CN1981191B - Sire流通检测器 - Google Patents
Sire流通检测器 Download PDFInfo
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Abstract
本发明涉及一种装置和方法用以快速检测在液体流中的低分子物质。
Description
技术领域
本发明涉及一种装置，用于快速检测在微量渗析探针、过滤单元、发酵罐、细胞悬液、化学反应器、人体、组织或动物体的液体流中的低分子物质，和用于药物或者活性物质(例如但不限于如胰岛素或代谢物)的剂量确定、调制和控制，以及发酵罐、细胞悬液或化学反应器中的化学或生物处理。
背景技术
液体色谱的年世界交易量从1960年初时至今日已经迅猛发展，这个领域的市场领头羊是如Pharmacia & Upjohn AB，Applied Biosystems Inc，Bioanalytical Systems，Hitatchi Instruments和Waters Corporation等公司。
与此发展的同时，诸如微量渗析探针等仪器已经被制造用于患者和动物的活体监测。致力于这个领域的公司包括CMA Microdialyls AB(瑞典)和SpectRx Inc(美国)。
涉及监测和控制化学作用和发酵罐的第三领域正在发展中。活跃在这个领域的公司有诸如Applikon(荷兰)，YSI Inc(美国)和Trace BiotechAg(德国)。后者已经发展了微量渗析类型的仪器用于在无菌环境下从发酵罐中取样。
所提及的三个领域的共同点是它们都依赖于检测系统，优选为流通检测器类型的检测系统。采用不同类型的流通检测器可以识别和量化几种重要化学物质。依靠物理测量原理，不同类型的检测器只能用于解决不同种类的问题。在某些情况下几种检测器已经展现了优良的效果。当代谢物诸如葡萄糖，乳酸盐和乙酸盐要被检测时，可使用生物传感器。由于生物传感器的不稳定性，测量性能上的要求还不能实现。
自从1995年以来，一种新型生物传感器技术，SIRE(基于识别元素的注入的传感器，Sensors based on Injection of the Recognition Element)生物传感器已被研发，其是基于注入可识别元素(SE510733(1999)，US6214206(2001)和US6706160(2004))。该技术已经解决了通常涉及测量化学物质的许多技术问题。本发明可以更确切地并入所提及的技术，由于它可以使用可注入的化学酶作为试剂，但不同之处是它基于一项新技术结构，其用新颖的和无法预料的方式解决了源自液体流中的化学物质的定性和定量测量的问题。
时至今日没有技术解决办法被提出以解决使用传统流通检测器来确定低分子物质(Mw＜5kDa)这一方法中所存在的大多数问题，低分子物质例如是(但不限于)葡萄糖，乳酸盐，抗坏血酸盐，麦芽糖，半乳糖，尿素，乙醇，甲醇，过氧化氢，抗坏血酸，乳糖，麦芽糖，苹果酸，谷氨酸盐和蔗糖。
上述问题包括需要近距离连接流通检测器和取样点(从而可达到缩短由于样品传输导致的分析时间和减少样品流量的数量)，特殊测量，快速测量，抗温度效应性(包括周围和液体流的温度)，以及避免人工操纵样品。
本申请中描述的流通检测器，提供了分析所述低分子物质的新颖和独特的方法。本发明是全新方式解决源自液体流测量中的不同种类问题的强有力的解决方案。本发明的主要优点是：新陈代谢的活性低分子物质可以定性和定量的确定，本发明可以近距离连接取样点并且对在此类测量中普遍具有的受温度波动影响的结果不敏感。
用来鉴别化学物质的不同种类的流通检测器已被披露。业已使用不同种类的物理测量原理，例如光学吸收测量(GB2089062)，萤光测量(TakeuchiT.And Miwa T.Anal.Chim.Acta 311，231-236，1995)，喇曼光谱分析测量(Cabalin L.M.et.al.Talanta 40，1741-1747，1993)，FTIR分光光度测量(Hellgeth J.W.and Taylor L.T.Anal.Chem.59，295-300，1987))，光-声测量(Voigtman E.et.al.Anal.Chem.53，1921-1923，1981)，电-光测量(Hill E.et.al.J.Chromatography 370，427-437，1986)，放射性测量(De KorteD.et.al.J.Chromatography 415，383-387，1987)，电化学测量(Sagar K.A.Talanta 42，235-242，1995)。这些是基于其它类型的结构，无法解决上面所述的问题。
早些时候，用于样品中酶活性测定的仪器已被报道(JP2-208551(1990))。然而，酶是具有分子量通常大于5kDa的高分子物质，并且它们可以通过半透膜的能力减小。所述的报道描述了一种流通检测器，其缺少主要元件，即，在本申请中描述的存在于本发明的所述半透膜。而且温度传感器，加热/冷却元件也没提及。
发明内容
本发明是一装置，其特征在于它包括了由半透膜(由尺寸范围在0.1到900纳米的纳米孔冲孔而成)分开的最少为两个的流通腔、检测器、温度传感器、一个或多个电缆连接器，这里所述各流通腔中包含所述检测器的一个流通腔具有入口和出口，用于含有酶试剂的液体流，其它流通腔中的每个都具有从采样点来的液体流的入口和出口。
