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EP1169633A1 - Cuvette a echantillons pour la mesure de la fluorescence par reflexion interne totale - Google Patents

Cuvette a echantillons pour la mesure de la fluorescence par reflexion interne totale

Info

Publication number
EP1169633A1
EP1169633A1 EP00920681A EP00920681A EP1169633A1 EP 1169633 A1 EP1169633 A1 EP 1169633A1 EP 00920681 A EP00920681 A EP 00920681A EP 00920681 A EP00920681 A EP 00920681A EP 1169633 A1 EP1169633 A1 EP 1169633A1
Authority
EP
European Patent Office
Prior art keywords
chamber
catchers
walls
pair
sample
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00920681A
Other languages
German (de)
English (en)
Inventor
Per-Johan Ulfendahl
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.)
Gyros Protein Technologies AB
Original Assignee
Gyros AB
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 Gyros AB filed Critical Gyros AB
Publication of EP1169633A1 publication Critical patent/EP1169633A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
    • 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
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"

Definitions

  • the present invention relates to equipment for so-called total internal reflection fluorescence analysis (TIRF), and more specifically to a chamber for accommodating a sample for TIRF analysis.
  • TIRF total internal reflection fluorescence analysis
  • Total internal reflection fluorescence is an optical technique utilized in measurement of the presence of fluorescent molecules at solid-liquid interfaces, such as the interface between a transparent substrate, e.g. a silica substrate, and a liquid, e.g. water, exhibiting a lower index of refraction than the substrate.
  • TIRF is based on the principle that a beam of light that is traveling through the substrate is totally reflected against the interface and back into the substrate provided that the beam of light is travelling with a proper angle of incidence.
  • the substrate acts as a waveguide.
  • the basic principle for TIRF measurement utilized with the present invention is, for example, described in US 5,512,492, US 5,667, 166, WO 9427137 and WO 9735203, all of which are incorporated by reference.
  • TIRF substrates, each having a wall being provided with patches of different catcher compositions are described in WO 9427137 and WO 9735203, respectively.
  • the incident beams and the reflected beams interfere in the substrate to produce an electromagnetic standing wave at the interface.
  • the standing wave yields an exponentially decaying electric field, the evanescent field, on the outside of the substrate.
  • the evanescent field decays over a distance of approximately 1000 to 2000 A.
  • the TIRF technology utilizing planar waveguides and measurement of fluorescence from the waveguide surface has earlier been used for assaying the presence or absence of analytes in samples.
  • the analytes have typically been organic compounds (biomolecules) having one or more structures selected among, for instance, peptide structures (including oligo- and/ or polypeptide structures) , carbohydrate structures, nucleotide/deoxynucleotide structures (including nucleic acid structures), lipid structures (including steroid and glyceride structures) etc. This use has included qualitative as well as quantitative measurements.
  • conventional TIRF analysis equipment is characterized in that a chamber is provided for accommodating a sample to be analyzed, and "catchers" are attached to the inner surface of one wall of the chamber.
  • catcher is used throughout the present application as a general term to indicate a chemical reactant or certain kinds of affinity reactants coupled directly or via a linker, for instance a polymer or the like, to a substrate surface.
  • the reactant is a chemical compound that can be associated with a corresponding chemical compound such that there is a mutual attraction between the compounds of the pair.
  • examples of chemical ligands include the individual members of the thiol/ reactive disulphide pair and the epoxy/amine pair.
  • Affinity reactants include the individual members of the lectin/ carbohydrate pair, the nucleic acid/ complementary nucleic acid pair, the enzyme/ substrate pair, the enzyme /cofactor pair and the biotin/streptavidin pair.
  • Particularly important pairs of affinity reactants in the context of the present invention are those amongst which at least one, preferably both, of the members in a pair doesn't exhibit a polypeptide structure. This latter in particular applies to pairs of complementary nucleic acids.
  • the sample is added to the chamber together with suitable reagents, a suitable buffer solution and fluorescent groups, such as fluorescently labeled nucleotides.
  • fluorescent groups such as fluorescently labeled nucleotides.
  • the remaining sample is washed away and substituted by an aqueous solution.
  • Light is introduced into the chamber wall provided with the catchers, and the resulting fluorescent light is registered for further steps of analysis.
  • a sample is often transferred from one chamber, which is provided with a first set of catchers and wherein the sample is analyzed in a first step, to a second chamber, which is provided with a second set of catchers and wherein the sample is analyzed in a second step.
  • steps including more chambers, may be utilized.
  • the present invention seeks to provide TIRF equipment and methods with improved analyzing capacity.
  • the present invention it is possible to perform more than one analyzing steps using one chamber only, thereby avoiding the time consuming transfer of the sample from one chamber to another chamber in sequence. This is achieved by providing the chamber with numerous activated chamber surfaces for detecting fluorescent groups.
  • Fig. 1 is a schematical perspective view of a sample chamber for use with the present invention
  • Fig. 2 is a cross sectional view of the chamber of Fig. 1 , taken along line I-I and illustrating catchers disposed according to an embodiment of the present invention
  • Fig. 3 is a cross sectional view according to fig. 2, illustrating a first analyzing step according to the present invention
  • Fig. 4 is a cross sectional view according to fig. 2, illustrating a second analyzing step according to the present invention
  • Fig. 5 is a schematical perspective view of another embodiment of a sample chamber for use with the present invention.
