扩散的氧化还原介质在工作电极与对电极之间的穿梭,将通过电荷(且将流过电流)。能从第一个电极对之间通过的电荷中减去第二个电极对中电极之间通过的少量电荷,以基本上消除由氧化还原介质的氧化态引起的误差,和/或消除由可扩散的氧化还原介质引起的本底电流。该方法也可降低与其他电解的干扰物如抗坏血酸、尿酸盐和乙酰氨基苯酚有关的误差,以及与电容充电和法拉第电流有关的误差。
优选地能通过在无任何液体时测定电极46(或在不含吸附剂时测定任一其他电极42、44)与相应的对电极之间的电容测定样品室的厚度。电极对的电容取决于电极的表面积、电极间距和极板之间物质的介电常数。空气的介电常数是一致的,这通常意味着该电极构造的电容为几个皮法(或者,假定大多数生物液体的介电常数约为75,如果电极与对电极之间存在液体,则为约100-1000皮法)。因此,由于电极的表面积已知,故电极对电容的测定使测定区厚度的测定在约1-5%内。
通过在加入液体之前和之后测定电极44(不含第二种电子转移剂)与相关对电极之间的电容能测定吸附剂中空隙容积的大小。加入液体后,由于液体具有更高的介电常数,电容明显提高。测定含或不含液体时的电容使得能测定电极之间的间距和吸附剂的空隙容积,从而测定反应区中液体的体积。
其他电极构造也能利用这些技术(即,在不含主要成份时的电容测定和库仑测定)降低背景噪音和由干扰物和不准确了解被测样品体积引起的误差。能发展包括一个或多个电极对和一个或多个上述测定的方案,其属于本发明的范围内。例如,电容测定只需要一个电极对,而为了方便可使用其他电极对。
填充指示器
当使用填充有1μL或更少液体的样品室时,通常希望能确定样品室何时充满。图18A-18C显示一种具有填充指示器结构的传感器。图18A显示第一个基底500,其上印制有一个工作电极502。在第一个基底500和工作电极502上形成一个间隔层504(图18B),例如粘合剂或双面粘合带层,在该层中形成一个沟槽506,形成样品室。第二个基底508上印有两个对电极510、512,如图18C所示(相对于图18A和18B翻转,以显示电极侧面)。在某些情况中,最靠近沟槽506的入口514的对电极510在样品室中具有至少两倍于,优选地至少5倍或10倍于另一个对电极512的表面积。
通过观察当传感器充满液体时能第二个对电极512与工作电极502之间的信号,能指示传感器充满。当液体到达第二个对电极512时,对电极产生的信号应改变。合适的观察信号包括,例如,第二个对电极512与工作电极502之间的电压、电流、电阻、阻抗或电容。此外,充满后可观测传感器,以确定信号值(例如,电压、电流、电阻、阻抗或电容)是否达到指示样品室充满。
在另一个实施方案中,对电极和/或工作电极可分成两个或更多部分,并观测来源于各部分的信号以确定传感器是否充满。在一个实施例中,工作电极与对电极和指示电极为面对面关系。在另一个实施例中,对电极、工作电极和指示电极不是面对面关系,但可能是例如并排的。在其他情况中,第二个电极对可利用来源于监测改变和/或接近特定值的第二个电极对的信号,确定传感器已充满。相比于工作电极和对电极,指示电极一般位于样品入口的更下游。
对于如图19A-19C和图20A-20C所示的侧面填充传感器,可在主对电极的任一侧放置两个指示电极。这使使用者可从左侧或右侧填充样品室,而指示电极位于更上游。这种三电极构造不是必需的。侧面填充传感器也可具有单一指示电极,和优选地指明哪个侧面应当与样品液体接触的标志。
在一个实施方案中,使用三个对/参比电极和/或指示电极检测样品室何时开始填充,样品室何时充满,以防止样品室的部分填充。在该实施方案中,两个指示电极保持与最大对/参比电极不同的电势。用指示电极与对/参比电极之间的电流指示样品室填充的开始与完成。
在其他情况中,每个对/参比电极的电势可以相同。当所有三个对/参比电极处的电势相同如为0伏时,则测定区开始填充,液体使工作电极与第一个对/参比电极之间有电接触,由于分析物与酶和介质的反应在第一个对/参比电极处产生电流。当液体到达第三个对/参比电极时,类似于第一个对/参比电极可检测到另一种电流,表明测定区充满。当测定区充满时,三个对/参比电极可一起短路,或者其信号可加成或以其他方式合并。
根据以上对多电极传感器所述的方法,也可用指示电极提高分析物测定的精度。指示电极可作为工作电极或作为对电极或对/参比电极。在图18A-18C的实施方案中,指示电极512能作为相对于工作电极502而言的第二个对电极或对/参比电极。来源于指示电极/工作电极对的量值能与来源于第一个对电极或对/参比电极/工作电极对的量值合并,获得更准确的量值。在一个实施方案中,指示电极可作为相对于对电极或对/参比电极的第二个工作电极。在另一个实施方案中,指示电极可作为带有第二个对电极或对/参比电极的第二个工作电极。在再一个实施方案中,指示电极可作为带有第二个工作电极的第二个对电极或对/参比电极。
