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US20060019243A1 - Method and device for mixing samples on a support - Google Patents

Method and device for mixing samples on a support Download PDF

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Publication number
US20060019243A1
US20060019243A1 US11/146,343 US14634305A US2006019243A1 US 20060019243 A1 US20060019243 A1 US 20060019243A1 US 14634305 A US14634305 A US 14634305A US 2006019243 A1 US2006019243 A1 US 2006019243A1
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US
United States
Prior art keywords
stream
gas
area
support
jet
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US11/146,343
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English (en)
Inventor
Karl-Heinz Mann
Thomas Mayer
Friedhelm Vieth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics Operations Inc
Original Assignee
Individual
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 Individual filed Critical Individual
Assigned to ROCHE DIAGNOSTICS GMBH reassignment ROCHE DIAGNOSTICS GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MANN, KARL-HEINZ, MAYER, THOMAS, VIETH, FREIDHELM
Assigned to ROCHE DIAGNOSTICS OPERATIONS, INC. reassignment ROCHE DIAGNOSTICS OPERATIONS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROCHE DIAGNOSTICS GMBH
Publication of US20060019243A1 publication Critical patent/US20060019243A1/en
Assigned to ROCHE DIAGNOSTICS GMBH reassignment ROCHE DIAGNOSTICS GMBH CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECTION OF INVENTOR NAME SPELLING: FRIEDHELM VIETH PREVIOUSLY RECORDED ON REEL 016659 FRAME 0086. ASSIGNOR(S) HEREBY CONFIRMS THE FREIDHELM VIETH. Assignors: MANN, KARL-HEINZ, MAYER, THOMAS, VIETH, FRIEDHELM
Assigned to ROCHE DIAGNOSTICS OPERATIONS, INC. reassignment ROCHE DIAGNOSTICS OPERATIONS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROCHE DIAGNOSTICS GMBH
Priority to US12/015,000 priority Critical patent/US9156012B2/en
Abandoned legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/38—Diluting, dispersing or mixing samples
    • 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
    • B01F33/40—Mixers using gas or liquid agitation, e.g. with air supply tubes
    • B01F33/407—Mixers using gas or liquid agitation, e.g. with air supply tubes by blowing gas on the material from above
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/23—Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
    • 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
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00479—Means for mixing reactants or products in the reaction vessels
    • B01J2219/00493—Means for mixing reactants or products in the reaction vessels by sparging or bubbling with gases
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00511—Walls of reactor vessels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • 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
    • G01N2035/00465—Separating and mixing arrangements
    • G01N2035/00534—Mixing by a special element, e.g. stirrer
    • G01N2035/00544—Mixing by a special element, e.g. stirrer using fluid flow
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation

