WO2006109073A2 - Ameliorations apportees a des procedes et des appareils d'analyse d'echantillons biologiques par spectrometrie de masse - Google Patents

Ameliorations apportees a des procedes et des appareils d'analyse d'echantillons biologiques par spectrometrie de masse Download PDF

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Publication number
WO2006109073A2
WO2006109073A2 PCT/GB2006/001356 GB2006001356W WO2006109073A2 WO 2006109073 A2 WO2006109073 A2 WO 2006109073A2 GB 2006001356 W GB2006001356 W GB 2006001356W WO 2006109073 A2 WO2006109073 A2 WO 2006109073A2
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Prior art keywords
test specimen
sample
laser
mass
tissue
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PCT/GB2006/001356
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English (en)
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WO2006109073A3 (fr
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Josephine Bunch
Alan G. Cox
Cameron William Mcleod
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The University Of Sheffield
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Publication of WO2006109073A2 publication Critical patent/WO2006109073A2/fr
Publication of WO2006109073A3 publication Critical patent/WO2006109073A3/fr

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    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • G01N33/6851—Methods of protein analysis involving laser desorption ionisation mass spectrometry

Definitions

  • the present invention relates to methods and apparatus for analyzing biological samples by mass spectrometry and more particularly to a method for analysing molecular and elemental components of biopsy tissue.
  • the method and apparatus may find application, for example, in the fields of medical imaging, analysis, monitoring and diagnostics.
  • biological material is to be interpreted broadly and can include, for example, nucleic acids, lipids, carbohydrates or any molecule covered in Stryer et al Biochemistry, 2002.
  • molecular analysis and imaging may be used as integral building blocks in strategies designed to locate specific proteins that are more highly expressed in tumors relative to normal tissue. Likewise, they may be used to locate specific proteins diminished in expression relative to normal tissue.
  • Laser Desorption Mass Spectrometry is a promising technique for analysis of low molecular weight molecules in tissue, first developed in the 1960's. UV laser spot sizes can be focused to under 5 ⁇ m, and so the technique is ideally suited to spatially resolved analyses. Laser Desorption Mass Spectrometry (LDMS) to obtain spatial information is often referred to as Laser Microprobe Mass Spectrometry (LMMS). The technique became widely available by the introduction of commercial instruments
  • Matrix-assisted laser desorption/ionisation (“MALDI”) mass spectrometry provides for the spectrometric determination of a mass of poorly ionising or easily fragmented analytes of low volatility by embedding them in a matrix of light-absorbing material.
  • the matrix material which is present in large excess relative to the analyte, serves to absorb energy from the laser pulse and to transform it into thermal and excitation energy to desorb and ionise the analyte.
  • This technique was introduced in 1988 by Hillenkamp and Karas [Karas, M. and Hillenkamp, F. (1988). Anal. Chem. 60:2299] for use with large biomolecules. Since then, the practice of MALDI mass spectrometry has advanced rapidly and has found applications in the mass determination of molecules ranging from small peptides, oligosaccharides and oligonucleotides to large proteins and synthetic polymers.
  • MALDI imaging has been developed as a method for spatially resolving peptides, proteins and drugs in biological tissue and is demonstrating potential as a means of measuring peptides, proteins, and drugs in tissue.
  • Methodologies include both direct tissue examination and indirect analysis of tissue imprinted membranes.
  • U.S 5,808,300 describes a method and apparatus for imaging biological samples, for example, mammalian tissue, with MALDI MS. Its techniques can be used to generate images of samples in one or more m/z pictures, providing the capability for mapping the concentrations of specific molecules in X, Y coordinates of the original biological sample. Analysis of a biological sample can be carried out directly on a tissue slice or indirectly on an imprint of a tissue sample. The image attained in the analysis can be displayed in individual m/z values as a selected ion image, as summed ion images, or as a total ion image. The imaging process may also be applied to other separation techniques where a physical track or other X, Y deposition process is utilized, for example, in the CE/MALDI MS combination where a track is deposited on a membrane target.
  • US 6756586 describes a further method of analyzing proteins within a sample.
  • a specimen including an energy absorbent matrix is generated.
  • the specimen is interrogated with a laser beam such that a predetermined first laser spot on the specimen releases first sample proteins.
  • the atomic mass of the released first sample proteins is measured over a range of atomic masses.
  • the specimen is moved relative to the laser beam a predetermined linear distance functionally related to a size of the predetermined first laser spot.