传感器或传感器读数器可包括一种标记(例如可视标志或声音信号),其可响应指示电极而激活,警告使用者测定区已充满。在某些情况中,传感器或传感器读数器可构造为,当指示电极表明测定区已充满时,在警告或不警告使用者的情况下开始读数。例如,可通过在工作电极与对电极之间施加电势,并开始监测工作电极产生的信号,来开始读数。
样品的加热
可加热样品以提高分析物扩散、氧化或还原速度。这种加热可经多种技术实现,包括将传感器置于加热环境中或在传感器中使用加热装置。
另一种技术包括在传感器上添加一种加热元件,如能将电能转化为热能的金属线或印剂(ink)。这种金属线或印剂能添加在例如基层材料如聚合物膜相对于一个或多个工作、对、参比或对/参比电极的对侧,或添加于工作、对、参比或对/参比电极外周。在某些情况中,样品可加热至达初始温度以上5-20℃。在其他情况中,可不知样品温度,但可对金属线或印剂使用恒定量的功率或电流。
实施例
本发明通过下列实施例进一步表征。这些实施例不是意在限制前面充分叙述的本发明的范围。本发明的概念的变化为本领域技术人员所明知。
实施例1
用于葡萄糖浓度测定的小容积体外传感器的制造
构造一种对应于图1所示本发明的实施方案的传感器。工作电极构建于MylarTM膜(DuPont)上,MylarTM膜厚度为0.175mm,直径约2.5cm。在MylarTM膜上筛网印制直径约1cm约12微米厚的碳垫。碳电极上覆盖厚度为12μm,在中心有一个直径4mm的开口的水溶性介电绝缘体(Insulayer)。
未覆盖介电体的碳电极的中心覆盖有一种不可滤出的氧化还原介质。该氧化还原介质的形成方法是,如Taylor等人,电分析化学杂志(J.Electroanal.Chem.)396:511(1995)所述,将聚(1-乙烯基咪唑)与Os(4,4’-二甲氧基-2,2’-联吡啶)2Cl2络合,随后用聚乙二醇二缩水甘油醚(PEGDGE)交联葡萄糖氧化酶与锇聚合物。氧化还原介质中锇与咪唑官能基之比接近1:15。介质沉积于工作电极上形成厚度0.6μm、直径4mm的层。电极上介质的覆盖度约为60μg/cm2(干重)。间隔层材料置于电极上介质覆盖的电极表面周围。间隔层由聚四氟乙烯(PTFE)制成,厚度约为0.040mm。
吸附剂与介质覆盖的工作电极表面接触。吸附剂由尼龙(Tetko Nitex尼龙3-10/2)制成。吸附剂直径为5mm,厚度为0.045mm,空隙容积约为20%。由吸附剂和电极的尺寸和特征计算测定区中样品的体积。测定区直径为4mm(介质覆盖的电极表面的直径),厚度为0.045mm(尼龙吸附剂的厚度),体积为0.57μL。在该间隙中,约80%充满尼龙,其余20%为尼龙吸附剂内的空隙空间。测定区内的样品体积约为0.11μL。
对/参比电极与间隔层和吸附剂相对于工作电极的一侧接触,使得两个电极彼此面对。对/参比电极构建于厚度为0.175mm,直径约为2.5cm的MylarTM膜上,其上筛网印制了直径约1cm、12微米厚的银/氯化银层。
用电极组件任一侧上的极板将电极、吸附剂和间隔层压在一起。极板由聚碳酸酯塑料制成,牢固夹紧使传感器结合在一起。电极在使用前在空气中贮存48小时。
接头从工作电极和对/参比电极中伸出,并将与分析装置电接触。用一个恒电位仪在工作电极与对/参比电极之间施加+200mV的电势差,工作电极为阳极。无样品时电极之间无电流,这是预期的,因为在电极之间不存在导电通路。
样品经尼龙吸附剂的小接头加入,该接头形成为样品室尼龙吸附剂的伸出部分。当样品与吸附剂接头接触时,液体经毛细作用吸入吸附剂中。当样品室充满且样品接触电极时,电流在电极之间流动。当样品中的葡萄糖分子接触工作电极上的葡萄糖氧化酶时,葡萄糖分子被电氧化为葡糖酸内酯。氧化还原介质中的锇氧化还原中心然后再氧化葡萄糖氧化酶。锇中心随后通过与工作电极反应被再氧化。这产生电流,可用库仑计(EG&G Princeton Applied Research #173型)测定并同时综合。
电化学反应继续进行,直到电流达到稳态值,这表明超过95%的葡萄糖已被电还原。积分以特定间隔测定电流所获得的电流曲线,来确定电化学反应过程中传递的电荷量。然后将这些电荷对已知的葡萄糖浓度作图,得到校正曲线。
用0.5μL等份在人造脑脊髓液中或对照血清(Baxter-Dade,MonitrolLevel1,Miami,FL)中含3-20mM已知浓度葡萄糖的溶液测试该传感器。人造脑脊髓液制备成下列盐的混合物:126mM NaCl、27.5mMNaHCO3、2.4mM KCl、0.5mM KH2PO4、1.1mM CaCl2·2H2O和0.5mMNa2SO4。
分析结果示于表1和图7中。在表1中,Qavg是用来电解3~6份相同待测样品中葡萄糖的平均电荷(图7对每份待测样品的电荷作图),90%的上升时间对应于90%葡萄糖被电解所需的时间长度。数据显示10-20%的传感器精度,表明传感器对于低葡萄糖浓度及在生理相关范围(30μg/dL~600μg/dL)中有足够的灵敏度。
表1 使用葡萄糖氧化酶的传感器结果
测定样品数 | Qavg(TC) | 90%上升时间(秒) | |
