CN1639206A - 由含有杂环氮的聚合物组成的生物传感器膜 - Google Patents

由含有杂环氮的聚合物组成的生物传感器膜 Download PDF

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CN1639206A
CN1639206A CNA028133331A CN02813333A CN1639206A CN 1639206 A CN1639206 A CN 1639206A CN A028133331 A CNA028133331 A CN A028133331A CN 02813333 A CN02813333 A CN 02813333A CN 1639206 A CN1639206 A CN 1639206A
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polymer
electrochemical sensor
crosslinking agent
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毛飞
赵炫
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Therasense Inc
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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Abstract

描述了新的膜，其包括含有杂环氮基团的各种聚合物。这些膜可用于电化学传感器，诸如电流生物传感器。更具体地讲，这些膜有效地调节在电化学传感器中分析物向测量电极的迁移，从而在重要的分析物浓度范围内改进了电化学传感器的功能。还描述了装备有这类膜的电化学传感器。

Description

由含有杂环氮的聚合物组成的生物传感器膜
发明领域
本发明一般地涉及分析物-迁移(flux)-限制膜。更具体地讲，本发明涉及由含杂环氮聚合物组成的膜。所述的膜是在生物传感器中的一个有用组件，特别是用于可以植入活体的生物传感器中。
发明背景
基于酶的生物传感器是这样的设备，其中基于分析物浓度的生物化学反应信号被转化为一个可测量的物理信号，如光信号或电信号。这类生物传感器在临床、环境、农业和生物工艺学应用中被广泛用于分析物的检测。在人体体液的临床分析中可测量的分析物包括例如葡萄糖、乳酸盐、胆甾醇、胆红素和氨基酸。检测在生物液体——如血液——中的分析物对于许多疾病的诊断和监测是很重要的。
人们非常感兴趣的是通过电信号测定分析物的生物传感器，诸如借助于电流(电流生物传感器)或电荷(电量生物传感器)的生物传感器，因为在许多重要的生物分析物的生物化学反应中涉及到了电子转移。例如，葡萄糖与葡萄糖氧化酶的反应涉及从葡萄糖到所述酶的电子转移，生成葡糖酸内酯和还原的酶。在电流葡萄糖生物传感器的一个实例中，葡萄糖在体液中通过葡萄糖氧化酶-催化反应被氧气氧化，形成葡糖酸内酯和过氧化氢，于是过氧化氢被电氧化，并且与体液内葡萄糖的浓度相关联(Thomé-Duret，V.等，Anal.Chem.，68，3822(1996)；和Van Antwerp.的US5882494)。在另一个电流葡萄糖生物传感器的实例中，葡萄糖到葡糖酸内酯的电解氧化由聚合的氧化还原介体调节，该介体在电子上将所述酶的反应中心连接到电极上。参见Csregi，E.等，Anal.Chem.，66，3131(1994)；Csregi，E.等，Anal.Chem.，67，1240(1995)；Schmidtke，D.W.等，Anal.Chem.，68，2845(1996)；Schmidtke，D.W.等，Anal.Chem.，70，2149(1998)；和Schmidtke，D.W.等，Proc.Natl.Acad.Sci.U.S.A.，95，294(1998)。
电流生物传感器通常使用两个或三个电极，包括至少一个测量或工作电极和一个参考电极。在双电极系统中，参考电极也用作对电极(counter-electrode)。在三电极系统中，第三电极是一个对电极。所述测量或工作电极由抗蚀的碳或金属导体组成，通过一个回路——诸如一个恒电位器——连接到参考电极。
一些生物传感器被设计成植入活动物体内的形式，仅作为例子，诸如植入哺乳动物或人体内。在可植入电流生物传感器中，工作电极通常由传感层构成，其与电极的导电材料直接接触，在传感层的顶部有一个扩散-限制膜层。所述传感层通常由酶、酶稳定剂——如牛血清白蛋白(BSA)——和交联传感层成分的交联剂组成。或者，所述传感层由酶、聚合的介体和交联传感层成分的交联剂组成，如在上述的导线-酶(wired-enzyme)”生物传感器中。
在可植入电流葡萄糖传感器中，为了调节或限制葡萄糖向传感层迁移，膜通常是有利的或必要的。作为说明，在无膜葡萄糖传感器中，葡萄糖向传感层的迁移随着葡萄糖的浓度线性增加。当达到在传感层的所有葡萄糖耗尽时，测量的输出信号与葡萄糖的迁移成线性正比，因此与葡萄糖浓度成线性正比。但是，当在所述传感层葡萄糖的消耗被化学动力学或电化学活性所限制时，测量的输出信号不再由葡萄糖的迁移控制，从而不再与葡萄糖的迁移或浓度成线性正比。在这种情况下，在传感器变得饱和前，到达传感层的葡萄糖只有一小部分被消耗，于是测量信号停止随着葡萄糖的浓度增强，或只有稍微的增加。另一方面，在装备有扩散-限制膜的葡萄糖传感器中，所述膜降低了葡萄糖向传感层的迁移，从而传感器没有变得饱和，因此可在更宽的葡萄糖浓度范围内有效地操作。
更具体地讲，在这些装备了膜的葡萄糖传感器中，葡萄糖消耗率是由通过所述膜的葡萄糖的扩散或迁移控制，而不是由传感层的动力学控制。葡萄糖通过所述膜的迁移由膜对葡萄糖的渗透性——通常是恒定值——和被监测溶液或生物液体中的葡萄糖浓度确定。当所有到达传感层的葡萄糖耗尽时，葡萄糖通过所述膜向传感层的迁移随着葡萄糖在溶液中的浓度线性变化，并决定了测量的转换速率或信号输出，从而其也与溶液中葡萄糖的浓度成线正比。虽然不是必要的，但是在输出信号和溶液中葡萄糖浓度之间的线性关系对于可植入传感器的校准是理想的。
如上所述，基于过氧化氢电解氧化的可植入电流葡萄糖传感器需要过量的氧反应物，以保证传感器输出只受到被监测的体液或组织中葡萄糖浓度的控制。即，传感器被设计成不受通常存在于体液或组织中的氧气的影响。在通常植入葡萄糖传感器的体组织中，氧气的浓度可能非常低，诸如从约0.02mM到约0.2mM，而葡萄糖的浓度可高达约30mM或以上。在没有葡萄糖扩散-限制膜的情况下，传感器将在非常低的葡萄糖浓度非常迅速地变得饱和。因此，所述传感器得益于具有足够氧气-可透性的膜，所述的膜限制了葡萄糖迁移到传感层，因此减少或消除了所谓的“缺氧问题”，即，发生氧气不足不能充分感应的情况。