  • Fig. 6 is a schematical perspective view of a set of sample chambers according to the present invention disposed in a rotating disk;
  • Fig. 7 is a schematical perspective view of the rotating disk of fig. 6, illustrating the fluorescence detection arrangement
  • Fig. 8 is a cross sectional view similar to the view of Fig. 3, showing an alternative embodiment of light introducing prisms;
  • Fig. 9 is a cross sectional view similar to the view of Fig. 3, showing yet another embodiment of a light introducing means
  • a first embodiment of a chamber according to the invention is shown schematically in the perspective view of Fig. 1 , and in cross-section of Fig. 2.
  • the chamber 6 is formed in a cell 1 , said cell being made of any suitable transparent material, such as glass or a chemically resistant plastic.
  • the cell is typically assembled from an upper part 1A sealed with a suitable adhesive to a lower part IB which is provided with recesses forming the chamber 6, an inlet channel 14 and an outlet channel 15, as is well known in the art.
  • the upper cell wall is provided with a prism 7 for introducing a ray of light at an angle with respect to the upper cell wall into the upper wall.
  • the lower cell wall is provided with a prism 8 for introducing a ray of light at an angle with respect to the lower cell wall into the lower wall.
  • the chamber 6 formed inside the cell 1 exhibits an upper inner wall 3 and a lower inner wall 2.
  • catchers 5 are attached to these upper and lower inner walls 2, 3.
  • fluorescent groups 4 are provided on the catchers 5, either as separate components in a sample containing DNA and/ or RNA, or as groups that in a previous step have already been coupled to the DNA or RNA groups of the sample.
  • fluorescent groups 4 are provided on the catchers 5, either as separate components in a sample containing DNA and/ or RNA, or as groups that in a previous step have already been coupled to the DNA or RNA groups of the sample.
  • the protocol for the provision of fluorescent groups on each inner chamber surface 2,3 provided with suitable catchers, as described above, includes the steps of
  • the duration of the incubation step will differ depending on the reagents used. When very fast reactions are utilized, the incubation duration may approach zero or close thereto, meaning that those two steps in principle may coincide.
  • the fluorescent group may be a fluorescence-doped substance selected from the group consisting of individual members of the above-mentioned pairs of affinity or chemical reactants, with preference for nucleic acids (DNA, RNA, nucleic acid analogues such as LNA, PNA etc) , and epoxy- or amino- containing compounds, thiol- or reactive disulf ⁇ de-containing compounds etc.
  • the catcher on the inner walls 2,3 of the chamber may be located in a number of sub-areas, for instance in the form of spots, on each respective inner wall.
  • the catcher of each sub-area may differ with respect to kind and/or density (number of molecules per unit area).
  • the number of sub-areas (spots) per unit area (cm 2 ) may be from two up to 100, 1000, 10.000 or even 100.000.
  • Appropriate techniques for applying different kind of catchers to small sub- areas are known in the field, as is suggested in US 5.445.934 and US 5.807.522, hereby incorporated by reference.
  • the inner walls of the chamber are prepared for analysis in that those catchers 5 that where sensitive to components present in the liquid axe now provided with fluorescent groups 4.
  • the chamber walls that have been provided with catchers are analyzed in sequence. More specifically, in a first analyzing step one of the chamber walls is irradiated with light using the TIRF principle to energize the fluorescent groups attached to that wall, followed by the detection of these groups with a fluorescence detecting device. In a second analyzing step the measures of the first step are repeated for a second inner wall. Thus, the analyzing steps are repeated for each wall of the chamber that has been provided with catchers.
  • the analyzing steps are typically run with the chamber filled with the appropriate liquid, preferably an aqueous solution.
  • a general cleaning step for restoring the chamber could be performed after each analyzing step.
  • the first and second analyzing steps described above are illustrated for a double-sided TIRF chamber in Fig. 3 and 4, respectively.
  • a substantially monochromatic light source 10A such as a laser or a lamp with a filter for selecting the proper wavelength, emits light that is guided into the upper part 1A of the cell through a prism 7.
  • the prism 7 and the position of the light source 10A are selected such that the ray of light 1 1 hits the interface between the upper wall 3 and the liquid in the chamber 6 at the angle of incidence necessary to produce a total internal reflection.
  • the ray of light propagates in the wall, thereby producing an evanescent field that excites the fluorescent groups 4' associated with that wall. These groups 4' now emit light.
  • a fluorescence detecting device 20A such as a CCD camera with a suitable filter, is arranged to monitor the transparent upper wall area of the upper cell part 1A to detect and register those positions where excited fluorescent groups emit light for further analysis in a subsequent step not described herein.
  • the second analyzing step which is performed after the first analyzing step, corresponds to the first analyzing step in substantially all respects, i.e. the incoming ray of light 12 from a second source of light 10B enters through a prism 8 in the lower part IB of the cell to excite the fluorescent groups 4 of the lower wall 2 catchers 5.
  • a second fluorescence-detecting device 20B registers the positions for the present fluorescent groups.
  • a second embodiment of the invention differs from the embodiment described above in that only one source of light 10A and one fluorescence-detecting device 20A are provided, making Fig. 3 useful also for this second embodiment.
  • the prisms 7, 8 are disposed symmetrically with respect to each other.
  • the second analyzing step of the method of the invention is performed by simply turning the cell 1 around to position the previously lower cell wall upwards.
  • the same effect is achieved by changing the positions of the light source 10A and the fluorescence-detecting device 20A instead of turning the cell, or by redirecting the light with any suitable reflecting device.