单独缓冲液 | 4 | 9.9±1.8 | 13±6 |
3mM葡萄糖/缓冲液 | 5 | 17.8±3.5 | 19±5 |
6mM葡萄糖/缓冲液 | 4 | 49.4±4.9 | 25±3 |
10mM葡萄糖/缓冲液 | 6 | 96.1±12.4 | 36±17 |
15mM葡萄糖/缓冲液 | 5 | 205.2±75.7 | 56±23 |
20mM葡萄糖/缓冲液 | 4 | 255.7±41.0 | 62±17 |
4.2mM葡萄糖/血清 | 3 | 44.2±4.3 | 44±3 |
15.8mM葡萄糖/血清 | 3 | 218.2±57.5 | 72±21 |
用一种或多种方程式拟合葡萄糖浓度的平均测定值以产生校正曲线。图8显示表1的葡萄糖/缓冲液数据的校正曲线。从这些计算中忽略15.0mM葡萄糖的量值之一,因为它比测定平均值高两个标准差。较高的葡萄糖浓度(10-20mM)用线性方程式拟合。较低的葡萄糖浓度用二阶多项式拟合。
图9显示在误差网格上作图的表1的数据,该误差网格由Clarke等人,糖尿病护理(Diabetes Care)5,622-27,1987提出,用于根据不精确的葡萄糖浓度测定法测定误差的结果。该图将“真实”的葡萄糖浓度对测定的葡萄糖浓度作图,其中通过对图7的每一数据点用图8的校正曲线计算葡萄糖浓度,来确定测定的葡萄糖浓度。A区中的点是准确的,B区中的点是临床可接受的,C、D和E区中的点可引起越来越不恰当且最终危险的处理。
有34个数据点。这些数据点中的91%落入A区,6%落入B区,3%落入C区。只确定了一个读数在C区中。该读数超出范围,未在图9中显示。因此,97%的读数落入临床可接受的A区和B区。
通过还原所有Os,然后在样品室中用不含葡萄糖的缓冲液电氧化,测定Os原子的总数。这产生59.6±5.4μC的电荷。该结果与表1中不含葡萄糖缓冲液的结果的对比表明,在加入样品之前不到20%的Os为还原形式。还原态锇数量的变异性不到存在的锇的总量的5%。
实施例2
葡萄糖传感器对干扰物的反应
用与以上实施例1所述相同的方法构造的传感器测定传感器对干扰物的反应。血糖测定的主要电化学干扰物是抗坏血酸、乙酰氨基苯酚和尿酸。这些常见干扰物的正常生理或治疗(对于乙酰氨基苯酚)浓度范围为:
抗坏血酸:0.034-0.114mM
乙酰氨基苯酚:0.066-0.200mM
尿酸(成年男性):0.27-0.47mM
Tietz,《临床化学教科书》,C.A.Burtis和E.R.Ashwood编,W.B.Saunders Co.,Philadelphia,1994,2210-12页。
在以上列出的生理或治疗范围的高限之干扰物浓度检测不含葡萄糖的缓冲干扰物溶液。每种情况中注射的样品体积均为0.5μl。在电极之间施加+100mV或+200mV的电势。通过从用存在的干扰物记录的平均信号中减去从只含缓冲液(即不含干扰物)的溶液中获得的平均本底电流,计算平均电荷(Qavg)。将得到的平均电荷与表1中4mM和10mM葡萄糖浓度的信号比较,确定由干扰物引起的百分误差。
表2 葡萄糖传感器的干扰物反应
溶液 | E(mV) | n | Qavg(TC) | 误差@4mM葡萄糖 | 误差@10mM葡萄糖 |
0.114mM抗坏血酸 | 100 | 4 | 0.4 | 2% | <1% |
0.114mM抗坏血酸 | 200 | 4 | -0.5 | 2% | <1% |
0.2mM乙酰氨基苯酚 | 100 | 4 | 0.1 | <1% | <1% |
0.2mM乙酰氨基苯酚 | 200 | 4 | 1.0 | 5% | 1% |
0.47mM尿酸 | 100 | 4 | 6.0 | 30% | 7% |
0.47mM尿酸 | 200 | 4 | 18.0 | 90% | 21% |
这些结果表明,尤其对于低电势测定而言,抗坏血酸和乙酰氨基苯酚不是葡萄糖传感器构造的明显干扰物。然而,尿酸导致明显的干扰。通过校准传感器对0.37mM尿酸浓度的反应,例如,通过从传感器的所有葡萄糖测定结果中减去用外推法确定的适量电荷,能使这种干扰减至最小。由尿酸浓度(成年男性尿酸浓度为0.27~0.47)0.10mM变化引起的误差在4mm葡萄糖和100mV时约为6%。
实施例3
含葡萄糖脱氢酶的传感器
制造一种类似于实施例1所述的传感器并用于本实施例,不同之处在于将葡萄糖氧化酶替换为吡咯并喹啉醌葡萄糖脱氢酶,与实施例1中的+200mV电势不同,只施加+100mV的电势。结果示于下面的表3中并在图10中作图。
表3 应用葡萄糖脱氢酶的传感器结果
n | Qavg(TC) | 90%上升时间(s) | |
缓冲液 | 4 | 21.7±5.2 | 14±3 |
3mM葡萄糖/缓冲液 | 4 | 96.9±15.0 | 24±6 |
6mM葡萄糖/缓冲液 | 4 | 190.6±18.4 | 26±6 |
10mM葡萄糖/缓冲液 | 4 | 327.8±69.3 | 42±9 |
