WO2000009991A1 - Dispositif et procede pour melanger des echantillons a proximite de l'interface dans des systemes biocapteurs - Google Patents

Dispositif et procede pour melanger des echantillons a proximite de l'interface dans des systemes biocapteurs Download PDF

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Publication number
WO2000009991A1
WO2000009991A1 PCT/EP1999/005813 EP9905813W WO0009991A1 WO 2000009991 A1 WO2000009991 A1 WO 2000009991A1 EP 9905813 W EP9905813 W EP 9905813W WO 0009991 A1 WO0009991 A1 WO 0009991A1
Authority
WO
WIPO (PCT)
Prior art keywords
mixing
magnetic field
liquid
sensor
cuvette
Prior art date
Application number
PCT/EP1999/005813
Other languages
German (de)
English (en)
Inventor
Gunnar Brink
Henning Groll
Jakob Tittel
Original Assignee
Biotul Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biotul Ag filed Critical Biotul Ag
Priority to AU55130/99A priority Critical patent/AU5513099A/en
Publication of WO2000009991A1 publication Critical patent/WO2000009991A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • G01N21/553—Attenuated total reflection and using surface plasmons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/44—Mixers with shaking, oscillating, or vibrating mechanisms with stirrers performing an oscillatory, vibratory or shaking movement
    • B01F31/441—Mixers with shaking, oscillating, or vibrating mechanisms with stirrers performing an oscillatory, vibratory or shaking movement performing a rectilinear reciprocating movement
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/45—Magnetic mixers; Mixers with magnetically driven stirrers
    • B01F33/451—Magnetic mixers; Mixers with magnetically driven stirrers wherein the mixture is directly exposed to an electromagnetic field without use of a stirrer, e.g. for material comprising ferromagnetic particles or for molten metal
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1048—General features of the devices using the transfer device for another function
    • G01N2035/1058—General features of the devices using the transfer device for another function for mixing
    • G01N2035/106—General features of the devices using the transfer device for another function for mixing by sucking and blowing