在那些如上所述使用导线-酶电极的可植入电流葡萄糖传感器中，没有缺氧的问题，因为氧气不是必要的反应物。仍然，这些传感器需要葡萄糖-扩散-限制膜，因为通常对于没有这种膜的葡萄糖传感器，在大约或低于10mM的葡萄糖浓度，输出电流达到最高程度，这个浓度远远低于临床上相应葡萄糖浓度的最高值30mM。
在使用导线-酶电极的生物传感器中，扩散-限制膜也是有利的，因为所述膜显著降低了在传感层中化学和生物化学的反应性，并因此降低了可能破坏酶的游离基的生成。扩散-限制膜还可同时作为机械保护层，阻止传感器成分从传感器层洗出并降低与移动相关的随机干扰。
人们已经进行了各种尝试开发一种机械强度高、生物相容性并且容易制备的葡萄糖扩散-限制膜。例如，已经公开了一种带有机械性孔的层压微孔膜(Young等的US4759828)，还已知由聚氨酯形成的膜(Shaw，G.W.等，Biosensors and Bioelectronics，6，401(1991)；Bindra，D.S.等，Anal.Chem.，63，1692(1991)；Shichiri，M.等，Horm.Metab.Res.，Suppl.Ser.，20，17(1988))。按照推测，在这些各式各样的膜中葡萄糖通过机械性孔或裂缝扩散。此外，例如已经描述了一种异质膜，具有不连续的疏水性和亲水性区域(Gough的US4484987)，以及具有疏水性和亲水性官能度两者的同质膜(Allen等人的US5284140和US5322063)。但是，所有这些已知的膜难以制备，并且物理性能不足。
在US5777060(Van Antwerp)、US5786439(Van Antwerp等)和US5882494(Van Antwerp)中已经描述了一种改进的膜，由二异氰酸酯、二醇、二胺和硅氧烷聚合物的多元混合物形成。如其中所述，这种膜材料在烧瓶中同时聚合并交联；得到的聚合物材料溶于强有机溶剂，如四氢呋喃(THF)；然后将得到的溶液施用到传感层上形成所述的膜。令人遗憾地，非常强的有机溶剂，如THF，可能使传感层中的酶变性，并且还会从溶解导电的墨水材料和任何可能是传感器的一部分的塑料材料。此外，由于在反应烧瓶中完成聚合和交联反应，当将溶液用于传感层形成所述膜时，没有发生进一步的产生结合的反应。因此，在膜层和传感层之间的粘附力可能不足。
在公开的国际公开号为WO 01/57241 A2的专利合作条约(PCT)申请中，Kelly和Schiffer描述了一种通过光解聚合小亲水性单体生产葡萄糖-扩散-限制膜的方法。使用这种膜的灵敏度大大增强，但是在膜生产方法中缺乏必要的控制。此外，因为聚合涉及非常小的分子，很可能在聚合后残留小的可溶性分子，其可能从传感器浸出。因此，使用这种葡萄糖-扩散-限制膜的葡萄糖传感器可能不适合于植入活体。
发明概述
本发明涉及由含杂环氮基团的交联聚合物组成的膜，特别是聚乙烯基吡啶和聚乙烯基咪唑聚合物，并且本发明还涉及装备有这种膜的电化学传感器。所述膜用于在电化学传感器中限制分析物向工作电极的迁移，从而在分析物浓度很大的浓度范围内传感器成线性响应，并且容易被校准。装备有本发明的膜的电化学传感器在各种条件下显示出可观的灵敏度和稳定性以及大的信噪比。
根据本发明的一个方面，通过在醇-缓冲溶液中就地交联聚合物形成膜，所述的聚合物被两性离子片断、非吡啶共聚物成分和任选是亲水性或疏水性的和/或具有其它所希望性质的另一种片段改性。所述改性聚合物由含有杂环氮基团的前体聚合物制备。优选，所述前体聚合物是聚乙烯基吡啶或聚乙烯基咪唑。当用于电化学传感器时，所述膜限制分析物达到传感器的传感层，诸如“导线-酶”电极的含有酶的传感层，并且进一步保护所述的传感层。膜的这些特性显著地扩大了传感器的线性检波范围和稳定性。
在形成所述膜的方法过程中，非吡啶共聚物成分通常提高聚合物溶解度，并且可以为聚合物或得到的膜提供另外的所希望的物理或化学性质。可任选使用亲水性或疏水性改性剂以“调整”所得的膜对一种使人感兴趣的分析物的渗透性。任选的亲水性改性剂，如聚(乙二醇)、羟基改性剂或多羟基改性剂，可用来提高聚合物或所得膜的生物适应性。在形成本发明的膜时，认为除通常由共价键产生的基本交联以外，聚合物的两性离子片断通过分子间静电结合提供了交联附加层，因此认为强化了所述的膜。
本发明的另一个方面涉及制备一种基本上均匀的、分析物-扩散-限制膜，其可用于生物传感器，诸如用于一种可植入的电流生物传感器。通过将交联剂的醇-缓冲溶液和改性聚合物施用在含有酶的传感层上并让所述溶液固化1至2天，就地形成所述的膜。在传感层上施加交联剂-聚合物溶液可通过将一滴或数滴溶液滴到传感器上，通过在所述溶液中浸渍传感器等方法进行。通常，膜厚度的控制是通过溶液的浓度、施用溶液的滴数、传感器在所述溶液中浸渍的次数或这些要素的任意组合。装备有本发明扩散-限制膜的电流葡萄糖传感器在大葡萄糖浓度范围内对葡萄糖浓度显示出极好的稳定性和快速线性响应。
附图说明
图1是根据本发明的分析物-扩散-限制膜的截面典型结构说明。
图2A是根据本发明的二电极葡萄糖传感器的一部分侧视示意图，该传感器具有一个工作电极、一个合并的对/参考电极和一个包封两个电极的浸涂膜。图2B和2C分别是示意性的图2A葡萄糖传感器部分顶视图和底视图。在此，图2A、2B和2C可总称图2。
图3是对于具有根据本发明葡萄糖-扩散-限制膜的传感器和缺少这种膜的传感器基于均值的电流对葡萄糖浓度曲线。
图4是对于具有根据本发明葡萄糖-扩散-限制膜的传感器和缺少这种膜的传感器在固定葡萄糖浓度输出电流对时间的曲线。
图5是基于均值，对于具有根据本发明的葡萄糖-扩散-限制膜的传感器，在不同水平的葡萄糖浓度输出电流对时间的曲线。
图6是对于具有根据本发明葡萄糖-扩散-限制膜的传感器和缺少这种膜的传感器，在不同的葡萄糖浓度，在搅拌和不搅拌的条件下，输出电流对时间的曲线。
图7A是基于均值，对于四批独立制备的具有根据本发明的葡萄糖-扩散-限制膜的传感器，输出电流对葡萄糖浓度的曲线。图7B-7E是分别对于上述四批独立制备的具有根据本发明的葡萄糖-扩散-限制膜的每批传感器，输出电流对葡萄糖浓度的曲线。在此，图7A、7B、7C、7D和7E可总称为图7。
发明详述
当在此使用时，引号中的术语定义如下。
术语“烷基”包括直链或支链的饱和脂肪族烃。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基等。除非另有说明，术语“烷基”包括烷基和环烷基。
术语“烷氧基”描述的是烷基通过一个氧原子连接到结构的其他部分。烷氧基的例子包括甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基等。另外，除非另有说明，术语“烷氧基”包括烷氧基和环烷氧基。
术语“烯基”描述的是具有至少一个碳-碳双键的不饱和直链或支链的脂肪族烃。烯基的例子包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-甲基-1-丙烯基等。