结果表明,由葡萄糖脱氢酶传感器获得的电荷大大高于相应的葡萄糖氧化酶传感器,尤其是对于低浓度葡萄糖而言。对于4mM葡萄糖浓度,两种传感器所获得的量值相差5倍。另外,葡萄糖脱氢酶传感器在较低电势下操作,因而降低了干扰物反应的影响。
另外,与实施例1的结果不同,表3的结果全部用线性校正曲线拟合,如图10所示。为简化传感器结构和操作,特别优选单一线性校正曲线。
同样,假定表2的干扰结果适用于该传感器,则对于100mV电势时的3mM葡萄糖溶液,所有干扰物都将产生不到7%的误差。
实施例4
液流中乳酸浓度的测定
用具有玻璃态碳电极的流动测定池(BioAnalytical Systems,Inc,#MF-1025)构建该实施例的传感器。在流动测定池的电极上包涂有一种氧化还原介质,形成工作电极。在此情况中,氧化还原介质是一种聚合物,它是通过将聚(1-乙烯基咪唑)与Os(4,4’-二甲基-2,2’-联吡啶)2Cl2以每15个咪唑官能基1个锇的比例络合形成的。乳酸氧化酶与该聚合物通过聚乙二醇二缩水甘油醚交联。该介质以500μg/cm2的覆盖度和5Tm的厚度包涂于电极上。该介质覆盖有一层径迹蚀刻的聚碳酸酯膜(Osmonics-Poretics #10550)以改善在液流中的粘性。该膜然后再覆盖一层50Tm厚的间隔垫圈(BioAnalytical Systems,Inc,#MF-1062),其含有限定了样品室和相应测定区的空隙。传感器的装配通过连接含有流动测定池的参比电极与辅助电极的测定池组件(BioAnalytical Systems,Inc,#MF-1005)完成。
在此情况中,样品室对应于与表面积为0.031cm2的介质包被的电极接触的50Tm厚圆筒(间隔垫圈的厚度)。该传感器测定区中的计算样品体积约为0.16TL。
液流的流速为5TL/min。标准三电极恒电位仪与测定池导线连接,并在氧化还原介质包被的玻璃态碳电极与参比电极之间施加+200mV的电势。该电势足以引发酶介导的乳酸氧化。
当液流流经传感器时,测定与乳酸浓度成比例的稳态电流。以周期性间隔停止液流,并使电流在电极之间流动,直到测定区中几乎全部乳酸被电氧化,这由达到稳定的稳态电流指示。通过积分从流动停止到电流达到稳态所记录的不同电流得到乳酸电氧化所需的总电荷Q。然后用下列方程式计算浓度:
[乳酸]=Q/2FV (4)
其中V是测定区中的样品体积,F是法拉第常数。
用标称乳酸浓度为1.0、5.0和10.0mM的乳酸溶液进行该测定。该试验所测浓度分别为1.9、5.4和8.9mM。
实施例5
与聚(1-乙烯基咪唑)络合的Os(4,4’-二甲氧基-2,2’-联吡啶)2Cl+/+2氧化态的测定
具有三电极设计的传感器从英格兰Long Hanborough的EcossensorsLtd.商品获得,其模型名称为“大面积一次性电极”。该传感器含有平行的和共面的工作、参比和对电极。工作表面积(0.2cm2)和对电极由印制的碳构成,参比电极由印制的Ag/AgCl构成。碳工作电极上覆盖一种氧化还原介质。该氧化还原介质的形成方法是,将聚(1-乙烯基咪唑)与Os(4,4’-二甲基-2,2’-联吡啶)2Cl2以每个Os阳离子15个咪唑基的比例络合,随后用聚乙二醇二缩水甘油醚将锇聚合物与葡萄糖氧化酶交联。
该电极在室温下熟化24小时。然后将共面电极阵列浸入缓冲电解液中,并在工作电极与参比电极之间施加+200mV的电势(足以使Os(II)转化为Os(III))。
一施加电势,即有低于1μC的不可检测的电荷通过。随后氧化还原介质的还原和再氧化产生足以使全部Os从Os(II)转化为Os(III)的65 TC的电荷。因此,氧化还原介质中超过98%的Os阳离子为希望的Os(III)氧化态。
实施例6
与聚(4-乙烯基吡啶)络合的Os(4,4’-二甲氧基-2,2’-联吡啶)2Cl+/+2氧化态的测定
用相同的工作/对/参比电极构造进行与实施例5类似的实验,不同之处在于工作电极上的氧化还原介质改为Os(4,4’-二甲氧基-2,2’-联吡啶)2Cl2与聚(4-乙烯基吡啶)的络合物,它是以每个Os阳离子12个吡啶基的比例络合,并经聚乙二醇二缩水甘油醚与葡萄糖氧化酶交联的。
构造两种传感器。这两种传感器的电极在室温下熟化24小时。然后将电极浸入缓冲电解液中,并在工作电极与参比电极之间施加+200mV的电势。
对电极施加电势后,两个传感器中即分别通过2.5TC和3.8TC的电荷。随后氧化还原介质的还原和再氧化分别产生27.9TC和28.0TC的氧化电荷。因此,传感器最初含有91%和86%的为希望的Os(III)氧化态的Os阳离子。
实施例7
光学传感器
通过向透光支持物(如载玻片上)添加含交联的酶的氧化还原聚合物膜构造一种光学传感器。氧化还原介质的量等于或大于(在化学计量意义上)预计可充满测定区的分析物的最大量。间隔材料、吸附剂和面对面支持物牢固夹紧。使样品室通过装配的传感器向光密度检测器或向发光和/或荧光检测器透光。当样品充满样品室且氧化还原介质氧化时,样品室中氧化还原介质的吸收、透射、反射或发光和/或荧光的改变与样品中葡萄糖的量相关联。
