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WO1998033052A1 - Procede permettant de prevenir l'evaporation dans des echantillons liquides de petits volumes - Google Patents

Procede permettant de prevenir l'evaporation dans des echantillons liquides de petits volumes Download PDF

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Publication number
WO1998033052A1
WO1998033052A1 PCT/SE1998/000095 SE9800095W WO9833052A1 WO 1998033052 A1 WO1998033052 A1 WO 1998033052A1 SE 9800095 W SE9800095 W SE 9800095W WO 9833052 A1 WO9833052 A1 WO 9833052A1
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WO
WIPO (PCT)
Prior art keywords
liquid
sample
covering
covering liquid
temperature
Prior art date
Application number
PCT/SE1998/000095
Other languages
English (en)
Inventor
Erik Litborn
Johan Roeraade
Original Assignee
Erik Litborn
Johan Roeraade
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 Erik Litborn, Johan Roeraade filed Critical Erik Litborn
Priority to AU57879/98A priority Critical patent/AU5787998A/en
Publication of WO1998033052A1 publication Critical patent/WO1998033052A1/fr

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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
    • B01J19/16—Preventing evaporation or oxidation of non-metallic liquids by applying a floating layer, e.g. of microballoons
    • 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
    • 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
    • G01N2035/00178—Special arrangements of analysers
    • G01N2035/00277—Special precautions to avoid contamination (e.g. enclosures, glove- boxes, sealed sample carriers, disposal of contaminated material)
    • G01N2035/00287—Special precautions to avoid contamination (e.g. enclosures, glove- boxes, sealed sample carriers, disposal of contaminated material) movable lid/cover for sample or reaction tubes

