CN1573324A - 电化学生物传感器 - Google Patents
电化学生物传感器 Download PDFInfo
- Publication number
- CN1573324A CN1573324A CNA2004100283721A CN200410028372A CN1573324A CN 1573324 A CN1573324 A CN 1573324A CN A2004100283721 A CNA2004100283721 A CN A2004100283721A CN 200410028372 A CN200410028372 A CN 200410028372A CN 1573324 A CN1573324 A CN 1573324A
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- Prior art keywords
- biosensor
- acid
- sample
- electrode
- glucose
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Abstract
本发明提供了可以显著降低由血球引起的测量偏差的试剂层组合物。向由酶、电子转移介体和几种水溶性聚合物组成的常用试剂层组合物中加入脂肪酸(4-20碳原子)和季铵盐,不仅降低了与血球含量相关的偏差,还提供了非常稳定的延长期性能。还公开了适合使用本发明的试剂层组合物的各种类型的亚微升试样体积电化学生物传感器。
Description
技术领域
本发明涉及电化学生物传感器。更具体而言,本发明涉及包含导致由血球(hematocrits)引起的测量偏差急剧降低的试剂层组合物的电化学生物传感器。该试剂层组合物含有酶、电子转移介体、水溶性聚合物、脂肪酸(烷基链长度:4-20个碳原子),和季铵盐。还公开了适用于本发明的试剂层组合物的各种类型的亚微升试样体积电化学生物传感器。
背景技术
糖尿病的诊断和预防需要定期监测血糖含量。通过单独使用为手持式读出装置设计的条状生物传感器很容易进行。许多商用生物传感器采用以下反应量化总血样中的葡萄糖含量:
(其中GOx表示葡萄糖氧化酶;GOx-FAD和GOx-FADH2分别表示葡萄糖氧化酶的氧化态和还原态;且Mox和Mred分别表示氧化的和还原的电子转移介体。如反应中所示,葡萄糖通过将GOx-FAD还原成GOx-FADH2而被氧化为葡糖酸。还原的葡萄糖氧化酶将电子转移到介体Mox上,并转移到工作电极上。反应环的串连由施加在工作电极上的阳极电位驱动,并测量与葡萄糖含量成比例的氧化还原电流。
尽管电化学生物传感器方便地用于监测和控制血糖含量,但它们的精度受到血样中存在的各种易氧化物质(例如抗坏血酸、尿酸、醋氨酚等)的极大影响。另一种严重的测量偏差由血液中的血球导致。来自易氧化物质的干扰可以通过采用具有比试剂层中的干扰物质更低的氧化电位的电子转移介体而降低。然而,提出很少的实际溶液来降低来自血液中血球的测量偏差。它们教导了使用另外血球分离或分布在试剂层上的不含红细胞的层(JP 1134461,JP 2000338076和US 5658444),用氧化硅填料配制的可印刷试剂/血液分离糊料(US 6241862 B1),以及与双重激励电位结合的化学计量学校正方法(WO 01/57510 A2)。然而公开的方法不能通过试剂混合物在工作电极上的简单分散来实现,而要求在制造过程中额外的步骤或在印刷试剂层中大量损耗试剂来实现。
对于用一次性生物传感器条进行血糖含量常规监测的人而言,依赖于大量血球的偏差可以导致造成错误的判断,甚至会付出生命的代价。
发明内容
发明概述
因此,本发明的一个目的是提供能用于制备血球含量相关的偏差急剧降低的一次性生物传感器的试剂层组合物。本发明中提供的试剂层组合物可以直接滴状分散在生物传感器条的工作电极上,从而显著提高批量生产能力。
本发明的另一个目的是提供各种生物传感器设计,其在用本发明的试剂层组合物制备时,其电分析性能得到提高。
附图说明
