EP1397672A1 - Capteurs d'oxygene sur plaque de microtration - Google Patents

Capteurs d'oxygene sur plaque de microtration

Info

Publication number
EP1397672A1
EP1397672A1 EP02748791A EP02748791A EP1397672A1 EP 1397672 A1 EP1397672 A1 EP 1397672A1 EP 02748791 A EP02748791 A EP 02748791A EP 02748791 A EP02748791 A EP 02748791A EP 1397672 A1 EP1397672 A1 EP 1397672A1
Authority
EP
European Patent Office
Prior art keywords
oxygen
matrix
water
dye
permeable
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
EP02748791A
Other languages
German (de)
English (en)
Inventor
Ingo c/oTechnische Universität Graz KLIMANT
Christian Krause
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.)
Presens Precision Sensing GmbH
Original Assignee
Presens Precision Sensing 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 Presens Precision Sensing GmbH filed Critical Presens Precision Sensing GmbH
Publication of EP1397672A1 publication Critical patent/EP1397672A1/fr
Ceased 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
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • 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"
    • 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"
    • G01N2021/6432—Quenching
    • 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"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
    • 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"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
    • G01N2021/6441—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks with two or more labels
    • 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
    • G01N2021/6482—Sample cells, cuvettes
    • 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
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/27—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands using photo-electric detection ; circuits for computing concentration
    • G01N21/274—Calibration, base line adjustment, drift correction

