GB2293117A - Mixing of chemical reaction components using ultrasound - Google Patents

Mixing of chemical reaction components using ultrasound Download PDF

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Publication number
GB2293117A
GB2293117A GB9418440A GB9418440A GB2293117A GB 2293117 A GB2293117 A GB 2293117A GB 9418440 A GB9418440 A GB 9418440A GB 9418440 A GB9418440 A GB 9418440A GB 2293117 A GB2293117 A GB 2293117A
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United Kingdom
Prior art keywords
chemical reaction
ultrasonic wave
wave energy
reaction
block
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.)
Withdrawn
Application number
GB9418440A
Other versions
GB9418440D0 (en
Inventor
Ronnie Aurun Ray
Andrew Jeremy Wakefield
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INCELTEC Ltd
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INCELTEC Ltd
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 INCELTEC Ltd filed Critical INCELTEC Ltd
Priority to GB9418440A priority Critical patent/GB2293117A/en
Publication of GB9418440D0 publication Critical patent/GB9418440D0/en
Publication of GB2293117A publication Critical patent/GB2293117A/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • 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
    • B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
    • 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
    • B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
    • B01F31/86—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations with vibration of the receptacle or part of it
    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
    • B01J19/10—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing sonic or ultrasonic vibrations
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5306—Improving reaction conditions, e.g. reduction of non-specific binding, promotion of specific binding
    • 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
    • B01J2219/00484—Means for mixing reactants or products in the reaction vessels by shaking, vibrating or oscillating of the reaction vessels
    • B01J2219/00486—Means for mixing reactants or products in the reaction vessels by shaking, vibrating or oscillating of the reaction vessels by sonication or ultrasonication
    • 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
    • B01J2219/00495—Means for heating or cooling the reaction 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
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Toxicology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

Continuous permeabilisation of cells during intracellular nucleic acid chemical reaction is performed using ultrasound. An ultrasound wave generating block 1, driven by a motion generator 4, is disposed over a temperature-transmitting surface 2 of a temperature-controlling surface 3. Samples are arranged in chambers 8 of the block 1. The technique can be used for the polymerase chain reaction (PCR) and primed in situ extension (PRINS). <IMAGE>