实施例8
上臂刺血针穿刺得到的血液体积
用刺血针多次刺破个体的前臂,以确定用该方法获得的血液体积的可重复性。尽管在每个前臂的前部和左前臂的背部进行超过30次的刺血针穿刺,但个体自称每次穿刺实际上无痛苦。
前臂用Payless Color刺血针刺破。用1μL毛细管收集每次穿刺的血液,并通过测定血柱的长度确定体积。每次穿刺获得的体积示于以下的表4中。
表4 刺血针穿刺的体积
左前臂前侧(nL) | 右前臂前侧(nL) | 左前臂背侧(nL) | |
1 | 180 | 190 | 180 |
2 | 250 | 180 | 300 |
3 | 170 | 120 | 310 |
4 | 150 | 100 | 300 |
5 | 100 | 210 | 60 |
6 | 50 | 140 | 380 |
7 | 90 | 120 | 220 |
8 | 130 | 140 | 200 |
9 | 120 | 100 | 380 |
10 | 100 | 320 | |
11 | 260 | ||
12 | 250 | ||
13 | 280 | ||
14 | 260 | ||
平均值 | 138±58nL | 140±40nL | 264±83nL |
实施例9
含有可扩散的氧化还原介质的传感器
通过在聚酯基底上印染石墨墨水(石墨#G4491,Ercon,Wareham,MA)制成一种传感器。5.5μg/cm2[Os(二甲氧基联吡啶)2(乙烯基咪唑)Cl]Cl、23.7μg/cm2 PQQ-葡萄糖脱氢酶和18.2μg/cm2 Zonyl 表面活性剂(E.I.duPont de Nemours & CO.,Inc.,Wilmington,DE)的混合物沉积于工作电极的一部分上。然后在工作电极上使用150μm厚的压敏胶粘带,使得只有工作电极的一部分暴露,形成样品室。在压敏胶粘带之上具有置于该膜上、具有对电极的第二种聚酯膜。该对电极是通过将Ag/AgCl墨水(银/氯化银#R414,Ercon,Wareham,MA)置于第二种聚酯膜上形成的。Ag/AgCl对电极上覆盖约100μg/cm2用PEGDGE交联的甲基化聚(乙烯基咪唑)。
实施例10
在0V电势下用含可扩散氧化还原介质的传感器测定葡萄糖
如实施例9所述制造传感器,并用于测定葡萄糖浓度为0、90、180、270和360mg/dL的葡萄糖/缓冲溶液。在图15中用图表示了对每一溶液随时间测定的电荷。在不含葡萄糖时,传感器指示约3mg/dL的葡萄糖浓度。图16显示在每一葡萄糖浓度时三种传感器测定的相对于葡萄糖浓度的电荷。测定的电荷随葡萄糖浓度线性变化,这类似于应用不可滤出的氧化还原介质的传感器所观察到的。
实施例11
用可扩散的氧化还原介质制成的其他传感器
传感器A和B通过聚酯基底上印染石墨墨水(石墨#G4491,Ercon,Wareham,MA)制成。对于传感器A,8.0μg/cm2[Os(二甲氧基联吡啶)2(乙烯基咪唑)Cl]Cl、34.7μg/cm2PQQ-葡萄糖脱氢酶和26.6μg/cm2 Zonyl表面活性剂(E.I.duPont de Nemours & CO.,Inc.,Wilmington,DE)的混合物沉积于工作电极的一部分上。对于传感器B,24μg/cm2[Os(二甲氧基联吡啶)2(乙烯基咪唑)Cl]Cl、104μg/cm2PQQ-葡萄糖脱氢酶和80μg/cm2 Zonyl 表面活性剂(E.I.duPont de Nemours &CO.,Inc.,Wilmington,DE)的混合物沉积于工作电极的一部分上。然后在每一传感器的工作电极之上使用200μm的压敏胶粘带,使得只有工作电极的一部分暴露,形成样品室。在压敏胶粘带之上具有置于该膜上、具有对电极的第二种聚酯膜。每一传感器的对电极是通过将Ag/AgCl墨水(银/氯化银#R414,Ercon,Wareham,MA)置于第二种聚酯膜上形成的。Ag/AgCl对电极上覆盖约100μg/cm2用PEGDGE交联的甲基化聚(乙烯基咪唑)。
实施例12
改变传感器中可扩散的氧化还原介质的量
测试传感器A和B,确定分析物电解所需的时间长度。图17显示其结果。提高样品中可扩散的氧化还原介质的量可降低传感器的响应时间。
实施例13
小容积传感器的临床准确度
对应于图24A、24B和24C所示的本发明的实施方案构建该实施例的传感器。如实施例11所述,在MelinexTM聚酯膜(DuPont,Wilmington,Delaware)上印制碳工作电极。碳电极上覆盖有18μg/cm2 Os[(MeO)2bpy]2(1-乙烯基咪唑)Cl3、162μg/cm2 GDH(东京,日本)、1.35μg/cm2PQQ(Fluka,Mila,Wisconsin)和60μg/cm2 Zonyl FSO(DuPont,Wilmington,Delaware)。在18℃和50%相对湿度下对工作电极进行包被。在碳电极上放置粘合剂(50μm厚),围绕包被的表面并形成宽度约为0.04英寸的沟槽。