本发明还涉及一种方法，其中采用根据本发明所述的装置用于液体流中的低分子化学物质的实时和/或接近于实时的探测。
本发明还涉及一种方法，其中特别采用根据本发明所述的装置来作为液体色谱法(例如毛细管液体色谱法，HPLC，FPLC，亲和色谱法，凝胶过滤法)中的流通检测器，并用来检测在微量渗析探针、过滤单元、发酵罐、细胞悬液、化学反应器、人体、组织或动物体中的低分子物质，和用于药物或活性物质(例如但不限于如胰岛素或代谢物)的剂量确定、调制和控制，以及发酵罐、细胞悬液、化学反应器或组织中的化学或生物处理。
附图说明
图1示出根据本发明所述装置的原理图。包含待测低分子物质的液体流通过入口A引入到流通腔B，其中所述物质可以通过半透膜G的纳米孔 扩散到流通腔E，或者从流通腔B随着液体流被引导通过出口C。当所述提到的物质在流通腔E中时，它们能与已通过入口D引入到该腔体中的酶试剂起化学反应。酶促反应生成的产物扩散到检测器H，并产生一个电信号，该电信号与从入口A引入的所述液体流中的所述低分子物质的量定量地相关。进入的液体、酶、未反应的低分子物质和反应产物通过出口F离开流体腔E。所述入口和出口可以颠倒，因此可实现相反方向的流动。参照前面提及的SIRE生物传感器原理，检测器H也可以用来探测背景信号。该检测器H还可以包括一个温度传感器和/或生热/冷却元件。
具体实施方式
根据本发明的一个方面，所述装置特征在于所述流通腔的每一个具有介于0.1到5000微升的腔体积。
根据本发明的另一方面，所述装置特征在于其包含一个三电极系统，一个由铂制成的工作电极，一个由银制成的参考电极，和一个由铂或银制成的对电极(counter electrode)。
根据本发明的再一方面，所述装置特征在于所述工作电极具有比所述参考电极的电位高200-1000mV的电位。
根据本发明的又一方面，所述装置特征在于其配备有温度传感元件，该温度传感元件例如是(但不限于)Pt100、Pt1000、DS1820、LM35或KTY81-120，用来作为测量中的温度补偿。
根据本发明的又一方面，所述装置特征在于其装配了生热/冷却源，该生热/冷却源例如是(但不限于)电阻器或珀耳帖元件，用来将所述装置的温度恒定在介于5-80摄氏度的一个常温。
根据本发明的又一方面，所述装置特征在于所述半透膜由例如(但不限于)醋酸纤维素、高氟化树脂(Nafion)、陶瓷材料、冶金材料和具有分子截断大小介于0.1kDa到500kDa的限制高分子物质渗透性的聚合物物质制成，该高分子物质的例子是但不限于酶、蛋白质、细胞、细胞成分和聚合物。
根据一个方面，所述测量原理是基于在本专利申请前部提及的所谓的SIRE生物传感器技术。
图1示出了本发明的原理图。包含待测低分子物质的液体流通过入口A引入到流通腔B，其中所述物质可以通过半透膜G的纳米孔扩散到流通腔E，或者随着所述液体流被运输，从流通腔B被引导通过出口C。当所述物质在流通腔E中时，它们能够与通过入口D引入到该腔体中的酶试剂起化学反应。酶促反应生成的反应产物扩散到检测器H，并产生一个电信号，该电信号与通过入口A引入的所述液体流中的低分子物质的含量定量地相关。进入的液体、酶、未反应的低分子物质和反应产物通过出口F离开流体腔E。
进口和出口可以重新定向，因此可得到相反方向的流体。根据前面所述的SIRE生物传感器原理，检测器也可以用来检测背景信号。该检测器还可以包括一个温度传感器和/或生热/冷却元件。
低分子物质的实例可以是在所述专利文献中大量描述的由微量渗析探针、发酵罐、细胞悬液、化学反应器、人体、组织或动物体的液体流量中的低分子物质。
基于例如可见光/紫外光或传导性的传统的流通单元不能定性或定量地确定在微量渗析探针、发酵罐、细胞悬液、化学反应器、人体、组织或动物体的液体流中出现的大部分低分子物质。
本发明能够解决该问题是由于，其特异性和所用试剂的酶化能力馈送给检测器以足够量的化学信号物质，例如象由氧化酶形成的过氧化氢，能定性上确定所述的低分子物质的量。
Claims (10)
1.一种生物传感器装置，包含具有平均剖面介于0.1-900纳米的纳米孔的半透膜，其中所述半透膜隔离开两个流通腔，其中第一流通腔包含一电流计型检测器和用于包含酶试剂的液体流的入口和出口，其中第二流通腔具有用于液体流的入口和出口，所述液体流包含用来进行定性和/或定量探测的化学物质。
2.如权利要求1所述的装置，其特征在于其还配备了温度传感器用于所述定性和/或定量探测中的温度补偿。
3.如权利要求2所述的装置，其特征在于所述温度传感器的型号为Pt100、Pt1000、DS1820、LM35或KTY81-120。
4.如权利要求1或2所述的装置，其特征在于其还配备了生热或冷却元件，用来将所述装置恒定在一个介于5-80摄氏度的恒定温度。
5.如权利要求1或2所述的装置，其特征在于所述检测器包含由一个铂制成的工作电极，一个由银制成的参考电极和一个由铂制成的对极板。
6.如权利要求5所述的装置，其特征在于所述工作电极具有比所述参考电极的电位高200-1000mV的电位。
7.如权利要求1或2所述的装置，其特征在于前述两个流通腔中的每一个都具有介于0.1-5000μl的腔体体积。