Definitions

  • the present invention is within the field of handling small liquid sample volumes and performing chemistry therewith. More specifically it relates to a method of preventing evaporation from the liquid sample in such operations, which method makes it possible to perform rapid and reliable operations in a simple way even with ultra-small sample volumes.
  • biocomponents peptides/proteins
  • peptides/proteins are present in high concentra tions due to the small (in the order of femtoliters) volume of the cell.
  • bioreactions can proceed at high speed.
  • Another important feature of chemistry in ultra-small volumes is that the small amounts of chemicals employed in such systems allow the use of rare, expensive chemicals at a reasonable cost.
  • Other advantages include the reduced bench space, needed for performing chemistry in small volumes. Additionally, environmental pollution and personal hazard risks from chemicals (solvents etc.) are minimized, due to the low consumption of materials.
  • vials can be produced in different mate ⁇ rials like polymers, glass, silicon, quartz etc. Manufacturing procedures can range from making simple indentations in plastic with a tiny hard object (a pin) to advanced lithographic processes and subsequent isotropic or anisotropic etching (ref 9, 10). Chemistry can also be performed in tiny sample droplets , placed on a flat surface in a defined position.
  • a schematic view of a typical structure with a multiple number of microvials (ref 11) , anisotropically etched in silicon will be shown later on in figure 1.
  • the lithographically produced structures have the advantage that a great number of vials (e.g. 100.000) can be made on a substrate with comparatively little effort.
  • a large number of chemical operations could be carried out on e.g. a silicon wafer.
  • reactions could be carried out on e.g. a silicon wafer.
  • a fundamental problem, related to the use of the open microvials or droplets on a surface as described above, is the evaporation of solvent in which the sample is dissolved . It is easy to understand that, due to the increased surface/volume ratio, nL - pL sized volumes of e.g.
  • a further drawback of this approach is that the vials have to be enclosed in a gas tight surrounding, to allow a saturation of the air above the vials with solvent. This impairs the access to the vials with dispensing devices, such as capillary tubing, syringes etc.
  • An additional technique to deal with the mentioned problem of evaporation is to continuously add solvents to the nL - pL sized vials, or to droplets on a flat sur- face. As long as the temperature of the vial (and the solvent within it) is moderate in relation to the boiling point of the solvent (e.g. 30-40°C for water solutions), this is a satisfactory technique. Even when using an array of vials, it is possible to use a matching array of solvent supplying capillaries , and the solvent level in the individual vials can be held constant for several hours (this has e.g. been performed by the inventors with a row of eight vials and capillaries during 2-4h at 37°C) . A schematic of the process will be shown below in figure 2.
  • Still another technology is utilized, to prevent evaporation of small amounts of solvent from miniature containers. This is by covering the solvent/sample with a thin layer of oil or molten wax, floating on top of the sample. As this liquid does not evaporate at the relevant operating temperature, a shield of the oil is formed which prevents evaporation of the sample.
  • a typical ap- plication is found in commercially available PCR reactors, where water based sampled are temperature- cycled between 60 and 95 °C. The sample is covered with a mineral oil during the temperature cycles, to prevent evaporation of water from the sample.
  • this technology is not useful in practice, because it becomes difficult to separate the oil from the sample after the reaction has been completed. Attempts to do this have either failed or have been associated with very large sample losses.
  • a new technology is proposed to prevent evaporation of liquid from a small volume sample during any handling or chemical operation thereof.
  • the basic principle is that during or in connection with the operation referred to the liquid sample is covered with a volatile liquid which is immiscible with the sample liquid.
  • covered with means that said volatile liquid (covering liquid) is of such a density relative to the liquid sample that it floats on top of the sample and acts as a liquid lock, or if a reversed geome- try is used, the liquid sample floats on top of the cover liquid.
  • volatile liquid this means that it evaporates or can be evaporated from the liquid sample without interfering or interacting with or decomposing any of the components thereof, i.e. neither the ingredients of the sample nor the solvent used. Furthermore, it should be completely evaporable from the liquid sample after the operation has been finalized, also in this case without decomposing or negatively influencing upon the same.
  • the cover liquid is selected so as to be volatilizable or evaporable at a temperature below the decomposition temperature of the components of the liquid sample. Moreover it should preferably be evaporable already at the temperature at which the operation is performed, as will be described more in detail below.
  • volatile is used in the common sense meaning vaporizing or evaporating quickly, or similar, and that the operation referred to, and thereby the method claimed, is performed (well) below the decomposition temperature of the compo- nentns of the liquid sample.