“反应性基团”是分子的一个官能团，其能够与另一个化合物反应，将其它化合物的至少一个部分结合到该分子上。反应性基团包括羧基、活化的酯、磺酰卤、磺酸酯、异氰酸酯、异硫氰酸酯、环氧化物、氮杂环丙烷、卤化物、醛、酮、胺、丙烯酰胺、硫醇、酰基叠氮、酰基卤、肼、羟胺、烷基卤化物、咪唑、吡啶、苯酚、烷基磺酸酯、卤代三嗪(halotriazine)、亚氨基酯、马来酰亚胺、酰肼、羟基和光反应性的叠氮基芳基。如本领域所认为的，活化的酯通常包括丁二酰亚氨基、苯并三唑基或被诸如磺基、硝基、氰基或卤素的吸电子基取代的芳基的酯、或被碳二亚胺活化的羧酸。
“取代的”官能团(例如取代的烷基、烯基或烷氧基)包括至少一个选自下列的取代基：卤素、烷氧基、巯基、芳基、烷氧羰基、烷基氨基羰基、二烷基氨基羰基、-OH、-NH2、烷基氨基、二烷基氨基、三烷基铵、烷酰基氨基、芳基酰胺基、肼基、烷硫基、烯基和反应性基团。
“交联剂”是一个分子，其含有至少两个反应性基团，所述的反应性基团能够将至少两个分子连接在一起，或将相同分子的至少两个部分连接在一起。至少两个分子的连接被称作分子间交联，相同分子的至少两个部分的连接被称作分子内交联。具有两个以上反应性基团的交联剂可以进行分子间交联，同时能够进行分子内交联。
术语“前体聚合物”是在连接各种改性剂基团形成改性聚合物之前的起始聚合物。
术语“杂环氮基团”是指在结构的环中含有一个sp2杂化氮的环状结构。
术语“聚乙烯基吡啶”是指聚(4-乙烯吡啶)、聚(3-乙烯吡淀)或聚(2-乙烯吡啶)，以及乙烯吡啶和第二或第三种共聚物成分的任意共聚物。
术语“聚乙烯基咪唑”是指聚(1-乙烯基咪唑)、聚(2-乙烯基咪唑)或聚(4-乙烯基咪唑)。
“膜溶液”是含有用于交联和形成膜的所有必要成分的溶液，包括改性的含有杂环氮基团的聚合物、交联剂和缓冲剂或醇-缓冲剂混合溶剂。
“生物液体”是任何体液或体液衍生物，其中分析物是可测量的，例如血液、组织液、血浆、皮肤液体(dermal fluid)、汗液和泪液。
“电化学传感器”是一个装配的设备，用于通过电化学氧化或还原反应测定样品中分析物的存在或测量其浓度或含量。通常，这些反应转换成电信号，所述的电信号可与分析物的量或浓度相关。
“氧化还原介体”是一种电子-转移试剂，用于在分析物、分析物还原酶或分析物氧化酶和电极之间直接地或通过一种或多种另外的电子-转移试剂传送电子。包括一个聚合骨架的氧化还原介体还可以称为“氧化还原聚合物”。
术语“参考电极”包括a)参考电极和b)参考电极，除非另有说明，它们还起对电极的作用(即对电极/参考电极)。
术语“对电极”包括a)对电极和b)对电极，除非另有说明，它们还起参考电极的作用(即对电极/参考电极)。
通常，通过在醇-缓冲剂混合溶剂中交联含有杂环氮基团的改性聚合物，然后将膜溶液固化一段时间形成本发明的膜。所述聚合物包括作为骨架部分的聚(含杂环氮的成分)和附加成分，包括两性离子片断、疏水性片断和任选的生物相容性片断。得到的膜能够限制分析物从一个空间——诸如与生物液体相关的空间——迁移到另一个空间——诸如与含酶传感层相关的空间。由传导酶传感层和本发明葡萄糖-扩散-限制层构成的电流葡萄糖传感器是非常稳定的，并且具有一个很大的线性检测范围。
含杂环氮的聚合物
本发明的聚合物具有下列通式1a：
Figure A0281333300251
其中水平线表示一个聚合物骨架；A是被水溶性基团取代的烷基，取代基优选是带负电的基团，如磺酸盐、磷酸盐或羧酸盐等，更优选是强酸基团，如磺酸盐，从而其连接的季化的杂环氮是两性离子；D是所述聚合物的共聚物成分，在下文对其进一步描述；每个n、l和p独立地是相关聚合物单元或左边紧邻括号中所示聚合物单元的平均数；q是骨架中所示一个或多个聚合物单元的数量。
式1a的杂环氮基团非限制性地包括吡啶、咪唑、噁唑、噻唑、吡唑或其任意的衍生物。优选所述的杂环氮基团独立地是乙烯吡啶，如2-、3-或4-乙烯吡啶，或乙烯基咪唑，如1-、2-或4-乙烯基咪唑。更优选所述杂环氮基团独立地是4-乙烯吡啶，从而更优选的聚合物是聚(4-乙烯吡啶)的衍生物。本发明这样的聚(4-乙烯吡啶)的一个例子具有下述通式1b：
Figure A0281333300261
其中A、D、n、l、p和q相应于上文式1a中所述。
虽然本发明的聚合物具有上述通式1a或式1b，应该注意到的是，当A是强酸时，诸如比羧酸更强的酸，所述D成分是任选的，因此p可能等于零。本发明这样的聚合物具有下列通式1c：
Figure A0281333300262
其中A是一个强酸，所述杂环氮基团、n、l和q全部如上所述。磺酸盐和氟化羧酸是合适的强酸的例子。认为当A是足够强的酸时，其所连接的杂环氮变成两性离子，因此在膜形成期间能够与交联剂形成分子间静电键合。相信这些分子间静电键合提供了除典型交联共价键以外的另一水平的交联，因此得到的膜更强。因此，当A是一个适当的强酸时，可以从上述式1a和1b聚合物省去D成分，该成分通常是一个强化成分，如苯乙烯。当A是一个较弱的酸时，所述杂环氮不是两性离子或不能够形成分子间静电键合，如上述式1a和1b所示，本发明的聚合物应包括D。
A的例子非限制性地包括磺丙基、磺丁基、羧丙基和羧戊基。在本发明的一个实施方案中，基团A具有式-L-G，其中L是C2-C12直链或支链烷基连接基团，其任选独立地被芳基、烷氧基、烯基、炔基、-F、-Cl、-OH、醛、酮、酯或酰胺基取代，G是带负电的羧基或磺酸盐基团。L的取代基的烷基部分具有1-6个碳，优选是芳基、-OH或酰胺基。
利用烷基化试剂A可通过季铵化作用连接到所述杂环氮基团，所述烷基化试剂含有合适的连接基L和带负电的基团G或者一个前体基团，该前体基团可在后继步骤中转化为带负电的基团G。合适的烷基化试剂的例子非限制性地包括2-溴乙磺酸酯、丙磺内酯、丁磺内酯、溴乙酸、4-溴丁酸和6-溴己酸。含有前体基团的烷基化试剂的例子非限制性地包括溴乙酸乙酯和6-溴已酸甲酯。这些前体的乙基和甲基酯基可通过标准水解容易地转化为带负电的羧基。
或者，可用含有一个附加反应性基团的烷基化试剂通过季铵化反应将A连接到所述杂环氮基团，随后通过标准方法将该附加反应性基团与另一个含有带负电基团G和一个反应性基团的分子结合。通常，所述反应性基团之一是亲电基团，另一反应性基团是亲核基团。选择的反应性基团的例子和它们相互作用形成的键如表1所示。
    表1：反应性基团的例子和形成的键
第一反应性基团 第二反应性基团 形成的键
活化的酯* 胺 酰胺
丙烯酰胺 硫醇 硫醚
酰基叠氮 胺 酰胺
酰基卤 胺 酰胺
羧酸 胺 酰胺
醛或酮 肼 腙
醛或酮 羟胺 肟
烷基卤化物 胺 烷基胺
烷基卤化物 羧酸 酯
烷基卤化物 咪唑 咪唑鎓
烷基卤化物 吡啶 吡啶鎓
烷基卤化物 醇/酚 醚
烷基卤化物 硫醇 硫醚
烷基磺酸酯 硫醇 硫醚
烷基磺酸酯 吡啶 吡啶鎓
烷基磺酸酯 咪唑 咪唑鎓
烷基磺酸酯 醇/酚 醚
酸酐 醇/酚 酯
酸酐 胺 酰胺
氮杂环丙烷 硫醇 硫醚
氮杂环丙烷 胺 烷基胺
氮杂环丙烷 吡啶 吡啶鎓
环氧化物 硫醇 硫醚
环氧化物 胺 烷基胺
环氧化物 吡啶 吡啶鎓
卤代三嗪 胺 氨基三嗪
卤代三嗪 醇 三嗪基醚
亚氨基酯 胺 脒
异氰酸酯 胺 脲
异氰酸酯 醇 尿烷
异硫氰酸酯 胺 硫脲
马来酰亚胺 硫醇 硫醚
