CN1103488A - 改善电化学传感器性能的技术 - Google Patents

改善电化学传感器性能的技术 Download PDF

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CN1103488A
CN1103488A CN93121405A CN93121405A CN1103488A CN 1103488 A CN1103488 A CN 1103488A CN 93121405 A CN93121405 A CN 93121405A CN 93121405 A CN93121405 A CN 93121405A CN 1103488 A CN1103488 A CN 1103488A
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glucose
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K·W·约翰逊
J·J·马斯特罗托塔罗
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
    • C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/38—Cleaning of electrodes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood

Abstract

一种改善电化学葡萄糖传感器性能的方法，通过 降低其沉积时间又降低其对干扰化合物的灵敏度来 完成。具体地说，利用一种恒定电流密度的负电流来 对工作电极进行预处理以改善电化学葡萄糖传感器 的沉积时间。在测定葡萄糖浓度的过程中通过使传 感器工作在一降低了的电压下来降低传感器对干扰 化合物的灵敏度。

Description

本发明概括地说涉及电化学传感器，特别涉及下述方法，即通过减少其沉积时间并降低其对干扰化合物的敏感程度来改善葡萄糖氧化酶基的电化学传感器之性能。
对于电流测定式传感器的商业化来说，特别是酶化的葡萄糖传感器，其中一个主要的难点就是它的沉积时间。沉积时间是这样一种时间量，即给传感器加上一个初始电势之后，来自传感器的电流输出达到一个稳定值所需的时间。在这段时间中，工作电极和与之相对应的反电极的表面上有一个双电荷层被加上电荷，法拉第反应被建立。
电流测定式的电酶化葡萄糖传感器的沉积时间能够持续几个小时。例如Koudelka（人名，译者注）等人已报道在活体内植入的90分钟沉积时间。参见Koudelka，Rohner-Jeanrenaud，Terrettaz，Bobbioni，Rooij以及Jeanrenaud等人的文章“在活体内皮下植入的微型葡萄糖传感器的性能”（In-Vivo Behavior of Hypodermically Implanted Microfabmcated Glucose Sensors）生物传感器和生物电子学31（1991）。类似地，Velho（人名，译者注）等人也报道了对于一种植入的针型葡萄糖传感器的至少一小时的沉积时间。参见Velho，Sternberg，Thevenot以及Reach的论文”针型葡萄糖传感器在活体外以及在活体内电极电势的稳定性（In Vitro and in Vivo Stability of Electrode Potentials in Needle-type Glucose Sensors）”38Diabetes（糖尿病学）164（1989）。用于活体内的传感器需要2-4个小时的沉积时间，这由Rebrin等人报道，参见Rebrin，Fischer，Woedtke、Abel以及Brunstein的论文“在患糖尿病的狗体上皮下葡萄糖浓度的自动反馈控制”（Automated Feedback Control of Subcutaneous Glucose Concentra-tion in Diabetu Dogs）32 Diabetologia 573（1989）。类似的沉积时间已由其它的研究者观察到并报道。人们可以理解，这样的沉积时间是不利于电流测定式传感器的商用化的，而且这样的沉积时间成为电化学传感器在急救条件下使用的障碍。
根据本发明的一个方面，通过对传感器的工作电极进行预处理，可以减少电酶化葡萄糖传感器的沉积时间。尽管这样的方法在以前未加以说明，但是电极的电化学预处理已知用于其它的目的。例如，电化学方法已经被用于从贵金属电极的表面去除杂质，以提高电极的灵敏度和选择性，并且去除某些化合物的氧化电势。但是，迄今还没有人提议并报道利用这种处理办法对电流测定式葡萄糖传感器进行电化学预处理达到减少其沉积时间的目的。