8.如权利要求1或2所述的装置，其特征在于所述半透膜包含醋酸纤维素、高氟化树脂、陶瓷材料，冶金材料和具有分子截断大小介于0.1kDa到500kDa的聚合物的物质。
9.一种测量方法，其中采用如权利要求1-8中任一项所述的装置来定性和/或定量确定在微量渗析探针、发酵罐、细胞悬液、化学反应器、人体、组织或动物体的液体流中的满足Mw＜5kDa的低分子物质。
10.一种用于化学或生物处理的方法，其中采用如权利要求1-8中任一项所述的装置来优化、控制或调制在发酵罐、细胞悬液或化学反应器中的化学或生物处理。
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| SE04018149 | 2004-07-08 | ||
| SE0401814A SE527196C2 (sv) | 2004-07-08 | 2004-07-08 | SIRE genomflödesdetektor |
| SE0401814-9 | 2004-07-08 | ||
| PCT/SE2005/000911 WO2006006905A1 (en) | 2004-07-08 | 2005-06-15 | Sire flow detector |
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| CN1981191A CN1981191A (zh) | 2007-06-13 |
| CN1981191B true CN1981191B (zh) | 2011-05-18 |
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| JP (1) | JP4801062B2 (zh) |
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| CN (1) | CN1981191B (zh) |
| CA (1) | CA2573071A1 (zh) |
| MX (1) | MX2007000024A (zh) |
| SE (1) | SE527196C2 (zh) |
| WO (1) | WO2006006905A1 (zh) |
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| SE0402078L (sv) * | 2004-08-25 | 2006-02-07 | Chemel Ab | Kalibrerbar genomflödesdetektor |
| JP4769939B2 (ja) * | 2006-01-12 | 2011-09-07 | 国立大学法人九州工業大学 | マイクロ流体酵素センサ |
| CN102175739A (zh) * | 2010-12-31 | 2011-09-07 | 北京工业大学 | 酶注射式葡萄糖生物传感器 |
| HUE042040T2 (hu) | 2012-09-27 | 2019-06-28 | Merus Nv | Bispecifikus IGG antitestek mint T-sejt kapcsolók |
| DE102013007872B4 (de) * | 2013-05-08 | 2015-01-22 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Elektrochemischer Gassensor, Verfahren zu dessen Herstellung und dessen Verwendung |
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| US4025308A (en) * | 1974-06-07 | 1977-05-24 | United Kingdom Atomic Energy Authority | Method and apparatus for monitoring low concentrations of ions in a flowing fluid |
| CN85107234A (zh) * | 1985-09-24 | 1987-04-01 | 物理传感器公司 | 使用导纳调制膜的化学选择传感器 |
| CN1372135A (zh) * | 2001-02-28 | 2002-10-02 | 清华大学 | 生物机－电芯片及应用 |
| US6706160B2 (en) * | 1995-01-03 | 2004-03-16 | Chemel Ab | Chemical sensor and use thereof |
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| US4052308A (en) * | 1975-08-25 | 1977-10-04 | Edward Wilford Higgs | Contamination entrapment and cleaning device for motor vehicle engine liquid cooling system coolant |