本发明优选实施方案的应用可参考附图更好地理解,其中相同的参考数字用于相同和相应的部件,其中:
图1是带有根据本发明的进样部件的电化学生物传感器的分解透视图;
图2是根据本发明优选实施方案构建的逆向电极型生物传感器的分解透视图;
图3是表示带有根据本发明的进样部件和流体测定电极的逆向型电化学生物传感器的分解透视图;
图4是逆向型葡萄糖传感器上各种干扰物质的影响曲线图:(a)葡萄糖;(b)葡萄糖+醋氨酚(660μM);(c)葡萄糖+抗坏血酸(570μM);(d)葡萄糖+尿酸(916μM);
图5是表示逆向型葡萄糖传感器对于葡萄糖标准溶液的灵敏度的校正曲线的图;和
图6是用计时安培分析法获得的逆向型葡萄糖传感器对于葡萄糖标准溶液的动力学曲线图。
图7是举例说明试样流动性(作为时间的函数)与血球含量之间的关系图。
发明详述
本发明的电化学生物传感器包含:a)下层和上层基材;b)分别在下层基材或上层基材上形成的工作电极和参考(或反)电极;c)包含工作电极上形成的酶、电子转移介体、水溶性聚合物和脂肪酸或其盐的反应层;和d)下层与上层基材间形成的衬垫,其中衬垫提供有进样槽、排气管,以及进样槽与排气管交叉处的空隙的切割图案。
本发明的电化学生物传感器条包含:a)下层和上层基材(典型地为聚合物膜),其上通过导电材料(例如碳或金属糊料、金属蒸汽和导电聚合物)的丝网印刷或沉积形成了工作和辅助(反或参考)电极;b)Γ形试样孔,其密封在由双面粘合剂衬垫分开的两个基材之间;c)试剂层,其提供依赖于实质上减少的血球含量的偏差。
可在相同的底层基材上,或在下层和上层基材上形成电极***:即(1)在相同底层基材上形成的工作电极和辅助电极(或参考电极);和(2)分别在底层和面层基材上形成的,互相面对面排列的工作电极和辅助电极(逆向型电极:参见E.K.Bauman等,Analytical Chemistry,37卷,第1378页,1965;K.B.Oldham的“Microelectrodes:Theory and Applications,”KluwerAcademic Publishers,1991)。可在工作电极后面的底层基材上提供另外的电极,以测量全血试样的流动性。由于血球改变血液的流动性和电导率,通过生物传感器条的毛细孔的取样时间随全血试样中的血球含量而成比例变化。这种血液试样流动性的变化可用于校正血糖测量中与血球含量相关的偏差。
Γ形试样孔可以快速、准确和方便地从生物传感器条尖端引入血样。进样孔包括进样槽、排气管和空隙,其中进样槽与槽端下面的排气管交叉,在交叉处留下空隙。该空隙有助于保持不变的和准确的试样体积,用于槽内测量,通过排气管排出多余的试样,并且该空隙还可以进一步用于放置流动性测量电极。
简单地通过分配含有酶(例如葡萄糖氧化酶、乳酸盐氧化酶等)、电子转移介体、水溶性聚合物(例如乙酸纤维素、聚乙烯醇、聚吡咯等),和血球干扰还原剂(具有4-20碳原子的烷基链的脂肪酸),以及亲脂季铵盐的试剂层组合物溶液在生物传感器条的工作电极上而形成本发明的试剂层。
此外,本发明的生物传感器包含在上层基材上的观察孔,其位于试样孔的交叉封盖处。观察孔可以通过部分上层基材看到下层基材上的流动性测定电极,以观察试样充填情况。
参考图1,电化学生物传感器包含:用于形成电化学传感器和进样孔的衬垫200和下层基材400及上层基材300。衬垫200的一端内形成进样槽101、排气管102和空隙103。值得注意的是,在衬垫条中部形成的窄孔形进样槽101,在略低于槽形孔端部处以大致垂直的方式,与排气管102连接,在连接点后形成空隙103。总体而言,进样槽101、排气管102和空隙103构成进样部分100。
进样槽101是可以将试样引入生物传感器的通道,而且排气管102是空气的通道。由于毛细管作用,将待测试的试样引入进样部分100中,并且通过排气管102排出空气。
空隙103提供空位,并减少在进样槽101与排气管102的连接点处经常发生的气囊现象。气囊现象的发生导致测量不准确,因此空隙103保证了准确和可重复的取样。
排气管102与进样槽101的宽度间的比值(排气管102的宽度与进样槽101的宽度的比值)不大于1∶2。最优选的范围为1∶5-1∶2。比值低于1∶2保证了进样槽101中包含准确量的试样,使通过排气管102溢出充注的量最少。