Definitions

  • the invention relates to a new type of sensor that can be used to measure oxygen in microtiter plates or similar systems. With a new sensor principle, measurements can be made faster and it is less influenced by the surrounding medium.
  • microtiter plates in various formats are used in a variety of ways.
  • the associated microtiter plate readers are based on the measurement of absorption, flow resi nce time, flow reso nce time or fluorescence polarization. These methods tend to be very specific, which limits their application to selected systems. For this reason, alternatives have to be developed that are based on the sensors of widely applicable parameters such as oxygen.
  • the measurement of the oxygen concentration as a biological parameter has been known for many years. Its importance lies not only in the field of screening processes, but also in medical diagnostics, environmental analysis and analytical chemistry. Monitoring the consumption of dissolved oxygen by microorganisms as a parameter for their metabolism has been investigated for many years. For example, C.E. Cliffcon 1937 measured the oxygen consumption of microorganisms over a period of several days using a Warburg bottle. This procedure measured the change in oxygen concentration in a slow and cumbersome manner.
  • Clark electrode a newer electrochemical device, is also commonly used to measure dissolved oxygen.
  • the Clark electrode consumes oxygen during use (thereby reducing the oxygen available to the microorganisms). Therefore, the electrode is typically only used to measure volumes of 100 ml or more to prevent the electrode from affecting the measurements.
  • a “miniature” Clark electrode has been described, but this electrode is a complex, multi-component part that must also be in contact with the solution to be measured. While an oxygen permeable membrane can be used to prevent the electrode components of the device from interacting with the components of the test solution, the oxygen still has to balance between the test solution and the measuring system and is consumed as soon as it passes through the membrane.
  • Optical systems that can provide oxygen concentration values have been developed to overcome the shortcomings of Clark's electrode systems.
  • the main advantage of such optical methods is that the instruments required to determine the quantitative value itself have no physical contact with the test solution.
  • Optical methods that allow both colorimetric and fluorometric oxygen analyzes, which can be carried out quickly and reproducibly, are known and the costs for such analyzes are often quite low.
  • various methods of luminescence for determining oxygen have been described based on the ability of oxygen to quench the fluorescent or phosphorescent emission of a variety of compounds. However, such methods have not yet been adapted to the special needs of the screening.
  • DE 3 346 810 C2 describes a sensor apparatus for determining the presence of oxygen in an environment which comprises luminescent material whose luminescence intensity and duration can be extinguished by oxygen, the luminescent material being built into a carrier material which is relatively permeable to oxygen and is relatively impermeable to annoying extinguishers.
  • the apparatus requires a comparative indicator that is hermetically sealed against the oxygen to be determined.
  • EP 0 509 791 B1 discloses a method and an apparatus for detecting the presence of breathing aerobic bacteria in a liquid. A decrease in the fluorescence intensity occurs under the influence of oxygen.
  • the fluorescence sensor is in a matrix that is impermeable to water and non-gaseous solutes, however has a high permeability to oxygen.
  • the presence of a non-water permeable matrix is necessary in order to reduce the influence of the sensor by components of the sample.
  • this structure leads to major disadvantages.
  • the water-impermeable matrix forms an oxygen reservoir, which can falsify the measurement result. Another disadvantage is the low sensitivity of the method.
  • the sensitivity for the application described in EP 0 509 791 B1 is sufficient to detect the presence of breathing aerobic bacteria in a liquid, since at the beginning there is a solution saturated with oxygen, the oxygen concentration of which then decreases sharply in order to increase a plateau at a lower value reach, so that large differences in the oxygen concentrations can be detected.
  • mammalian cells for example, consume much less oxygen, so that the small changes in oxygen concentration that can be achieved require a method that has a significantly higher sensitivity.
  • the water-impermeable matrix of the fluorescence sensor must be in equilibrium with the liquid surrounding it before it can show a change in the signal due to the change in the oxygen content of the liquid.
  • the present application relates to a device for the detection of oxygen according to claim 1.
  • Preferred embodiments of this device are the subject of dependent claims 2 to 13.
  • the device can be used to detect oxygen in a sample, in particular in a biological sample, for example in a culture of microorganisms or higher cells or in the case of enzymatic reactions.
  • a preferred embodiment of the optical oxygen sensor in the device according to the invention consists of the following components: a luminescent dye, the phosphorescence of which is quenched by oxygen in the sample. This dye is enclosed in small polymer particles (with diameters from a few nm to a few ⁇ m). The material of these particles is characterized by the fact that it has water-repellent properties. This ensures that the built-in water-insoluble dye is not washed out by proteins.
  • the individual oxygen-sensitive nano- or microparticle is already a completely shielded sensor.
  • Cross-sensitivities caused by water or other substances dissolved in the water are essentially excluded. It is therefore not necessary to enclose the particles in a hydrophobic matrix, which ensures the shielding of the luminescence sensor. This means that the particles can be installed in any layer, which is also permeable to water.
  • the response time of the sensors is significantly reduced. Response times in the range of seconds are possible. This is due to the fact that on the one hand the sensor layer is not a crucial oxygen reservoir, and on the other hand the same reactions can take place in the swollen matrix as in the protruding sample.
  • Linear ethanol-soluble hydrogels can be used as the incorporation matrix. This considerably simplifies the process of manufacturing the microtiter plates. The matrix does not need to be crosslinked, and cleavage products do not have to be removed from the sensors by complex washing procedures. This shortens the manufacturing process considerably and reduces production costs.
  • the device according to the invention comprises an additional coating from solutions of e.g. Polylysine, fibronectin and / or collagen, e.g. to improve cell growth.
  • solutions of e.g. Polylysine, fibronectin and / or collagen e.g. to improve cell growth.
  • the device may comprise two or more spectrally different luminescent dyes.
  • One dye can be designed as an indicator, while another serves as a reference dye.
  • two spectrally different dyes are used, the first being oxygen-sensitive and the second being essentially oxygen-sensitive in comparison to the first.
  • the oxygen sensitivities should differ measurably from one another, where, under conditions of use, the sensitivity of the indicator dye is higher than that of the reference dye, for example by a factor> 10, preferably> 100, more preferably> 1000.
  • the second dye is preferably selected from the group consisting of rhodamines, xanthenoids, styryl dyes and merocyanines.
  • the first dye can preferably be selected from the group consisting of Pt (II) porphyrins, Pd (II) porphyrins and Ru (II) complexes with poly-N heterocycle, for example polypyridyl ligands.
  • Two luminescences are read out for signal acquisition. The signal is the quotient of the two luminescence intensities or decay times. An internally referenced signal is obtained.
  • the reference dye does not have to be included in the first matrix, but can also be present outside. In some applications, such a measurement with two luminophores can be advantageous, since greater accuracy can be achieved, since time fluctuations in the light intensity of the light source used and time fluctuations in the sensitivity of the readout unit used are largely referenced and non-wavelength-dependent superimpositions of the sensor signal Self-luminescence of the sample can be largely referenced.
  • the two dyes can be mixed in a constant ratio during production, so that the resulting signal is independent of the amount of dye mixture used, which allows greater tolerances in the coating of the absolute amount of sensor used. Due to the larger tolerance allowed during production, smaller amounts of substance can be used for the coating.
  • a Manufacturing instructions for oxygen-sensitive particles :
  • the cocktail described in B2) contains a rhodamine reference dye.
  • 96'Well format 1.5 ⁇ l of the cocktail described under B1) and B2) are dispersed in each well of the MPT. After evaporation of the solvent, the plate can be y-sterilized.
  • Figure 1 shows a fluorescence spectrum of a sensor according to the invention, oxygen-free or air-saturated. From Fig. 1 it can be seen that the intensity of the fluorescence decreases considerably due to saturation with air. (Excitation: 540 nm)
  • Figure 2 illustrates the response time of a sensor according to the invention as a function of the air saturation [%]. Even at low air contents, the sensor according to the invention shows a comparatively short response time.
  • Figure 3 shows the comparison of the oxygen signal for a sensor (1) according to the invention and a sensor according to EP 0 509 791 B1 (2). It can be seen that the sensor according to the invention has a significantly shorter response time.

