EP1573776A2 - Procede de production d'un support d'echantillons pour spectrometrie de masse de type maldi - Google Patents

Procede de production d'un support d'echantillons pour spectrometrie de masse de type maldi

Info

Publication number
EP1573776A2
EP1573776A2 EP03795893A EP03795893A EP1573776A2 EP 1573776 A2 EP1573776 A2 EP 1573776A2 EP 03795893 A EP03795893 A EP 03795893A EP 03795893 A EP03795893 A EP 03795893A EP 1573776 A2 EP1573776 A2 EP 1573776A2
Authority
EP
European Patent Office
Prior art keywords
maldi matrix
points
maldi
flat structure
layer
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.)
Granted
Application number
EP03795893A
Other languages
German (de)
English (en)
Other versions
EP1573776B1 (fr
Inventor
Karsten Reihs
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.)
Qiagen GmbH
Original Assignee
Qiagen GmbH
Sunyx Surface Nanotechnologies GmbH
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 Qiagen GmbH, Sunyx Surface Nanotechnologies GmbH filed Critical Qiagen GmbH
Publication of EP1573776A2 publication Critical patent/EP1573776A2/fr
Application granted granted Critical
Publication of EP1573776B1 publication Critical patent/EP1573776B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0409—Sample holders or containers
    • H01J49/0418—Sample holders or containers for laser desorption, e.g. matrix-assisted laser desorption/ionisation [MALDI] plates or surface enhanced laser desorption/ionisation [SELDI] plates