  • evaporate has the common meaning to drive out or draw off in the form of vapour.
  • time aspect is of course to be considered to avoid decomposition of the components of the liquid sample. That is, even if working below said decomposition temperature (where generally normal or atmospheric pressure is referred to) biological samples are often so sensitive that prolonged exposure to such tem- perature will have a negative impact on the sample.
  • temperature and time conditions are to be chosen so as to avoid the decomposition referred to.
  • use of temperatures below said decomposition temperature for oils or other non- volatile liquids will require such prolonged exposures that the sample will be negatively affected.
  • small volume sample this includes any of the previously known small volume operations, such as micro or nano litre operations.
  • the new technology presented broadens the small volume operational range to include also the nano to femto litre range.
  • an especially valuable aspect of the invention is that the method can be performed in a simple, rapid and reliable way also in the range of nano to femto litre volumes, e.g. pico to femto litre volumes. The technique might even be refined so as to enable operations with even smaller volumes, for instance atto litre volumes.
  • the handling or chemical operation referred to can be any of those operations which have previously been used in connection with small volume samples.
  • the chemical operation can be e.g. a synthesis, a biochemical assay or an analysis operation and the method is extremely well suited for use in con- nection with liquid samples containing biomolecules.
  • Such samples are generally very sensitive to higher temperature levels and temperature changes as well as to prolonged exposure to even moderately elevated temperatures and since the new technique according to the invention is very versatile as to temperature control levels it can be tailored for any biomolecular sample. Thus, it can be performed in minutes or even in seconds, for instance merely by discontinuing the feed of covering liquid.
  • biomolecular samples to which the present method is especially applicable are peptides, proteins (e.g. enzymes) and nucleic acids (e.g. DNA) .
  • the present invention relates to a method of preventing evaporation from a small volume liquid sample, especially an ultra-small volume liquid sample, during any handling or chemical operation thereof, which comprises performing said operation with the sample covered by a layer of a liquid which is substanti- ally immiscible with said liquid sample and which is eva ⁇ porable at such temperature and time conditions at which decomposition of the components of the liquid sample is avoided.
  • the covering .liquid is volatile, or evaporable, already at the temperature at which the operation in question is performed.
  • a great advantage with such a choice of cover liquid thus is that this enables a rapid, complete evaporation of said cover liquid once the operation has been terminated making the sample immedia ⁇ tely ready for the next step without any complicated or time-consuming separation being needed.
  • This is extremely important for most biomolecules as they are very sensitive to prolonged exposure to elevated temperatures.
  • such short times as less than 1 minute, or less than 30 seconds or even less than 20, 15 or 10 seconds to evaporate the covering liquid may be applicable in optimum cases. Otherwise, evaporation times less than 30 minutes, such as less than 20, 10 or even 5 minutes, can be regar- ded valuable contributions to this specific technical field.
  • cover liquid which is evaporated during the operation in such a case supplementary or additional cover liquid is added during the operation.
  • Said addition can be performed intermittently or continuously, continuous addition or feed being preferred.
  • said additional covering liquid is added at substantially the same rate as the evaporation rate thereof as this me- ans a smooth and steady state operation.
  • the additional covering liquid is added in an amount in excess of the amount evaporating from the sample, the appropriate layer thickness of covering liquid above the sample being controlled via any conventional overflow system.
  • the covering liquid also acts as a protection shield against the surrounding, for instance to continuously remove dust attracted from the surrounding by the overflow of cover liquid.
  • the sample is generally present in a plurality of individual containers, vials or droplets, etc., and a preferable embodiment of the invention is here represented by a simple technique where a common supply (and preferably also a common outlet) of covering liquid is utilized for a number of individual liquid samples.
  • said covering liquid in addition to the properties or characteristics referred to above, said covering liquid is also preferably chosen so as to be evaporable at a temperature level not too high above the operation temperature referred to and preferably relatively close thereto. Generally this means that the boiling point of the covering liquid is at most 100°C above the temperature at which the operation is perfor- med. Preferably it is at most 80°C above and more preferably at most 50°C above said operation temperature.
  • said boiling point is generally chosen so as to be above, preferably at least 5°C above, said operation temperature as otherwise the covering liquid will be continuously boiling away. More preferably said boiling point is at least 10°C above the operation temperature.