Description

APPARATUS FOR IMPROVING EVEN DISTRIBUTION OF CHEMICAL REACTION COMPONENTS WITHIN CELLS ON A SURFACE OR IN SOLUTION.
The invention relates to an apparatus which permits even distribution of chemical reaction by permeabilising cell preparations in solution or on a surface by emission of ultrasonic wave energy and/or even permits distribution of chemical reaction components during reaction by physical random agitation motion. Ultrasonic wave energy means mechanical radiant energy generally with a frequency greater than 20,000 cycles per second.
Crosslinking fixatives, for example 10% buffered formalin, are used extensively in the processing of samples in diagnostic histopathology. For performing intracellular chemical reaction; for example antibody detection of intracellular or cell surface antigens, or for example intracellular reactions involving nucleic acid RNA and/or DNA; a permeabilising step is generally required in reversing the crosslinking effects of fixation in order to increase access of reaction substrates into the cell.
A number of different permeabilising methods are available which are generally either physical, for example several alternating cycles of warming and cooling to low temperatures; or chemical, for example enzymes such as proteinase K and/or detergents such as Nonidet (trade name). When cellular permeabilisation is required, the permeabilising methods in prior art are almost universally employed before commencing intracellular chemical reaction.
Many chemical reactions are performed at one designated temperature, for example many immunohistochemical antibody reactions used in the detection of intracellular or cell surface antigens. By contrast, a variety of intracellular chemical reactions may be undertaken at a pleurality of temperatures, for example the prehybridisation and hybridisation steps during in situ hybridisation for the detection of intracellular nucleic acids, or for example nucleic acid replication and/or amplification reactions.
ln situ hybridisation (ISH) is a method for detecting a specific nucleic acid sequence within cells (Nagai et al (1987) Intl.J.Gyn.Path. 6:366-379). The technique involves allowing a labelled probe to hybridise to the sequence of interest within the cells and then visualising the probe, usually by a microscopic technique. Labelling is by immobilised nonisotopic (fluorescent or absorbance) or isotopic (autoradiographic) signal attached to the probe. A major problem with ISH is that it is not very sensitive, generally requiring tens to hundreds of copies of the target sequences per cell for adequate detection. In these reactions, the temperatures may require strict control in order to ensure signal specificity and to reduce nonspecific background.Many chemical reactions such as nucleic acid reactions require a predetermined cycle of heating and cooling steps to be performed with a minimum of intervention. For example, there are now a number of methods known for the amplification and/or replication of nucleic acid sequences. These include the polymerase chain reaction (PCR) for amplifying DNA sequences, reverse transcription-PCR (RT-PCR for amplifying RNA sequences, the selfsustained sequence replication (3SR) for amplifying RNA and DNA sequences, the ligase chain reaction to amplify DNA as well as to discriminate a single base mutation and the primed in situ extension (PRINS) reaction. These processes are now coming into more general use and are particularly suited to utilisation of the apparatus in accordance to the present invention.
When a pleurality of temperatures or a predetermined succession or cycles of heating and cooling steps are employed during intracellular chemical reaction, the effect of initial permeabilisation performed before commencing intracellular chemical reaction may be altered or abolished during or after chemical reaction. This may be particularly relevant to intracellular chemical reaction performed for cells in solution; or for cells or tissues on a surface such as a glass slide.
Chemical permeabilisers such as enzymes or detergents used during intracellular chemical reaction might alter the kinetics or prevent the performance of the said intracellular chemical reaction in an unpredictable manner, for example by destroying reaction components. In addition, the chemical permeabilisers themselves may be affected either by the components used for the intracellular chemical reaction or by the relatively high temperatures required for some intracellular chemical reactions.
Chemical permeabilisers also frequently compromise morphology rendering histological evaluation difficult to perform. Physical permeabilisation methods such as successive steps of heating and cooling to very low temperatures (for example approximately 0 C), is clearly impractical with temperature dependent intracellular chemical reaction; lesser differences in temperature between heating and cooling steps are unlikely to result in sufficient permeabilisation. Furthermore, physical methods of permeabilisation may exert their effect in an unpredictable manner.
The maintenance of permeabilisation should preferably be performed during intracellular chemical reaction in a controlled manner, in addition to permeabilisation before reaction. Ultrasound wave energy technology admirably fulfils this role since it would not significantly affect the intracellular chemical reaction or morphological detail at the levels of energy used, and the emission of ultrasonic waves could be administered in a controlled manner throughout the reaction. Specifically therefore the invention partly relates to an apparatus that permits cellular permeabilisation by ultrasound wave energy before or after or during chemical reaction. The emission of ultrasonic wave energy may be controlled in the said apparatus to emit ultrasonic wave energy according to preset specifications, or may he manually adjusted as desired.
Ultrasonic wave energy also possesses benefit in assisting the components for chemical reaction in mixing evenly. This is particularly valuable in situations where reaction solutions are viscous, or when reaction solution volumes used are relatively large, or where convection currents are poor, such as in low temperature intracellular chemical reactions, for example in antibody dependent chemical reactions. The effect of ultrasonic wave energy in mixing reaction components might be of particular benefit where a thermal-cycling dependent intracellular chemical reaction is performed within cells on a surface, since the effect of a permeabilising steps before reaction may be reversed or compromised during reaction. The methods of generating ultrasonic wave energy are by well-known in the art.
The cells containing the target nucleic acid sequence are generally eukaryotic cells, generally animal or human cells, though plant or prokaryotic cells can be used.
The cells may be in a tissue section (ie a solid sample of biological tissue), a cytospin (ie a cell suspension which has been spun by centrifugation onto the first surface), a biopsy (eg a needle biopsy, a mucosal biopsy, a mucosal curetting or a bone biopsy), a touch preparation, or other cytological specimen (eg exfoliate material, a smear, an aspiration or fine needle material). The method of the invention could also be applied to liposomes or enclosed vesicles containing nucleic acid.