Definitions

  • the invention concerns a method for detecting analytes in a liquid in which the liquid is subjected to a mixing treatment on an area of a support preferably of a biochip which in particular has immobilized reactants.
  • the invention especially concerns methods for improving the mixing treatment of a liquid and in this connection methods for improving the way in which analytes in the liquid are brought to reactants that are immobilized on an area of the support and in particular of the biochip that is occupied by the liquid.
  • the following problem occurs in biochip applications and especially in immunoassay applications in which binding reactions are detected between reactants that are immobilized on a support surface and analytes that are present in a liquid that wets the support surface.
  • the binding of analytes to immobilized reactants lowers the concentration of analytes in the liquid in a boundary layer on the support surface resulting in a depletion of analytes in the sample liquid in a boundary layer.
  • Due to the usually low analyte diffusion rate which is normally only a few ⁇ m/s or less, new analyte molecules are not resupplied rapidly enough from the sample liquid volume so that long incubation times are required for immunological tests or such like to achieve an adequate measuring effect.
  • a method and device for mixing samples near the interface in biosensor systems, namely biochips is known from WO 00/10011.
  • the liquid in the biochip is excited in this known method by mechanical waves (sound, ultrasound or surface waves) which is intended to improve mixing of the sample liquid especially at the chip/liquid boundary layer in order to enhance the diffusion of the analyte.
  • a device for controlling the temperature and mixing the contents of vessels of a microtitration plate for immunological tests is known from EP 0 281 958 A2.
  • This known device comprises a cover which defines a hollow space into which a gas line discharges.
  • a boundary wall of the cover that faces the titration plate is provided with gas outlet openings which are arranged eccentrically relative to the vessel axes of the individual vessels of the microtitration plate and are aligned at an angle to the surfaces of the liquids in the individual vessels.
  • Temperature control and generation of a rotary mixing movement of the liquid in the individual vessels is achieved by blowing in warm air through the gas outlet openings.
  • U.S. Pat. No. 6,063,564, U.S. Pat. No. 4,479,720 and U.S. Pat. No. 5,009,998 for example also concern the improved mixing of sample liquids in sample tubes as liquid containers.
  • the present invention relates to a method for mixing a liquid sample comprising an analyte, the method comprising providing a support comprising an area comprising a reactant immobilized thereon and the sample, wherein the sample wets the area, and providing a stream of gas that impinges upon and sweeps across at least a part of the area in a scanning manner, the stream of gas being provided by means of a jet directed toward the area, thereby causing a mixing of the liquid sample and thereby causing the analyte to be available for reaction with the immobilized reactant.
  • the invention further relates to a method for detecting an analyte in a liquid sample comprising providing a support comprising an area comprising a reactant immobilized thereon and the sample, wherein the sample wets the area, providing a stream of gas that impinges upon and sweeps across at least a part of the area in a scanning manner, the stream of gas being provided by means of a jet directed toward the area, thereby causing a mixing of the liquid sample and thereby causing the analyte to be available for binding with the immobilized reactant, and detecting the binding of the analyte with the immobilized reactant.
  • the invention further relates to a device for detecting an analyte in a liquid sample, the device comprising a holder, a support held by the holder and comprising an area comprising a reactant immobilized thereon, the support containing the liquid sample which wets the area, a gas supply device comprising a jet for supplying a stream of gas to the area, and a drive device for generating relative movement between the jet and the holder whereby the stream of gas sweeps across at least a part of the area in a scanning manner, thereby mixing the sample and causing the analyte to be available for reaction with the immobilized reactant.
  • FIG. 1 shows a greatly simplified schematic representation of a diagrammatic sketch to illustrate the method comprising a trough-shaped biochip and a gas jet that can be moved above it and
  • FIG. 2 shows a greatly simplified schematic representation of a device according to the invention.
  • the object of the invention is to propose a method of the type stated above which increases the measuring sensitivity or reduces the incubation time required to achieve an adequate measuring effect when performing tests based on binding reactions between analytes in a sample liquid and reactants on a support wetted by the sample liquid and thus for typical biochip applications. Furthermore, the binding reaction between analytes and reactants should occur homogeneously and independently of the location over the entire chip. This means that reactants that are in the middle or at the edge of the support or microarray chip can bind the analyte essentially at the same rate and efficiency.
  • the invention proposes that the liquid is impinged upon by a stream of gas that sweeps across at least some areas in a scanning manner by means of a jet directed towards the support surface during the mixing treatment.
  • the zone where the sample liquid is intensively mixed on the bottom of the chip migrates across the support surface such that new analytes are supplied in an accelerated manner to the boundary layer that is initially depleted of analyte due to prior binding reactions.
  • This increases the probability of further binding reactions between the analytes and the immobilized reactants which can thus increase the sensitivity or reduce the incubation period and improve the homogeneity and especially the position-independent homogeneity of analyte binding compared to conventional methods.
  • the stream of gas is preferably an air stream in particular a stream of humidified air.
  • the air humidification prevents the biochip from drying.
  • the gas stream can also alternatively be a stream of inert gas.
  • a relative movement is generated between the jet and the support in order to sweep the area with the gas stream in a scanning manner. It can be swept several times and in particular periodically. This can for example be achieved by moving the jet in a predetermined manner while holding the support or by moving the support while holding the jet. This also does not exclude the possibility of moving the jet as well as the support in order to impinge the sample liquid in a scanning manner.