如实施例11所述,两个Ag/AgCl对/参比电极印制于第二个MelinexTM聚合物膜上。然后使该膜接触粘合剂和工作电极膜,使工作电极和两个对电极彼此面对。对/参比电极上覆盖142μg/cm2甲基化的聚乙烯基咪唑、18μg/cm2PEGDGE(PolySciences,Warington,Pennsylvania)和7μg/cm2Zonyl FSO(DuPont,Wilmington,Delaware)。在其他对电极下游的一个对电极用作指示电极,以确定样品室何时充满。用手压滚经三次辊压将传感器制成薄层,并在室温下于CaSO4上老化3天。
构建传感器,使得当指示电极与对/参比电极之间流过足够的电流时,外电路能发出可见信号,指示工作电极上的沟槽中充满了血液。
在使用该传感器前几天,进行干电容测量来确定样品室容积的一致性。电容的变化反映电极的失调和/或粘合剂厚度的变化。测定的平均电容为7.49pF,标准差为0.28pF或3.8%。测定的最大电容为8.15pF,测定的最小电容为6.66pF。
用该传感器测定采自23人的血样中的葡萄糖浓度。在该研究中,人们为26~76岁,14人为男性,9人为女性。6人诊断为1型糖尿病,16人诊断为2型糖尿病,1人不知糖尿病分型。受试者的平均血细胞比容为40.7%,标准差为3.9%。最大血细胞比容为49%,最小血细胞比容为33.2%。
通过刺破受试者的手指收集每人的一份血样。小容积传感器中填充剩余的血液。
然后用2mm CareletTM刺臂将每人的三份血样收集于小容积传感器中。如果在10秒钟内未获得足够的样品,则按揉穿刺伤口的区域,然后填充传感器。69份样品中的16份需要按揉伤口。
经静脉穿刺收集每人三份血样。至少对一份样品进行YSI血糖测定和血细胞比容测定。46个小容积传感器中也填充这些样品的血液。
在施加的0mV电势下进行传感器测定。在加入任何样品之前BAS恒电位仪(CV50W,West Lafayette,Indiana)为“开”,使得当条带充满时立即电解。集电持续150秒(该电荷被称为“完全”电解),但大多数测定基本上在150秒前完成。未舍弃任何结果。进行三次连续的传感器血糖测定。
用YSI血糖测定仪(Yellow Springs Instruments,2300型化学葡萄糖分析仪)进行对照样品的测定。
将数据对YSI静脉结果作图,并由这些数据确定线性函数。所有数据均收集自传感器中葡萄糖的“完全”(150秒)电解。
图28显示69个小容积传感器检测采自臂的血液的数据。R2为0.947,平均CV(变异系数)为4.8%,RMS(均方根)CV为5.7%。
图29显示23个小容积传感器检测采自手指的血液的数据。R2为0.986。
图30显示46个小容积传感器检测静脉血的数据。R2为0.986。平均CV为3.8%。RMS CV为4.6%。
已参照多种具体和优选的实施方案和技术叙述了本发明。然而,本领域技术人员应当明白,在本发明的精神和范围内可进行多种变化和修改。
本说明书中的所有公开文本和专利申请均表现出本发明所属领域中技术人员的水平。所有公开文本和专利申请均在此引用作为参考,以使每一公开文本或专利申请均具体且单独地引用作为参考。
Claims (49)
1.一种用于测定样品液中分析物浓度的传感器,该传感器包括:
一个包括工作电极和对电极的电极对,其中至少工作电极的一部分距对电极的一部分不超过200μm,任选地,该对电极是一种对/参比电极;
一个任选的参比电极;
一个样品室,其用于使样品液与工作电极、对电极和参比电极—如果有的话—电解接触,该样品室包括一个与工作电极、对电极和参比电极—如果有的话—相邻的测定区,其中该测定区的大小可含有体积不超过约1μL的样品液,任选地,该样品室的大小可含有不超过约1μL的样品液;和
位于测定区中的一种分析物反应性酶和一种可扩散的氧化还原介质;
其中构造并排列该传感器,使得可扩散的氧化还原介质产生的本底信号不超过:
(a)平均正常生理量的分析物氧化或还原所产生信号的5倍;或
(b)相应于平均正常生理量的分析物的平均偏差之一定量分析物氧化或还原所产生信号的5倍。
2.一种用于测定样品液中分析物浓度的传感器,该传感器包括:
一个包括工作电极和对电极的电极对,其中工作电极和对电极分开25-1000μm的最近距离;
一个容纳样品液的样品室,该样品室包含一个与工作电极和对电极相邻放置的测定区,其中该测定区的大小可含有体积不超过约1μL的样品;和
置于测定区中的一种分析物反应性酶和一种可扩散的氧化还原介质;
其中构造并排列该传感器,使得可扩散的氧化还原介质产生的本底信号不超过5mM分析物氧化或还原所产生信号的5倍。
3.根据权利要求1和2任一项的传感器,其中构建并排列该传感器,使得可扩散的氧化还原介质产生的本底信号相同或低于平均正常生理量的分析物氧化或还原所产生的信号。
4.根据权利要求1和2任一项的传感器,其中构建并排列该传感器,使得可扩散的氧化还原介质产生的本底信号不超过分析物氧化或还原所产生信号的25%,优选地不超过分析物氧化或还原所产生信号的5%。