在图1中,所示意的进样槽101与排气管102间的连接角(φ)为90°。但是,根据本发明的另一个实施方案,该角度可在约45°至约135°,优选的约75°至约105°的范围内变化。
也如图1所示,空隙103从进样槽101延伸过连接点。为了保证不形成气泡的准确量的试样,要求对包括空隙103的进样槽101进行亲水处理。
本发明的进样部分100具有引入0.1-3.0μl试样的容量。更优选此容量为0.1-1.0μl;最优选为0.3-0.7μl。小于0.1μl的试样太少,不能在现有生物传感器的误差范围内进行准确测量。同时大于3.0μl的试样又太多。在优选的实施方案中,对正好0.5μl的试样获得了准确的测量。
压制由聚酯、聚氯乙烯或聚碳酸酯构成的有机聚合物膜产生了下层和上层基材间的垫片200的引入。它可通过压制由有机聚合物制成的双面粘合剂膜,或丝网印刷具有图1所示图案的粘合剂层来制备。
以下详细描述进样部分100的工作原理。
首先,当试样刚与进样槽101的入口接触,就借助毛细管作用将试样导入进样槽101,使进样槽101充满试样至空隙103。然后多余试样前进到排气管102。在此,通过将排气管102宽度与进样槽101宽度之比控制在1∶2以下,可使试样溢出最小,且亲水空隙103消除了在进样槽101与排气管102之间的连接点处发生的气袋形成现象。
根据本发明优选实施方案,假定进样容量0.5μl,根据血球含量、血样储存条件和所用抗凝剂类型,进样部分100在约200-2000ms内充注血样。作为血球含量的函数,新鲜血样通常在约200-800ms内充注0.5μl的试样管。
本发明的进样部分100可用于各种类型的生物传感器,包括平板型生物传感器(仅在底部基材上形成电极)、逆向型生物传感器(其工作电极和反电极分别形成于底部基材和上层基材上)、差分平板型生物传感器、差分逆向型生物传感器,或带有流动性测定电极的逆向型生物传感器。
图2举例说明具有进样部分100的逆向型生物传感器,其特征在于,底部基材400,其上印刷有工作电极104和电极连接器106,并且氧化酶和电子转移介体固定在工作电极104上;具有进样部分100的进样垫片200;在底部印刷了参考电极105和电极连接器106的上层基材300。可以如图所示形成进样部分100,但只要进样槽101与排气管102相通,并在相通点形成空隙103即可使本发明满足;也可进行如上详述改进空隙103的结构。
可以与具有进样部分100的平板型生物传感器相同的方式完成具有进样部分100的逆向型生物传感器的构成。
图3表示具有试样流动性测定能力的逆向型生物传感器,其特征在于:下层基材400,其上印刷了工作电极104、电极连接器106、流动性测量电极107和生物传感器识别电极108,且工作电极104上固定了氧化酶和电子转移介体;包括进样部分100的进样垫200;以及上层基材300,其底部印刷了参考电极105和电极连接器106。注意参考电极可印刷在除充注试样的观察孔和注册商标条的区域外的整个上层基材上,以提供更精致的外观。可以如图所示形成进样部分100,但只要进样槽101与排气管102相通,并在相通点形成空隙103即可以使本发明满足;也可以如上详述改进空隙103的结构。试样流动性作为接近进样口的电极105的第一接触点与位于空隙103或排气管102处的流动性测定电极107之间的试样充注速度的函数确定。
可以由陶瓷、玻璃或聚合物材料制成用于上述生物传感器的下层或上层基材的任何基材,其中优选聚酯、聚氯乙烯或聚碳酸酯的有机聚合物。可以使用导电材料,例如银环氧化物(Silver epoxy)、银/氯化银、碳、氧化还原电偶,或含有树脂粘合剂的改性导电碳糊料实现诸如参考电极、工作电极和辅助电极的电极的制备。可以将这些材料通过丝网印刷法、气相沉积然后刻蚀的方法,或导电胶带粘合形成为参考电极、反电极和工作电极。
上述具有进样部分100的生物传感器具有许多优点。
(1)当将试样快速导入生物传感器时,可以减少进样槽与排气管间相通点处发生的气囊现象。