Definitions

  • the present invention relates to a method for producing a sample carrier with a large number of MALDI matrix points, a flat structure obtainable with the method according to the invention and a long-term stable flat structure.
  • Mass spectrometry has become increasingly popular for the analysis of samples, for example in drug chemistry or in biological research and production.
  • Mass spectrometry with ionization through matrix-assisted laser desorption and ionization (MALDI) is preferably used for the analysis of biomolecules in the samples.
  • MALDI In the MALDI process, in particular biomolecules and / or biological material in the form of a drop of liquid are metered onto a so-called MALDI matrix point, for example pipetted, and dried.
  • the crystals that form are examined, for example, with a MALDI-TOF mass spectrometer in linear or reflector mode.
  • Nordhoff et. al. "MALDI-MS as a new method for the analysis of nucleic acid (DNA and RNA) with molecular masses up to 150,000 Dalton, Application of modern mass spectrometric methods to plant science research, Oxford University press, (1996) pages 86-101 which is hereby introduced as a reference and is therefore considered part of the disclosure.
  • the MALDI matrix points are produced according to the prior art by applying the matrix substance as a solution in the form of a drop of liquid to a sample carrier and drying it there.
  • this process is very complex despite automation techniques.
  • the shape of the MALDI matrix points is not uniform and is not homogeneous in itself.
  • the position of the matrix points on the sample carrier is relatively inaccurate. In order to prevent two neighboring points from running into one another, their spacing must be chosen to be correspondingly large. It is therefore an object of the invention to provide a method for producing a flat structure with a large number of MALDI matrix points which does not have the disadvantages of the prior art.
  • the object is achieved according to the invention with a method for producing a flat structure, preferably a sample carrier, with a multiplicity of MALDI matrix points, in which the MALDI matrix points are applied to the sample carrier by precipitation of the MALDI matrix substance from the gas phase become.
  • the MALDI matrix points can have any shape. They can be produced very reproducibly, are very homogeneous and have a surface structure with which very good mass spectra can be achieved.
  • a flat structure in the sense of the invention is any shaped body with an arbitrarily designed surface.
  • the fabric is preferably a plate with a flat surface, very particularly preferably a sample carrier, which, however, preferably has no indentations.
  • the sheet according to the invention is most preferably a film.
  • a MALDI matrix point in the sense of the invention essentially consists of at least one MALDI matrix substance familiar to the person skilled in the art. preferred
  • MALDI matrix substances are 3-hydroxypicolinic acid, ⁇ - cyano-4-hydroxycinnamic acid, 2,5-dihydroxybenzoic acid, sinapic acid, 2,4,6-trihydroxyacetophenone nitrobenzyl alcohol, nicotinic acid, ferulic acid, caffeic acid, 2-aminobenzoic acid, picolinic acid, 3 -Aminobenzoic acid, 2,3,4-trihydroxyacetophenone, 6-aza-2-thiothymidine, urea, succinic acid, adipic acid, malonic acid or a mixture thereof.
  • the MALDI matrix substance ⁇ - cyano-4-hydroxycinnamic acid is very particularly preferred.
  • SY0036PCT A compound is preferably chosen as the MALDI matrix substance, which sublimes on the fabric and is visible to the human eye.
  • the MALDI matrix points are generated by precipitation of the MALDI matrix substance from the gas phase.
  • Precipitation from the gas phase in the sense of the invention is any process in which the MALDI matrix substance is transferred from the gas phase to the fabric. Condensation or sublimation may be mentioned as examples.
  • the MALDI matrix points are preferably applied to the fabric by sublimation.
  • Sublimation in the sense of the invention includes that the MALDI matrix substance is transferred as a solid into the gas phase and / or is deposited in a solid form from the gas phase on the fabric.
  • Sublimation preferably takes place in a vacuum.
  • the solid is particularly preferably heated for sublimation.
  • MALDI matrix substances are particularly preferably used in parallel or sequentially.
  • the MALDI matrix substances can be used to produce different MALDI matrix points.
  • a MALDI matrix point it is also conceivable for a MALDI matrix point to have a substructure, for example partial points which are present separately from one another, each of which is composed of a different MALDI matrix substance.
  • a substructure can also be, for example, concentric circular rings, which each consist of a different MALDI matrix substance.
  • the sample carrier is preferably covered during the precipitation from the gas phase, particularly preferably sublimation, by a shaped body, a so-called mask, which has continuous recesses. It is only in the area of these recesses that the MALDI matrix substance is deposited on the fabric and forms a MALDI matrix point or partial point there.
  • This mask can have any number of recesses, which can have any shape.
  • the recesses can be round, rectangular, square, triangular or oval, to name just a small number of the possible shapes.
  • the shape can be used to differentiate the respective MALDI matrix substances on a flat structure.
  • the fabric can also be originally covered by several masks, which are then removed one after the other
  • SY0036PCT 3 are used, for example, to apply different MALDI matrix substances to different areas of the fabric according to the invention.
  • the mask has further recesses with which information can be transferred to the flat structure.
  • the MALDI matrix substance is deposited on the fabric so that the information is visible there. Examples of information in the sense of the invention are the labeling of the rows and columns of a grid, abbreviations for the MALDI matrix substance used, but also adjustment points which allow an exact adjustment of the fabric in the corresponding analysis device.