5.根据权利要求1-4中任一项的传感器,其中该传感器包括:
(a)具有一个近端和一个远端的第一个基底,这第一个基底限定了从第一个基底近端延伸到远端的电化学传感器的第一个侧边和第二个侧边,构建并排列远端以用于插入传感器读数器;
(b)置于第一个基底上的第二个基底,工作电极置于第一个和第二个基底之一上,而对电极置于第一个和第二个基底之一上;
(c)置于第一个和第二个基底之间的间隔层,其形成了沿传感器第一个侧边的第一个孔和沿传感器第二个侧边的第二个孔,样品室从第一个孔延伸到第二个孔;和
(d)至少一个指示电极,其置于第一个和第二个基底中的至少一个上,并相对于测定区或样品室放置,用来确定测定区或样品室何时含有样品。
6.根据权利要求1-4中任一项的传感器,其中该传感器包括:
(a)具有一个近端和一个远端的第一个基底,构建并排列远端以用于插入传感器读数器,第一个基底限定了从第一个基底近端延伸到远端的电化学传感器的第一个侧边和第二个侧边;
(b)置于第一个基底上的第二个基底,工作电极置于第一个和第二个基底之一上,而对电极置于第一个和第二个基底之一上;
(c)置于第一个和第二个基底之间的间隔层,其形成了沿传感器近侧端的第一个孔和沿传感器第一个侧边的第二个孔,样品室从第一个孔延伸到第二个孔;和
(d)至少一个指示电极,其置于第一个和第二个基底中的至少一个上,并相对于测定区或样品室放置,用来确定测定区或样品室何时含有样品。
7.根据权利要求1-4中任一项的传感器,其中该传感器包括一个置于传感器中的指示电极,用来指示测定区中何时含有样品或样品室中何时含有样品。
8.根据权利要求5-7中任一项的传感器,其中该指示电极也是一个工作电极或对电极。
9.根据权利要求5-8中任一项的传感器,其还包括一种与指示电极连接的视觉或听觉标志,其在指示电极指示测定区或样品室中含有样品时激活。
10.根据权利要求5-9中任一项的传感器,其中指示电极以与工作电极和对电极之一面对面的关系放置。
11.根据权利要求5-10中任一项的传感器,其中该传感器含有至少两个置于传感器中的指示电极,其中第一个指示电极指示测定区或样品室中何时开始填充样品,而第二个指示电极指示测定区或样品室中何时基本上充满样品。
12.根据权利要求5-10中任一项的传感器,其中该传感器包括至少两个置于传感器中的指示电极,其中两个指示电极包括第一个对/指示电极和第二个对/指示电极,对电极置于每一个和第二个对/指示电极之间。
13.根据权利要求1-12中任一项的传感器,其中测定区和样品室具有相同的容积。
14.根据权利要求1-13中任一项的传感器,其中分析物是葡萄糖,而分析物反应性酶是葡萄糖反应性酶。
15.根据权利要求1-13中任一项的传感器,其中分析物是一种药物。
16.根据权利要求1-15中任一项的传感器,其中测定区至少两侧被工作电极和对电极定界,任选地,工作电极和对电极形成面对面电极对,测定区位于工作电极和对电极之间。
17.根据权利要求1-16中任一项的传感器,其中构建并排列该传感器,使得介质氧化分析物,并且如用循环伏安法在pH7的0.1M NaCl中测定的,氧化还原介质的半波电位相对于对/参比电极的电位不超过约+100毫伏。
18.根据权利要求1-17中任一项的传感器,其中构建并排列该传感器,使得介质氧化分析物,并且如用循环伏安法在pH7的0.1M NaCl中测定的,氧化还原介质的半波电位约与对/参比电极的电位相同。
19.根据权利要求1-18中任一项的传感器,其中构建并排列该传感器,使得介质氧化分析物,并且如用循环伏安法在pH7的0.1M NaCl中测定的,氧化还原介质的半波电位相对于对/参比电极的电位不超过约-150毫伏。
20.根据权利要求1-19中任一项的传感器,其中在该传感器内,氧化还原介质通过样品液的有效扩散系数低于分析物通过样品液的有效扩散系数,并且优选地,至少比分析物通过样品液的有效扩散系数低10倍。
21.根据权利要求1-20中任一项的传感器,其中可扩散的介质具有至少5000道尔顿的分子量。
22.根据权利要求1-21中任一项的传感器,其中构建并排列该传感器,使得氧化还原介质在工作电极上比在对电极上更易电解。
23.根据权利要求1-22中任一项的传感器,其中该传感器包含一定摩尔量的氧化还原介质,其以化学计量计不多于平均正常生理量的分析物,优选地,该传感器包含一定摩尔量的氧化还原介质,其以化学计量计不多于平均正常生理量的分析物的20%。
24.根据权利要求1-23中任一项的传感器,其中工作电极具有暴露于测定区中的不超过约0.01cm2的表面积。
25.根据权利要求1-24中任一项的传感器,其中酶活性不超过1单位/cm3。
26.根据权利要求1-25中任一项的传感器,其中构建并排列该传感器,使得可扩散的氧化还原介质在对电极处反应时沉淀。
27.根据权利要求1-26中任一项的传感器,其中构建并排列该传感器,使得当样品液充满测定区时氧化还原介质的有效扩散系数和氧化还原介质浓度的数学乘积不高于1×10-12mol cm-1sec-1。