(2)由于进样部分100通过狭窄入口和排气管封闭很好,因此本发明的生物传感器通过最小的蒸发而保持恒定的试样浓度,从而提高分析的再现性。此外,当采用条形并从仪器移开时,本发明比其他类型的进样方式可以更好地包容试样,从而显著减少污染的可能性。
(3)其中进样槽和排气管以大致垂直的方式相通的配备有进样部分100的生物传感器能快速导入预定量的血样,增加准确性和再现性。
(4)当本发明应用于人体器官时,更容易允许通过生物传感器尖端采血。
简单地通过分散一滴(约300-500nL)试剂层组合物溶液,可以在工作电极上形成试剂层。试剂层组合物溶液可以含有用于目标分析物的酶(氧化酶、酯酶或脱氢酶)、电子转移介体、各种水溶性聚合物和血球干扰还原剂。
对于血糖测量生物传感器***,可采用葡萄糖氧化酶或葡萄糖脱氢酶。在此,应当注意尽管描述了用于分析血糖含量的生物传感器,本发明可以将合适的酶和电子转移介体引入电极体系,使得可以定量地分析各种试样,其包括生物物质,如代谢物例如胆固醇、乳酸、肌酸酐、蛋白质、过氧化氢、醇、氨基酸,和酶如GPT(谷丙转氨酶)和GOT(谷草转氨酶),环境材料,农业和工业材料,以及食品材料。例如,可以分别使用葡糖氧化酶、乳酸氧化酶、胆固醇氧化酶、机酸酐氧化酶、辣根过氧化物酶或醇氧化酶来定量分析胆固醇、乳酸、肌酸酐、过氧化氢和醇。
为工作电极提供的电子转移介体可采用二茂铁或其衍生物、醌或其衍生物、有机传导盐或viologen。优选的电子转移介体是能形成氧化还原电子对的混和价化合物,包括六胺氯化钌(III)、铁***、亚铁***、二甲基二茂铁、二茂铁、二茂铁(ferocene)-一羧酸、7,7,8,8-四氰基醌二甲烷、四硫富瓦烯、二茂镍、N-甲基酸鎓(methylacidinium)、四硫代并四苯、N-甲基菲鎓(methylphenazinium)、氢醌、3-二甲氨基苯甲酸、3-甲基-2-苯并噻唑啉酮腙(benzothiozolinone)、2-甲氧基-4-烯丙基酚、4-氨基安替比林、二甲基苯胺、4-氨基安替比林、4-甲氧基萘酚、3,3’,5,5’-四甲基联苯胺、2,2-连氮基-二[3-乙基苯并噻唑啉(ethylbenzthiazoline)磺酸酯]、邻联二茴香胺、邻甲苯胺、2,4-二氯苯酚、4-氨基非那宗、联苯胺和普鲁士蓝。在这些当中,优选用于建议的生物传感器体系的电子转移介体是六胺氯化钌(III),因为它满足几个条件:(1)其氧化态和还原态在水溶液中都是稳定和可逆的;(2)还原的电子转移介体对氧无反应性;(3)其表观电位低足以使干扰物质如抗坏血酸、尿酸和醋氨酚的影响最小化;(4)还原的电子转移介体的氧化对pH值不敏感;和(5)它不与电化学干扰物质如抗坏血酸、醋氨酚和尿酸反应。
水溶性分子(溶解在PBS缓冲液中之前的固体成分为0.1-10重量%,pH6.5)选自水溶性聚合物,如聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)、全氟磺酸酯、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羰甲基纤维素(CMC)、乙酸纤维素、聚酰胺等。将水溶性分子加入至试剂层组合物溶液中有助于分散或稳定酶。优选PVP和HPC用于制备本发明的试剂层组合物溶液。
可以将含有4-20碳原子的直链烷基链的脂肪酸溶解在水或可混溶水的溶剂中,并且以所有固体成分的0.1-20重量%的量加入至试剂溶液中。优选使用含有6-12碳原子的烷基链的饱和脂肪酸或其盐:它们包括己酸、庚酸、辛酸、壬酸、癸酸、十一酸和月桂酸。脂肪酸的加入极大地有助于减小与血球相关的偏差。另一方面,脂肪酸倾向于缩短生物传感器的线性动态范围,特别是在高浓度区域。
季铵盐如十二烷基三甲基铵、肉桂基三甲基铵、十六烷基三甲基铵、十八烷基三甲基铵、四己基铵等的卤化物化合物与脂肪酸补救了这一问题,同时基本上减小了与血球相关的偏差。季铵盐以所有成分的0.1-30重量%的量加入到试剂层组合物溶液中。
通过以下实施例可以更好地理解本发明,但实施例的提出是为了举例说明,而不认为是限制本发明。
具体实施方式
实施例1:不含脂肪酸的试剂层组合物溶液的制备