Definitions

  • the invention relates to devices and methods for the near-surface mixing of samples in biosensor systems, in particular sensor systems, which use surface binding reactions as an ⁇ ensor reaction.
  • the invention relates to a device and a method for mixing substances in a biosensor, preferably in a surface plasmon resonance sensor.
  • a first method relates to a cuvette system in which a chamber or a pot is used in which a side wall or the bottom forms the sensor surface.
  • a second method relates to a flow system in which the liquid is pumped past the measurement surface via flow channels.
  • a flow injection analysis method is often used and the liquid is often in a Liquid loop passed over the measuring surface.
  • the preferred system here is the cuvette system, but the invention also applies to a river system.
  • a third method uses a fiber optic sensor (as shown, for example, in DE-A-40 33 741), in which a glass fiber or another optical element is immersed in the liquid flow or in the standing liquid.
  • Optical biosensors are generally based on the fact that particles (molecules, bacteria, viruses, etc.) are bound to the optical measuring surface via a ligand-receptor interaction, which among other things changes the optical layer thickness of a thin film on the measuring surface . This change is verified using an optical method.
  • the optical signal is a measure of the binding strength or the concentration of the binding partner. Binding is determined near the surface by the concentration of binding molecules available. If molecules or larger particles from the liquid have already bound to the surface due to previous binding events, depletion or a concentration gradient occurs locally in the immediate vicinity of the surface (up to 1 - 10 ⁇ m), which falsifies the further measurement. Especially when kinetic phenomena are to be measured, it is often not the reaction rates but the diffusion that are measured.
  • the surface signal is measured with a clock frequency of approximately 1 to 10 Hz, it can be assumed that a space of several ⁇ m height above the measuring surface must be brought into a liquid flow connection with the rest of the volume as well as possible in order to obtain correct measured values.
  • the object of the invention is to provide improved measuring devices and measuring methods. This object is achieved with the features of the claims.
  • the invention is based on the basic idea of generating a liquid exchange or a thorough mixing of the liquid in the immediate vicinity of the surface (i.e. a few ⁇ m). Bodies are moved back and forth in a field in one or more directions and / or rotated about an axis.
  • the mixing takes place with magnetic bodies or beads.
  • These bodies, beads or spheres preferably consist of a superparamagnetic material and float in the liquid to be examined.
  • the bodies preferably consist of iron oxide, which is provided with different coatings. These shells can either be functionalized in a targeted manner or designed so that no non-specific adsorption takes place.
  • Such a casing preferably consists of dextran.
  • the diameter of these bodies is preferably in a range from approximately 50 nm to a few 1/10 mm.
  • the mixing takes place by applying magnetic fields, as a result of which the superparamagnetic bodies in the liquid are moved without contact.
  • magnetic fields For example, two different magnetic fields are created, one magnetic field below the sensor surface and the other whose magnetic field is arranged above.
  • the magnetic fields are generated by a magnetic coil under the gold layer of a surface plasmon resonance sensor and by a magnetic coil in the middle of a cuvette.
  • a magnetic field paramagnetic bodies are drawn in the direction of greater field strength.
  • the bodies are moved from the sensor surface into the liquid and back again to the sensor surface, which results in very good mixing on the sensor surface.
  • the advantage of these superparamagnetic bodies is that they lose their magnetism as soon as there is no longer any external magnetic field. This prevents any falsification of the measurement by magnetic fields.
  • the size of the bodies is preferably in the range of a few ⁇ m, since they are approximately the same size as the thickness of the depletion layer and thus penetrate deeply into them when they are pulled to the surface by the magnetic fields.
  • ferromagnetic bodies can be used. By applying a suitable magnetic field, ferromagnetic bodies can be rotated around their own axis or any axis. If the bodies are to be rotated about their own axis, bodies with an asymmetrical shape are preferably used. The rotation of the bodies causes the liquid to mix.
  • the bodies, beads or beads can be used to determine the start time of an affinity measurement and thus the start time of the reaction. To do this, follow the steps below.
  • the cuvette contains either a buffer solution or a regenerator solution in which the bodies swim freely.
  • the bodies are then drawn to the sensor surface by a magnetic field before the Solution is suctioned off.
  • There are preferably so many bodies in the solution that approximately 2 to 5 monolayer bodies lie on the surface when a magnetic field is applied.
  • the buffer or regenerator is suctioned off and the analyte is added. Since the bodies lie on the surface, the analyte cannot penetrate to the surface and the reaction is initially prevented.
  • the surface reaction to be examined can now be started in a targeted manner by pulling the bodies off the surface. This targeted start of the reaction is of great advantage for the determination of the kinetic data of enzyme reactions.
  • the liquid is mixed with movable networks.
  • one or more nets are drawn into the bottom of the cuvette, i.e. close to the gold layer, which can be moved either magnetically, piezoelectrically or acoustically. These nets are already close to the surface or on the surface of the liquid in the state of rest, so that a good mixing takes place during their movement.
  • Fig. La u. b a first embodiment according to the invention, in which the mixing takes place with magnetic beads;
  • Fig. 2a u. b a second embodiment according to the invention, in which the mixing takes place with magnetic beads and
  • Fig. 3 shows a third embodiment of the invention, in which movable networks are used for mixing.
  • FIGS. 1 and b show the same first embodiment according to the invention. The only differences are in the differently applied magnetic fields.
  • a substrate 31 with a sensor surface 32 is shown in FIGS.
  • the sensor surface is preferably a gold surface.
  • a cuvette 3, which is filled with liquid, is located on this sensor surface 32.
  • Paramagnetic or superparamagnetic beads are in the liquid.
  • Both figures la and b show schematically the below the sensor surface arranged magnetic field generator 34, both disposed above the cuvette magnetic field generator 35.
  • the magnetic field generator 35 is shown in Figures la and lb preferably above de "r cuvette. In another execution form can this magnetic field generator may also be arranged at a medium height around the cuvette Electromagnets are preferably used for the magnetic field generators 34 and 35.
  • the magnet 34 below the sensor surface is activated, while the second magnet 35 does not generate a magnetic field when in use
  • the conditions are just reversed, ie the magnet 35 arranged above (or also around the liquid) is activated, while the magnet 34 is deactivated and b different Mag Net fields have the effect that, on the one hand, the magnetic beads are located on the bottom of the cuvette, that is to say directly above the sensor surface, while according to FIG. 1b they have migrated away from the sensor surface into the liquid and thus ensure that the liquid is mixed.
  • the measuring device has a similar structure.
  • This measuring device has a substrate 41 with a sensor surface 42 and a cuvette which is filled with liquid.
  • a magnetic field generator 45 preferably an electromagnet, is shown below the sensor surface. In this embodiment, only this one magnetic field generator is provided.
  • the movement of the ferromagnetic beads in the liquid and the resulting passage Mixing of the liquid is effected according to this embodiment in that the current flowing through the magnet is constant in FIG. 2a, while an alternating current flows through the magnet according to FIG. 2b.
  • the measuring device shows an embodiment in which the mixing takes place with movable networks.
  • a cuvette 54 filled with liquid is provided on the sensor surface 52 arranged above the substrate 51.
  • a movable network 53 is provided in the cuvette 54 above the sensor surface 52 and is moved via a corresponding actuator 56 and a coupling element 55 located between the network and the actuator.
  • Both the actuator and the coupler can be mechanical in nature.
  • a field generator is provided as the actuator and the coupling to the mobile network takes place via the correspondingly generated fields.
  • Electromagnet e.g. Electromagnet
  • 35 magnetic field generators e.g. Electromagnet
  • Electromagnet it does not have to sit above the cuvette, it can also be placed at a medium height around the cuvette
  • Electromagnet Re. Fig. 3 45 magnetic field generators, e.g. Electromagnet Re. Fig. 3:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

L'invention concerne un dispositif et un procédé permettant de mélanger, à proximité de l'interface, des liquides, dans un biocapteur. Le mélange intime est obtenu par le déplacement de petites billes magnétiques ou au moyen de filets mobiles.
PCT/EP1999/005813 1998-08-10 1999-08-10 Dispositif et procede pour melanger des echantillons a proximite de l'interface dans des systemes biocapteurs WO2000009991A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55130/99A AU5513099A (en) 1998-08-10 1999-08-10 Method and device for mixing samples near the interface in biosensor systems