Landscapes

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

Abstract

L'invention concerne un nouveau type de capteur faisant intervenir des plaques de microtitration ou des supports analogues, contenant des cavités de réception d'échantillon pour la détection d'oxygène. Les cavités des plaques de microtitration contiennent des colorants luminescents ou fluorescents (par ex. des complexes platine, palladium, ou ruthénium, contenant des ligands phénantroline, porphyrine ou pyridine), intégrés dans des particules d'une matrice perméable aux gaz mais imperméable à l'eau. Cette matrice est un dérivé polystyrol ou un copolymère polystyrol. Les particules sont quant à elles dispersées dans une deuxième matrice perméable à l'eau constituée d'un polymère hydrophile tel que par ex. polyhydroxyméthacrylate, polyvinylalcool ou polyvinylpyrrolidone.
EP02748791A 2001-06-18 2002-06-17 Capteurs d'oxygene sur plaque de microtration Ceased EP1397672A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US29837601P 2001-06-18 2001-06-18
US298376P 2001-06-18
PCT/EP2002/006662 WO2002103334A1 (fr) 2001-06-18 2002-06-17 Capteurs d'oxygene sur plaque de microtration

Publications (1)

Publication Number Publication Date
EP1397672A1 true EP1397672A1 (fr) 2004-03-17

Family

ID=23150221

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02748791A Ceased EP1397672A1 (fr) 2001-06-18 2002-06-17 Capteurs d'oxygene sur plaque de microtration

Country Status (3)

Country Link
US (1) US20040171094A1 (fr)
EP (1) EP1397672A1 (fr)
WO (1) WO2002103334A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4231010A1 (fr) 2022-02-16 2023-08-23 University College Cork-National University of Ireland Cork Capteur opto-chimique et ses utilisations
DE102022002116A1 (de) 2022-06-13 2023-12-14 aquila biolabs GmbH Verfahren und Vorrichtung zur Überwachung des Inhalts durchmischter Reaktoren
WO2023241869A1 (fr) 2022-06-13 2023-12-21 aquila biolabs GmbH Procédé et dispositif de surveillance de contenu de réacteurs mixtes

Families Citing this family (17)

