EP1307729A1 - Procede d'identification - Google Patents

Procede d'identification

Info

Publication number
EP1307729A1
EP1307729A1 EP01960019A EP01960019A EP1307729A1 EP 1307729 A1 EP1307729 A1 EP 1307729A1 EP 01960019 A EP01960019 A EP 01960019A EP 01960019 A EP01960019 A EP 01960019A EP 1307729 A1 EP1307729 A1 EP 1307729A1
Authority
EP
European Patent Office
Prior art keywords
waveguide grating
bio
chemosensitive
grating structure
structure unit
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.)
Ceased
Application number
EP01960019A
Other languages
German (de)
English (en)
Inventor
Kurt Tiefenthaler
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.)
Artificial Sensing Instruments ASI AG
Original Assignee
Artificial Sensing Instruments ASI AG
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 Artificial Sensing Instruments ASI AG filed Critical Artificial Sensing Instruments ASI AG
Publication of EP1307729A1 publication Critical patent/EP1307729A1/fr
Ceased 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
    • H01J49/10—Ion sources; Ion guns
    • H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
    • H01J49/161—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission using photoionisation, e.g. by laser
    • H01J49/164—Laser desorption/ionisation, e.g. matrix-assisted laser desorption/ionisation [MALDI]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N21/7746—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides the waveguide coupled to a cavity resonator