将含有30mg的六胺氯化钌(III)(41.6重量%)、1mg的羧甲基纤维素(1.4重量%)、1mg的***(Triton)X-100(1.4重量%),和40mg的葡萄糖氧化酶(55.6重量%)的混合物溶解在1ml的PBS缓冲溶液中(pH6.5)(pH6.4),并滤除溶液中残余的颗粒。将试剂溶液置于气动分配器(EFDXL100)的注射器中。
实施例2:包含脂肪酸的试剂层组合物溶液的制备
将含有30mg的六胺氯化钌(III)(32.6重量%)、1mg的羧甲基纤维素(0.8重量%)、5mg的聚乙烯吡咯烷酮(4重量%)、1mg的***X-100(0.8重量%),20mg的月桂酸(15.7重量%)、30mg的肉豆蔻基三甲基溴化铵(23.6重量%),和40mg的葡萄糖氧化酶(31.5重量%)的混合物溶解在1ml的PBS缓冲液中(pH6.4),并滤除溶液中残余的颗粒。将试剂溶液置于气动分配器(EFD XL100)的注射器中。
实施例3:逆向型双电极生物传感器的制备
如图2所示,用导电碳糊料丝网印刷工作电极104和电极连接器106,并且在140℃下固化5分钟。然后,在电极连接器106一端用银糊料丝网印刷电路连接器。用碳糊料丝网印刷具有印刷电极作为参考(辅助)电极105的上层基材并固化。最后,将参考电极105的端部用银糊料丝网印刷为电路连接器,制备生物传感器。
通过按压由聚酯制成的双面胶带,将包含进样槽101、排气管102和空隙103的进样垫片200放置于下层基材上。排气管102与进样槽101的宽度之比为2∶1,并将=进样部分100中的血样总量调节到0.5μl。
将实施例1或实施例2的试剂层组合物溶液涂布在工作电极104上,并在45℃下放置30分钟至干燥。
将上层基材300按压在进样垫片200上,以使其与分散了试剂的下层基材400的电路连接器连接,完成图2所示的生物传感器。
实施例4:带有流动测定电极的生物传感器的制备
具有流动性测定电极107的生物传感器是逆向型生物传感器,根据与实施例3所举例说明的相同的方式制备,不同的是在整个上层基材上印刷反电极(图3)。流动性测定电极的尖端置于进样部分的空隙103处。
将实施例1或实施例2的试剂层组合物溶液涂布在工作电极104上,并在45℃下放置30分钟至干燥。
将上层基材300按压在进样垫片200上,使其与分散了试剂的下层基材400的电路连接器连接,完成图3所示的生物传感器。
<试验实施例1>干扰物质在逆向型葡萄糖传感器上的影响
在如实施例3所述制备的逆向型葡萄糖传感器上,通过以下试验测量干扰物质如抗坏血酸、醋氨酚或尿酸的影响。葡萄糖传感器的平均体积为0.5μl。
具体而言,分别测量对下列溶液的总响应电流:(a)含有177mg/dL葡萄糖的磷酸盐缓冲剂(pH6.4)(pH7.4)标准溶液,(b)含有177mg/dL葡萄糖+660μM醋氨酚的磷酸盐缓冲液,(c)含有177mg/dL葡萄糖+570μM抗坏血酸的磷酸盐缓冲液,或(d)含有177mg/dL葡萄糖+916μM尿酸的磷酸盐缓冲液。通过在工作电极104(与参考电极比较)上施加+0.2V电位后5秒读取计时电流响应来测量该电流。结果示于图4。
图4所示为在施加+0.2V的电位时,传感器受干扰物质存在的影响不明显。
<试验实施例2>逆向型葡萄糖传感器对标准葡萄糖溶液的校正曲线
检验在实施例3中制备的逆向型葡萄糖传感器对葡萄糖标准溶液的灵敏度。
具体而言,在相对于参考电极施加0.2V电位的电场下,在每个浓度0、50、150、300、450或600mg/dL下测量电流值10次。施加到进样部分的试样量为0.5μl,充注时间不超过200ms。在通过施加0.2V达3秒以导入试样后2秒进行测量,在5秒内读取电流值。由此获得的校正曲线示于图5。
由此获得的动态曲线示于图6,其中相应的曲线表示:葡萄糖浓度为0mg/dL(曲线a)、50mg/dL(曲线b)、150mg/dL(曲线c)、300mg/dL(曲线d)、450mg/dL(曲线e)和600mg/dL(曲线f)。
如图6所示,斜率为0.093[μA/(mg/dL)],相关系数为0.997。从这些结果,证实电化学生物传感器具有优异的线性灵敏度(图5)。