  • the specimen is struck again with the laser beam such that a predetermined second laser spot on the specimen releases second sample proteins.
  • the atomic mass of the released second sample proteins is measured over a range of atomic masses.
  • An atomic mass window of interest within the range of atomic masses is analysed to determine the specific proteins within the sample.
  • the determined specific proteins can be mapped as a function of the spatial arrangement.
  • the technology is stated to be applicable to MALDI MS and may be used for the analysis of peptides and proteins present on or near the surface of samples such as tissue
  • LA- ICP-MS Laser ablation (LA) inductively coupled plasma mass spectrometry (ICP-MS) has been widely used as a powerful analytical technique for solid micro sampling analyses in geological, biological, environmental, nuclear, and metallurgical applications.
  • LA- ICP-MS a high energy laser beam is directed onto the surface of a solid leads to the evaporation of a micro amount of sample.
  • the micro amount of the laser-ablated material is transported by a carrier gas to a second excitation process (e.g., ICP).
  • ICP second excitation process
  • the ablated material is evaporated, atomized, and excited by the second energy source.
  • An advantage of this two-step operation is the potential of increased efficiencies during the evaporation, atomization, and excitation steps.
  • Recently LA-ICP-MS has been proposed as a technique for mapping of metals distribution in organ tissues (see Kindness et al, Clinical Chemistry 2003; 49: 1916-1923).
  • US 5,372,719 and US 5,453,199 disclose techniques for preparing a chemically active surface so that when a sample is exposed to this surface, a chemical image of the sample is deposited on the surface.
  • the disclosed methods involve the separation of molecules by sorbents.
  • a second laser source for generating a high energy laser beam, which may be the same or different from the first laser source, for sequentially interrogating the first test specimen or the second test specimen with a laser beam at a plurality of laser spots on the first or second test specimen, thereby sequentially ablating sample molecules from each laser spot;
  • the invention provides a method of preparing a tissue specimen for matrix-assisted laser desorption/ionisation ("MALDI”) mass spectrometry, which comprises directing at the tissue surface a cone-shaped gas-atomized spray of a solution of a matrix-assisted laser desorption/ionisation crystalline matrix material dissolved in a suitable solvent to form a relatively homogeneous matrix crystal layer in terms of crystal morphology and crystal distribution of said matrix material on said tissue sample.
  • MALDI matrix-assisted laser desorption/ionisation
  • Test specimens in step (a) in accordance with the invention may be generated from any suitable tissues, although in general the invention finds particular application in the analysis of mammalian tissues.
  • the test specimen may be animal or human tissue and may be healthy or diseased.
  • diseased tissues include cancerous tissues, for example, testicular, prostate, liver, breast, colon, kidney, lymph, and brain cancerous tissues.
  • steps (e) to (g) the operation is repeated until the specimen has been effectively scanned.
  • a window of interest is defined from among the range of molecular masses encompassed by the molecules released from the specimen by the laser beam.
  • This window of interest may include the entire range of molecular masses of the released molecules or any portion thereof.
  • masses of the desorbed/ionised molecules may be selected so that the spatial arrangement of these molecules may be displayed, as a function of original location within the sample. Any suitable mapping/graphical techniques may be applied to enable this data manipulation.
  • a second test specimen comprising a second layer of the tissue sample proximate to the first layer is optionally generated.
  • the elemental atomic mass analysis on the first test specimen in order to ensure that the superimposed spatial arrangements of molecular and elemental maps are strictly comparable.
  • two test specimens they are preferably prepared from microtomed adjacent sections of tissue and care should be taken to ensure that there are no significant observable differences between the adjacent microtomed tissue sections.
  • step (j) the specimen is interrogated with a second laser beam having high energy sufficient to ablate sample molecules from the surface of the specimen.
  • the ablated material if sufficiently ionised, may be directly measured by mass spectrometry, preferably employing a quadrupole mass analyser. Alternatively, ablated material may be transferred to a high temperature ICP source for atomization/ionisation prior to mass spectrometric measurement.
  • the preferred laser for use in steps (b) and (j) is an Nd:YAG laser, operating at 266nm, in either low or high energy modes for MALDI or LA respectively. Whilst a dual mode laser is preferred for many applications it is possible within the invention to use two or more lasers, as appropriate.
  • steps (1) to (n) the procedure is repeated with translation of the specimen so that elemental information is acquired across the entire sample area, permitting selected ions of interest to be extracted from the data acquired from each location and represented graphically as a display of the spatial distribution of selected elements within the tissue section, as in step (o).