The invention provides therefore an ultrasonic emitting apparatus suitable for performing permeabilisation of cells in solution or on a surface, but is also suited to other chemical reactions on a surface in which ultrasonic energy is dissipated with predetermined or controlled levels.
According to present inventions therefore an ultrasonic wave energy emitting apparatus suitable for performing permeabilisation of cells in solution or on a surface in which ultrasonic wave energy is dissipated in accordance with predetermined or controlled levels.
According to the present invention therefore there is provided an ultrasound wave energy emitting apparatus comprising; a means of generating ultrasonic wave energy a chamber or a surface in which one or more samples are maintained, a means of administering ultrasonic wave energy to an arrangement for performing chemical reaction control means, therefor A preferred embodiment of the apparatus is a device that permits the additional ability of applying physical random agitation motion to a sample in order to permit even mixing of the components for intracellular chemical reaction when the said chemical reaction is performed with cells on a surface or within cells in solution.The device that permits even distribution of components for chemical reaction may be incorporated into the apparatus that emits ultrasonic wave energy, or may be used alone without the apparatus that emits ultrasonic wave energy.
In an especially preferred embodiment, the apparatus that emits ultrasonic wave energy and/or the apparatus for applying physical motion to a sample is placed over a surface whose temperature may be controlled, for example the flat surface of a thermal cycling machine. A chamber to accommodate one or more samples may be created between either the apparatus for emitting ultrasonic wave energy or the device for applying physical motion, and the surface whose temperature may be controlled.
A sample may include a surface on which cells are maintained, or a container in which cells or liberated target material are kept in solution including components for intracellular chemical reaction. The said surface on which cells are maintained may be covered with a reaction mixture contained within a well formed by a bio-compatible semi-adhesive filler which surrounds the cellular sample; the well is then covered by a coverslip in a similar manner to that previously described (PCT GB9406841.8).
Alternatively, the said surface on which cells are maintained may be covered by a reaction mixture enclosed in a preformed reaction container which is specifically designed to surround the cells on the surface, for example as described in another previous patent application (UK.94()2205.0). The said surface on which cells are maintained may include a microscopic glass or transparent plastic slide. It will be appreciated that more than one sample can be subject to ultrasonic energy at the same time. In accordance with the conventional practice in this field the energy generated may be recorded by a device for detecting and measuring ultrasonic wave energy.The invention will now be further described by way of illustration only, with reference to the accompanying drawings wherein Figure 1 shows in diagrammatic form of an ultrasonic wave energy generating apparatus in accordance to the present which may be used in combination with the device for applvin physical random agitation motion to a sample, or independently to the said device; and a surface whose temperature may be controlled.
Figure 2 shows in diagrammatic form in accordance to the present in which the device for applying random physical agitation motion to a sample may be used in combination with the ultrasound generating appar;ltils or detached as required; and a surface whose temperature may be controlled.
The apparatus in accordance to the present invention is herein described with particular reference initially to Figure 1. An ultrasound wave energy generating block (1) is disposed over a rapid temperature-transmitting, heat-resistant surface (2) which overlaps a surface whose temperature may be controlled (3). The surface whose temperature may be controlled (3) may include the flat surface of a thermal cycling machine. A device (4) permitting physical random agitation motion of the ultrasound wave energy generating block (1) is attached to at least one surface of the block (5).
Alternatively, the device (4) to permit physical random agitation motion of the ultrasonic wave energy generating block (1) and its attachment (5) to the said block (1) may be omitted. The emission of ultrasonic wave energy from the generating block (1) and, when present the speed of physical motion of the said block (1) by the device permitting physical motion (4), may be altered or programmed by a control panel (6). The control panel (6) is provided with control input activators (7) as known in the art, except that the control input activators (7) provide a different arrangement of programmes in accordance with the chemical reactions required and /or cellular specimens used.
Chambers (8) may be disposed at the base of the ultrasonic wave energy generating block (1) such that a sample may be disposed therein, and that at least part of the said sample shall be in contract with the rapid-temperature transmitting, heat-resistant surface (2) and will therefore receive the heat energy generated from the surface whose temperature may be controlled (3). A device for measuring ultrasonic waves emitted (9) should preferably be included which is itself connected to the control panel (6).In addition, ribs (10) may be attached to the side walls of the chambers (8) disposed within the ultrasound wave energy generating block (1) in order that the samples under study present within the chambers may be simultaneously in contact with the rapid temperature-transmitting heat-resistant surface (2) and the ultrasound wave energy block (1), and may if desired be moved by physical motion produced by device (4).
An alternative arrangement of the apparatus in accordance with the present invention is illustrated in Figure 2. An ultrasonic wave energy generating block (11) may be placed over or attached to a second block (12) capable of undergoing physical motion. The block capable for undergoing physical motion (12) is disposed above a rapid temperature-transmitting heat-resistant surface (2). The rapid temperdture- transmitting heat-resistant surface (2) is itself positional above a surface whose temperature may be controlled (3) in a similar manner to that described in Figure 1.
The block capable of undergoing physical motion (12) is attached (13) to a device capable of producing physical random agitation motion (14). The ultrasonic wave energy emitted from the ultrasonic wave energy generating block (11), and the movement of the block capable of undergoing physical motion (12) may be controlled together or independently by a control panel (15), by means of control input activators (16) as known in the art, except that the control input activators (16) provide a different arrangement of programmes in accordance with the chemical reactions required and/or cellular specimens used. A device for measuring ultrasonic wave energy emitted (17) may be included, which is itself connected to the control panel (15). The ultrasonic wave energy generating block (11) may be omitted altogether, thereby allowing the operation of the block permitting physical random agitation motion (12) alone.