<试验实施例3>血液流动性的测量和血球偏差的校正
如实施例4所述,制备配备有流动性测定电极的生物传感器。向工作电极104和流动性测定电极107施加200mV的电位(相对于参考电极105)。当通过进样槽101导入血样时,检测到电流的突变,并且开始时间测量。一旦试样到达空隙103,检测第二个峰值电流,并记录第一和第二峰值电流间的时间间隔。进样时间与血球含量间的关系示于图7。试验用经氟化钠处理的含有180mg/dL葡萄糖和不同血球含量的全血进行。
由以上结果得到拟合方程。
[数学式1]
Y=-72.23+0.58691X-0.00084073X2-1.1211×10-6X3+5.7521×10-9X4-9.1172×10-12X5。
(其中Y是由用流动性测定电极测量的试样充注时间X估计的血球含量。)
表1所示为由试样充注速度和时间估计的血球含量。
表1.由实施例4制备的生物传感器的试样充注时间估计的血球含量
制备试样的血球(%) 速度(ms) 估计血球(%) |
30% 326 30.3%35% 352 32.8%40% 530 41.8%45% 634 44.0%50% 1129 50.1%55% 1791 54.7% |
在单个试验中,校正曲线用各种血球含量的全血获得,并公式化了血球含量与相应斜率之间的关系(表2)。
表2、不同血球含量下的校正曲线
血球 方程式(y=电流μA;x=葡萄糖) |
30% y=0.035934x-1.722835% y=0.030559x-1.3181540% y=0.025831x-1.013745% y=0.021752x-0.8094550% y=0.018322x-0.705455% y=0.015539x-0.70155 |
用这种方式派生出的校正因子用于再校正相对于具有40%血球含量的全血测量的葡萄糖含量,得到提供与血球无关的葡萄糖浓度的生物传感器。首先从表头读取进样速度,确定血样中的血球含量,然后查阅提供了相应的校正曲线的表,并从所测电流确定葡萄糖含量。表3表示如上进行的试验结果。
表3、全血中的葡萄糖浓度;用流动性测定电极测量的进样速度和用
表2中的校正曲线估计全血中的葡萄糖含量
血球% 葡萄糖 修正的血球YSI2300(mg/dL) (mg/dL) |
111 11730% 202 186381 392 |
138 14135% 200 207276 277 |
107 11240% 196 195266 264 |
103 10545% 190 189367 363 |
102 10750% 142 143253 256 |
125 14455% 241 240332 331 |
流动性测定电极还区别异常流动的血样,即血球含量太高或太低的试样,和由于形成气泡而堵塞了导入的血样。在此情况下,可以将测量装置设置成为对测量发出报警信号或错误代码。
<试验实施例4>由含脂肪酸试剂层减小的干扰血球
如实施例4所述,制备生物传感器条。将用肝素处理的全血样离心分离血浆和血球,并重新混和得到三种不同血球含量(20、40和60%)的血样。用实施例1和实施例2的试剂层制备的生物传感器评价三种不同葡萄糖浓度下的血球对葡萄糖测量的影响。结果列于表4和5。很明显用实施例2的试剂制备的生物传感器显著降低了血球的影响,提供的对于40%血球含量的相对误差在临床上可接受的范围内。
表4、血球对用实施例1的试剂层制备的生物传感器测量葡萄糖的影响
试样 | 1 | 2 | 3 | ||||||
血球含量 | 20 | 40 | 60 | 20 | 40 | 60 | 20 | 40 | 60 |
YSI葡萄糖含量(mg/dL) | 137 | 126 | 113 | 264 | 238 | 228 | 389 | 377 | 339 |
基于实施例1试剂的生物传感器 | 175 | 125 | 88 | 365 | 231 | 146 | 544 | 369 | 114 |
与40%血球含量相关的偏差%* | 29 | 0 | -22 | 42 | 0 | -34 | 43 | 0 | -66 |