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19836109A DE19836109A1 (de) 1998-08-10 1998-08-10 Vorrichtung und Verfahren zur grenzflächennahen Mischung von Proben in Biosensorsystemen
DE19836109.2 1998-08-10

Publications (1)

Publication Number Publication Date
WO2000009991A1 true WO2000009991A1 (fr) 2000-02-24

Family

ID=7877029

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/005813 WO2000009991A1 (fr) 1998-08-10 1999-08-10 Dispositif et procede pour melanger des echantillons a proximite de l'interface dans des systemes biocapteurs

Country Status (3)

Country Link
AU (1) AU5513099A (fr)
DE (1) DE19836109A1 (fr)
WO (1) WO2000009991A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718072B2 (en) 2002-04-26 2010-05-18 Abbott Laboratories Structure and method for handling magnetic particles in biological assays
CN102586225A (zh) * 2011-01-14 2012-07-18 博奥生物有限公司 一种操纵磁珠分离目标分子的方法
DE102012210077A1 (de) * 2012-06-15 2013-12-19 Siemens Aktiengesellschaft Verfahren und Anordnung zur Markierung von Zellen in einer Zellsuspension

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101903760A (zh) * 2007-12-20 2010-12-01 皇家飞利浦电子股份有限公司 磁性线圈在传感器装置中的定位

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB876070A (en) * 1957-05-20 1961-08-30 Hoffmann La Roche An improved countercurrent extraction apparatus
US3752443A (en) * 1971-12-13 1973-08-14 Technicon Instr Magnetic mixer
EP0240862A1 (fr) * 1986-04-07 1987-10-14 Migrata Uk Ltd Appareil et procédé de mélange
DE4033741A1 (de) * 1989-11-02 1991-05-08 Falko V E Dipl Phys Tittel Einmal-biosensor zum nachweis von antigen/antikoerperbindungen im vollblut zur anwendung als antihiv-bestaetigungstest mit verbalem ergebnis auf einer fluessigkeitskristallanzeige
WO1994028396A1 (fr) * 1993-05-28 1994-12-08 Fisons Plc Appareil d'analyse
EP0670483A2 (fr) * 1994-02-25 1995-09-06 Fuji Photo Film Co., Ltd. Procédé de mélange de liquides
WO1997002357A1 (fr) * 1995-06-29 1997-01-23 Affymetrix, Inc. Dispositif de diagnostic nucleotidique integre

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE9406339U1 (de) * 1994-04-14 1994-07-14 Gonotec Gesellschaft für Meß- und Regeltechnik mbH, 10823 Berlin Vorrichtung zur Analyse in ionisierten Flüssigkeiten
DE19541033C1 (de) * 1995-11-03 1997-06-26 Inst Chemo Biosensorik Elektrochemisches Verfahren zur quantitativen Bestimmung von Bindungsproteinen

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB876070A (en) * 1957-05-20 1961-08-30 Hoffmann La Roche An improved countercurrent extraction apparatus
US3752443A (en) * 1971-12-13 1973-08-14 Technicon Instr Magnetic mixer
EP0240862A1 (fr) * 1986-04-07 1987-10-14 Migrata Uk Ltd Appareil et procédé de mélange
DE4033741A1 (de) * 1989-11-02 1991-05-08 Falko V E Dipl Phys Tittel Einmal-biosensor zum nachweis von antigen/antikoerperbindungen im vollblut zur anwendung als antihiv-bestaetigungstest mit verbalem ergebnis auf einer fluessigkeitskristallanzeige
WO1994028396A1 (fr) * 1993-05-28 1994-12-08 Fisons Plc Appareil d'analyse
EP0670483A2 (fr) * 1994-02-25 1995-09-06 Fuji Photo Film Co., Ltd. Procédé de mélange de liquides
WO1997002357A1 (fr) * 1995-06-29 1997-01-23 Affymetrix, Inc. Dispositif de diagnostic nucleotidique integre

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718072B2 (en) 2002-04-26 2010-05-18 Abbott Laboratories Structure and method for handling magnetic particles in biological assays
US8211301B2 (en) 2002-04-26 2012-07-03 Abbott Laboratories Structure and method for handling magnetic particles in biological assays
US8728311B2 (en) 2002-04-26 2014-05-20 Abbott Laboratory Structure and method for handling magnetic particles in biological assays
CN102586225A (zh) * 2011-01-14 2012-07-18 博奥生物有限公司 一种操纵磁珠分离目标分子的方法
CN102586225B (zh) * 2011-01-14 2014-07-09 博奥生物集团有限公司 一种操纵磁珠分离目标分子的方法
DE102012210077A1 (de) * 2012-06-15 2013-12-19 Siemens Aktiengesellschaft Verfahren und Anordnung zur Markierung von Zellen in einer Zellsuspension

Also Published As

Publication number Publication date
AU5513099A (en) 2000-03-06
DE19836109A1 (de) 2000-03-02

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