Claims (10)

1. An ultrasonic wave energy generating apparatus comprising: a means of administering ultrasonic wave energy to an arrangement for performing chemical reaction a means for generating ultrasonic waves control means therefor.
2. An apparatus according to Claim 1 wherein said block is adapted to perform a plurality of ultrasonic wave energy emissions to cells in solution or on a surface during chemical reaction.
3. An apparatus according to either of Claims 1 or 2 wherein the ultrasonic wave emissions may be measured and controlled.
4. An apparatus according to Claims 1 to 3 wherein the ultrasonic wave energy generating block is in close contact with a surface whose temperature may be controlled and to the arrangement capable of performing chemical reaction.
5. A block capable of permitting physical random agitation motion to an apparatus for performing chemical reaction, wherein the said apparatus is positioned above a surface whose temperature may be controlled, in order to ensure even distribution of reagents for chemical reaction.
6. An apparatus according to Claims 1 - 5 wherein the arrangement capable of performing chemical reaction is in contact with or in close proximity to a block capable of emitting ultrasonic energy, and to a block capable of performing physical random agitation motion, and to a surface whose temperature may be controlled.
7. An apparatus for performing chemical reaction according to any of Claims 1 to 6 wherein the sample comprises an ultrasonic wave energy and a heat energy transparent first surface including a well formed therein or thereon surrounding cellular material and containing a reaction solution, said well being associated with an ultrasound and heat energy transparent cover slip.
8. An apparatus for performing chemical reaction according to any of Claims 1 to 6 wherein the sample comprises an ultrasound and heat energy transparent container, chamber or tube, enclosing a reaction solution and cellular material or free target nucleic acid.
9. An apparatus according to Claims 1 - 8 wherein chemical reaction is performed within cells.
10. A method according to any of claims 1 to 9 wherein the reaction solution includes reagents necessary for performing chemical reaction such as a nucleic acid synthesis mixture (including a transcription or PRINS or amplification mixture) and wherein the heating and cooling cycling steps are repeated according to a preset program thereby to synthesise a target nucleic acid sequence.
GB9418440A 1994-09-13 1994-09-13 Mixing of chemical reaction components using ultrasound Withdrawn GB2293117A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB9418440A GB2293117A (en) 1994-09-13 1994-09-13 Mixing of chemical reaction components using ultrasound