使用电化学传感器测定某一特定化合物例如葡萄糖的浓度可遇到的另外一个问题是由于体内其它化合物的氧化所造成的“干扰”。例如，在活体内植入时所能遇到的通常的干扰化合物为抗坏血酸、尿酸、半胱氨酸、乙酰氨基苯。这些干扰化合物可能导致一种错误的正向偏移，当对糖尿病病人进行葡萄糖水平计量时，上述正向偏移是不能接受的。
已设计了几种方法以使干扰化合物对电酶化葡萄糖传感器的干扰效果减至最小。例如，在工作电极和覆盖在该电极之上的酶层之间加入一种再生的纤维素膜或一种带负电荷的乙酸纤维素膜。这些膜允许过氧化氢渗透到膜层中，但是由于尺寸和/或电荷相斥这样一些膜特征，抗坏血酸和尿酸干扰化合物是不能通过的。
在另一种技术中使用了两个电极。一个电极用氧化酶覆盖，而另一电极上所述酶被变性或从另一个电极上脱离。这样，通过分析来自两个电极的电流输出的差别可以使源于干扰化合物的电流消失。
这些用于减小传感器对干扰化合物灵敏性的技术不能引起人们的兴趣，因为附加的膜和/或电极会增加制造传感器的成本。另外，引入另外一种膜层去排除干扰化合物将增加传感器的响应时间而且减小了电流输出值。
还有另外一种技术，即引入一种化学物质，它起电子吸收剂的作用，以代替氧，使来自酶的氧化还原中心的电子移到工作电极表面。这种化学物质称为氧化还原介质。这种类型的传感器已被报道为是对氧不灵敏的，能在厌氧环境下起作用。这些化合物具有低的氧化还原势，它减小了电活性化合物的干扰机会。然而，不幸的是这种化合物难以从传感器内部回收，而且，有的还有毒性。
因此，存在着一种需要，即通过减少沉积时间，以及通过改进其能力以在某一所希望的化合物上提供出的精确的数据，而不管干扰化合物的存在，来改善电化学葡萄糖传感器性能的方法。本发明就是针对这种需要开发的。
简短地说，本发明通过减少沉积时间和其对干扰化合物的灵敏度来提供一种改善电化学葡萄糖传感器性能的方法。具体地说，电化学葡萄糖传感器的沉积时间的减少是通过在传感器的电极上施加恒定电流以对传感器的工作电极进行预处理来实现的、电化学葡萄糖传感器对干扰化合物的灵敏度的降低是通过在葡萄糖浓度的测定过程中减小使传感器工作的电压来完成的。
本发明的一个目的是提供一种电化学葡萄糖传感器，它具有减小了的沉积时间。
本发明的另一个目的是提供一种方法，即使用一种电化学葡萄糖传感器的方法，该传感器降低了它对干扰化合物的灵敏度。
本发明的其它目的和优点将由下面的说明来揭示。
图1是根据本发明一个优选实施例的电化学葡萄糖传感器的透视图。
图2是一种未经处理的电极的“正常”沉积时间曲线，它示出的是在37℃温度下100mg/dL的葡萄糖溶液中，在一个未处理的传感器上施加上+0.60V的初始极化电压时的一段时间上的电流输出。
图3是一种经预处理的电极的沉积时间曲线，它说明的是在37℃温度下100mg/dL的葡萄糖溶液中，在一个已处理的传感器上施加+0.60V初始极化电压后一段时间上的电流输出。该传感器在施加电压之前利用一恒定电流（-516nA）进行了两分钟的预处理。
图4是说明被植入一麻醉的猎狗的皮下组织中的已预处理的传感器在施加上+0.60V初始极化电压后一段时间上电流输出的情况。极化之后10分钟注入一种静脉葡萄糖块以显示出传感器的适当功能。
图5说明了在葡萄糖溶液（100mg/dL）和乙酰氨基苯溶液（4mg/dL）中，在37℃下，以5mv/sec的速度从+0.3V到+0.7V扫描时产生的伏安曲线图（Voltammogram）扫描正程部分。用于PBS缓冲剂的背景扫描从每一伏安曲线图中减得。
图6示出的是在所施加的电势的范围内，乙酰氨基苯氧化电流与葡萄糖（过氧化氢）氧化电流之比率的曲线。
图7说明的是在100mg/dL葡萄糖溶液中37℃下一种传感器的电流输出与时间的关系曲线。它说明了当+0.35V的电势被施加时该传感器具有长期性能稳定性。
图8说明的是利用一个传感器在+0.60V电势被施加时，测量到的等离子葡萄糖浓度对皮下葡萄糖浓度的相互关系曲线。
图9说明的是利用一种传感器，在+0.35V电势被施加时所测量的等离子葡萄糖浓度对皮下葡萄糖浓度的相互关系曲线。
为了更好地理解本发明的原理，将参照本发明的优选实施例并用一种具体的语言对此加以说明。然而可以理解本发明的范围并不局限于此，对于本领域的普通技术人员来说，本发明的另外的方案和进一步的改型以及这里介绍的本发明的原理的其它应用都将是可能的。
本发明涉及一种改善电化学葡萄糖传感器性能的方法。其中一个方面是这样的，在一个传感器用于测定液体介质中的葡萄糖之前，利用一电流对该传感器的工作电极进行预处理，由此来减小该传感器的沉积时间。本发明的另一个方面是这样的，通过使该传感器在某一电势下工作来降低该传感器对干扰化合物的灵敏度，所述电势施加在这样的传感器上一般要大大低于+0.6V。本发明的第三个方面是通过接使用上述这两种方法可以改进一种电化学葡萄糖传感器的性能。