磺酰卤 胺 磺酰胺
*如本领域所认为的，活化的酯通常包括丁二酰亚氨基、苯并三唑基或被诸如磺基、硝基、氰基或卤素的吸电子基取代的芳基的酯、或被碳二亚胺活化的羧酸。
例如，利用6-溴己酸季铵化杂环氮，然后将羧基与3-氨基-1-丙磺酸在碳二亚胺偶合剂存在下结合，可将A连接到聚合物的杂环氮基团上。
D是式1a或1b聚(杂环氮-共-D)聚合物的一个成分。D的例子非限制性地包括苯基烷基、烷氧基苯乙烯、羟烷基，烷氧基烷基、烷氧基羰基烷基和含有聚(乙二醇)或多羟基基团的分子。合适作为用于本发明的原料的一些聚(杂环氮-共-D)聚合物是市售的。例如聚(2-乙烯吡啶-共-苯乙烯)、聚(4-乙烯吡啶-共-苯乙烯)和聚(4-乙烯吡啶-共-甲基丙烯酸丁酯)可从Aldrich Chemical Company，Inc.获得。其它的聚(杂环氮-共-D)聚合物可用公知方法由任何高分子化学领域的技术人员容易地合成。优选，D是聚乙烯基吡啶-聚D——如聚(4-乙烯基吡啶-共-苯乙烯)或聚(4-乙烯吡啶-共-甲基丙烯酸丁酯)，更优选前者——的苯乙烯或C1-C18甲基丙烯酸烷基酯成分。D可能有助于所述膜的各种所希望特性，其非限制性地包括疏水性、亲水性、溶解度、生物适应性、弹性和强度。从而在聚合物制成的膜对分析物的渗透性及其对于例如干扰组分的不希望成分的非渗透性方面，可以选择D对其进行优化或“调整”。
字母n、l和p分别表示在各个聚合物单元中各个共聚物成分的平均数。对于嵌段共聚物，字母q是1；或对于具有许多重复聚合物单元的共聚物，q是大于1的数。例如，本发明聚合物的q值可≥约950，其中n、l和p分别是1、8和1。字母q因此与所述聚合物的总分子量相关。优选聚合物的平均分子量大于约50000，更优选大于约200000，最优选大于约1000000。
本发明的聚合物可以含有另一种任选的共聚物，如下列通式2a所示：
其中聚合物骨架、A、D、n、l、p和q如上式1a-1c中所述；m是结合的聚合物单元的平均数或在紧邻的左侧括号中所示的聚合物单元的平均数；B是改性剂。当所述杂环氮基团是优选的4-取代的吡啶时，本发明的聚合物是聚(4-乙烯吡啶)的衍生物，具有下述通式2b：
另外，当A是适当的强酸时，如上所述，D共聚物是任选的，而在这样情况下本发明的聚合物具有如下通式2c：
在任意的式2a-2c中，B是改性基团，其可为所述的膜增加任何期望的化学、物理或生物学特性。这类所期望的特性包括分析物选择性、疏水性、亲水性、弹性和生物适应性。改性剂的例子包括下列：带负电的分子，其可将带负电的干扰性化合物进入所述膜的入口最小化；疏水的烃分子，其可增强在所述膜和传感器基底材料之间的粘附力；亲水性的羟基或多羟基分子，其可帮助水合并增加所述膜的生物适应性；硅聚合物，其可增加所述膜的弹性和其它特性；和聚(乙二醇)成分，已知其可增加生物材料的生物适应性(Bergstrom，K.等，J.Biomed.Mat.Res.，26，779(1992))。B的其它例子非限制性地包括金属螯合剂，诸如钙螯合剂，以及其它可生物相容的材料。适合所述膜的生物适应性改性的聚(乙二醇)通常具有从约100至约20000的分子量，优选从约500至约10000，更优选从约1000至约8000。
改性剂B可直接或间接地连接到所述聚合物的杂环氮上。在直接连接时，杂环氮基团可与含有烷基化基团的改性剂反应。合适的烷基化基团非限制性地包括烷基卤化物、环氧化物、氮杂环丙烷和磺酸酯。在间接连接时，用具有一附加反应性基团的烷基化试剂将所述聚合物的杂环氮原子季铵化，然后连接到具有所希望特性和一个合适的反应性基团的分子上。
如上所述，所述含B的共聚物任选存在于本发明的膜中，因此，当式2a-2c的m是零时，所述的膜分别具有式1a-1c的通式。含有A的杂环氮基团、任选的含有B的杂环氮基团、杂环氮基团和D这四种共聚物成分的相对含量可用百分比分别表示如下：[n/(n+m+l+p)]×100％、[m/(n+m+l+p)]×100％、[l/(n+m+l+p)]×100％和[p/(n+m+l+p)]×100％。合适的百分比分别是1-25％、0-15％(当所述含B的杂环氮基团是任选的)或1-15％、20-90％和0-50％(当D是任选的)或1-50％，优选的百分比分别是5-20％、0-10％(当所述含B的杂环氮基团是任选的)或1-10％、60-90％和5-20％。
合适的聚合物的具体例子具有如下所示的通式3-6。
Figure A0281333300311
Figure A0281333300321
聚乙烯基吡啶聚合物的合成实施例
根据本发明的各种聚乙烯基吡啶聚合物合成的实施例如下所述。提供的数字是近似值。
实施例1：式3聚合物的合成
为了具体说明，现提供上述式3聚合物的合成实施例。聚(4-乙烯吡啶-共-苯乙烯)(～10％苯乙烯含量)(20g，Aldrich)在100mL二甲基甲酰胺(DMF)中的溶液在90℃搅拌，加入在15-20mL DMF中的6-溴己酸(3.7克)。得到的溶液在90℃搅拌24小时，然后倾入1.5L乙醚中，再轻轻倒出溶剂。剩下的粘性固体溶于甲醇(150-200mL)，通过中等孔的过滤漏斗抽滤，除去任何不溶的固体。将滤液缓慢地加入在烧杯内快速搅拌的乙醚(1.5L)中。得到的沉淀通过抽滤收集，在高真空下在50℃干燥2天。所述聚合物具有下列参数：[n/(n+l+p)]×100％≈10％；[l/(n+l+p)]×100％≈80％；和[p/(n+l+p)]×100％≈10％。
实施例2：式5聚合物的合成
为了具体说明，现提供上述式5聚合物的合成实施例。在90℃搅拌聚(4-乙烯吡啶-共-苯乙烯)(～10％苯乙烯)(20g，Aldrich)在100mL无水DMF中的溶液，加入甲磺酸(～80mg)，然后加入在15-20mL无水DMF中的2g的甲氧基-PEG-环氧化物(分子量5000)(Shearwater Polymers，Inc.)。所述溶液在90℃是搅拌24小时，加入在10mL无水DMF中的1，3-丙磺酸内酯(2.32g)。得到的溶液在90℃连续搅拌24小时，然后冷却至室温，倾入800mL乙醚中。轻轻倒出溶剂，将剩下的沉淀溶于热甲醇(～200mL)，抽滤，再次从1L的乙醚中沉淀，然后在50℃、高真空下干燥48小时。得到的聚合物具有下列参数：[n/(n+m+l+p)]×100％≈10％；[m/(n+m+l+p)]×100％≈10％；[l/(n+m+l+p)]×100％≈70％；和(p/(n+m+l+p))×100％≈10％。
实施例3：含有多羟基改性剂B的聚合物的合成
为了具体说明，如下述示意图所说明，现提供含有多羟基改性剂B的聚合物的合成实施例。已知各种多羟基化合物具有生物适应性特性。(U.S.专利No.6011077)以下合成说明了如何将具有所期望特性的改性剂基团通过连接基连接到聚合物骨架。
Figure A0281333300341