  • a window of interest is defined from among the range of atomic masses encompassed by the elements ablated from the specimen by the laser beam.
  • This window of interest may include the entire range of atomic masses of the ablated elements or any portion thereof.
  • masses of the ablated/ionised elements may be selected so that the spatial arrangement of these elements may be displayed, as a function of original location within the sample. Any suitable mapping/graphical techniques may be applied to enable this data manipulation.
  • step (q) the molecular map (the first X,Y plot) and the elemental map (the second X, Y plot) are combined to obtain a graphical depiction of the spatial arrangement of molecules and elements of interest in the tissue sample.
  • the overlaid spatial data can relate, for example, to the distribution of a single protein and metal, or to groups of proteins and metals as appropriate. Other biomolecules and elements can of course be chosen as desired.
  • the MALDI and LA-ICP-MS analyses are preferably carried out on a single test specimen using a dual function laser.
  • the specimen is mounted on a single translation stage movable within a sample inlet source.
  • the apparatus is provided with ion extraction to a Q-TOF mass analyser for molecular (MALDI) and atomic (LA-MS and LA-ICP-MS) mass spectrometry measurement.
  • MALDI-MS and LA-MS or LA-ICP-MS measurements can be carried out on the test specimen sequentially and processed to produce the desired overlaid spatial data.
  • a tissue specimen for MALDI and/or LA - ( ICP)-MS is prepared by directing at the tissue surface a cone-shaped gas-atomized spray of a solution of a MALDI matrix material in a volatile solvent to form a continuous matrix layer on the tissue surface.
  • the spray is dispensed using a nebuliser.
  • it has been found that improved more homogeneous crystal coating (in terms of crystal morphology and uniform distribution of crystals upon the sample tissue) of matrix material is obtained when the nebuliser and the sample are in a fixed spatial arrangement, that is to say, the matrix material is deposited without moving either the nebuliser or the sample.
  • FIG. 1 there is shown a tissue section 1, a molecular image 2 produced by MALDI analysis, an elemental image 3 produced by LA-ICP-MS analysis and a combined molecular and elemental image 4 produced by overlaying the molecular image 2 and the elemental image 3.
  • the method of the invention enables the overlaying of any selected molecular mass image and element image to obtain a plot of the spatial distribution of the molecule(s) and element(s) of interest.
  • FIG. 1 there is shown a mass spectrometer illustrated generally at 10, which comprises a computer controlled XYZ translation stage 11, a dual mode laser 12, a mass analyser 13 and a workstation 14 for data analysis.
  • a matrix-coated tissue specimen 15 is mounted on the translation stage 11 in a sample inlet source 16.
  • the specimen 15 is connected to the mass analyser 13 by an ion extraction means 17.
  • An optional inductively coupled plasma (ICP) device 18, illustrated by broken lines, is connected by carrier gas line 19 to the vacuum environment of the sample inlet source 16 and by ion extraction means 20 to the mass analyser 13. All components of the described instrumentation except for the ICP source and the workstation are enclosed within a vacuum chamber 21.
  • ICP inductively coupled plasma
  • the tissue specimen 15 such as, for example, a matrix coated tissue is mounted on the translation stage 11 and interrogated with the laser 12, operating at low power. Desorbed molecules from the specimen are transferred by the ion extraction means 17 to the mass analyser 13 for measurement of molecular mass via quadruple, quadruple-time of flight or sector field.. Between each reading the specimen 15 is moved to a new position by the translation stage 11. In this way data can be collected providing information about the spatial distribution of a molecule of interest across the surface of
  • the specimen 15, or a similar specimen prepared from a tissue section taken from a proximate region of the tissue sample, is interrogated with the laser 12, operating at high power.
  • Ablated molecules, if sufficiently ionised, are collected in the ion extraction means 17 and transferred to the mass analyser 13 for measurement of atomic mass.
  • the ablated molecules are collected by the carrier gas line 19 and transferred to the ICP device 18 for ionisation/atomization. Ions from the ICP device 18 are then transferred to the mass analyser 13 by the ion extraction means 20 for measurement of atomic mass.
  • the specimen 15 is moved to a new position by the translation stage 11. In this way data can be collected providing information about the spatial distribution of an element of interest across the surface of the specimen.
  • Images obtained from the MALDI and LA - ICP - MS mapping were overlaid by processing in a Hewlett Packard computer with a Pentium 4 processor and sent to a display screen and printer.
  • the method and apparatus of the invention can be applied to the analysis of samples of a wide range of polymeric materials, for example, polyolefins and other industrially important polymers, for the determination of the spatial distribution of additives and high and low molecular weight species within the polymer structure.