*与40%血球含量相关的偏差%={(生物传感器的葡萄糖含量/YSI的葡萄糖含量)/(生物传感器在40%血球下的葡萄糖含量/YSI在40%血球下的葡萄糖含量)-1}×100
表5、血球对用实施例2的试剂层制备的生物传感器测量葡萄糖的影响
试样 | 1 | 2 | 3 | ||||||
血球含量 | 20 | 40 | 60 | 20 | 40 | 60 | 20 | 40 | 60 |
YSI葡萄糖含量(mg/dL) | 120 | 111 | 107 | 212 | 199 | 191 | 435 | 398 | 374 |
基于实施例2试剂的生物传感器 | 133 | 114 | 99 | 241 | 201 | 185 | 423 | 382 | 334 |
与40%血球含量相关的偏差%* | 8 | 0 | -10 | 13 | 0 | -4 | 1 | 0 | -7 |
表5中总结的结果表明,基于实施例2试剂的生物传感器表现出对不同血球含量(从20%到60%)的干扰响应显著降低,其相对于40%血球含量的测量偏差小于10%。
借助于本发明优选实施方案描述了实施例。然而,不应该理解为这种公开限于本发明的清楚说明。将本发明的说明书和权利要求解释为覆盖本发明真实范围内的所有变化和修正。
Claims (18)
1、一种电化学生物传感器,其包含:
下层基材;
上层基材;
分别在所述的下层基材或所述上层基材上形成的工作电极和参考(或反)电极;
在所述工作电极上形成的反应层,所述的反应层含有酶、电子转移介体、水溶性聚合物和脂肪酸或其盐;和
在所述下层和上层基材间形成的垫片,其中所述垫片提供了切割图案的进样槽、排气管,和在进样槽与排气管交叉处的空隙。
2、根据权利要求1所述的生物传感器,其中所述工作电极和参考电极形成于同一基材上。
3、根据权利要求1所述的生物传感器,其中所述工作电极和参考电极形成于不同基材上。
4、根据权利要求1所述的生物传感器,其在所述下层基材上还包含流动性测定电极。
5、根据权利要求1所述的生物传感器,其中所述的脂肪酸或其盐含有4-20个碳原子的烷基链,并且其加入量为所有成分的0.1-20重量%。
6、根据权利要求1所述的生物传感器,其中所述脂肪酸选自饱和脂肪酸、己酸、庚酸、辛酸、壬酸、癸酸、十一酸、月桂酸、十三酸、肉豆蔻酸、十五酸、棕榈酸、十七酸、硬脂酸、十九酸和花生酸。
7、根据权利要求1所述的生物传感器,其中所述脂肪酸产生了降低由血球引起的测量偏差的效果。
8、根据权利要求1所述的生物传感器,其中所述反应层还含有所有成分的0.1-30重量%的季铵盐。
9、根据权利要求8所述的生物传感器,其中所述的季铵盐选自十二烷基三甲基铵、肉桂基三甲基铵、十六烷基三甲基铵、十八烷基三甲基铵和四己基铵的卤化物化合物。
10、根据权利要求1所述的生物传感器,其中所述的酶选自葡萄糖氧化酶、葡萄糖脱氢酶、胆固醇氧化酶、胆固醇酯酶、乳酸盐氧化酶、抗坏血酸氧化酶、醇氧化酶、醇脱氢酶和胆红素氧化酶。
11、根据权利要求1所述的生物传感器,其中所述电子转移介体选自六胺氯化钌(III)、铁***、亚铁***、二甲基二茂铁、二茂铁、二茂铁-一羧酸、7,7,8,8-四氰基醌二甲烷、四硫富瓦烯、二茂镍、N-甲基酸鎓、四硫代并四苯、N-甲基菲鎓、氢醌、3-二甲氨基苯甲酸、3-甲基-2-苯并噻唑啉酮腙、2-甲氧基-4-烯丙基酚、4-氨基安替比林、二甲基苯胺、4-氨基安替比林、4-甲氧基萘酚、3,3’,5,5’-四甲基联苯胺、2,2-连氮基-二[3-乙基苯并噻唑啉磺酸酯]、邻联二茴香胺、邻甲苯胺、2,4-二氯苯酚、4-氨基非那宗、联苯胺和普鲁士蓝。
12、根据权利要求11所述的生物传感器,其中所述电子转移介体是六胺氯化钌(III)。
13、权利要求1所述的生物传感器,其中所述水溶性聚合物用于分散和稳定所述酶,并选自聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)、全氟磺酸酯、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羧甲基纤维素(CMC)、乙酸纤维素酯、葡聚糖和聚酰胺。