1，3-丙磺酸内酯(0.58g，4.8毫摩尔)和6-溴己酸(1.85g，9.5毫摩尔)加入到聚(4-乙烯吡啶-共-苯乙烯)(～10％苯乙烯)(10g)在60mL无水DMF中的溶液中。所得到的溶液在90℃搅拌24小时，然后冷却到室温。然后在该溶液中顺序加入O-(N-琥珀酰亚氨基)-N，N，N′，N′-四甲基脲阳离子四氟硼酸盐(TSTU)(2.86g，9.5毫摩尔)和N，N-二异丙基乙基胺(1.65mL、9.5毫摩尔)。在搅拌所述溶液5小时后，加入N-甲基-D-葡糖胺(2.4g，12.4毫摩尔)，所得溶液在室温搅拌24小时。将所述溶液倾入500mL乙醚中，通过抽滤收集沉淀。然后将收集的沉淀溶于MeOH/H2O，所得溶液进行膜超滤，使用相同的MeOH/H2O溶剂，除去小分子。将渗出的溶液蒸干，得到的聚合物具有下列参数：[n/(n+m+l+p)]×100％≈10％；[m/(n+m+l+p)]×100％≈10％；[l/(n+m+l+p)]×100％≈70％；和[p/(n+m+l+p)]×100％≈10％。
交联剂
本发明的交联剂是具有至少两个反应性基团的分子，诸如具有二、三或四个官能团，其能够与所述聚合物的A、B或D上所含的杂环氮基团、吡啶基团或其它反应性基团反应。优选交联剂的反应性基团是慢反应的烷基化基团，其可将聚合物的杂环氮基团——如吡啶基团——季化。合适的烷基化基团非限制性地包括聚(乙二醇)或聚(丙二醇)的衍生物、环氧化物(缩水甘油基)、氮杂环丙烷、烷基卤化物化物和磺酸盐酯。优选交联剂的烷基化基团是缩水甘油基。优选缩水甘油基交联剂具有从约200到约2000的分子量，并且是水溶性的，或可以溶于可与水混溶的溶剂中，例如醇。合适的交联剂的实例非限制性地包括具有一个分子量约200至约600的聚(乙二醇)二缩水甘油醚和N，N-二缩水甘油基-4-缩水甘油基氧基苯胺。
理想的是在膜溶液的配制期间交联反应缓慢，从而使得膜涂覆溶液在大规模生产中具有适当的罐储寿命。快速的交联反应会导致涂层溶液的粘度迅速改变，这导致涂覆困难。理想的是，交联反应在配制膜溶液期间缓慢，在室温或可能的提高的温度固化所述膜时加速。
膜的形成和传感器的制造
现描述用于制备本发明膜的方法的实例。在这个实例中，本发明的聚合物和合适的交联剂溶于含有缓冲剂的溶剂中制备膜溶液，该含有缓冲剂的溶剂通常是缓冲剂-醇混合溶剂。优选所述缓冲剂具有约7.5至约9.5的pH，所述的醇是乙醇。更优选所述缓冲剂是10mM的(2-(4-(2-羟乙基)-1-哌嗪)乙烷磺酸盐)(HEPES)缓冲剂(pH8)，乙醇对缓冲剂的体积比为约95∶5至约0∶100。为了产生交联化学过程，必须有最低量的缓冲剂，特别是如果使用环氧化物或氮杂环丙烷交联剂时。溶解聚合物和交联剂需要的溶剂的量可根据聚合物和交联剂的性质变化。例如，可能需要更高百分比的醇溶解相对疏水的聚合物和/或交联剂。
聚合物对交联剂的比例对于最终膜的性质非常重要。例如，如果使用的交联剂的量不是大大过量，交联就不充分，并且膜不牢固。另外，如果使用超过足够量的交联剂，所述膜就会过分交联，从而膜会非常易碎和/或会阻碍分析物扩散。因此，对用于制备所希望的或有用的膜的给定聚合物和给定交联剂有一个最佳比例。例如，对于上述式3-6任一聚合物和在和分子量为约200到400的聚(乙二醇)二缩水甘油醚交联剂而言，聚合物对交联剂的最佳重量比通常为约4∶1至约32∶1。最优选该范围是约8∶1到约16∶1。另外，例如，对于下述聚合物和交联剂最佳的聚合物对交联剂重量比通常为约16∶1：上述式4的聚合物，其中[n/(n+l+p)]×100％≈10％，(l/(n+l+p))×100％≈80％，和[p/(n+l+p)]×100％≈10％，；或上述式5的聚合物，其中[n/(n+m+l+p)]×100％≈10％，[m/(n+m+l+p)]×100％≈10％，[l/(n+m+l+p)] ×100％≈70％，[p/(n+m+l+p)]×100％≈10％和r≈110；聚(乙二醇)二缩水甘油醚交联剂具有分子量约200。
膜溶液可涂覆在各种生物传感器上，它们可得益于在含有酶的传感层上涂覆一层膜。这样的生物传感器的实例非限制性地包括葡萄糖传感器和乳酸盐传感器(参见Heller等人的美国专利No.6134461，其全文引用在此作为参考)。涂覆工艺可以包括任何常用方法，诸如在所述传感层上旋涂、浸涂或分配膜溶液的液滴等，随后在室温下通常固化1至2天。涂覆工艺的特定细节(如浸涂持续时间、浸涂频率、浸涂次数等)可以根据例如聚合物、交联剂、膜溶液、溶剂和缓冲剂的特性(即，粘度、浓度、组成等)改变。常规设备可用于所述涂覆工艺，诸如英国NIMA Technology的DSG D1L-160浸涂或浇铸体系。
传感器的制造实施例
传感器的制造通常包括在一个工作电极上沉积含酶的传感层，在该传感层上浇铸扩散-限制膜层，并任选、但优选在对电极和参考电极上浇铸扩散-限制膜层。下文的方法涉及诸如在图2A-2C描述的双电极传感器的制造。具有其它结构的传感器，诸如三电极型传感器，可用类似方法生产。
现提供一个制造传感器的详细实施例，其中数字是近似值。用7.5mM HEPES溶液(0.5μL、pH8)制备传感层溶液，其含有1.7μg聚合锇介体化合物L(其在专利合作条约(PCT)申请国际公开号WO01/36660 A2中公开，该文献全文引用在此作为参考)；2.1μg葡萄糖氧化酶(Toyobo)；和1.3μg聚(乙二醇)二缩水甘油醚(分子量400)。化合物L如下所示。
Figure A0281333300381
将传感层溶液沉积在碳-墨水(carbon-ink)工作电极上，在室温固化两天，制备多个传感器。上述式4聚合物以64mg/mL溶解在80％EtOH/20％HEPES缓冲剂中(10mM、pH8)，聚(乙二醇)二缩水甘油醚(分子量200)以4mg/mL溶解在80％EtOH/20％HEPES缓冲剂中(10mM、pH8)，将4体积式4聚合物溶液与1体积的聚(乙二醇)二缩水甘油醚溶液混合制备膜溶液。上述传感器在该膜溶液中浸三次，每次浸渍约5秒，在连续浸渍期间时间间隔约10分钟。然后在室温和正常湿度固化所述传感器24小时。
根据本发明制备的典型的膜，其截面的近似化学结构如图1所示。这样的膜用于各种传感器，诸如此前描述的双电极或三电极传感器。例如，如下所述，这种膜可用于如图2A-2C(称为图2)所示的双电极电流葡萄糖传感器。
图2的电流葡萄糖传感器10包括一个底基12，其设置在通常是碳基的工作电极14和Ag/AgCl反/参考电极16之间。传感器或传感层18设置在该工作电极上。膜或膜层20包封了整个葡萄糖传感器10，包括Ag/AgCl反/参考电极。
如上述公开的PCT申请国际公开WO01/36660A2所述，葡萄糖传感器10的传感层18由交联的葡萄糖氧化酶和低电位聚合锇配合物介体组成。可用于该传感层的含酶配方和含介体配方、将它们使用到电极系统上的方法是本领域已知的，例如可从美国专利No.6134461获知。根据本发明，膜外涂层的形成是将传感器在膜溶液中浸渍三次，膜溶液包括4mg/mL的聚(乙二醇)二缩水甘油醚(分子量约200)和64mg/mL的上述式4聚合物，其中[n/(n+l+p)]×100％≈10％；[l/(n+l+p)]×100％≈80％；和[p/(n+l+p)]×100％≈10％，并在室温和正常湿度下将三次浸渍后的传感器固化至少24小时，如约1至2天。对于这种膜外涂层，所述q值可能是≥约950，其中n、l和p分别是1、8和1。