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Abstract

L'invention concerne un procédé et un appareil de mappage du contenu biomoléculaire et élémentaire d'échantillons tissulaires au moyen de deux techniques spectrométriques de masse complémentaires. Dans un mode de réalisation, les techniques comprennent MALDI et LA - ICP - MS ou LA-MS.
PCT/GB2006/001356 2005-04-13 2006-04-13 Ameliorations apportees a des procedes et des appareils d'analyse d'echantillons biologiques par spectrometrie de masse WO2006109073A2 (fr)

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GB0507457A GB2425178A (en) 2005-04-13 2005-04-13 Analysis of biological samples by mass spectrometry

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Cited By (4)

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US8237113B2 (en) 2006-12-18 2012-08-07 Bruker Daltonik Gmbh Preparation of a matrix layer for spectrometry
US8481925B2 (en) 2006-08-15 2013-07-09 Dvs Sciences Inc. Apparatus and method for elemental analysis of particles by mass spectrometry
CN108709834A (zh) * 2012-12-06 2018-10-26 艾博特健康公司 生物流体样本成像方法和生物流体样本成像设备
US10577648B2 (en) 2006-02-13 2020-03-03 Fluidigm Canada Inc. Methods of using inductively coupled plasma mass spectroscopy systems for analyzing a cellular sample

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DE102006019530B4 (de) * 2006-04-27 2008-01-31 Bruker Daltonik Gmbh Probenvorbereitung für massenspektrometrische Dünnschnittbilder
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WO2016142669A1 (fr) 2015-03-06 2016-09-15 Micromass Uk Limited Spectrométrie de masse à ionisation par évaporation rapide (« reims ») à guidage physique
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CN107530064B (zh) 2015-03-06 2021-07-30 英国质谱公司 气态样品的改进电离
EP3265822B1 (fr) 2015-03-06 2021-04-28 Micromass UK Limited Analyse tissulaire par spectrométrie de masse ou par spectrométrie de mobilité ionique
CA2981085A1 (fr) 2015-03-06 2016-09-15 Micromass Uk Limited Analyse spectrometrique
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CN112964625B (zh) 2015-03-06 2024-06-07 英国质谱公司 细胞群体分析
EP3570315B1 (fr) 2015-03-06 2024-01-31 Micromass UK Limited Analyse par spectrométrie de masse par ionisation par évaporation rapide et spectrométrie de masse par ionisation par electronébulisation par désorption d'échantillons de biopsie
GB2587288B (en) * 2015-03-06 2021-07-28 Micromass Ltd Detection of bacteria in swab samples using desorption ionisation and mass spectrometry
JP6783240B2 (ja) 2015-03-06 2020-11-11 マイクロマス ユーケー リミテッド 生体内内視鏡的組織同定機器
WO2016142690A1 (fr) 2015-03-06 2016-09-15 Micromass Uk Limited Instrumentation d'admission pour analyseur d'ions couplé à un dispositif de spectrométrie de masse d'ionisation par évaporation rapide ("reims")
GB201517195D0 (en) 2015-09-29 2015-11-11 Micromass Ltd Capacitively coupled reims technique and optically transparent counter electrode
US11454611B2 (en) 2016-04-14 2022-09-27 Micromass Uk Limited Spectrometric analysis of plants

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
US10577648B2 (en) 2006-02-13 2020-03-03 Fluidigm Canada Inc. Methods of using inductively coupled plasma mass spectroscopy systems for analyzing a cellular sample
US10745743B2 (en) 2006-02-13 2020-08-18 Fluidigm Canada Inc. Methods of using inductively coupled plasma mass spectroscopy systems for analyzing a cellular sample
US8481925B2 (en) 2006-08-15 2013-07-09 Dvs Sciences Inc. Apparatus and method for elemental analysis of particles by mass spectrometry
US8803079B2 (en) 2006-08-15 2014-08-12 Fluidigm Canada Inc. Apparatus and method for elemental analysis of particles by mass spectrometry
US8237113B2 (en) 2006-12-18 2012-08-07 Bruker Daltonik Gmbh Preparation of a matrix layer for spectrometry
CN108709834A (zh) * 2012-12-06 2018-10-26 艾博特健康公司 生物流体样本成像方法和生物流体样本成像设备

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