| US4172770A (en) * | 1978-03-27 | 1979-10-30 | Technicon Instruments Corporation | Flow-through electrochemical system analytical method |
| JP2775055B2 (ja) * | 1989-02-08 | 1998-07-09 | 新日本無線株式会社 | バイオセンサ |
| US5607565A (en) * | 1995-03-27 | 1997-03-04 | Coulter Corporation | Apparatus for measuring analytes in a fluid sample |
| DE19618597B4 (de) * | 1996-05-09 | 2005-07-21 | Institut für Diabetestechnologie Gemeinnützige Forschungs- und Entwicklungsgesellschaft mbH an der Universität Ulm | Verfahren zur Bestimmung der Konzentration von Gewebeglucose |
| DE10038835B4 (de) * | 2000-08-04 | 2005-07-07 | Roche Diagnostics Gmbh | Mikrodialyseanordnung |
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- 2005-06-15 CA CA002573071A patent/CA2573071A1/en not_active Abandoned
- 2005-06-15 CN CN2005800222542A patent/CN1981191B/zh not_active Expired - Fee Related
- 2005-06-15 EP EP05752632A patent/EP1774305A1/en not_active Ceased
- 2005-06-15 US US11/629,974 patent/US20080282780A1/en not_active Abandoned
- 2005-06-15 KR KR1020077003006A patent/KR101130900B1/ko active IP Right Grant
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4025308A (en) * | 1974-06-07 | 1977-05-24 | United Kingdom Atomic Energy Authority | Method and apparatus for monitoring low concentrations of ions in a flowing fluid |
| CN85107234A (zh) * | 1985-09-24 | 1987-04-01 | 物理传感器公司 | 使用导纳调制膜的化学选择传感器 |
| US6706160B2 (en) * | 1995-01-03 | 2004-03-16 | Chemel Ab | Chemical sensor and use thereof |
| CN1372135A (zh) * | 2001-02-28 | 2002-10-02 | 清华大学 | 生物机－电芯片及应用 |
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| Title |
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| JP平2－208551A 1990.08.20 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1774305A1 (en) | 2007-04-18 |
| WO2006006905A1 (en) | 2006-01-19 |
| SE527196C2 (sv) | 2006-01-17 |
| JP2008506109A (ja) | 2008-02-28 |
| SE0401814L (sv) | 2006-01-09 |
| KR101130900B1 (ko) | 2012-03-28 |
| KR20070043826A (ko) | 2007-04-25 |
| SE0401814D0 (sv) | 2004-07-08 |
| CN1981191A (zh) | 2007-06-13 |
| US20080282780A1 (en) | 2008-11-20 |
| MX2007000024A (es) | 2007-05-23 |
| JP4801062B2 (ja) | 2011-10-26 |
| CA2573071A1 (en) | 2006-01-19 |
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