  • a vessel for the sample liquid it is preferable to use a trough-shaped vessel in particular having an essentially flat bottom as the support surface for the immobilized reactants.
  • a biochip with an array of individual surface areas on which the reactants are located is suitable as a support.
  • a trough-shaped vessel can be used as a sample vessel which contains separate support elements such as solid phase microparticles for the immobilized reactants.
  • a continuous, essentially uniform stream of air is preferably used as an air stream to impinge on the liquid.
  • a modulated and in particular a pulsing stream of air is used.
  • a particular advantage of the invention is that the proposed mixing treatment of the liquid enables a good homogeneity of the binding reaction between analytes and immobilized reactants independent of the position over the entire support surface.
  • Another subject matter of the invention is a device for carrying out the method, the device being characterized by a holder for holding at least one support in particular a biochip which has a bottom surface with reactants immobilized thereon or optionally a bottom surface for depositing support elements with reactants immobilized thereon, a gas supply device comprising at least one jet for ejecting a gas stream towards the bottom surface of a support located in the holder and a drive device for generating a relative movement between the jet and the holder such that a stream of gas discharged from the jet sweeps across at least some areas of the bottom surface in a scanning manner.
  • the holder is movably mounted and the drive device is designed to move the holder relative to the jet.
  • the jet is movably mounted and the drive device is designed to move the jet relative to the holder.
  • the gas supply device is designed to generate a jet of air that is discharged by means of the jet.
  • the gas supply device advantageously comprises an air moistening device.
  • the holder is designed to hold a plurality of supports or sample vessels and that each support or sample vessel is allocated at least one jet.
  • the system according to the invention can be readily adapted to biochips that can be designed relatively freely having a flat analyte reservoir and a flat bottom.
  • a plurality of biochips can be easily processed in parallel since a pressure reservoir can simultaneously supply many jets in a defined manner.
  • FIG. 1 shows a trough-shaped biochip 1 having an essentially flat trough bottom 3 on which reactants or capture molecules are immobilized preferably in a microarray arrangement.
  • the bottom surface 3 is wetted by a sample liquid 5 which contains analytes that can bind with reactants on the bottom 3 of the biochip 1 where for example this binding can be detected by measuring the fluorescence.
  • a gas jet 7 is moved according to FIG. 1 over the surface of the sample liquid 5 such that the point of impact of the gas stream 9 on the liquid surface sweeps across the support area 3 while maintaining an inter-mediate layer of liquid 5 .
  • the liquid 5 is displaced in the area of the respective impact point of the gas stream 9 . Only a very thin film of sample liquid 13 remains in the area of this zone 11 .
  • the liquid in the area of the film 13 is well mixed such that the “analyte depletion zone” is locally broken through at this position and new analytes are available for binding to the reactants. Since the zone 11 can be guided over the entire area of the bottom 3 that is of interest, it is possible to distribute the increased supply of analyte uniformly over this surface area 3 .
  • the method according to the invention increases the efficiency of bindings per unit of time which is associated with a reduction of the required incubation time to achieve an adequate measuring effect such as in immunoassay applications.
  • FIG. 2 shows a greatly simplified schematic structure of a device according to the invention comprising an air pump 15 which is for example designed as a membrane pump to generate an air current.
  • An air flow sensor 17 connected to the pressure side of the pump 15 is used to monitor the air current and thus serves as an actual value transmitter to regulate the air current. In test measurements an air current of about 7 ml/s has proven to be advantageous.
  • the air supplied to the jet 7 is moistened by an air moistening device 26 .
  • an air moistening device 26 In the example shown in FIG. 2 a pressure vessel 19 partially filled with water is used for this purpose.
  • the air conveyed by the pump 15 is blown into the water reservoir 23 through the line 21 .
  • the pressurized air with an increased moisture content which then rises above the water reservoir 23 in the container volume 25 then reaches jet 7 via the line 27 .
  • the moistened air is then blown onto the biochip 1 in the stream from the jet 7 in order to achieve the effect elucidated in connection with FIG. 1 .
  • the biochip 1 is on a holder 30 which can for example be a carriage moved by a motor.
  • the holder 30 can be moved in such a manner that the stream of air directed towards the bottom of the biochip through the fixed jet 7 can scan the support area of the biochip 1 that is occupied with immobilized reactants.
  • it can be designed such that the holder 30 can execute horizontal backward and forward motions indicated by the double arrow 33 and also a reciprocating motion at right angles thereto.
  • jets 7 having gas outlet slits of different shapes can be used.
  • one jet has an elongate outlet slit which for example approximately overlaps the complete width of a biochip 1 .
  • the sequence of movements when the biochip is moved relative to the jet 7 can then be reduced to a simple forwards and backwards motion.
  • the gas stream 9 impacts the liquid approximately vertically.
  • the gas stream strikes the liquid at a tilted angle relative to the vertical.
  • jets having several exit slits or capillaries It is also possible to use jets having several exit slits or capillaries.
  • a jet comprising two parallel steel capillaries was used that were spaced 1.4 mm apart and which each had an inner diameter of 0.5 mm.
  • the capillary length is 10 mm.
  • the distance between the jet opening and the sample fluid surface was ca. 2 mm in the tests.
  • the filling level of the sample liquid in the biochip was ca. 1 mm.
  • the analyte-sensitive zone of the biochip had an area of about 2.5 ⁇ 6 mm 2 .
  • a stepping motor drive was used for the reciprocating movement of the biochip under the jet at a frequency of about 0.5 Hz.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Clinical Laboratory Science (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Physics & Mathematics (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Mixers With Rotating Receptacles And Mixers With Vibration Mechanisms (AREA)
US11/146,343 2004-06-11 2005-06-06 Method and device for mixing samples on a support Abandoned US20060019243A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/015,000 US9156012B2 (en) 2004-06-11 2008-01-16 Method and device for mixing samples on a support