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DE102004051830B4 (de) * 2004-10-25 2007-12-13 Roche Diagnostics Gmbh Multifunktionales Referenzsystem bei Analytbestimmungen durch Fluoreszenz
WO2007075595A2 (fr) * 2005-12-20 2007-07-05 Vertex Pharmacueticals Incorporated Essai de biofilm
DE102005062003A1 (de) * 2005-12-22 2007-06-28 Endress + Hauser Conducta Gesellschaft für Mess- und Regeltechnik mbH + Co. KG Vorrichtung und Verfahren zur Detektion und/oder quantitativen Messung eines Zielmediums
US7569395B2 (en) * 2006-03-13 2009-08-04 Cryovac, Inc. Method and apparatus for measuring oxygen concentration
US7749768B2 (en) * 2006-03-13 2010-07-06 Cryovac, Inc. Non-invasive method of determining oxygen concentration in a sealed package
WO2008095960A1 (fr) * 2007-02-08 2008-08-14 Dsm Ip Assets B.V. Capteur de gaz
WO2010066273A1 (fr) 2008-12-11 2010-06-17 Luxcel Biosciences Limited Elément actif de capteur optochimique, procédé associé de préparation et d'utilisation
US8398922B2 (en) * 2009-10-08 2013-03-19 The United States of America as represented by the Secretary of Commerce, the National Institute of Standards and Technology Highly sensitive oxygen sensor for cell culture
EP2625266B8 (fr) * 2010-10-04 2016-12-21 Medizinische Hochschule Hannover Procédé de production d'un tissu tridimensionnel
DE102010061182B4 (de) 2010-12-13 2013-02-07 Presens Precision Sensing Gmbh Sensoranordnung, Verfahren und Messsystem zur Erfassung der Verteilung wenigstens einer Veränderlichen eines Objekts
DE102013108659B3 (de) 2013-08-09 2014-07-03 Presens - Precision Sensing Gmbh Optischer Sensor und Messanordnung zum quantitativen Nachweis eines Analyten in einer Probe
ES2920777T3 (es) 2014-02-17 2022-08-09 Eaton Intelligent Power Ltd Sensor de oxígeno que comprende una fibra óptica recubierta en la punta con un diámetro grande
DE102014107837B4 (de) 2014-06-04 2021-09-02 Presens Precision Sensing Gmbh Optischer Sensor zum quantitativen Nachweis eines Analyten in einer Probe und Verfahren zur Herstellung des Sensors
ES2554077B1 (es) * 2014-06-12 2016-09-20 Juan Antonio DÍAZ MARTÍN Microsensor químico polimérico con sonda molecular fluorogénica, proceso de fabricación y uso para la liberación controlada de sustancias bioactivas y otras aplicaciones
EP3168616A1 (fr) 2015-11-10 2017-05-17 PreSens Precision Sensing GmbH Polymère réticulé optiquement actif
EP3184994B1 (fr) 2015-12-21 2021-11-03 CSEM Centre Suisse d'Electronique et de Microtechnique SA - Recherche et Développement Couche de capteur optique pour détecter une espèce chimique, système comprenant une telle couche de capteur et procédé de fabrication d'une telle couche de capteur
NL2019813B1 (en) 2017-10-26 2018-11-06 R&R Mechatronics Int B V A device for assessing changes in erythrocyte deformability, such as erythrocyte sickling tendency

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WO1997012227A1 (fr) * 1995-09-28 1997-04-03 Optical Sensors Incorporated Detecteur optique de gaz carbonique et procedes correspondants de fabrication et d'utilisation

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US4719182A (en) * 1985-03-18 1988-01-12 Eastman Kodak Company Fluorescent labels and labeled species and their use in analytical elements and determinations
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4231010A1 (fr) 2022-02-16 2023-08-23 University College Cork-National University of Ireland Cork Capteur opto-chimique et ses utilisations
DE102022002116A1 (de) 2022-06-13 2023-12-14 aquila biolabs GmbH Verfahren und Vorrichtung zur Überwachung des Inhalts durchmischter Reaktoren
WO2023241869A1 (fr) 2022-06-13 2023-12-21 aquila biolabs GmbH Procédé et dispositif de surveillance de contenu de réacteurs mixtes
DE102022002116B4 (de) 2022-06-13 2024-01-25 aquila biolabs GmbH Verfahren und Vorrichtung zur Überwachung des Inhalts durchmischter Reaktoren

Also Published As

Publication number Publication date
WO2002103334A1 (fr) 2002-12-27
US20040171094A1 (en) 2004-09-02

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