Definitions

  • Optical chemo- and biosensors based on integrated optical (bio) chemosensitive or (bio) chemofunctional waveguide grating structures allow the label-free detection of (bio) molecular interactions in real time and are described in the literature (see e.g. USP 4,815,843, USP 5 '071'248). Marking evidence is also possible (see e.g. WO 99/13320).
  • the method according to the invention represents not only a detection method, but also a separation technique, since the substance or substances to be detected are separated from the sample or from the matrix of samples by the substance (s) attached to the (s) on the sensor chip. n) (bio) chemosensitive layer (s) binds.
  • a label-free detection takes place, as described, for example, in USP 4,815,843, USP 507V248, USP 5738 25, USP 5,479,260 and EP 0,482,377.
  • the substance to be detected (or parts (fragments) thereof) bound to the (bio) chemo-sensitive layer on the sensor chip can then be analyzed more precisely in a mass spectrometer with a desorption stage (and ionization stage).
  • the present invention describes a detection methodology in that integrated optical chemo and biosensor technology (with or without labeling technology (index marker, fluorescent marker, luminescence marker, phosphorescence marker, enzyme marker)) are combined with mass spectroscopy with a desorption stage (and ionization stage).
  • the desorption stage detaches the molecules from the surface of the sensor chip.
  • the mass spectrometer measures the masses and / or the degree of ionization of the molecules (atoms, ions, biomolecules, fragments, etc.).
  • the present invention thus creates a detection methodology which further increases the detection sensitivity as well as the detection reliability.
  • a Waveguide grating structure consists of at least one waveguide grating structure unit (with or without a reference waveguide grating structure unit) or at least one sensor point (with or without a reference sensor point).
  • a waveguide grating structure comprises at least one grating.
  • a waveguide grating structure unit comprises at least one grating, but can also comprise at least one coupling-in grating and at least one coupling-out grating. Coupling grating and coupling grating can have the same or different grating periods.
  • a waveguide grating structure can also consist of only one large (unidiffractive or multidiffractive) grating.
  • a waveguide grating structure can contain a plurality of sensing pads (two, three, four, etc.) lying next to one another and / or one inside the other and / or one above the other, in order to, for example, a TE wave (preferably in the basic mode) in the forward and backward direction and a TM wave (preferably in the basic mode) in the forward and backward direction.
  • a waveguide structure can contain several layers, preferably at least one layer of which is highly refractive.
  • the waveguide (the waveguide structure) can also be light-absorbing.
  • the absorbent material can be embedded in a layer or in the substrate or there can also be an absorbent layer or an absorbent substrate.
  • An absorbent layer can e.g. a metal layer (chrome, aluminum, nickel, gold, silver etc.).
  • molecular binding partners such as antibodies, antigens, receptors, peptides, phages, 'single stranded' DNA (RNA) sections, genes, gene sections, targets, proteins, binding proteins, enzymes, inhibitors , Nucleic acids, nucleotides, oligonucleotides, SNP, allergens, pathogens, carbohydrates, metabolites, hormones, active substances, molecules with low molecular weight, lipids, signal substances etc.
  • RNA DNA
  • the binding processes can also take place here on the surface, in volume or both on the surface and in the volume of the (bio) chemofunctional layer.
  • the (bio) chemofunctional layer can lie on a (unidiffractive or multidiffractive) waveguide grating or between two (unidiffractive or multidiffractive) waveguide gratings (same or different grating period and / or modulation). In the latter case, the two gratings are understood as belonging to a waveguide grating structure unit.
  • the (bio) chemofunctional layer can also be located next to the waveguide grating.
  • the (bio) chemofunctional layers can also occupy a large waveguide grating in the form of an array (matrix or circular) without the
  • Bio chemofunctional layers overlap.
  • the (bio) chemofunctional layers (signal layers and / or reference layers) define the sensor locations.
  • a passivation material can (but does not have to) be between the (bio) chemosensitive layers, which may suppress non-specific binding (NSB).
  • the (bio) chemical-sensitive waveguide grating structure there can - but does not have to be - a (removable) sample receiving device (e.g. a (removable) cuvette, a (removable) well or a (removable) flow or capillary cell) or an array of sample receiving devices ,
  • the well is usually part of a corrugated sheet.
  • the sample receiving device can also be introduced into the waveguide grating structure. Suitable manufacturing processes are photolithography, laser ablation, glass (hot) embossing technology or plastic (hot) embossing technology or injection molding technology.
  • the depressions in the substrate act as wells.
  • a (channel-shaped) depression with a cover plate can act as a flow-through cell
  • a (channel-shaped) depression with (partial) cover can act as a capillary cell.
  • the waveguide grating structure does not necessarily have to be provided with a sample receiving device.
  • the samples can be applied in the form of drops using a pipetting robot.
  • the injection needles or pipette tips of the pipetting robot can (or may not) remain in contact with the sample drops applied to the sensor chip during the measurement (direct detection, marking detection).
  • the inside wall of a flow channel of a lab-on-chip can also be provided with a (bio) chemosensitive waveguide grating structure.
  • the (bio) molecules attached to the (bio) chemosensitive waveguide grating structure can be caused to desorb into the upper half space by a desorption process (e.g. LDI process or MALDI process).