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEDE102004028303.6 2004-06-11
DE102004028303A DE102004028303A1 (de) 2004-06-11 2004-06-11 Verfahren und Vorrichtung zum Nachweis von Analyten

Related Child Applications (1)

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US20060019243A1 true US20060019243A1 (en) 2006-01-26

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US11/146,343 Abandoned US20060019243A1 (en) 2004-06-11 2005-06-06 Method and device for mixing samples on a support
US12/015,000 Expired - Fee Related US9156012B2 (en) 2004-06-11 2008-01-16 Method and device for mixing samples on a support

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US (2) US20060019243A1 (zh)
EP (1) EP1604734B1 (zh)
JP (1) JP4205696B2 (zh)
KR (1) KR101035525B1 (zh)
CN (1) CN1707264B (zh)
AT (1) ATE395968T1 (zh)
CA (1) CA2508919C (zh)
DE (2) DE102004028303A1 (zh)
ES (1) ES2305945T3 (zh)
TW (1) TWI368025B (zh)

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US20120264624A1 (en) * 2009-10-28 2012-10-18 Roche Diagnostics Operations, Inc. Method and device for detecting analytes in a sample liquid

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DE102005034175A1 (de) 2005-07-21 2007-01-25 Roche Diagnostics Gmbh Verfahren und Vorrichtung zur Erzeugung eines Feuchtluftstromes mit definierter relativer Feuchte
FR2938062B1 (fr) * 2008-11-05 2014-02-28 Biomerieux Sa Dispositif de preparation et/ou de traitement d'un echantillon biologique
DE102013204646B4 (de) * 2013-03-15 2018-04-05 Leica Biosystems Nussloch Gmbh Gerät zum Bearbeiten von histologischen Proben
CN111356912B (zh) * 2017-11-21 2023-09-05 文塔纳医疗系统公司 使用调制气体射流的非接触式混合
US10512911B1 (en) * 2018-12-07 2019-12-24 Ultima Genomics, Inc. Implementing barriers for controlled environments during sample processing and detection
CN111112764A (zh) * 2019-12-26 2020-05-08 广东工业大学 一种脉冲气辅助掩模电解加工装置及方法

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TWI368025B (en) 2012-07-11
CN1707264B (zh) 2012-01-11
JP2005351900A (ja) 2005-12-22
HK1084446A1 (zh) 2006-07-28
EP1604734A3 (de) 2006-04-19
ES2305945T3 (es) 2008-11-01
US9156012B2 (en) 2015-10-13
CN1707264A (zh) 2005-12-14
CA2508919C (en) 2010-01-12
DE502005004166D1 (de) 2008-07-03
EP1604734A2 (de) 2005-12-14
KR101035525B1 (ko) 2011-05-23
US20080113450A1 (en) 2008-05-15
EP1604734B1 (de) 2008-05-21
KR20060049190A (ko) 2006-05-18
TW200540405A (en) 2005-12-16
DE102004028303A1 (de) 2005-12-29
CA2508919A1 (en) 2005-12-11
ATE395968T1 (de) 2008-06-15

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