  • the fluorescence-detecting device 20A could be provided at one side only of the chamber, regardless if one or several light sources are used. By correlating the readings from the fluorescence-detecting device 20A with information on which wall is actually irradiated, the fluorescence-detecting device 20A is able to register the fluorescent groups through the opposing wall of the chamber.
  • any of the prisms could, alternatively, be positioned inside the wall, as is illustrated with the prisms 107 and 108 in the detail view of Fig. 8.
  • Fig. 8 which shows a ray of light 1 1 1 from a light source 1 10 being introduced via the prism 107, all the components, except for the prisms, are similar to their corresponding components of Fig. 1 , 2 and 3.
  • Fig. 9 is shown an embodiment wherein a ray of light 21 1 from a light source 210 is introduced through the end surface 207 of an upper cell plate 201 A covering the chamber 206.
  • a bottom cell plate 20 IB having an end surface 208 adapted for introducing light, forms the bottom of the chamber 206.
  • the components of the embodiment according to Fig. 9 are similar to the corresponding components of the embodiment shown in Fig. 1 , 2 and 3.
  • An embodiment of a chamber 31 according to the invention is shown in Fig. 5.
  • the chamber 31 is provided with four inner walls 32-35, each inner wall being provided with catchers (shown for two inner walls hidden in Fig. 5). Prisms 38A-D are provided at one end of each outside wall, respectively.
  • the end openings 36, 37 act as inlet and outlet channels. For simplicity, light sources as well as fluorescence-detecting devices are not shown.
  • the method described above is useful also for the chamber 31 of Fig 5, wherein the analyzing step, according to the invention, is repeated for each wall, i.e. four times.
  • the method and the device of the invention provide the advantage that a number of analyzing steps, corresponding to the activated wall surfaces within the chamber, could be performed without transferring the sample to different chambers.
  • each step of transferring the sample gives rise to losses, since some components of the sample always diffuses into the transferring liquid, and is wasted during washing.
  • the present invention avoids this.
  • a chamber according to the invention provides more analyzing area per unit of spatial area than a conventional single-side chamber does.
  • Fig. 6 and 7 shows an embodiment of the invention wherein a number of double-sided chambers (three are shown in Fig. 6, one of which is shown in Fig. 7) are disposed in a disc member 42.
  • the disc 42 is made from a double layer transparent plastic material. Recesses are formed in opposing surfaces of the layers to form chambers 41 , inlet channels 43 and outlet channels 44 when the layers are properly sandwiched to form the disc 42, as is well known within the art.
  • the inlet channels 44 and the outlet channel 43 of each chamber 41 are in fluid communication with any suitable means, such as a pressure building device, another chamber, a sample inlet port, a waste outlet etc. (not shown).
  • the upper side of the disc 42 is provided with prisms 45, one for each chamber, while the lower side of the disc 42 is provided with corresponding prisms 46 (not shown for clarity) , one for each chamber 41.
  • the disc member 42 is adapted to be rotated around its axis. For this reason, the disc 42 is provided with a central hole 47 for accommodating a rotating shaft of a driving device (not shown) .
  • the chambers 41 are filled with sample liquid simultaneously or in any selected order.
  • the analysis is made according to the steps of the invention described earlier.
  • a chamber according to the invention has numerous uses.
  • a non-limiting example of this is the use for assaying an analyte in a sample, as indicated in the introductory part of the present application. This use comprises the steps:
  • step (a) The conditions for step (a) are selected to provide binding of the fluorescent group to the inner walls via a catcher on each respective wall in a manner which reflects the presence/absence and/or the amount of the analyte in the liquid. See, for example, the publications on TIRF referred to in the introductory part of the present application. In the most important variants this means that a complex comprising the fluorescent group and the catcher will be formed on at least one of the inner walls, when the analyte is present in the liquid.
  • the level of total internal reflection fluorescence (TIRF) of the fluorescent group of the surface will therefore in these variants represent the presence /absence and/or amount of the complex for a certain combination of catcher, fluorescent group and analyte, and thus also the presence /absence and/ or amount of the analyte concerned with the combination in the liquid incubated in step (a).
  • the fluorescent group and the analyte as present in the liquid may be the same entity, i.e. the analyte is fluorescent, for instance a fluorescently labeled analyte analogue.
  • the fluorescent group bound to the inner wall will respond to the evanescent field created by the TIRF method to emit light that is detectable with any suitable equipment, thereby providing information about the presence/absence and/or amount of the analyte as present in the liquid introduced into the chamber.
  • steps (a) and (b) there may be one or more steps in which the liquid used in step (a) is replaced with liquids not containing compounds disturbing the measurement of the light emitted by the fluorescent group bound to the inner wall, for instance washing liquids.
  • the liquid used in step (a) is replaced with liquids not containing compounds disturbing the measurement of the light emitted by the fluorescent group bound to the inner wall, for instance washing liquids.
  • each wall may have different sets of catchers, for instance with different kind and/ or density of catchers in separate sub areas of each inner wall.
  • analyte in the context of this example of use includes an original analyte as it occurs in an original sample or a processed original analyte (analyte analogue) as it appears in a processed sample.
  • An analyte analogue is related to the presence/ absence and/or amount of the analyte in the original sample.
  • the original sample with its original analyte or a processed sample together with an original analyte or an analyte analogue will or will not be included in the liquid placed in the chamber in step (a) .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Optics & Photonics (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