膜表面改性
本发明的聚合物具有大量杂环氮基团，如吡啶基团，其中只有百分之几在膜形成期间用于交联。因此，所述的膜在膜基质和膜表面上均存在过量的这些基团。任选，可通过将另一层材料放置在富杂环氮基团或富吡啶的膜表面上将所述膜进一步改性。例如，膜表面可以通过增加一层聚(乙二醇)改性以提高生物适应性。通常，改进可以包括用改性溶液涂覆膜表面，所述的改性溶液诸如是一种包括期望的具有烷基化反应性基团的分子的溶液，然后用适合的溶剂清洗涂层溶液以除去过量的分子。这种改性会得到所期望分子的单分子层。
图2所示的葡萄糖传感器10的膜20可用上述方法改性。
实验实施例
下文提供实验实施例，说明根据本发明的具有扩散-限制膜的传感器的特性和/或效果。提供的数字是近似值。
校准实验
在第一个实施例中，进行校准实验，其中同时测试15个没有膜的传感器(组1)，另外同时测试8个具有根据本发明的扩散-限制膜的传感器(组2)，两组测试均在37℃下进行。在组2中，膜是用上述式4的聚合物和分子量约200的聚(乙二醇)二缩水甘油醚(PEGDGE)交联剂制备的。在组1和组2每组校准实验中，传感器置于PBS-缓冲溶液(pH 7)，当葡萄糖浓度增加时，测量每个传感器的输出电流。然后将组1和组2的测量输出电流(组1为μA，组2为nA)分别平均，相对于葡萄糖浓度(mM)做图，曲线图如附图3校准图所示。
如图所示，在一个非常小的从零到约3mM、或最多到5mM的葡萄糖浓度范围，缺少膜的组1传感器的校准曲线近似线性。该结果表明，没有所述膜的传感器在诸如10mM的提高的葡萄糖浓度，对于葡萄糖浓度的变化敏感性不足，而10mM还远远低于大约30mM的临床相关浓度高端值。相反，如图3所示的最佳拟合线(y＝1.2502x+1.1951；R2≈0.997)，具有根据本发明的扩散-限制膜的组2传感器的校准曲线在例如从零到约30mM的相对较大的葡萄糖浓度范围基本上为线性。该结果说明，具有所述膜的感应膜在低、中和高葡萄糖浓度对于葡萄糖浓度具有相当的敏感性，并且在约30mM的临床相关葡萄糖浓度也具有特别的相关性。
稳定性实验
在第二个实施例中，进行稳定性实验，其中在37℃同时测试缺少膜的传感器和具有根据本发明的扩散-限制膜的传感器。在装备了膜的传感器上具有一层膜，制备该膜的聚合物和交联剂分别与制备上述校准实验中组2传感器所用膜的相同。在这个稳定性实验中，每个传感器置于PBS-缓冲溶液(pH7)中，缓冲液的固定葡萄糖浓度为30mM，测量每个传感器的输出电流。测量的输出电流(对于没有膜的传感器为μA；对于装备了膜的传感器为nA)对时间(小时)做图，结果如图4所示的稳定性曲线。
如图所示，关于无膜传感器的稳定曲线随时间迅速下降，每小时的下降率为约4.69％μA。该结果表明该无膜传感器缺乏稳定性。相反，关于根据本发明装备了膜的传感器的稳定曲线表明随着时间相对恒定，或随时间没有明显的下降，每小时的下降率只有约0.06％nA。该结果说明本发明的装备了膜的传感器具有可观的稳定性和可靠性。即，在30mM的葡萄糖浓度，在约20小时期间无膜的传感器灵敏度以几乎5％每小时的速度降低，在相同的时间内所示的根据本发明的装备了膜的传感器灵敏度几乎没有降低。
响应性实验
理想的是电化学传感器的膜不应阻碍在传感器的传感层和含有人们感兴趣的分析物的液体或生物液体之间的信息传递。即，膜应该迅速地感应分析物浓度的改变。
在第三个实施例中，进行响应性实验，其中在37℃对8个具有根据本发明扩散-限制膜的传感器同时进行测试。组3的传感器具有膜，制备该膜的聚合物和交联剂分别与制备上述校准实验中组2传感器所用膜的相同。在该响应性实验中，8个传感器置于PBS-缓冲溶液(pH7)中，该缓冲溶液的葡萄糖浓度如图5所示的葡萄糖浓度随时间逐步增加，测量每一传感器的输出电流。然后将组3测量的输出电流(nA)平均，对时间(实时，小时:分:秒)做图，响应性曲线如图5所示。
关于具有根据本发明扩散-限制膜的组3传感器，响应曲线具有不连续阶段，其以快速改变的方式模拟了葡萄糖浓度的逐步增加。如图所示，在葡萄糖浓度增加后，输出电流迅速地从一个平台跳跃到下一个平台。该结果说明本发明的装备了膜的传感器具有可观的响应性。这些装备了膜的电化学传感器的响应性使其能够理想地感应分析物，例如感应葡萄糖。
运动-灵敏度实验
理想的是，电化学传感器的膜不应受含有令人感兴趣的分析物的液体或生物液体的移动或运动的影响。对于植入体内——诸如人体——的传感器这一点特别重要，因为身体的运动可能导致与移动相关的干扰，这可能是非常频繁的。
在第四个实施例中，进行移动-灵敏度实验，其中同时分别测试缺少膜的传感器A和具有根据本发明的扩散-限制膜的传感器B，测试均在37℃进行。传感器B具有膜，制备该膜的聚合物和交联剂分别与制备上述校准实验中组2传感器所用膜的相同。在该实验里，对于每个测试，将传感器置于一个烧杯中，烧杯盛有PBS-缓冲溶液(pH7)并装有一个磁力搅拌器。溶液的葡萄糖浓度随时间逐步增加，用与上述响应性实验几乎相同的方法进行，在图6中以各个mM标记表示。在每次逐步增加葡萄糖浓度期间打开搅拌器，其后经过一段时间后停止，在图6中标记为“搅拌开始”和“搅拌停止”。在若干葡萄糖浓度水平循环重复这种打开和停止搅拌的操作，在整个实验中测量每个传感器的输出电流。测量的输出电流(对于传感器A为μA；对于传感器B为nA)对时间(分)做图，结果如图6的移动-灵敏度曲线所示。
如图所示，对于无膜传感器A，在实验中采用的葡萄糖浓度范围内，与无搅拌条件比较，输出电流受到搅拌的很大影响。相反，对于具有根据本发明扩散-限制膜的传感器B，在直到约10mM的葡萄糖浓度，与无搅拌条件比较，输出电流几乎不受搅拌影响，在约15mM的葡萄糖浓度，输出电流只受这些条件的轻微影响。该结果标明本发明装备了膜的传感器在搅拌和不搅拌的环境下均具有相当的稳定性。这些装备了膜的电化学传感器在流体运动的环境中的稳定性使其理想地在运动的体内感应分析物。
传感器重复性实验
膜的浸涂或浇铸通常使用浸渍机进行，诸如NIMA Technologyof the United Kingdom的DSG D1L-160。认为可重现的膜浇铸是非常难于实现的。参见Chen，T.等，In Situ Assembled Mass-TransportControlling Micromembranes and Their Application in ImplantedAmperometric Glucose Sensors，Anal.Chem.，Vol.72，No.16，p.3757-3763(2000)。令人惊奇的是，如现在所述的实验所示，本发明的传感器的制备再现性非常好。