  • the MALDI matrix points preferably have an area of 1 ⁇ m 2 - 10 mm 2 .
  • a drop of liquid can be deposited on such a surface and preferably anchored in such a way that it does not detach itself from the flat structure according to the invention when it hangs downwards.
  • the MALDI matrix points are preferably arranged along an exact grid, which enables simple control of metering and / or analyzing machines.
  • the MALDI matrix points can have any shape. Examples of possible shapes are rectangular, square, triangular or oval.
  • the shape of the MALDI matrix points can be used to differentiate them, because the shape can be recognized, for example, under a microscope in the mass spectrometer during the analysis. For example, a specific form can be assigned to a specific MALDI matrix substance.
  • a MALDI matrix point also preferably has a substructure. This substructure can consist of several sub-points which are isolated from one another and which preferably each consist of a different MALDI matrix substance. However, the substructure can also have several concentric circular rings.
  • the embodiment with several partial points has the advantage that a single drop of a substance to be analyzed, which is brought into contact with the MALDI matrix point, simultaneously wets several partial points and thus examinations with several different matrixes at one MALDI matrix point - Substances can be carried out.
  • the MALDI matrix points or partial points preferably represent regions which are better wettable than their surroundings and which are in each case completely surrounded by a region which is less wettable, preferably ultraphobic. This embodiment makes it possible to deposit a drop of liquid at a very specific location and anchor it there comparatively firmly.
  • the crystalline structure of the MALDI matrix points or partial points preferably has a crystallite size of ⁇ 1 ⁇ m.
  • This preferred embodiment of the present invention has the advantage, for example, that the MALDI matrix points are very well and uniformly dissolved by the substance to be tested and / or that a very good signal results.
  • Ultraphobic in the sense of the invention means that the contact angle of a drop of water and / or oil lying on an ultraphobic surface is more than 150 ° , preferably more than 160 ° and most preferably more than 170 ° and / or the roll angle 10 ° does not exceed.
  • the roll angle is understood to be the angle of inclination of a basically planar but structured surface against the horizontal, in which a standing water and / or oil drop with a volume of 10 ⁇ l is moved due to the force of gravity when the surface is inclined.
  • ultraphobic surfaces are described, for example, in WO 98/23549, WO 96/04123, WO 96/21523, WO 00/39369, WO 00/39368, WO 00/39239, WO 00/39051, WO 00/38845 and WO 96 / 34697, which are hereby introduced as a reference and are therefore considered part of the disclosure.
  • Such an ultraphobic surface is described in international patent application WO 99/10322, which is hereby introduced as a reference and is therefore considered part of the disclosure.
  • the fabric is designed as a disposable item.
  • a multilayer sheet with a first layer with an ultraphobic surface and a carrier layer is particularly suitable for this embodiment, the first layer being reversibly applied to the carrier layer and the maximum local deviation of the sheet from the flatness ⁇ 100 ⁇ m, particularly preferably ⁇ 20 ⁇ m over a length of 100 mm.
  • This flat structure has the advantage that the first layer with the ultraphobic surface can be detached from the carrier layer after one or more uses and can be replaced by a new first layer, so that it is excluded that this first layer has been contaminated by previous experiments ,
  • the first layer with the ultraphobic surface is particularly inexpensive to manufacture as a disposable item.
  • the flatness defined according to the invention ensures that the flat structure can be used in all common mass spectrometric and / or optical analysis devices.
  • the first layer is glued to the carrier layer.
  • the fabric according to the invention can be used in a variety of ways, but is preferably suitable for mass spectroscopic and / or optical analyzes.
  • SY0036PCT Another object of the present invention is a long-term stable sheet with at least one MALDI matrix point, characterized in that it is surrounded by a hollow body in which a vacuum prevails and which consists of a water vapor-impermeable material.
  • the fabric is completely surrounded by a hollow body in which there is a vacuum, preferably a pressure ⁇ 100 mbar.
  • the hollow body is made from a gas-impermeable, in particular water vapor-impermeable, material.
  • the hollow body is preferably opaque.
  • the hollow body is preferably made of a plastic film which is sealed on at least one side.
  • the plastic film particularly preferably has a gas barrier layer, in particular a water vapor barrier layer. This barrier layer is preferably made of aluminum.
  • the fabric according to the invention has the advantage that, in particular, the MALDI matrix points on the fabric are not subject to any or only a slight aging process over a period of at least several months.
  • Figure 1 shows the cross section of a multi-layer fabric according to the invention.
  • Figure 2 shows the surface of a fabric according to the invention.
  • FIG. 3 shows a mask for carrying out the method for producing a flat structure according to the invention.
  • FIG. 4 shows a MALDI matrix point obtainable with the method according to the invention.
  • FIG. 5 shows the use of the fabric according to the invention in the coupling of liquid chromatography and MALDI examinations.
  • a sample carrier was made as follows:
  • a roll-polished aluminum sheet (99.9%) with an area of 26 ⁇ 76 mm 2 and a thickness of 0.15 mm was degreased at room temperature with chloroform (pa) for 20 seconds in aqueous NaOH (5 g / l) at 50 ° C.
  • the mixture was then rinsed in distilled water for 30 s, then in NaHCO 3 (20 g / l) for 60 s at 40 ° C., then again in distilled water for 30 s and dried in a drying cabinet at 80 ° C. for 1 hour.