用于本发明优选实施例中的电化学葡萄糖传感器是按照下述文献所公开的技术来制作的，所述文献是由Mastrototaro、Johnson，Morff，Lipson、Andrew以及Allen所撰写的“在一柔性基底上制成的电酶化葡萄糖传感器”（An Electroenzymatic Glucose Sensor Fabricated On A Flexible Substrate）B5∶1-4“传感器与激励器”（Sensors and Actuators）139-44（1992），另一文献是由Johnson撰写的“Reproducible Electrodeposition of Biomolecules For The Fabrication of Miniature，Electroenzymatic Biosensors”B5∶1-4“Sensors and Actuators 85-89（1992）。所述的葡萄糖传感器是利用集成电路技术生产的，以便能开发出小型的、可靠的、再生性和生产性强的装置。所述传感器是批量生产的，每批由4个“4×4”的盘片构成，每个盘片有28个传感器。所述的处理方式已由美国专利5，108，819（1992，4，28）公开，有关部分在此也可作参考。处理过程总结如下：
用于所述传感器的基底是杜邦PI-2540聚酰亚氨的50μm厚的层。该层是利用旋涂法在洁净的10cm×10cm玻璃盘片上形成液体聚酰亚氨然后再对所形成的液体层热固化来制成的。这一步骤要重复进行，直到所希望的膜厚达到。可以得到并使用几种具有不同粘度的聚酰亚氨。
铬-金-铬三层是溅射沉积到所述盘片上的，并刻图以形成葡萄糖传感器的传导层。铬可用作金和聚酰亚氨之间的粘合促进剂。采用标准的光刻工艺将该金属层刻图。一旦该三层金属刻图后，第二个光刻步骤即被采用以去掉铬，并且，将在电极将要被安置的位置上下伏的金层暴露出来。所得到的层由刻图后的金属化构成以形成28个葡萄糖传感器的铬-金-铬导体，每个传感器具有三个金电极。
然后，所述盘片再覆盖上1.2μm厚的可光致成象的聚酰亚氨绝缘层（杜邦PI-2703D），该层经刻图以暴露出下伏的金电极的有源区域。该聚酰亚氨是以液态方式旋涂在每一盘片上的。然后，它再被预烘干、暴露在UV光使该层构成图形，喷雾显影，冲洗并热固化。
所述的盘片被浸泡在去离子蒸馏水中8-24个小时，以从玻璃盘片上去除传感器片。通过使水加热沸腾能加速上述处理过程。一旦传感器片完全从盘片上脱离开，就可将传感器片切成4个四分之一片，其中每片含7个传感器。然后对传感器进行显微观察，以确定哪些传感器在结构上是完善的。具有缺陷的传感器要再经过适当的处理，并且，不对其施行下面的电镀处理。
传感器的工作电极和相对的电极要被电镀上Pt黑，参考电极要被镀上Ag/AgCl。然后，采用下面将要说明的电沉积技术，使葡萄糖氧化酶可重复地沉积到工作电极上。这一技术由美国专利5，166，063公开（1992，11，24），相关部分可以在此引用。牛类的血清白蛋白同时被沉积上，它能使所得到的沉积层更稳定。该层在戊二醛溶液中被交链，整个传感器被覆盖上一层具有不同渗透性和生物适应性的外膜。这种专用的膜具有相对于葡萄糖而言对氧更大的渗透性，渗透性要强于葡萄糖2-3个数量级，所以，补偿了“氧效应”。这个膜可以在一种溶液中溶解，再被旋涂在传感器片上，在空气中干燥。
制备基本的传感器的最后一个步骤是将各个传感器切割开来。目前，每个传感器都是经人工散解剖刀将传感器片切开的。传感器最终的形状是：传感器的植入部分大约为2.5cm长，0.28mm宽，0.06mm厚。
为了电沉积酶以使其覆盖在电极上，要制备5%（重量）的葡萄糖氧化酶溶液，采用磷酸盐缓冲液体作为溶剂（pH＝7.4）。当将葡萄糖氧化酶溶解于其中并搅拌时，特别要注意防止泡沫的形成，因为这会使葡萄糖氧化酶发生变性，然后，在电沉积槽中注满上述这种溶液，两个电极，一个是将要在其上沉积酶的电极，一个是相对的反电极，都要浸放在槽中。电路是恒电流式的，所施加的电流的恒定电流密度在电极表面上为5mA/cm2。电流的流向是使电极表面的正电荷去吸引带负电荷的葡萄糖氧化酶分子。通电两分钟。在工作电极上的实际的电压随电阻而波动。然后将电极从酶溶液中移出并浸没在去离子蒸馏水中，不搅拌浸泡5秒钟，从而可去除残留的葡萄糖氧化酶。接下来，所述电极被浸泡到含2.5%（体积）戊二醛的磷酸盐缓冲剂溶液中（pH＝7.4）约30分钟，以使葡萄糖分子以共价键方式交链在一起，形成一个不溶水层（water-insoluble layer）。戊二醛的交链作用防止葡萄糖氧化酶回到溶液中。电极然后再被浸泡到去离子蒸馏水中5秒钟，再置于空气中干燥30分钟。生物传感器的酶成份这时即可起作用。
按照本发明的一个方面，所述传感器的工作电极要被预处理，也就是说，一旦电极被置放到它将要对其进行测试的环境中，就要向电极施加电流以进行预处理。在使用传感器对所感兴趣的物质的浓度进行测量之前，要在传感器的一个或多个电极上施加控制电流，所述电流所施加的电流密度及所施加的时间要能大大地减小电极的沉积时间，一种优选的方案是以恒定的电流密度施加恒定电流，但是，电流密度随施加电流的时间有些细微的变化也是可以接受的，而且可使用脉冲式电流、斜坡式电流和循环电流。