  • the covering liquid is chosen so as to be fully evaporable below 100°C and preferably below 80°C. In many cases, however, the sample may be sensitive also to such high temperature levels and consequently said cover liquid then may have to be evaporable already below 60°C or even below 50°C.
  • the covering liquid is chosen so as to be substantially inert relative to the sample and also preferably relative to the reaction products from the sample.
  • covering liquid is chosen so as to have the ability of extracting one or more components from the sample.
  • One preferable group of covering liquids is alkanes having appropriate boiling points, e.g. alkanes, especially n-alkanes, having 5-10 carbon atoms, such as penta- ne, hexane, heptane, octane, nonane and decane.
  • cover liquid also includes any mixtures (s) of liquids.
  • the boiling points of the preferred alkanes having 5-8 carbon atoms are as follows (for the n-alkanes) : pentane +36°C hexane +69°C heptane +98°C octane +126°C
  • covering liquids are (per) fluorocarbons, which are known for their minimal interference with biomolecules, similar considerations being made concerning boiling point ranges as in connection with the alkanes or other appropriate group of covering liquids.
  • the cover liquid can be simply and completely removed by natural or forced evaporation.
  • the operating temperature can be very close to the boiling point of the sample liquid.
  • reaction liquid Full accessibility to the reaction liquid is maintained at all time, since there is no mechanical lock. It is e.g. possible to add reagents or remove fluid from the sample during a reaction or incubation, while the reaction mixture is covered with covering liquid.
  • cover liquid If the covering liquid is added in excess during the reaction, dust attracted from the surrounding is continuously removed by the overflow of the cover liquid.
  • the cover liquid is therefore not only a barrier against evaporation. It also acts as a dynamic, protective shield against the surrounding.
  • Volatile covering liquids are often of low viscosity, in contrast to high boiling oils . This facilitates penetration through the cover layer, reduces the "stickiness” and counteracts the formation of emulsions.
  • the flowing covering liquid may contain reagents as well. In this way a reagent can be supplied to the vials. Alternatively the covering liquid may have properties to extract components from the sample. Also a procedure, where several reagents are sequentially added to the flow of covering liquid can be envisioned.
  • reaction products can be re-dissolved in an aliquot of the original or a different solvent to be able to remove the sample from the vial or the surface for subsequent analysis or other purposes.
  • One suitable way of operation is to add the solvent via a capillary tube in a continuous way ( according the principles shown in figure 2), while the sample can be withdrawn with another capillary tube.
  • this proce ⁇ dure will be shown in figure 7, where water is used as a solvent .
  • a dry sample can be placed in a vial or on a surface, followed by the application of the covering liquid.
  • the liquid (containing possible reagents) which dissolves the sample is added on top of the covering liquid. This liquid then positions itself under the covering liquid, due to gravitational forces, thereby dissolving the sample.
  • a covering liquid through which the sample (and subsequently reagents) are applied.
  • a particular way of dosing reagents , solvent or dissolved sample is in the form of tiny droplets of high velocity, generated by the same principle as in inkjet computer printers.
  • Such devices are commercially available for dispensing microdrops of various solutions (ref 14) Due to the high velocity of the droplets, a penetration of the cover layer is rapidly achieved (the sample is "shooting" through the surface cover layer) . This is facilitated by adjusting the thickness of the cover layer, which in its turn is adjusted by the supply of liquid and the evaporation rate of the same liquid.
  • ink-jet principle is also useful for a periodical makeup of sample liquid, to compensate for possible liquid losses, incurred during long term operation and/or at elevated temperatures .
  • Fig. 1 shows a schematic view of an anisotropically etched vial in silicon representing the prior art
  • FIG. 2 shows a schematic prior art process with continuous addition of solvent to a small volume sample
  • Fig. 3 shows schematically an embodiment of the method according to the invention with continuous addition of cover liquid
  • Fig. 4 shows one embodiment of an operational se ⁇ quence of the method according to the invention
  • Fig. 5 shows the principle of removing fluid from the sample during the method according to the invention
  • Fig. 6 shows an embodiment of the method according to the invention where covering liquid is added in excess
  • Fig. 7 shows an embodiment of the method claimed where solvent is added and sample is withdrawn after the operation has been discontinued
  • Fig. 8 shows a holder to be used for the mounting of silicon-chip based vials in a method according to the invention
  • Fig. 9 shows the results from a capillary electro- phoretic column analysis of a reaction mixture.
  • FIG. 1 shows an etched vial in silicon as disclosed e.g. in reference 2.
  • L is typically 25-400 ⁇ m.