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GB9418440A GB2293117A (en) 1994-09-13 1994-09-13 Mixing of chemical reaction components using ultrasound

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GB9418440D0 GB9418440D0 (en) 1994-11-02
GB2293117A true GB2293117A (en) 1996-03-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000049176A1 (en) * 1999-02-19 2000-08-24 Microbiological Research Authority Method and apparatus for nucleic acid strand separation
WO2002038808A2 (en) * 2000-11-08 2002-05-16 Hybaid Limited Slide or chip hybridisation unit
DE10117772A1 (en) * 2001-04-09 2002-10-17 Advalytix Ag Mixing device and mixing method for mixing small amounts of liquid
DE10142789C1 (en) * 2001-08-31 2003-05-28 Advalytix Ag Movement element for small amounts of liquid

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4575485A (en) * 1983-08-29 1986-03-11 Syntex (U.S.A.) Inc. Ultrasonic enhanced immuno-reactions
US4764021A (en) * 1983-02-22 1988-08-16 Corning Glass Works Apparatus for ultrasonic agitation of liquids
WO1991013674A1 (en) * 1990-03-14 1991-09-19 Public Health Laboratory Service Board Particle manipulation in an ultrasonic field
US5227312A (en) * 1989-03-14 1993-07-13 Public Health Laboratory Service Board Monitoring particle aggregation by the use of a meniscus
EP0555842A1 (en) * 1992-02-14 1993-08-18 Japan Science, Inc. A method of dissolving biological tissue
WO1993019367A2 (en) * 1992-03-10 1993-09-30 University College Cardiff Consultants Limited Particle aggregation method and apparatus
EP0567225A1 (en) * 1992-03-20 1993-10-27 Biwater Treatment Limited Treatment of water

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764021A (en) * 1983-02-22 1988-08-16 Corning Glass Works Apparatus for ultrasonic agitation of liquids
US4575485A (en) * 1983-08-29 1986-03-11 Syntex (U.S.A.) Inc. Ultrasonic enhanced immuno-reactions
US5227312A (en) * 1989-03-14 1993-07-13 Public Health Laboratory Service Board Monitoring particle aggregation by the use of a meniscus
WO1991013674A1 (en) * 1990-03-14 1991-09-19 Public Health Laboratory Service Board Particle manipulation in an ultrasonic field
EP0555842A1 (en) * 1992-02-14 1993-08-18 Japan Science, Inc. A method of dissolving biological tissue
WO1993019367A2 (en) * 1992-03-10 1993-09-30 University College Cardiff Consultants Limited Particle aggregation method and apparatus
EP0567225A1 (en) * 1992-03-20 1993-10-27 Biwater Treatment Limited Treatment of water

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000049176A1 (en) * 1999-02-19 2000-08-24 Microbiological Research Authority Method and apparatus for nucleic acid strand separation
WO2002038808A2 (en) * 2000-11-08 2002-05-16 Hybaid Limited Slide or chip hybridisation unit
WO2002038808A3 (en) * 2000-11-08 2003-10-02 Hybaid Ltd Slide or chip hybridisation unit
DE10117772A1 (en) * 2001-04-09 2002-10-17 Advalytix Ag Mixing device and mixing method for mixing small amounts of liquid
DE10117772C2 (en) * 2001-04-09 2003-04-03 Advalytix Ag Mixing device and mixing method for mixing small amounts of liquid
US8323985B2 (en) 2001-04-09 2012-12-04 Beckman Coulter, Inc. Mixing device and mixing method for mixing small amounts of liquid
DE10142789C1 (en) * 2001-08-31 2003-05-28 Advalytix Ag Movement element for small amounts of liquid

Also Published As

Publication number Publication date
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