要对电流的时间和数量加以选择，以使沉积时间相对于不经预处理的沉积时间来说得以减少。一般来说，沉积时间的至少20%的减少是特别期望的。对于某些传感器来说，实际获得沉积时间的减少程度会更大。沉积时间的任何减少都是有效的，因此这也是本发明所祈盼的。下面要进一步地说明，在某些实例中，沉积时间从2-3小时减少到5-10分钟。沉积时间的这些减少在急救环境中是特别重要的。在例如这样的情况下，即在某些疑难问题中要采用特定的传感器，例如特定传感器的操作或它要恰如其分地置放在组织中，那么，沉积时间的减少也是特别重要的。在另外一些情况下，沉积时间从大约24小时减小到1小时也是十分有利的。
在目前的实验中，较好地是采用负电流，并且以恒定密度施加电流，负电流的密度在约0.1mA/cm2和约1.0mA/cm2之间是较好的。在迄今所使用的传感器中，利用电流密度大约为0.5mA/cm2的负电流是最好的，施加电流的时间大约在1分钟到10分钟之间，两分钟的预处理时间是最好的。
当这种恒电流法预处理被执行时，已预处理的传感器的沉积时间可从2小时减到10分钟。沉积时间的减少在急救情形下是特别有价值的，因为这急救情形下2小时的沉积时间是不可以接受的。
本发明的另一个方面，是使用一种电势来使一种电化学葡萄糖传感器工作，所述电势大大地低于通常在这种传感器上使用的0.6V。已经发现，使用大约0.3V和0.4V的电势使传感器工作将大大地减少了由于化合物（例如乙酰氨苯）的氧化所产生的电流，因此，可以使体内这些化合物所造成的干扰减至最小，同时不对葡萄糖反应值造成显著影响。
下面引用的特定实施例均采用了上述方法。人们可以理解这些实施例对于本发明提供更完整的说明，但本发明并不局限于此。
例1
一个未处理的电化学葡萄糖传感器按下列步骤估计出它们的“正常”沉积时间。在这个例子中，是在活体外测定传感器的沉积时间的。
按照前面已讲述的方法，在一个洁净的室内环境下制备出所述的葡萄糖传感器。所得到的传感器有铂黑工作电极和反电极，以及一个Ag/AgCl参考电极。工作电极的表面积大约为0.1mm2。葡萄糖氧化酶以及牛的血清白蛋白的层厚约为5μm，它们是用电沉积法形成在工作电极的表面上并且用戊二醛进行交链的。
一种专用的外膜材料被覆盖在三个电极表面上。然而本发明并不限制于一种膜或任何一特定的膜的使用，这里所选择的膜仅仅是被选出来用在这个实例中的电极上。
所述外膜是均匀的膜，对氧和葡萄糖有渗透性，并且，由聚氨基亚酸乙酯构成，是由二异氰酸、聚环氧乙烷及脂族二烯反应的产物。这种类型的膜在美国专利申请07/771，658（申请日：1991，10，4）中已作说明，该申请题为“亲水的聚氨基亚酸乙脂膜用于电化学葡萄糖传感器”。这篇文献中的相关部分在此可作为参考。这种聚合物能够吸收重量为其干燥时重量的10-50%和水，而且对氧的扩散系数与对葡萄糖的扩散系数之比值最大为4000。
所有活体外实验都在37℃下保持在“Polystat”（商品名称，译者注）浸泡或循环机中和水浴中进行的。所得到的输出要么记录在双通道的刻度纸记录器上，要么由个人计算机收集和存储，该个人计算机包含能进行模/数（A/D）转换的数据采集区。所述数据同时被显示在监视器上并利用一种普通的软件包使之存储在硬盘中。
所有的活体外侧试都利用磷酸盐缓冲剂（PBS）作为辅助电解质溶液。该溶液在25℃下pH值为7.4。叠氮化钠，1.5mM，被加到该PBS溶液中作为一种杀菌剂。由右旋糖制成的葡萄糖储备液（10，000mg/dl）并允许在使用前进行一液的变旋作用。一部分储备液被加入到PBS中以产生葡萄糖浓度为100mg/dl的溶液，它接近于正常的生理水平。用于活体中浸渍的无菌葡萄糖溶液（0.5g/ml）被用作接收剂。
为了测试未经处理的传感器的正常沉积时间，要将一个传感器放入到一种葡萄糖溶液中并且在该传感器上加上电势。电流对时间的变化被记录下来并且作出了如图2所示的曲线。更具体地说，测试是在37℃下100mg/dL浓度的葡萄糖溶液中进行，所加电势为+0.6v，正如前面所指出的那样，这种葡萄糖浓度近似于正常的生理水平，所述电势也与通常应用在这种传感器上的电势是一样的。
图2是传感器被初始极化后传感器的电流输出对时间的变化曲线。从曲线中可以看出，当施加的电势为+0.6V时，传感器整个的沉积时间约为1.5小时。另外的一些其制备方法与图2的传感器相同的传感器已经发现当它们被植于猎狗、兔子和人的皮下组织中时，所需的沉积时间为2-4小时。
例2
按照下面的程序制备一种电化学葡萄糖传感器以减少沉积时间。在这个例子中，在活体外测定预处理的效果。
所述的葡萄糖传感器按前面的步骤来制备。其它的装置和试剂也如例1所述的那样被提供。