  • Fig. 3a shows a vial with a liquid sample 2 covered by a cover liquid 3 being added continuously via a capil ⁇ lary tube 4, the feed rate V/t for said additional cover liquid being the same as the evaporation rate V/t of said cover liquid 3.
  • Fig. 3b shows a schematic view of a device 5 for continuous feed, via a common inlet 6, of cover liquid to a number of individual vials with liquid samples 2 to prevent evaporation therefrom.
  • the supply rate is V 1+2 /t while the evaporation rate is V ⁇ /t, i.e. an excess of cover liquid is used, and an overflow 7 being used, the overflow rate being V 2 /t.
  • Fig. 3c schematically shows the principle of using a reversed geometry with sample liquid flowing on top of cover liquid.
  • a reversed chip is shown with sample liquid 2 in a vial and cover liquid 3 therebelow.
  • step 1 shows the starting vial with sample liquid, which is then evaporated to a dry sample in step 2, steps 1 and 2 being repeated for all reagents needed.
  • step 3 cover solvent and in step 4 sample solvent are added, while step 5 shows the reaction step.
  • step 6 evaporation is then performed to dry reaction products, while in step 7 new cover solvent is added and in step 8 new solvent is added to dissolve reaction products for further operation thereof.
  • Fig. 5 shows the principle for removing sample 2 from a vial via a capillary tube 8 during the reaction.
  • Fig. 6 is similar to Fig. 3b but specifically shows the action of the cover liquid as a dust shield, dust particles 9 from the surrounding being continuously removed by the excess of cover liquid drained via the over- flow 7.
  • Fig. 7 shows the principle for redissolving a sample with a supply of water and subsequent sample withdrawal. Since there is an equilibrium between surface evaporation and supply of water, the volume of the sample can be kept at a constant level. When this situation is reached, part of the sample can be withdrawn, e.g. with a capillary tube (right-hand-side tube) .
  • Example 1 The invention will now be exemplified by some working examples representing a few embodiments of the invention.
  • Example 1
  • a reaction was performed between a protein (myoglobin) and a proteolytic enzyme (trypsin) .
  • trypsin a proteolytic enzyme
  • these two compounds are brought together under specific conditions (temperature, pH)
  • the protein is digested by the enzyme and distinctly fragmented into a number of peptides.
  • An analysis of these fragments provides a kind of fingerprint of the protein. This procedure is there- fore an often used method for identification of proteins .
  • anisotropically etched silicon-chip based vials of the type previously shown in Fig. 1 were employed.
  • the chip was mounted in a stainless steel holder, which is shown in Fig. 8, Fig. 8a showing a side view and Fig. 8b showing a top view thereof.
  • the holder 10 contained a heating element 11 and a temperature sensor (not shown) , in order to allow the reaction to proceed under controlled temperature.
  • An internal channel 12 in the holder also provided the possibility to cool the holder.
  • the chip was mounted in a recessed area 13 on top of the holder. In said recess the temperature sensor referred to can also be positioned. The recessed area was accessed by in- and outlet holes 14 and 15 for the covering liquid, which in its turn were connected to in- and outlet side entries in the holder.
  • a controlled flow of covering liquid could be administered, to cover the entire silicon chip, while keeping a balance between supply and evaporation of the covering liquid.
  • the holder was mounted on a XY servo motor-controlled table. Samples and reagents were added from a container under controlled pressure or from a flow-controlled micro-pump, via narrow bore capillary tubes (ID 40 ⁇ m OD 105 ⁇ m) , which could be precisely po- sitioned with a motorized device near the square opening of a vial.
  • a mixture of myoglobin (8 mg/ml) and water-based buffer solution (NH 4 HC0 3 8 mM pH 7.9) was dosed in eight individual, parallel operated 15 nL-sized vials. Thereafter, the water was allowed to evaporate, which occurred in about 40 sec.
  • Octane was used as a covering liquid, and was guided over the chip surface from a pressurized container via the inlet hole in the recessed stainless steel surface. The excess of octane was removed by controlled suction via the drainage hole. When the octane level was stabilized, 15 nL of trypsin dissolved in water (0.2 mg/ml) was added to the individual vials.
  • the dry myoglobin and buffer salts attached to the walls of the vials were dissolved, which started the digest reaction.
  • the device was heated to 37 °C utilizing the build-in heating element and sensor. The temperature was controlled with a PID regulator. The reaction was sustained under 2 hrs. During this time, the level of the buffer solution was monitored under a microscope. No detectable reduction in volume could be observed during this period, which demonstrates the efficiency of the cover liquid
  • Samples from the reaction mixture were periodically withdrawn by means of capillary tubes or vacuum injected directly into a capillary electrophoretic column. After completion of the reaction, the flow of octane was discontinued and the octane as well as the water of the sam- pie evaporated.
  • CE Chips Electrophoretic conditions; capillary length 85 cm (60 cm to detection), separation buffer 0.01 M KH 2 P0 4 pH 7.0, 15 kV, 6 ⁇ A, on-column detection 210 nm. a) upper electropherogram; CE analysis of sample injected through the cover layer after 45 min reaction time b) lower electropherogram; CE analysis of re- dissolved sample after 2 hrs reaction time