  • a desorption process e.g. LDI process or MALDI process.
  • the MALDI matrix can be fed in via a sample loop, for example.
  • the lab-on-chip or the cover plate is transparent to the laser radiation that triggers the desorption.
  • the desorbed (bio) molecules move along the flow channel and end up in the vacuum of the mass spectrometer. If you are working in the liquid phase, the output of the flow channel can be connected to an electrospray ionization stage (ESI) and a mass spectrometer (quadrupole, tandem, time-of-flight mass spectrometer, etc.).
  • ESI electrospray ionization stage
  • mass spectrometer quadraturethane
  • the direct detection of a bond occurs in the event that the (bio) chemosensitive layer is on the grid, for example via a coupling angle measurement or a coupling angle measurement or a wavelength measurement (see US Pat. No. 4,815,843) or an interferometric measurement (see US Pat. Patent 5'479'260), and in the event that the (bio) chemosensitive layer is between two waveguide gratings (same or different grating period) via an interferometric measurement (see Biosensors & Bioelectronics 6 (1991), 215-225, European patent specification 0 226 604 B1).
  • Interferometric measurements can, for example, also be based on the Mach-Zehnder principle, with the two light paths being conducted separately from one another via the coupling-in grating and coupling-out grating.
  • One light path sees the (bio) chemofunctional layer, the other light path sees another or inert or no (bio) chemofunctional layer.
  • Such a measuring technique was developed by RG Heideman et al., "Development of an Optical Waveguide Interefrometric Immunosensor", Proceedings Eurosensors 4, Düsseldorf, 1990. In our case, transparent substrates are preferred to allow light to enter from the substrate side.
  • Another measurement technique is based on the measurement of emission light (fluorescence, luminescence, phosphorescence light) on waveguide (grating) structures in combination with a direct measurement.
  • emission light fluorescence, luminescence, phosphorescence light
  • waveguide grating
  • This layer can be, for example, a polymer layer (or a solid-like layer or a glass-like layer) with (high) intrinsic fluorescence or with embedded emission light molecules (fluorescence, luminescence, phosphorescence molecules).
  • the emission light wavelength is different from the excitation wavelength.
  • the measurement methodology is based on an angle of incidence scan mode or on a wavelength scan mode (with tunable light source), with a wavelength filter (blocking for the excitation light, transparent for the emission light) located in the beam path between the sensor chip and the detector.
  • a beam splitter can also be located between the sensor chip and the detector, in which case the wavelength filter is preferably located in the beam path between the beam splitter and the detector.
  • the excitation light can fall, for example, through the beam splitter onto the sensor chip ((bio) chemofunctional waveguide grating structure).
  • the excitation light can also fall obliquely from the substrate side or obliquely from the cover side onto the sensor chip, the beam splitter being present or not being present.
  • the emission light can also (preferably) be measured in a direction that does not correspond to the direction of reflection of the excitation light beam.
  • the incident light beam generates a guided light wave, but can also generate the emission light, which is amplified directly or indirectly (resonance-shaped) by the guided mode and / or shifted in terms of focus.
  • the (emitted and / or decoupled) emission light of the emission layer is imaged on the detector using a lens (lens system).
  • the outcoupled light of the excitation wave may or may not fall on the imaging lens.
  • the Coupled emission light may or may not fall on the imaging lens.
  • the measurement methodology is a combination of direct measurement with fluorescence (luminescence, phosphorescence) measurement.
  • the method can also be used to emit light-emitting modebeating patterns (between the TE mode and the TM mode) and light-emitting inferometric patterns with and without (unidiffractive or multidiffractive) grids with scanning mode (angle of incidence scanning mode or wavelength scanning mode) or without scanning mode ( Excitation of the modes TE and / or TM with flat or slightly focused waves) using a polarizer (for example 45 ° polarizer) located between the sensor chip and detector in the event of interference of TE and TM light and using the wavelength filter mentioned Measure the time of the mode excitation, the modes of the excitation wavelength being generated via grating coupling.
  • the corrugated plate can also be brought into contact with the vacuum in such a way that only the sensor points come into contact with the vacuum, but not the sample plate. This is done by inserting hollow cylinders into the wells, which are connected to each other again in a vacuum-tight manner. However, if the wells are introduced into the waveguide grating structure, the above complicated construction is obsolete.
  • sample plates made of glass or plastic, which can also be exposed to the vacuum.
  • An advantageous embodiment of an integrated optical (10) sensor chip or a 10 sensor chip plate is a microplate with, for example, 24, 48, 96, 384, 1536 wells or a sensor chip array (for example microarray) with any number of sensor locations.
  • Microplates are described in USP 5'738'825 and WO 99/13320.
  • WO 99/13320 also describes how a temperature-compensated, marking-free detection technique works.
  • the (bio) chemo-sensitive layers are advantageously applied in a matrix (or also in a ring) with a spotter or a 'contact-printing' robot.
  • a microarray - or generally one Waveguide grating structure - can have an absorbent or non-absorbent waveguide (location-dependent or not location-dependent).
  • a microarray - or generally a waveguide grating structure - can have a large (unidiffractive or multidiffractive) grating with an array of (bio) chemofunctional layers or an array of (bio) chemofunctional ones