为了进行恒电流预处理，当传感器放入葡萄糖溶液中时要在传感器上施加2分钟的恒定电流。然后立即在传感器上加上电势，并确定沉积时间。具体地说，在传感器加上电势之前，用电流密度大约为-0.5mA/cm2（-516nA）的恒定电流对传感器处理2分钟，该测试是在37℃下100mg/dL的葡萄糖溶液中进行的，电极被预处理之后，加上+0.6V的电势。
图3是预处理电极的沉积时间曲线。它显示出在+0.6V的初始极化之后的一段时间上电流输出的变化。从曲线中可以看出，预处理传感器在100mg/dL的葡萄糖溶液中的沉积时间少于10分钟。
在恒电流法预处理之后，基于传感器的沉积时间，使施加到传感器上的电流量和电流流动的方向选择最优方案。在整个研究过程中，在工作电极上施加电流的时间长度一律为2分钟，已发现，当所施加的电流为负的时，预处理有效。用于实验中的电势恒定器/电流恒定器都遵循美国的极性转化，即工作电极是阳极。在预处理过程中，反电极被用作为阴极。在工作电极上施加负电流的有益效果是合乎逻辑的，因为，当正电势加到传感器上时，工作电极也是阳极。反之，可以假设，如果一个传感器是基于工作电极上的还原反应，例如一个克拉化氧电极，那么采用正电流进行恒电流预处理将会是有益的。
电流密度也可根据所测试的传感器的性能进行优选。5.0mA/cm2的密度已被认为对于这种传感器来说是太高了，会引起金属导体的波痕。已观察到的有益效果是电流密度为0.5mA/cm2施加约2分钟时间，如图2所示。
例3
按照下列程序制备电化学葡萄糖传感器以减少沉积时间，在这个例子中，在活体中测定预处理的效果。
按照前面讲述的步骤在一个洁净的室内制备葡萄糖传感器。如前文中活体外的实例所述的一样，也要提供一些其它的装置和试剂。
用在这些研究中的动物样本是有目的饲养的杂种猎狗（16-22Kg）。一个静脉管和一个动脉管采用外科手术被植入动物体中，静脉管输液时用，动脉管用于提取血样以供分析，在传感器植入期间以及技术的执行过程中，猎狗用戊巴比妥钠（Sodium pentobarbitol）麻醉。
传感器在植入活体中之前，要将它放入到一个双腔聚乙烯管10的一个腔中，管10有一个已热密封的顶端11。在管10的壁上已切出一个开口12，以便当传感器植入后，能向传感器周围的组织暴露出它的电极13、14和15的有源表面（图1）、管10的第二个腔内填充进一片27个刻度的针套用于植入期间所需的刚性。整个传感器组装件用强度为2.5MRad的电子束辐射以消毒。
传感器被植入到猎狗的不重要部位的皮下。一个18刻度的针（3.8cm长）被插入到皮下组织中并立即取出以产生一个用于传感器的通道。传感器插入到这个通道之后，27刻度的针套从管上取出，传感器被埋在皮肤中。一个专用的连接器用来与传感器的三个导线实现电连接。
植入之后，在工作电极上施加2分钟的-500nA电流（0.5mA/cm2）。预处理之后，立即在传感器上施加+0.6V的电势。传感器的沉积时间少于5分钟，如图3所示。
一旦传感器被沉积，通过静脉注入一些无菌葡萄糖溶液（按每公斤猎狗体重50g葡萄糖计算）以计算出猎狗的血液葡萄糖浓度，从而显示出适当的传感器功能。图4说明了所述传感器的适当的功能。传感器从猎狗体内取出后所作的显微分析表明所述的处理无有害的效果。具体地说，没有观察到导体的剥落或膜起泡。这一过程在猎狗体中利用24个传感器成功地重复进行，并且另外有4个传感器是在兔子体内完成的。在所有情况下，对预处理的传感器来说，所观察到的沉积时间少于15分钟。
从前面的例子中可以看出，在向传感器上施加恒定电势之前施加一恒定电流，可以缩短传感器的沉积时间。可以假设这一有益效果是由于在未经处理的传感器的沉积过程中有一个恒定的电势加在其上造成了电流的指数衰减，例如，通过未处理传感器的工作电极的电流显著地小于在恒电流处理步骤中通过比较的传感器的工作电极的电流。具体地说，从图2中可以看出，在极化后的头两分钟，在未处理传感器的工作电极上测得的电流量远远地小于在预处理步骤的2分钟内施加在比较电极上的电流量500nA。在工作电极表面的电流量似乎控制着双层形成的速率以及电极被极化的速率。
人们也能观察到用同样的方法制备和预处理的传感器当它用在活体内和活体外时在沉积时间上的差别。例如图3示出的是恰恰低于10分钟的活体外沉积时间，而对于植于猎狗体内的同一传感器其沉积时间大约为5分钟（图4）。可以假设这种差别是由于在不同环境中的各个电极之间的电阻的差别所致。
根据本发明的另一方面，所述的电化学葡萄糖传感器在一个已降低的电势下工作，以使干扰化合物的影响减至最小。尽管葡萄糖传感器一般地说工作在+0.6V的电势下，但是，在这样的电势下可以观察到由化合物的氧化所产生的干扰电流，而不是所感兴趣的物质的电流。所以，研究出使用电化学传感器的某种方法是有好处的，这种方法能使由于干扰化合物的氧化所产生的电流减至最小，而且不会使传感器对葡萄糖的灵敏度降低。因此，在本发明的第二方面，传感器工作在低于+0.4V的电势下，以使干扰化合物（例如乙酰氨基苯）的氧化降到最小程度，同时人们可以看出，尽管传感器对乙酰氨基苯的氧化物的灵敏度大大降低，但不会在此方法中降低传感器对葡萄糖氧化物的灵敏度。