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Organic Chemistry (AREA)
  • Devices For Use In Laboratory Experiments (AREA)

Abstract

L'invention concerne un procédé permettant de prévenir l'évaporation dans un échantillon liquide de petit volume, notamment un échantillon liquide de volume extrêmement petit, lorsque cet échantillon fait l'objet d'une manipulation ou d'une opération chimique quelconque. Ce procédé comprend la réalisation de ladite opération sur l'échantillon recouvert d'une couche de liquide qui est sensiblement non miscible avec le liquide de l'échantillon et qui peut s'évaporer à une température et dans des conditions de temps avec lesquelles la décomposition des constituants de l'échantillon liquide est évitée. Il s'agit de choisir un liquide de recouvrement adéquat qui s'évapore pendant l'opération, du liquide de recouvrement additionnel étant ajouté pour compenser l'évaporation, et qui s'enlève facilement et rapidement une fois l'opération terminée.
PCT/SE1998/000095 1997-01-24 1998-01-22 Procede permettant de prevenir l'evaporation dans des echantillons liquides de petits volumes WO1998033052A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57879/98A AU5787998A (en) 1997-01-24 1998-01-22 A method of preventing evaporation from liquid samples in small volumes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9700207-5 1997-01-24
SE9700207A SE9700207D0 (sv) 1997-01-24 1997-01-24 A method of preventing evaporation from liquid samples in small volumes

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WO1998033052A1 true WO1998033052A1 (fr) 1998-07-30

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AU (1) AU5787998A (fr)
SE (1) SE9700207D0 (fr)
WO (1) WO1998033052A1 (fr)

Cited By (11)

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WO2000056446A1 (fr) * 1999-03-10 2000-09-28 Sequenom, Inc. Systeme et procede permettant d'effectuer des reactions dans un environnement non clos
WO2000063232A1 (fr) * 1999-04-17 2000-10-26 Genevac Limited Procedes et appareil permettant d'eviter une perte d'echantillon
WO2000067907A3 (fr) * 1999-05-11 2001-02-08 Aclara Biosciences Inc Regulation d'evaporation dans des echantillons
US6949633B1 (en) 1995-05-22 2005-09-27 Sequenom, Inc. Primers useful for sizing nucleic acids
WO2005042146A3 (fr) * 2003-10-24 2005-10-13 Aushon Biosystems Inc Appareil et procede permettant de distribuer des echantillons fluides, semi-solides et solides
US7132519B2 (en) 1996-12-10 2006-11-07 Sequenom, Inc. Releasable nonvolatile mass-label molecules
US7198893B1 (en) 1996-11-06 2007-04-03 Sequenom, Inc. DNA diagnostics based on mass spectrometry
US7323345B1 (en) 1998-10-30 2008-01-29 Norada Holding Ab Liquid microvolume handling system
EP1905513A1 (fr) * 2006-09-13 2008-04-02 Institut Curie Procédés et dispositifs de prélèvement des fluides
RU2731444C1 (ru) * 2015-09-30 2020-09-02 Нановэйпор Инк. Способ для подавления паров
CN112639432A (zh) * 2018-08-31 2021-04-09 株式会社岛津制作所 分析装置、分析方法、微量液体提取装置和微量液体提取方法