28.根据权利要求1-27中任一项的传感器,其中可扩散的氧化还原介质置于工作电极上。
29.根据权利要求1-28中任一项的传感器,其中分析物反应性酶置于工作电极上。
30.一种用于测定样品中分析物浓度的传感器,该传感器包括:
一个包括工作电极和对电极的电极对,任选地,工作电极与对电极以面对面关系放置;
一个包含与工作电极和对电极相邻的测定区的样品室,其中该测定区的大小可含有体积不超过1μL的样品,任选地,该样品室的大小可含有体积不超过1μL的样品;
置于样品室中的氧化还原介质;和
一个置于传感器中的指示电极,用于指示测定区中何时含有样品,并助于分析物的电解。
31.根据权利要求30的传感器,其中氧化还原介质是一种可扩散的氧化还原介质。
32.根据权利要求30和31任一项的传感器,其中该传感器包含指示测定区中何时开始填充样品的第一个指示电极和指示测定区中何时充满样品的第二个指示电极。
33.根据权利要求30-32中任一项的传感器,其进一步包括:
其上放置有工作电极的第一个基底;
其上放置有对电极的第二个基底;
放置于第一个基底上并与工作电极电连接的工作电极接触垫;
放置于第二个基底上并与对电极电连接的对电极接触垫;和
一个与指示电极电连接的指示电极接触垫,该指示电极和指示电极接触垫放置于第一个和第二个基底之一上,该指示电极接触垫靠近工作电极接触垫和对电极接触垫之一放置;
其中工作电极接触垫、对电极接触垫和指示电极接触垫暴露,用于通过第一个和第二个基底构成的切口区与仪表电连接。
34.根据权利要求30-33中任一项的传感器,其中该传感器含有至少两个放置于传感器中的指示电极,其中这两个指示电极包含第一个对/指示电极和第二个对/指示电极,对电极位于第一个和第二个对/指示电极之间。
35.一种测定样品中分析物浓度的方法,其包括下列步骤:
使样品与权利要求1-34的任一种电化学传感器接触;
在工作电极处产生传感器信号,和
用传感器信号确定分析物浓度。
36.根据权利要求35的方法,其中可扩散的氧化还原介质产生的本底信号不超过:
(a)平均正常生理量的分析物氧化或还原所产生信号的5倍;或
(b)相应于平均正常生理量的分析物的平均偏差之一定量分析物氧化或还原所产生信号的5倍;或
(c)5mM分析物氧化或还原所产生信号的5倍。
37.根据权利要求35-36任一项的方法,其中测定分析物的浓度包括经库仑法用传感器信号确定分析物的浓度。
38.根据权利要求35-36任一项的方法,其中测定分析物的浓度包括经电流分析法用传感器信号确定分析物的浓度。
39.根据权利要求35-36任一项的方法,其中测定分析物的浓度包括经电势分析法用传感器信号确定分析物的浓度。
40.根据权利要求35-36任一项的方法,其中测定分析物的浓度包括经计时电流法用传感器信号确定分析物的浓度。
41.根据权利要求35-36任一项的方法,其中测定分析物的浓度包括经计时电势法用传感器信号确定分析物的浓度。
42.根据权利要求35-36任一项的方法,其中测定分析物的浓度包括经科特雷耳测定技术用传感器信号确定分析物的浓度。
43.根据权利要求35-42中任一项的方法,其进一步包括:
为测量仪器提供关于一批电化学传感器的校准数据,该校准数据包括关于该批电化学传感器的本底电荷数值的信息;
其中测定分析物浓度的步骤包括用传感器信号和校准数据测定分析物浓度。
44.一种测定样品中分析物浓度的方法,该方法包括下列步骤:
使样品与权利要求1-34的任一种电化学传感器接触;
观测显示测定区含有样品的指示电极信号;
在工作电极与对电极之间施加电势,以电解样品中的分析物;
由于样品中分析物的电解,传感器产生分析物反应性信号;和
用分析物反应性信号确定分析物浓度。
45.一种制造权利要求1-34的任一种电化学传感器的方法,该方法包括:
(a)在第一个基底上形成多个工作电极;
(b)在第二个基底上形成多个对电极;
(c)在第一个和第二个基底之一上放置一个间隔层;
(d)除去间隔层的一部分,形成样品室区;
(e)将第一个和第二个基底一起制成薄层;和
(f)将多个电化学传感器从制成薄层的基底分开,每个电化学传感器包含至少一个工作电极、至少一个对电极和至少一个样品室区。
46.根据权利要求45的方法,其中第一个基底是一个基底的第一个区域,而第二个基底是该基底的第二个区域,且进一步包括
折叠该基底,以覆盖该基底的第一个和第二个区域。
47.根据权利要求45和46任一项的方法,其中分开多个电化学传感器包括切开第一个和第二个基底,以分开电化学传感器,并形成电化学传感器的样品室的至少一端。
48.根据权利要求45-47中任一项的方法,其进一步包括在第一个和第二个基底之一上形成多个指示电极。
49.根据权利要求45-48中任一项的方法,其中在将间隔层置于第一个和第二个基底之一上之后除去间隔层的一部分形成样品室区。
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