例4
一种电化学葡萄糖传感器工作在降低了的电势下以使干扰化合物的影响减至最低，具体来说，本技术提供了一种能力，以使乙酰氨基苯的影响减到最小程度。在这个例子中，该技术的效果在活体外得以检测。
按照前面所述的方式制备葡萄糖传感器。如前述的实例所说明的那样，也要提供一些其它的设备和试剂。
所有活体外实验都是这样进行的，即将传感器放入充满PBS溶液的100mL烧杯中，烧杯被浸放在37℃恒温水浴中。通过在PBS中渗入浓缩的葡萄糖溶液和乙酰氨基苯溶液，从而制备出浓度为100mg/dL的葡萄糖溶液和浓度为4mg/dL的乙酰氨基苯溶液。这种浓度的葡萄糖溶液一般等于通常的生理葡萄糖水平，而乙酰氨基苯的浓度是正常生理水平的两倍。
首先，在PBS溶液中和葡萄糖溶液中使用+0.6V和+0.35V电势的条件下检测出传感器的电流输出。表1示出的是在每一种电势下或者每一种溶液浓度变化时，在足够长的时间沉积之后两种电化学葡萄糖传感器的电流输出，这一研究表明，上述传感器的电流输出近似地等于在100mg/dL葡萄糖溶液中的电流输出。这说明低于+0.35V的施加电势仍处在过氧化氢的电化学氧化波的平顶处。
表1
传感器  施加电势  PBC37℃  100mg/dL的葡萄糖
溶液37℃
623A2  +0.60V  1.0nA  12.1nA
+0.35V  0.5nA  12.5nA
623A3  +0.60V  -  14.2nA
+0.35V  -  14.7nA
表1说明了对于施加+0.6V和+0.35V电势的传感器之一来说，在37℃下PBC溶液中的基线电流（baseline current）。可以用欧姆定律来解释在+0.35V电势下所观察到的较小电流。
为了进一步了解在+0.35V电势下所能观察的正确的结果，可使用一种循环式伏安卷表以选出最佳电势值。图5说明了两种溶液的扫描正程部分的伏曲线图，这两种溶液分别为生理葡萄糖溶液和其浓度两倍于生理水平的乙酰氨基苯溶液。较高浓度的乙酰氨基苯的使用是为了使电流信号能得以放大，并模拟可能的治疗学上的惯用水平。源自PBS溶液的基线伏安曲线图已从源自葡萄糖和乙酰氨基苯的伏安曲线图中减除。
所述的伏安曲线图说明了用于葡萄糖氧化物的所希望的平顶以及在较大施加电势下由于乙酰氨基苯氧化所致的增加的电流电平。
通过考察乙酰氨基苯氧化物电流与葡萄糖氧化物电流之比率作为所施加电势的函数，可以完成最佳电势的选择以检测葡萄糖和使干扰化合物，具体地说，乙酰氨基苯的影响减到最小。图6说明了上述比率，当施加电势从+0.3V变化到+0.7V时，从这个曲线中可以看出，当施加电势为+0.6V时产生于干扰化合物的氧化的电流多于施加电势为+0.35V时的同种电流。然而，在较低电流电平的情况下，例如低于+0.4V时，乙酰氨基苯的氧化所产生的电流并不是明显地大于葡萄糖的氧化所产生的电流。因此，这个曲线仅仅示范出使用低于+0.4V电压以使其它化合物的干扰减到最小这样的用途。
在传感器的72小时预期寿命下其功能的长期稳定性也是其性能的一个考察指标。传感器的长期稳定性，无论在活体内还是活体外，对于单独的测定都是必要的，以使其在整个研究阶段都是精确的。但是，人们并不期待在传感器的预期寿命中没有漂移被观察到，而是希望这些漂移发生在合理的和能预知的范围内。对于一个其上施加+0.60V电势的电化学葡萄糖传感器的长期漂移已预知在72小时的检测阶段低于5%。
例5
为了说明工作在+0.35V电势下的传感器的长期稳定性，一个传感器被浸放在37℃下的葡萄糖溶液中，并且在+0.35V的施加电势下工作90小时。在这段时间上可观察并记录下传感器的长期漂移。
图7示出了上述工作状态下的传感器的电流输出。从曲线上可以看出，在上述条件下的传感器的长期漂移小于5%，这样的长期漂移在可接受的范围内，该曲线还说明Ag/AgCl参考电极的电势的漂移实质上不能使源于过氧化氢氧化的平顶的工作电极的“实际”电势移动。如果所述漂移足以使源于过氧化氢的平顶的工作电极的电势移动，那么可以从传感器的输出中看到负漂移。
在下面的实例中，一个电化学葡萄糖传感器工作在降低的电势下，以使干扰化合物的影响降到最小程度，具体地说，该技术具有使乙酰氨基苯的干扰影响减到最小程度的能力。在这些例子中，该技术的效果在活体内进行检测。
用于这一研究的动物本是新西兰的白兔。采用外科手术将一个静脉管和一个动脉管植入白兔体内，静脉管用于输液，动脉管用于提取血样以供分析。在插入传感器之前允许动物苏醒过来，以便在植入部分的选择上找到正常的姿态。
传感器植入之前，要将它放到一个双腔聚乙烯管的一个腔中，该管的顶端已预先热密封。在管壁上切出一个开口，以使传感器植入后，传感器的活性电极表面能暴露给周围的组织（参见图1）。该管的另一个腔内放入一个27刻度的针套以使在植入过程中有足够的刚性。