  • Waveguide grating structure units exist.
  • a waveguide grating structure unit is at least partially covered by a (bio) chemosensitive layer.
  • the microarray can (but does not have to) be provided with a (removable) liquid container (cuvette, well, flow cell, capillary cuvette etc.).
  • the (bio) chemosensitive ((bio) chemofunctional) layers are preferably applied with a spotter or 'contact printing' robot or a liquid handler, with a linker between the (bio) chemofunctional layer and the waveguide grating structure Layer or a spacer layer (absorbent or non-absorbent).
  • Microarrays are e.g. used in genomics and proteomics.
  • the (bio) chemofunctional layers are e.g. Gene segments, nucleic acids, single stranded DNA (RNA), single nucleotide polymorphism (SNP) etc.
  • the (bio) chemofunctional layers are e.g. Proteins, phages etc.
  • lattice-based integrated optical chemo and biosensors can be automated, since each sensor point can be easily addressed via diffraction.
  • the sensor points can be illuminated sequentially or simultaneously. Simultaneous illumination of the sensor points can take place with several beams or with one expanded beam.
  • the beam may contain one or more wavelengths (discrete or continuous).
  • a desorption / ionization stage for the mass spectrometer e.g. a MALDI (matrix assisted laser desorption ionization) stage. This desorption process produces molecules in the ionized state.
  • the MALDI matrix is in some
  • LDDI Laser desorption and ionization
  • MALDI matrix can also be carried out without a MALDI matrix, or desorption and ionization can be carried out with another source. If necessary, a separate ionization stage is added.
  • different MALDI matrices are used.
  • the MALDI matrices are described in the literature. Typical MALDI matrices are derivatives of 'cinnamic acid', 'alpha-cyano-4-hydroxycinnamic acid', 'gentisic acid', 'dithranol', 'sinapinic acid' etc.
  • the desorption process can also be triggered by an ion source (or ion beam), an atom source (or atom beam), an electron source (or electron beam), an X-ray source (or X-ray beam) etc.
  • mass spectrometer e.g. a TOF (time of flight) mass spectrometer
  • Other mass spectrometers are 'magnetic sector mass spectrometer', 'ion trap mass spectrometer', 'quadrupole mass spectrometer,' tandem mass spectrometer ',' dual quadrupole mass spectrometer ',' triple quadrupole mass spectrometer ',' Fourier transform ion cyclotron resonance mass spectrometer ' Etc.
  • the (bio) chemosensitive waveguide grating structure can be used in an antechamber of the mass spectrometer. This antechamber is then evacuated. The chamber of the mass spectrometer remains under vacuum. If the antechamber is evacuated, the lock between the antechamber and the chamber can be opened. However, the (bio) chemosensitive waveguide grating structure can also be placed in the chamber of the
  • Mass spectrometer used and then the chamber evacuated.
  • the mass spectrometer measures e.g. in the mass spectrum the ratio m / z of mass to charge.
  • the peak height of a peak in the mass spectrum is a measure of the amount of analyte that is ionized and detected by the mass spectrometer.
  • the sensor chip e.g. single-channel chip, multi-channel chip, micropiate, microarray, lab-on-chip, disc chip, etc.
  • the sensor chip is inserted into the measuring device, the vacuum is then generated and the desorption process is then activated.
  • the desorbed molecules or ions are analyzed in the mass spectrometer.
  • Liquid samples can be ionized using an electrospray ionization stage (ESI) and then fed to a mass spectrometer.
  • ESI electrospray ionization stage
  • the MALDI matrix can be applied both in the liquid phase and in the gas phase to the sensor chip with a (bio) chemofunctional layer and (possibly) bound substance to be detected.
  • the MALDI matrix is made with a pulsed or non-pulsed laser
  • Pulsed lasers are e.g. a nitrogen laser or a (Q-switched) Nd-YAG laser with frequency doubling or frequency tripling or frequency quadrupling, or an erbium YAG laser.
  • the laser beam or the sensor chip (the waveguide grating structure) can be shifted.
  • the laser beam responsible for the desorption can strike the (bio) chemofunctional layer (with possibly bound substance) from the substrate side as well as from the cover side. Incidence from the substrate side requires transparency of the substrate with respect to the laser wavelength.
  • the laser beam responsible for desorption can also be coupled into the waveguide structure from the cover side or from the substrate side via a waveguide grating.
  • the electromagnetic field strength of the evanescent wave reaching into the (bio) chemofunctional layer is particularly high. In this case, the evanescent wave is at least involved in the desorption.
  • a direct detection in real time or as an end point measurement (with reference to the initial state)
  • the laser beam responsible for pulsed or non-pulsed
  • a second control laser e.g. HeNe laser or laser diode
  • optics and detectors and measuring devices for absolute measurement, such as those used for. B. are described in a second patent application with the same priority by Artificial Sensing Instruments ASI AG.
  • the detectors are preferably not in a vacuum, but can also be in a vacuum.
  • the MALDI matrix absorbs the laser light and triggers desorption. If marking substances are present on the (bio) chemofunctional layer or on the attached substance to be detected, the molecular weight (and the ionization) of the marking substance or the desorbed marking substance fragment must be taken into account in the mass spectrum.
  • the advantage of the detection method according to the invention is that the integrated optical chemo and biosensor technology enables rapid, direct detection at several sensor points (on a one-dimensional or two-dimensional array of sensor points) and then, in a vacuum, at selected sensor points a more time-consuming but more precise mass spectrometric analysis of the bound substance (or on parts thereof).