根据本发明，通过使用浇铸设备将传感器在膜溶液浸渍3次然后使其固化，分别制备四批传感器(第1-4批)。在四批的每一批中，用相同的方法从式4聚合物和分子量约200的聚(乙二醇)二缩水甘油醚(PEDGE)交联剂(如上述组2和其它组)制备膜溶液。用于第1和第2批的膜溶液的制备彼此独立，并独立于第3和第4批所用的膜溶液。用于第3和第4批的膜溶液是相同的，但是第3批和第4批传感器用不同的浇铸设备浸涂不同的次数。即，第1、2和3批用非工业制造的系统浸涂，第四批用上述标准的DSG D1L-160系统浸涂。
在37℃进行各批传感器的校准实验。对于每一批，将传感器置于PBS-缓冲溶液(pH7)，随葡萄糖浓度(mM)的增加测定每个传感器的输出电流(nA)。对于四批每一批的各个每个传感器，根据输出电流对葡萄糖浓度绘图，得到的校准曲线如附图所示：图7B(第1批：5个传感器)，图7C(第2批：8个传感器)，图7D(第3批：4个传感器)和图7E(第4批：4个传感器)。各批校准曲线的平均斜率如下：
第1批；平均斜率＝1.10nA/mM(CV＝5％)；
第2批；平均斜率＝1.27nA/mM(CV＝10％)；
第3批；平均斜率＝1.15nA/mM(CV＝5％)；和
第4批；平均斜率＝1.14nA/mM(CV＝7％)。
另外，对于每一批，同一批传感器的输出电流进行平均，对葡萄糖浓度做图，结果如图7A所示。第1-4批的平均斜率为1.17nA/mM(CV＝7.2％)。
各批内和各批之间曲线的斜率非常紧密地分布，说明几乎没有显著变化。该结果证明，根据本发明制备的传感器在一批之内和各批之间具有非常高的再现性。
上述实施例说明了本发明的膜和使用这样的膜的传感器的许多优点。使用本发明膜的传感器的特殊优点包括灵敏度、稳定性、响应性、运动适应性、校准容易度和制备的容易性和可重复性。
在看法或理论方面已经对本发明的各个方面和特征进行了说明和描述，但是很清楚，本发明不受任何特定看法或理论的束缚。基于说明书描述，适用于本发明的各种改进、工艺和许多装置对于本发明所属领域技术人员而言是显而易见的。虽然在此参照各个实施方案和具体的实施例已经描述了本发明的各个方面和特征，但是应认为本发明要求在所附权利要求的整个范围内受到保护。

Claims (89)

1.用于电化学传感器的膜，包括：
一种交联剂；和
一种具有下式的聚合物：
其中水平实线表示聚合物骨架；
A是被水溶性成分取代的烷基；
D选自苯基烷基、烷氧基苯乙烯、羟基烷基、烷氧基烷基、烷氧基羰基烷基、含聚(乙二醇)的成分和含多羟基的成分；和
每个n、l、p和q独立地是正数。
2.权利要求1的膜，其中A是带负电的。
3.权利要求1的膜，其中A选自磺酸盐、羧酸盐和磷酸盐。
4.权利要求1的膜，其中A选自选自磺丙基、磺丁基、羧丙基和羧戊基。
5.权利要求1的膜，其中A具有式L-G，其中L是C2-C12直链或支链烷基连接基，G是带负电的羧基或磺酸盐。
6.权利要求5的膜，其中L被芳基、烷氧基、烯基、炔基、F、-Cl、-OH、醛、酮、酯或酰胺取代。
7.权利要求1的膜，其中D是苯乙烯或甲基丙烯酸C1-C18烷基酯。
8.权利要求1的膜，其中所述聚合物具有选自下述的通式：
Figure A028133330003C2
和
Figure A028133330003C3
9.权利要求1的膜，其中聚合物的平均分子量大于约50000。
10.权利要求1的膜，其中聚合物的平均分子量大于约200000。
11.权利要求1的膜，其中聚合物的平均分子量大于约1000000。
12.权利要求1的膜，其中聚合物另外包括含B的共聚物，从而聚合物具有下式：
Figure A028133330004C1
其中B是改性剂，m是正数。
13.权利要求12的膜，其中B选自螯合剂、带负电的成分、疏水的烃成分、亲水性的羟基或多羟基成分、硅聚合物和聚(乙二醇)。
14.权利要求12的膜，其中B是分子量从约100到约20000的聚(乙二醇)。
15.权利要求12的膜，其中所述聚合物具有选自下述的通式：
和
Figure A028133330005C2
16.权利要求12的膜，其中[n/(n+m+l+p)]×100％为约1％到约25％。
17.权利要求12的膜，其中[m/(n+m+l+p)]×100％为约1％到约15％。
18.权利要求1 2的膜，其中[l/(n+m+l+p)]×100％为约20％到约90％。
19.权利要求12的膜，其中[p/(n+m+l+p)]×100％为约1％到约50％。
20.权利要求1或12的膜，其中聚合物的至少一个杂环氮成分独立地选自吡啶、咪唑、噁唑、噻唑、吡唑及其任意的衍生物。
21.权利要求1或12的膜，其中聚合物的至少一个杂环氮成分独立地选自2-乙烯基吡啶、3-乙烯基吡啶、4-乙烯基吡啶、1-乙烯基咪唑、2-乙烯基咪唑和4-乙烯基咪唑。
22.权利要求1或12的膜，其足以限制葡萄糖或乳酸盐穿过其迁移。
23.权利要求1或12的膜，其足以限制在体内葡萄糖或乳酸盐穿过其迁移。
24.权利要求1或12的膜，其中交联剂包括至少一个环氧化物反应性基团。
25.权利要求1或12的膜，其中交联剂具有从约200到约2000的分子量。
26.权利要求1或12的膜，其中交联剂是聚(乙二醇)或聚(丙二醇)的衍生物。
27.权利要求1或12的膜，其中聚合物对交联剂的重量比为约4∶1到约32∶1。
28.权利要求1或12的膜，其中聚合物对交联剂的重量比为约8∶1到约16∶1。
29.权利要求1的膜，进一步包括一层聚(乙二醇)。
30.一种电化学传感器，包括：
一个工作电极，所述的工作电极包括一个与电极的导电材料接触的传感层；
分布在传感层上的膜，所述的膜包括一种交联剂和一种具有下式的聚合物：
Figure A028133330007C1
其中水平实线表示聚合物骨架；A是被水溶性成分取代的烷基；D选自苯基烷基、烷氧基苯乙烯、羟基烷基、烷氧基烷基、烷氧基羰基烷基、含聚(乙二醇)的成分和含多羟基的成分；和每个n、l、p和q独立地是正数；和
一个与工作电极电化学连通的对电极。
31.权利要求30的电化学传感器，其中A是带负电的。
32.权利要求30的电化学传感器，其中A选自磺酸盐、羧酸盐和磷酸盐。
33.权利要求30的电化学传感器，其中A选自选自磺丙基、磺丁基、羧丙基和羧戊基。
34.权利要求30的电化学传感器，其中A具有式L-G，其中L是C2-C12直链或支链烷基连接基，G是带负电的羧基或磺酸盐。
35.权利要求34的电化学传感器，其中L被芳基、烷氧基、烯基、炔基、-F、-Cl、-OH、醛、酮、酯或酰胺取代。
36.权利要求30的电化学传感器，其中D是苯乙烯或甲基丙烯酸C1-C18烷基酯。
37.权利要求30的电化学传感器，其中所述聚合物具有选自下述的通式：
Figure A028133330008C2
和
Figure A028133330009C1
38.权利要求30的电化学传感器，其中聚合物的平均分子量大于约50000。
39.权利要求30的电化学传感器，其中聚合物的平均分子量大于约200000。
40.权利要求30的电化学传感器，其中聚合物的平均分子量大于约1000000。
41.权利要求30的电化学传感器，其中聚合物另外包括含B的共聚物，从而聚合物具有下式：
其中B是改性剂，m是正数。