  • the sheet treated in this way was coated with an approximately 50 nm thick gold layer by sputtering in a high vacuum. Finally, the sample was immersed in a closed vessel for 24 hours by immersion in a solution of the thiol CF 3 - (CF 2 ) 7 - (CH 2 ) 2 -SH in benzotrifluoride (pa, 1 g / l) at room temperature
  • the surface For water, the surface has a static contact angle of 178 °. If the surface is inclined by ⁇ 2 °, a water drop with a volume of 10 ⁇ l rolls off.
  • a high vacuum evaporation plant (Edwards E306)
  • 0.5 g of ⁇ -cyano-4-hydroxycinnamic acid is placed in a heatable quartz crucible with an upward opening of 10 mm in diameter.
  • a sample holder which is covered with a mask according to FIG. 3, is mounted at a distance of 150 mm.
  • the quartz crucible is heated with the help of external windings made of tungsten wire.
  • the temperature of the solid is regulated in the powder bed with a thermocouple at 180 ° C.
  • the layer thickness of the deposited film of o-cyano-4-hydroxycinnamic acid is determined with the aid of a quartz crystal thickness gauge, which is previously calibrated with an absolute layer thickness determination (e.g. atomic force microscope).
  • the sublimation is broken off at a layer thickness of 1 ⁇ m.
  • the MALDI matrix points obtained are shown by way of example in FIG. 4.
  • a mass spectrum of this MALDI matrix point was obtained as follows:
  • the peptides were prepared for mass spectrometric analysis as follows: 0.5 ⁇ l of an aqueous solution, each 5 fmol of peptides 1-6, 1 fmol of peptide 7 and a volume percent of trifluoroacetic acid and 1 mM of the nonionic detergent n-octyl-ß-D- contained glucopyranoside were pipetted onto the MALDI matrix point. After the solvent completely SY0036PCT 9 had evaporated, the sample thus prepared was washed once. For this purpose, the entire sample holder was exchanged for a 0.1% trifluoroacetic acid for 2 seconds and immediately thereafter, for the removal of remaining liquid residues, held in a nitrogen gas stream (2.5 bar) for 10 seconds.
  • the mass spectrum of positive molecular ions was recorded in a MALDI time-of-flight mass spectrometer from Bruker Daltonik, Bremen (Scout-MTP Autoflex) in reflector operating mode and with time-delayed ion extraction (delay time: 70 nanoseconds) and 20 kV acceleration voltage. To improve the signal-to-noise ratio, 100 single-shot spectra were added up.
  • FIG. 1 shows the fabric 1 that consists of a first layer 2 with an ultraphobic surface 3 and a carrier layer 4.
  • the first layer 2 is fixed on the carrier layer by means of an adhesive layer 5.
  • the person skilled in the art recognizes that the adhesive layer 5 does not necessarily have to be present.
  • the adhesive layer 5 consists of an electrically conductive material, so that there is an electrical contact between the first layer 2 and the carrier material.
  • FIG. 2 shows a flat structure according to the invention, onto which several MALDI matrix points 6 have been sublimed in a grid-like manner.
  • the MALDI matrix points in the respective rows 1-4 have different shapes which symbolize the user that different MALDI-Marix substances were used in each row.
  • the MALDI matrix point 2D is shown enlarged so that it can be seen that it consists of four partial points 8. These sub-points 8 are each made up of different MALDI matrix substances, so that four different analyzes can be carried out at this MALDI matrix point.
  • an inscription 7 has additionally been applied to the flat structure, which informs the user of the MALDI matrix substance used in this row.
  • the fabric has two centering crosses 9.
  • the inscription and the centering crosses are sublimed like the MALDI matrix points on the fabric by placing a mask over the fabric that has corresponding recesses.
  • the person skilled in the art recognizes that the rows 1-4 of the grid were produced one after the other.
  • Figure 3 shows the mask with 8 x 8 openings 12 with a diameter of 0.8 mm with a distance of the center points of 2.25 mm (not to scale).
  • FIG. 4 shows an optical micrograph of a matrix spot obtained with the mask from FIG. 3.
  • FIG. 5 shows the very advantageous use of the sample carrier according to the invention in the coupling of liquid chromatography and MALDI examination (LC-MALDI coupling).
  • SY0036PCT 11 Mixtures of substances are often first separated chromatographically before a MALDI examination. Examples are mixtures of peptides that have been generated by enzymatic (eg trypsin) peptide degradation. After the chromatographic separation, the fractions of the eluate are then applied to the MALDI matrix points 6 of the sample holder 1.
  • enzymatic eg trypsin
  • MALDI matrix points 6 are used for this, which are very close to each other, but are still completely enclosed by an ultraphobic area.
  • the distances (measured from center to center) of the MALDI matrix points are 1.5 times their diameter.
  • MALDI matrix points which were created by sublimation via masks, their location and size are very precisely defined. In this way it can be achieved that the liquid can run out of the opening 11 of the LC column 10 for application to the MALDI matrix points continuously. A separate collection of the fractions in vessels with subsequent pipetting onto the matrix points or a discontinuous generation of fractions by lingering the outlet opening over a MALDI matrix point and then quickly moving on to the next MALDI matrix point is omitted.
  • the sample carrier 1 is moved at a constant speed under the outlet opening 11.
  • Each MALDI matrix point now captures a constant volume of the liquid that is dispensed from the outlet opening.
  • the process is started at point A and meanders across all points to point E.
  • the MALDI matrix points then contain the entire eluate of the chromatography on the MALDI matrix points A to E in fractions that correspond to the constant volume, that every MALDI matrix point takes up. This volume can be changed by changing the speed at which the carrier 1 is displaced under the entrance opening 11.