L'invention concerne une chambre (6) à échantillons biochimiques, fabriquée dans un matériau transparent. Au moins deux des parois internes (2, 3) de la chambre jouent le rôle de substrats et sont pourvus d'éléments de capture (5), tels que des réactifs chimiques ou des réactifs agissant par affinité. En cours d'utilisation, ces éléments de capture sont couplés à des groupes fluorescents (4) présents dans l'échantillon suivant un motif représentatif de l'échantillon. Les groupes fluorescents (4) de chaque paroi (2, 3) de la chambre sont excités, au moyen d'une technique de réflexion interne totale, par de la lumière dirigée sur des prismes (7, 8) correspondant à chaque paroi intérieure qui a été pourvue d'éléments de capture. Les groupes fluorescents excités émettent de la lumière qui est détectée. Ainsi, l'espace interne de la chambre est utilisé très efficacement, ce qui permet d'obtenir une capacité d'analyse qui est deux fois supérieure à celle obtenue avec une chambre unique.
EP00920681A 1999-04-09 2000-04-07 Cuvette a echantillons pour la mesure de la fluorescence par reflexion interne totale Withdrawn EP1169633A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9901306A SE9901306D0 (sv) 1999-04-09 1999-04-09 Improved TIRF chamber
SE9901306 1999-04-09
PCT/EP2000/003185 WO2000062042A1 (fr) 1999-04-09 2000-04-07 Cuvette a echantillons pour la mesure de la fluorescence par reflexion interne totale