所述传感器被植入肩胛骨之间的皮下组织上，或者植入接近于最尾部肋骨的腰部肌肉群的上方。在插入传感器之前，植入的部位要作局部麻醉，用利度卡因盐酸盐作局麻。一个18刻度的针（3.8cm长）被插入到皮下组织中并立即取出以产生一个用于传感器的通道。在传感器插入到这个通道之后，27刻度的针套从管中取出，传感器置放在皮肤中。在传感器植入以及数据采集期间，白兔保持在被抑制状态。
一种专用的连接器用来完成与传感器的三个导线的电连接。其上或施加+0.6V的电势，或加上+0.35V的电势。在这一实例中，不采用预处理步骤，在初始极化后允许传感器有近2个小时的沉积。这就提供了足够的时间用于局部麻醉的消退。
在每一次葡萄糖输入研究的整个过程中，在15分钟间隔就采集一次动脉血样。所得到的样本经离心处理后，可以确定所得到的等离子葡萄糖浓度、在血样采集的时刻传感器的电流输出可以被记录下来用于进一步分析，以两种不同的速率不断地进行无菌葡萄糖溶液的静脉注射，可以计算出白兔的血液葡萄糖浓度，这两个速率为15mg/kg/min以及30mg/kg/min。
仅仅由于干扰化合物的氧化所致的传感器中的电流实际量可以在植入活体内之前通过使传感器上的葡萄糖氧化酶变性来确定。如果将酶浸在沸水浴中5分钟，酶就失去了活性。活性的失去可以通过活体外实验（在生理葡萄糖溶液进行）来证实。乙酰氨基苯对这种传感器的影响可以通过一个胶块的注入来测试，所述胶块（bolus）使白兔达到约15mg/dL葡萄糖浓度。这种水平的葡萄糖浓度差不多是正常生理水平的七倍。
例6
传感器在活体内的性能可以通过将一个已（在活体外）预校定的传感器植入到白兔的皮下组织中来估算。在正常的、基础的葡萄糖浓度水平下可以建立一种稳定的电流输出，然后将一种已浓缩的葡萄糖溶液注射进去以估算出血液的葡萄糖水平。利用所述从体外测试得到的校准方程，可以将来自皮下组织中的传感器的电流转换成视在的活体内葡萄糖浓度。然后，等离子葡萄糖浓度与采集血样时传感器所指示的视在的葡萄糖浓度相关联。
图8示出的是从施加电势为+0.60V的传感器上得出的等离子葡萄糖浓度与视在的葡萄糖浓度的关系曲线。对于三个变量中的两个变量，传感器的性能似乎是可以接受的，其斜率近似等于1.0（m＝0.97），其响应完全是线性的（R2＝0.98）。然而不幸的是由Y截距值（b＝30.98mg/dL）示出一个正偏差。这一偏差将导致对生理葡萄糖水平（100mg/dL）而言的约30%误差，比多数临床视为可接受的10%的误差明显大得多。
图9是与图8相似的关系曲线，只是施加电势为+0.35V。这个实验所用的白兔与用于图8的数据产生所使用的兔子完全相同，所以可以假设在体内干扰化合物的浓度在每一实验中是相似的。这个传感器活体的性能是可以接受的，因为其偏差（Y截距）减小到3mg/dL，同时，其线性关系和接近1斜率也得以保留，这个实验指出：不使用附加的排斥膜、电极、酶或介质，体内干扰化合物的氧化所致的电流能降低到一个可以允许的水平。另外，利用证明有效地并且精确地监测皮下组织的葡萄糖值的传感器来测定皮下组织中等离子葡萄糖值和葡萄糖浓度的关系将是最佳的。
实例7
为了验证这一假设，将与前面的实验中所使用的传感器一致的传感器放入到沸水中以使葡萄糖氧化酶变性。这一处理过程说明了酶的活性失去，并且传感器的电流全不是由于葡萄糖所产生的，取而代之的是电流输出全部是来自于背景和干扰氧化电流。
表2示出的是一种其葡萄糖氧化酶层失去活性的传感器的活体内输出电流。用+0.60V电势产生的基线电流高于通常在PBS中所见到的活体外基线电流值（表1），可认为近似于3.5nA的差是由于工作电极上的干扰物的氧化所致。反之，当施加电势减到+0.35V时，同一传感器具有0.6nA的电流输出。这一电流值差近似等于表1所示的+0.35V下PBS中活体外的基线电流值，这证实了降低施加电势可以降低由于干扰物的氧化的影响和所形成的误差。
表2
施加电势  基线电流  来自乙酰氨基苯块的电流
增加(15mg/dL)
+0.60V  4.5nA  9.0nA
+0.35V  0.6nA  0.5nA
实例8
通过向白兔的静脉管中注射乙酰氨基苯酸块并监测传感器的响应可以得到更多的证据。所述胶块（bolus）使白兔体内乙酰氨基苯的浓度增加约15mg/dL，大约是正常生理水平的七倍。考虑到一部分药在扩散到皮下组织之前会有代谢，所以注射的药量要大一些。如表2所示，对于两种施加电势值而言，同样的乙酰氨基苯的注入会使传感器电流输出的增加完全不同。对于+0.6V施加电势值而言，由于乙酰氨基苯胶块所致的电流增加大约是18倍于+0.35V施加电势的传感器上测得的电流增加。
上面的实例说明通过使施加电势从+0.6V减到+0.35V，对于设计用于活体内的测电流式电酶化葡萄糖传感器而言，干扰化合物的影响可以被大大降低，而不影响传感器对葡萄糖的响应。这一过程的完成不需要其它的膜层、电极、酶或介质。活体外进行的实验说明这一技术对于减少乙酰氨基苯的影响是有效的。活体内实验，它实际上包括了所有生物体存在的干扰物，也取得了同样的结果。