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  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

La présente invention concerne un procédé de production d'un support d'échantillons présentant une pluralité de points de matrice MALDI, un produit plat pouvant être obtenu par ce procédé, ainsi qu'un produit plat stable à long terme.
EP03795893.1A 2002-12-13 2003-12-15 Procédé de production d'un support d'échantillons pour spectromètrie de masse de type maldi Expired - Lifetime EP1573776B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10258674A DE10258674A1 (de) 2002-12-13 2002-12-13 Verfahren zur Herstellung eines Probenträgers für die MALDI-Massenspektrometrie
DE10258674 2002-12-13
PCT/EP2003/014230 WO2004055857A2 (fr) 2002-12-13 2003-12-15 Procede de production d'un support d'echantillons pour spectrometrie de masse de type maldi

Publications (2)

Publication Number Publication Date
EP1573776A2 true EP1573776A2 (fr) 2005-09-14
EP1573776B1 EP1573776B1 (fr) 2017-12-06

Family

ID=32336361

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03795893.1A Expired - Lifetime EP1573776B1 (fr) 2002-12-13 2003-12-15 Procédé de production d'un support d'échantillons pour spectromètrie de masse de type maldi

Country Status (6)

Country Link
US (1) US20060121599A1 (fr)
EP (1) EP1573776B1 (fr)
JP (1) JP2006514738A (fr)
AU (1) AU2003298183A1 (fr)
DE (1) DE10258674A1 (fr)
WO (1) WO2004055857A2 (fr)