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US5225325A (en) * 1990-03-02 1993-07-06 Ventana Medical Systems, Inc. Immunohistochemical staining method and reagents therefor
US5549848A (en) * 1993-11-15 1996-08-27 Ventana Medical Systems, Inc. High temperature evaporation inhibitor liquid

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EP0159603A2 (fr) * 1984-04-23 1985-10-30 Abbott Laboratories Lamelles de contrôle pour analyses immunologiques de cellules
US5225325A (en) * 1990-03-02 1993-07-06 Ventana Medical Systems, Inc. Immunohistochemical staining method and reagents therefor
US5549848A (en) * 1993-11-15 1996-08-27 Ventana Medical Systems, Inc. High temperature evaporation inhibitor liquid

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6949633B1 (en) 1995-05-22 2005-09-27 Sequenom, Inc. Primers useful for sizing nucleic acids
US7198893B1 (en) 1996-11-06 2007-04-03 Sequenom, Inc. DNA diagnostics based on mass spectrometry
US7501251B2 (en) 1996-11-06 2009-03-10 Sequenom, Inc. DNA diagnostics based on mass spectrometry
US7132519B2 (en) 1996-12-10 2006-11-07 Sequenom, Inc. Releasable nonvolatile mass-label molecules
US7323345B1 (en) 1998-10-30 2008-01-29 Norada Holding Ab Liquid microvolume handling system
US6225061B1 (en) 1999-03-10 2001-05-01 Sequenom, Inc. Systems and methods for performing reactions in an unsealed environment
WO2000056446A1 (fr) * 1999-03-10 2000-09-28 Sequenom, Inc. Systeme et procede permettant d'effectuer des reactions dans un environnement non clos
US6485913B1 (en) 1999-03-10 2002-11-26 Sequenom, Inc. Systems and methods for performing reactions in an unsealed environment
US6521464B1 (en) 1999-04-17 2003-02-18 Genevac Limited Methods and apparatus for preventing sample loss
GB2375976B (en) * 1999-04-17 2003-04-30 Genevac Ltd Methods and apparatus for preventing sample loss
GB2375976A (en) * 1999-04-17 2002-12-04 Genevac Ltd Method of removing sample loss from TFA-containing mixtures using unspillable inkwell
WO2000063232A1 (fr) * 1999-04-17 2000-10-26 Genevac Limited Procedes et appareil permettant d'eviter une perte d'echantillon
US6555389B1 (en) 1999-05-11 2003-04-29 Aclara Biosciences, Inc. Sample evaporative control
WO2000067907A3 (fr) * 1999-05-11 2001-02-08 Aclara Biosciences Inc Regulation d'evaporation dans des echantillons
WO2005042146A3 (fr) * 2003-10-24 2005-10-13 Aushon Biosystems Inc Appareil et procede permettant de distribuer des echantillons fluides, semi-solides et solides
US7585463B2 (en) 2003-10-24 2009-09-08 Aushon Biosystems, Inc. Apparatus and method for dispensing fluid, semi-solid and solid samples
EP2322278A3 (fr) * 2003-10-24 2013-05-15 Aushon Biosystems, Inc. Appareil et procédé de distribution de fluide, échantillons semi-solides et solides
US9527085B2 (en) 2003-10-24 2016-12-27 Aushon Biosystems, Inc. Apparatus and method for dispensing fluid, semi-solid and solid samples
WO2008032276A3 (fr) * 2006-09-13 2008-08-21 Inst Curie Procédés et dispositifs permettant d'échantillonner des matériaux liquides
EP1905513A1 (fr) * 2006-09-13 2008-04-02 Institut Curie Procédés et dispositifs de prélèvement des fluides
US8741661B2 (en) 2006-09-13 2014-06-03 Institut Curie Methods and devices for sampling flowable materials
RU2731444C1 (ru) * 2015-09-30 2020-09-02 Нановэйпор Инк. Способ для подавления паров
CN112639432A (zh) * 2018-08-31 2021-04-09 株式会社岛津制作所 分析装置、分析方法、微量液体提取装置和微量液体提取方法

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