42.权利要求41的电化学传感器，其中B选自螯合剂、带负电的成分、疏水的烃成分、亲水性的羟基或多羟基成分、硅聚合物和聚(乙二醇)。
43.权利要求41的电化学传感器，其中B是分子量从约100到约20000的聚(乙二醇)。
44.权利要求41的电化学传感器，其中所述聚合物具有选自下述的通式：
Figure A028133330010C1
和
45.权利要求41的电化学传感器，其中[n/(n+m+l+p)]×100％为约1％到约25％。
46.权利要求41的电化学传感器，其中[m/(n+m+l+p)]×100％为约1％到约15％。
47.权利要求41的电化学传感器，其中[l/(n+m+l+p)]×100％为约20％到约90％。
48.权利要求41的电化学传感器，其中[p/(n+m+l+p)]×100％为约1％到约50％。
49.权利要求30或41的电化学传感器，其中聚合物的至少一个杂环氮成分独立地选自吡啶、咪唑、噁唑、噻唑、吡唑及其任意的衍生物。
50.权利要求30或41的电化学传感器，其中聚合物的至少一个杂环氮成分独立地选自2-乙烯基吡啶、3-乙烯基吡啶、4-乙烯基吡啶、1-乙烯基咪唑、2-乙烯基咪唑和4-乙烯基咪唑。
51.权利要求30或41的电化学传感器，其中所述的膜，其足以限制葡萄糖或乳酸盐穿过其迁移。
52.权利要求30或41的电化学传感器，其中所述的膜，其足以限制在体内葡萄糖或乳酸盐穿过其迁移。
53.权利要求30或41的电化学传感器，其中交联剂包括至少一个环氧化物反应性基团。
54.权利要求30或41的电化学传感器，其中交联剂具有从约200到约2000的分子量。
55.权利要求30或41的电化学传感器，其中交联剂是聚(乙二醇)或聚(丙二醇)的衍生物。
56.权利要求30或41的电化学传感器，其中聚合物对交联剂的重量比为约4∶1到约32∶1。
57.权利要求30或41的电化学传感器，其中聚合物对交联剂的重量比为约8∶1到约16∶1。
58.权利要求30的电化学传感器，其中所述膜还包括一层聚(乙二醇)。
59.权利要求30的电化学传感器，其中传感层包括一种酶、一种酶稳定剂和一种交联剂。
60.权利要求30的电化学传感器，其中传感层包括一种酶、一种聚合的介体和一种交联剂。
61.用于电化学传感器的膜，包括：
一种交联剂；和
一种具有下式的聚合物：
其中水平实线表示聚合物骨架；
A是强酸；和
每个n、l、p和q独立地是正数。
62.权利要求61的膜，其中A使得其所结合的杂环氮为两性离子。
63.权利要求61的膜，其中A是比羧酸更强的酸。
64.权利要求61的膜，其中聚合物另外包括含B的共聚物，从而聚合物具有下式：
Figure A028133330013C1
其中B是改性剂，m是正数。
65.权利要求61的膜，其中B选自螯合剂、带负电的成分、疏水的烃成分、亲水性的羟基或多羟基成分、硅聚合物和聚(乙二醇)。
66.权利要求61或64的膜，其中聚合物的至少一个杂环氮成分独立地选自2-乙烯基吡啶、3-乙烯基吡啶、4-乙烯基吡啶、1-乙烯基咪唑、2-乙烯基咪唑和4-乙烯基咪唑。
67.权利要求61或64的膜，其足以限制葡萄糖或乳酸盐穿过其迁移。
68.权利要求61或64的膜，其足以限制在体内葡萄糖或乳酸盐穿过其迁移。
69.权利要求61或64的膜，其中交联剂包括至少一个环氧化物反应性基团。
70.权利要求61或64的膜，其中交联剂具有从约200到约2000的分子量。
71.权利要求61或64的膜，其中交联剂是聚(乙二醇)或聚(丙二醇)的衍生物。
72.权利要求61或64的膜，其中聚合物对交联剂的重量比为约4∶1到约32∶1。
73.权利要求61或64的膜，其中聚合物对交联剂的重量比为约8∶1到约16∶1。
74.一种电化学传感器，包括：
一个工作电极，所述的工作电极包括一个与电极的导电材料接触的传感层；
分布在传感层上的膜，所述的膜包括一种交联剂和一种具有下式的聚合物：
其中水平实线表示聚合物骨架；A是强酸；和每个n、l、p和q独立地是正数；和
一个与工作电极电化学连通的对电极。
75.权利要求74的电化学传感器，其中A使得其所结合的杂环氮为两性离子。
76.权利要求74的电化学传感器，其中A是比羧酸更强的酸。
77.权利要求74的电化学传感器，其中聚合物另外包括含B的共聚物，从而聚合物具有下式：
Figure A028133330015C1
其中B是改性剂，m是正数。
78.权利要求77的电化学传感器，其中B选自螯合剂、带负电的成分、疏水的烃成分、亲水性的羟基或多羟基成分、硅聚合物和聚(乙二醇)。
79.权利要求74或77的电化学传感器，其中聚合物的至少一个杂环氮成分独立地选自吡啶、咪唑、噁唑、噻唑、吡唑及其任意的衍生物。
80.权利要求74或77的电化学传感器，其中聚合物的至少一个杂环氮成分独立地选自2-乙烯基吡啶、3-乙烯基吡啶、4-乙烯基吡啶，1-乙烯基咪唑、2-乙烯基咪唑和4-乙烯基咪唑。
81.权利要求74或77的电化学传感器，其足以限制葡萄糖或乳酸盐穿过其迁移。
82.权利要求74或77的电化学传感器，其足以在体内限制葡萄糖或乳糖穿过其迁移。
83.权利要求74或77的电化学传感器，其中交联剂包括至少一个环氧化物反应性基团。
84.权利要求74或77的电化学传感器，其中交联剂具有从约200到约2000的分子量。
85.权利要求74或77的电化学传感器，其中交联剂是聚(乙二醇)或聚(丙二醇)的衍生物。
86.权利要求74或77的电化学传感器，其中聚合物对交联剂的重量比为约4∶1到约32∶1。
87.权利要求74或77的电化学传感器，其中聚合物对交联剂的重量比为约8∶1到约16∶1。
88.权利要求74的电化学传感器，其中传感层包括一种酶、一种酶稳定剂和一种交联剂。
89.权利要求74的电化学传感器，其中传感层包括一种酶、一种聚合的介体和一种交联剂。
CNA028133331A 2001-05-15 2002-05-15 由含有杂环氮的聚合物组成的生物传感器膜 Pending CN1639206A (zh)

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CN103462615A (zh) * 2013-09-13 2013-12-25 上海移宇科技有限公司 微米尺度葡萄糖传感器微电极
CN103462615B (zh) * 2013-09-13 2015-12-16 上海移宇科技有限公司 微米尺度葡萄糖传感器微电极
CN111867469A (zh) * 2018-03-13 2020-10-30 普和希控股公司 生物传感器探针用保护膜材料
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CN114981271A (zh) * 2019-12-26 2022-08-30 爱-森新株式会社 新型有机电子转移介体和包括其的装置

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