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DE102005022823A1 (de) * 2005-05-02 2006-11-09 Qiagen Gmbh Bioprobenträger für massenspektroskopische Analysen
JP5020742B2 (ja) * 2007-08-27 2012-09-05 日本電子株式会社 Ｍａｌｄｉイオン源を備えた質量分析装置およびｍａｌｄｉイオン源用サンプルプレート
WO2010014512A2 (fr) * 2008-07-30 2010-02-04 The Brigham And Women's Hospital, Inc. Préparation de plaques de test pour désorption-ionisation laser assistée par matrice
EP2157432A1 (fr) * 2008-08-15 2010-02-24 Qiagen GmbH Procédé d'analyse d'un échantillon complexe par spectrométrie de masse
US20120112058A1 (en) * 2009-07-09 2012-05-10 Koninklijke Philips Electronics N.V. Surface coating for laser desorption ionization mass spectrometry of molecules
WO2011027819A1 (fr) * 2009-09-02 2011-03-10 公益財団法人野口研究所 Procédé de spectrométrie de masse
JP5359924B2 (ja) * 2010-02-18 2013-12-04 株式会社島津製作所 質量分析装置
US9211542B2 (en) * 2010-05-21 2015-12-15 Eidgenossische Technische Hochschule Zurich High-density sample support plate for automated sample aliquoting
WO2014162557A1 (fr) * 2013-04-04 2014-10-09 株式会社島津製作所 Procédé de préparation d'un échantillon pour maldi et dispositif associé
DE102015003440A1 (de) * 2015-03-16 2016-09-22 Friedrich-Schiller-Universität Jena Verfahren zur MALDI-MSI Analytik von Objekten, insbesondere biologischen Gewebeproben, und Target zur Analytik sowie dessen Herstellung

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GB9518429D0 (en) * 1995-09-08 1995-11-08 Pharmacia Biosensor A rapid method for providing kinetic and structural data in molecular interaction analysis
US5854486A (en) * 1996-12-27 1998-12-29 R. T. Hodgson Method and apparatus for MALDI mass spectrometry
NZ516848A (en) * 1997-06-20 2004-03-26 Ciphergen Biosystems Inc Retentate chromatography apparatus with applications in biology and medicine
DE19754978C2 (de) * 1997-12-11 2000-07-13 Bruker Daltonik Gmbh Probenträger für die MALDI-Massenspektrometrie nebst Verfahren zur Herstellung der Platten und zum Aufbringen der Proben
DE19834070B4 (de) * 1998-07-29 2007-02-15 Bruker Daltonik Gmbh Ionisierung hochmolekularer Substanzen durch Laserdesorption aus flüssigen Matrices
DE59908917D1 (de) * 1998-12-24 2004-04-22 Sunyx Surface Nanotechnologies Ultraphobe oberfläche
EP1181705A2 (fr) * 1999-04-29 2002-02-27 Ciphergen Biosystems, Inc. Support d'echantillons a revetement hydrophobe pour spectrometre de masse en phase gazeuse
DE19923761C1 (de) * 1999-05-21 2001-02-08 Bruker Daltonik Gmbh Aufreinigende Probenträger für die MALDI-Massenspektrometrie
DE10005600A1 (de) * 2000-02-09 2001-08-16 Bayer Ag Ultraphobes Flächengebilde mit einer Vielzahl von hydrophilen Bereichen
DE10043042C2 (de) * 2000-09-01 2003-04-17 Bruker Daltonik Gmbh Verfahren zum Belegen eines Probenträgers mit Biomolekülen für die massenspektrometrische Analyse

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Also Published As

Publication number Publication date
DE10258674A1 (de) 2004-06-24
JP2006514738A (ja) 2006-05-11
WO2004055857A2 (fr) 2004-07-01
AU2003298183A1 (en) 2004-07-09
EP1573776B1 (fr) 2017-12-06
US20060121599A1 (en) 2006-06-08
WO2004055857A3 (fr) 2005-12-22

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