在上述实施例中所述的本发明在应用中可以有多种改型，但都忠实于本发明的基本思想，因此，当在实例中详细地说明本发明时，同样可理解为不是对本发明的限定。人们可以懂得这里仅仅示出并说明了优选的实施例，在本发明精神下的所有变化和改型都是本发明所希望保护的。

Claims (31)

1、降低一种含一个或多个电极的电化学传感器的沉积时间的方法，包括：
预处理该电化学传感器：使用该传感器去测量所感兴趣的物质的浓度或存在之前，将传感器放入一种介质中，通过在传感器的一个或多个电极上施加一控制电流来对该传感器进行预处理；其中，按某一密度施加控制电流，施加电流的时间要足以使电极的沉积时间显著减少。
2、根据权利要求1的方法，其中预处理包括施加一恒定电流。
3、根据权利要求1的方法，其中电流被施加，以使电极的沉积时间减少到少于15分钟。
4、根据权利要求1的方法，其中在所述的预处理过程中，所述的电流密度是约0.1mA/cm2和约1.0mA/cm2之间的一个恒定的电流密度。
5、根据权利要求4的方法，其中在所述的预处理过程中，所述恒定的电流密度大约为0.5mA/cm2
6、根据权利要求1的方法，其中在所述的预处理过程中，以恒定电流密度所施加的电流施加时间大约为1分钟到10分钟。
7、根据权利要求6的方法，其中在所述的预处理过程中，以恒定电流密度施加的电流大约施加2分钟。
8、根据权利要求1的方法，其中所述电流是负电流。
9、测量液体介质中葡萄糖浓度的方法，包括以下步骤：
使含葡萄糖的介质与具有电极的一电化学传感器接触;
通过在电极上以电流密度施加一控制电流来对电极预处理，电流施加的时间要足以使电极的沉积时间显著减少;接着
在电极上加上一恒定的电势使传感器工作;
当H2O2从电极上的葡萄糖、氧和水中产生时测量电流变化的速率;以及
将电流变化速率转换成葡萄糖浓度值。
10、根据权利要求9的方法，其中预处理包括施加一恒定电流。
11、根据权利要求9的方法，其中电流的施加要足以使电极上的沉积时间减少到少于15分钟。
12、根据权利要求11的方法，其中在预处理过程中，电流密度是0.1mA/cm2到1.0mA/cm2之间的某一恒定电流密度。
13、根据权利要求12的方法，其中在预处理过程中恒定的电流密度大约为0.5mA/cm2。
14、根据权利要求11的方法，其中在预处理过程中，电流以恒定电流密度施加大约1分钟到10分钟。
15、根据权利要求14的方法，其中在预处理过程中，电流的恒定电流密度施加大约2分钟。
16、根据权利要求11的方法，其中电流是负电流。
17、根据权利要求11的方法，其中电化学传感器包括一个铂黑工作电极、一个铂黑反电极以及一个Ag/AgCl参考电极。
18、测定液体介质中葡萄糖浓度的方法，包括下列步骤：
使含葡萄糖的介质与一个电化学传感器接触，该传感器具有一个工作电极、一个反电极和一个参考电极;
在工作电极上施加大于0.10V小于0.40V的电势;
当H2O2从传感器的工作电极上的葡萄糖、氧和水中产生时，测量电流变化的速率;
将电流变化速率转换成葡萄糖浓度值。
19、根据权利要求18的方法，其中所施加的电势大约为+0.35V。
20、根据权利要求18的方法，其中含葡萄糖的介质也包含干扰化合物。
21、根据权利要求20的方法，其中含葡萄糖的介质也包含乙酰氨基苯作为干扰化合物。
22、根据权利要求18的方法，其中工作电极是阳极，反电极是阴极。
23、根据权利要求18的方法，其中工作电极和反电极是铂黑的，参考电极是Ag/AgCl。
24、测定在一液体介质中的葡萄糖浓度的方法，包括以下步骤：
使含葡萄糖的介质与具有电极的电化学传感器接触;
通过将某一电流密度的控制电流加到电极上来对电极进行预处理，电流施加的时间要足以使电极的沉积时间显著下降，接着
在该传感器的工作电极上施加大于0.1V小于0.40V的一个恒定电势以使传感器工作;
当H2O2从传感器的工作电极上的葡萄糖、氧和水中生成时，测定电流变化的速率;
将电流变化速率转换成葡萄糖浓度值。
25、根据权利要求24的方法，其特征在于预处理包括施加一恒定的电流。
26、根据权利要求24的方法，其中电流被施加以使电极的沉积时间下降到少于15分钟。
27、根据权利要求24的方法，其中在所述的预处理过程中，电流密度是一种在约0.1mA/cm2和1.0mA/cm2之间恒定的电流密度。
28、根据权利要求27的方法，其中在所述的预处理过程中，恒定的电流密度大约为0.5mA/cm2。
29、根据权利要求24的方法，其中在所述的预处理过程中电流以恒定电流密度施加大约1分钟到10分钟。
30、根据权利要求24的方法，其中所施加的电势大约为+0.35V。
31、根据权利要求24的方法，其中工作电极有葡萄糖氧化酶沉积在其上。
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