Publications (1)

Publication Number Publication Date
EP1169633A1 true EP1169633A1 (fr) 2002-01-09

Family

ID=20415189

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00920681A Withdrawn EP1169633A1 (fr) 1999-04-09 2000-04-07 Cuvette a echantillons pour la mesure de la fluorescence par reflexion interne totale

Country Status (4)

Country Link
EP (1) EP1169633A1 (fr)
AU (1) AU4116900A (fr)
SE (1) SE9901306D0 (fr)
WO (1) WO2000062042A1 (fr)

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Publication number Priority date Publication date Assignee Title
EE04249B1 (et) * 1999-04-21 2004-02-16 Asper O� Meetod biopolümeermaatriksi lugemiseks ja fluorestsentsdetektor
SE9902474D0 (sv) 1999-06-30 1999-06-30 Amersham Pharm Biotech Ab Polymer valves
SE0004296D0 (sv) 2000-11-23 2000-11-23 Gyros Ab Device and method for the controlled heating in micro channel systems
CA2441206A1 (fr) 2001-03-19 2002-09-26 Gyros Ab Caracterisation de variables de reaction
US7429354B2 (en) 2001-03-19 2008-09-30 Gyros Patent Ab Structural units that define fluidic functions
EP1483052B1 (fr) 2001-08-28 2010-12-22 Gyros Patent Ab Microcavite microfluidique de retention microfluidique et autres structures microfluidiques
US6919058B2 (en) 2001-08-28 2005-07-19 Gyros Ab Retaining microfluidic microcavity and other microfluidic structures
DE60237289D1 (de) 2001-09-17 2010-09-23 Gyros Patent Ab Einen kontrollierten strom in einer mikrofluidvorrichtung ermöglichende funktionseinheit
WO2004067444A1 (fr) 2003-01-30 2004-08-12 Gyros Ab Parois interieures de dispositifs microfluidiques
SE0300823D0 (sv) 2003-03-23 2003-03-23 Gyros Ab Preloaded Microscale Devices
WO2004103891A1 (fr) 2003-05-23 2004-12-02 Gyros Patent Ab Fonctions fluidiques basees sur des surfaces non mouillables
SE0400181D0 (sv) 2004-01-29 2004-01-29 Gyros Ab Segmented porous and preloaded microscale devices
DE102004039564B4 (de) * 2004-08-13 2006-06-29 Institut für Lasertechnologien in der Medizin und Meßtechnik an der Universität Ulm Vorrichtung zum optischen Screening von Oberflächen biologischer Proben in zweidimensionaler Anordnung
US9993819B2 (en) 2014-12-30 2018-06-12 Stmicroelectronics S.R.L. Apparatus for actuating and reading a centrifugal microfluidic disk for biological and biochemical analyses, and use of the apparatus

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Publication number Priority date Publication date Assignee Title
EP0184600B1 (fr) * 1984-12-10 1990-03-14 Prutec Limited Méthode pour la détermination optique de paramètres d'espèces chimiques dans un échantillon liquide
CA1341592C (fr) * 1989-07-07 2009-04-14 Abbott Laboratories Reactifs pour la capture d'ions et methodes pour effectuer des depistages de liaison
PL323257A1 (en) * 1995-05-12 1998-03-16 Ciba Geigy Ag Detection platform for simultaneously detecting plurality of analytes using hypercritically excited luminescence

Non-Patent Citations (1)

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Also Published As

Publication number Publication date
WO2000062042A1 (fr) 2000-10-19
AU4116900A (en) 2000-11-14
SE9901306D0 (sv) 1999-04-09

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