14、根据权利要求1所述的生物传感器,其中所述排气管宽度与进样槽的宽度之比不大于1∶2。
15、根据权利要求1所述的生物传感器,其中所述进样槽具有保持0.1-1.0μl液体试样的能力。
16、根据权利要求1所述的生物传感器,其中所述进样槽与排气管以75-105°的角度相交,且从相交点到槽端部提供所述的空隙。
17、根据权利要求4所述的生物传感器,其中所述流动性测定电极用于修正与血球含量相关的偏差。
18、根据权利要求1所述的生物传感器,在所述上层基材上进一步包含位于试样管的交叉封盖处的观察孔。
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CN102947697A (zh) * | 2010-03-31 | 2013-02-27 | 丹麦技术大学 | 用于检测气或液相中的分析物或其混合物的多传感器阵列 |
CN102947697B (zh) * | 2010-03-31 | 2015-12-16 | 丹麦技术大学 | 用于检测气或液相中的分析物或其混合物的多传感器阵列 |
CN103534585A (zh) * | 2011-05-18 | 2014-01-22 | 六号元素有限公司 | 具有金刚石电极的电化学传感器 |
CN103534585B (zh) * | 2011-05-18 | 2015-11-25 | 六号元素有限公司 | 具有金刚石电极的电化学传感器 |
CN103842518A (zh) * | 2011-09-30 | 2014-06-04 | 爱-森斯株式会社 | 用于电化学生物传感器的氧化还原试剂组合物及包含所述组合物的生物传感器 |
CN103842518B (zh) * | 2011-09-30 | 2016-10-12 | 爱-森斯株式会社 | 用于电化学生物传感器的氧化还原试剂组合物及包含所述组合物的生物传感器 |
US10000785B2 (en) | 2011-09-30 | 2018-06-19 | I-Sens, Inc. | Composition of redox-reagents for electrochemical biosensor and biosensor comprising the same |
CN105102972A (zh) * | 2013-01-11 | 2015-11-25 | 东北大学 | 唾液葡萄糖监测*** |
CN109781821B (zh) * | 2017-11-10 | 2023-10-24 | 上海瀚联医疗技术股份有限公司 | 一种血糖检测仪 |
CN113999889A (zh) * | 2021-10-08 | 2022-02-01 | 东南大学 | 一种采用普鲁士蓝纳米酶的干式葡萄糖试纸条及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
ATE346161T1 (de) | 2006-12-15 |
EP1486778A3 (en) | 2005-01-05 |
JP2005003679A (ja) | 2005-01-06 |
KR20040105429A (ko) | 2004-12-16 |
US7288174B2 (en) | 2007-10-30 |
JP4018082B2 (ja) | 2007-12-05 |
CN1323293C (zh) | 2007-06-27 |
EP1486778B1 (en) | 2006-11-22 |
KR100554649B1 (ko) | 2006-02-24 |
DE602004003288T2 (de) | 2007-05-31 |
US20050000808A1 (en) | 2005-01-06 |
EP1486778A2 (en) | 2004-12-15 |
DE602004003288D1 (de) | 2007-01-04 |
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