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  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Plasma & Fusion (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Optics & Photonics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

La présente invention concerne un procédé permettant d'identifier de manière plus sûre et/ou plus sensible une ou plusieurs substances se trouvant dans un échantillon ou dans une matrice d'échantillons, par combinaison de procédés d'identification basés d'un côté sur l'identification directe à l'aide de structures réticulaires de guide d'ondes (bio)chimiosensibles optiques intégrées et d'un autre côté sur une identification par spectrométrie de masse, réalisée au moyen d'un processus de désorption.
EP01960019A 2000-08-09 2001-08-09 Procede d'identification Ceased EP1307729A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH15582000 2000-08-09
CH155800 2000-08-09
PCT/CH2001/000487 WO2002012866A1 (fr) 2000-08-09 2001-08-09 Procede d'identification

Publications (1)

Publication Number Publication Date
EP1307729A1 true EP1307729A1 (fr) 2003-05-07

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Application Number Title Priority Date Filing Date
EP01960019A Ceased EP1307729A1 (fr) 2000-08-09 2001-08-09 Procede d'identification

Country Status (4)

Country Link
US (1) US6818886B2 (fr)
EP (1) EP1307729A1 (fr)
AU (1) AU2001281633A1 (fr)
WO (1) WO2002012866A1 (fr)

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EP2275802A1 (fr) * 2000-08-09 2011-01-19 Artificial Sensing Instruments ASI AG Structure de grille conductrice d'ondes et agencement de mesure optique
US7027163B2 (en) * 2003-01-24 2006-04-11 General Dynamics Advanced Information Systems, Inc. Grating sensor
US7403284B2 (en) * 2004-12-16 2008-07-22 Andevices, Inc. Integrated optics based high-resolution spectrophotometer
US7349080B2 (en) * 2004-12-30 2008-03-25 Corning Incorporated Label-independent detection of unpurified analytes
WO2006108183A2 (fr) 2005-04-05 2006-10-12 Corning Incorporated Biocapteurs et cellules sans etiquette
US20060223051A1 (en) * 2005-04-05 2006-10-05 Ye Fang System and method for performing G protein coupled receptor (GPCR) cell assays using waveguide-grating sensors
US7871811B2 (en) * 2005-04-07 2011-01-18 Corning Incorporated Method for eliminating crosstalk between waveguide grating-based biosensors located in a microplate and the resulting microplate
CN104076162A (zh) 2005-07-20 2014-10-01 康宁股份有限公司 无标记高通量生物分子筛选系统和方法
US7976217B2 (en) * 2006-09-15 2011-07-12 Corning Incorporated Screening system and method for analyzing a plurality of biosensors
WO2008130488A1 (fr) * 2007-04-19 2008-10-30 Corning Incorporated Signaux de l'intrusion de pathogènes sur une cellule vivante et procédés associés
US20090309617A1 (en) * 2007-08-24 2009-12-17 Ye Fang Biosensor antibody functional mapping
US8426148B2 (en) 2007-10-06 2013-04-23 Corning Incorporated Label-free methods using a resonant waveguide grating biosensor to determine GPCR signaling pathways
US8703428B2 (en) 2007-10-06 2014-04-22 Corning Incorporated Single-cell label-free assay
US20090181409A1 (en) * 2008-01-10 2009-07-16 Ye Fang Optical biosensor method for cell-cell interaction
US20110207789A1 (en) * 2010-02-19 2011-08-25 Ye Fang Methods related to casein kinase ii (ck2) inhibitors and the use of purinosome-disrupting ck2 inhibitors for anti-cancer therapy agents
US9868578B2 (en) 2014-10-31 2018-01-16 Sealed Air Corporation Retention frame for a packaging assembly
DE102016210357A1 (de) * 2016-06-10 2017-12-14 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Verfahren und Vorrichtung zur Erfassung einer Belegung einer Oberfläche mittels induzierter Fluoreszenz

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Also Published As

Publication number Publication date
US6818886B2 (en) 2004-11-16
WO2002012866A1 (fr) 2002-02-14
US20030168587A1 (en) 2003-09-11
AU2001281633A1 (en) 2002-02-18

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