WO2015028571A1 - Procédé amélioré de mesure de capteur - Google Patents

Procédé amélioré de mesure de capteur Download PDF

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Publication number
WO2015028571A1
WO2015028571A1 PCT/EP2014/068308 EP2014068308W WO2015028571A1 WO 2015028571 A1 WO2015028571 A1 WO 2015028571A1 EP 2014068308 W EP2014068308 W EP 2014068308W WO 2015028571 A1 WO2015028571 A1 WO 2015028571A1
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Prior art keywords
substance
binding
refractive index
amount
wavelength
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PCT/EP2014/068308
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English (en)
Inventor
Anders Hanning
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Episentec Ab
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Publication of WO2015028571A1 publication Critical patent/WO2015028571A1/fr

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    • 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
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings

Definitions

  • the present invention relates to the field of optical sensors based on reflectometric light interferometry, and the use of such sensors for determining the amount of substances binding to or releasing from the sensor surface.
  • Such sensors usually consist of two distinguishable elements.
  • One element provides the chemical or biochemical selectivity of the sensor; this element usually consists of a selective layer attached to a solid surface.
  • the selectivity may be provided by e.g. a selectively absorbing matrix, a chelating agent, an antibody, a selectively binding protein, a nucleic acid strand, or a receptor.
  • the determination of an analyte of interest in a sample usually involves the binding or release of the analyte, or the analyte influencing the binding or release of some other species, to or from the selective layer, respectively.
  • the second element provides the monitoring of the binding or release of species to and from the sensor surface, respectively.
  • optical sensors One important class of sensors is based on optical monitoring of the binding event; such sensors are called optical sensors.
  • Refractometric sensors give a measure of the refractive index of the medium close to the sensor surface, and consequently the change of the refractive index upon the binding or release of substances to or from the surface, respectively.
  • Most refractometric sensors makes use of an exponentially decaying evanescent wave to probe the optical changes at the surface; in this way the refractive index within a fixed zone, the thickness of which corresponds to about one wavelength of light, is monitored.
  • Examples of such refractometric sensing methods include e.g. surface plasmon resonance (SPR), grating couplers, and Bragg gratings.
  • Reflectometric sensors monitor the change in optical thickness of a layer close to the sensor surface upon the binding or release of substances to or from the surface, respectively.
  • Optical thickness is the product of geometrical thickness and refractive index, so as opposed to refractometric sensors,
  • reflectometric sensors measure an actual change of the thickness of an optical layer. Reflectometric sensing methods are often based on some kind of interferometry: light reflecting off a first and off a second surface of an optical layer recombines, resulting in an interferometric signal, the characteristics of which depend on the optical thickness of the optical layer.
  • the optical layer is thus a solid or semi-solid layer, which most often is identical to the chemically selective layer of the sensor.
  • the optical layer functions as an interferometric etalon or a modified Fabry-Perot interferometer.
  • Reflectometric sensors are, in general, less sensitive to temperature variations, since a temperature-dependent volume increase of the optical layer is more or less compensated by a temperature-dependent refractive index decrease of the optical layer, and vice versa. Refractometric sensors are more sensitive to temperature variations, since the refractive index as such varies significantly with the temperature. Also, reflectometric sensors are, in general, less sensitive to variations of the composition of the bulk liquid adjacent to the sensor surface, since they only monitor the optical properties of the solid optical layer, while refractometric sensors monitor the refractive index of the entire evanescent wave zone, including any bulk liquid.
  • the two sensing principles refractometric and reflectometric, share some common disadvantages, mainly related to limited sensitivity - the ability to measure low concentrations - and specificity - the ability to measure one specific compound in the presence of several other compounds.
  • the sensitivity is often inadequate for the detection of small analyte molecules, for compounds that bind weakly or slowly, or when there is a low density of binding sites on the sensor surface. Sensitivity is further discussed in e.g. M. Piliarik and J.
  • the present invention provides such methods and procedures.
  • the present invention is based on the notion that a method of determining the concentration, amount, or binding of a first substance in a sample solution, using a sensor based on reflectometric light interferometry, generating an interferogram within a finite wavelength interval, wherein the concentration, amount, or binding, respectively, of said first substance directly or indirectly influences the amount of a second substance binding to or releasing from a sensor surface of said sensor, is improved if the method is made to comprise the steps of:
  • the expression “finite wavelength interval” is used to denote either a continuous wavelength interval or an interval made up of a number of, at least two, discrete wavelengths.
  • the discrete wavelengths may correspond to the detector pixels of e.g . a diode array detector or a CCD detector.
  • the expression “binding of a first substance” may be interpreted as the first substance binding to another substance, which substance may be in solution or attached to the sensor surface.
  • the binding may be of any chemical or biochemical nature, including but not l im ited to protein/protein , antibody/antigen , n ucleic acid/n ucleic acid , and receptor/I igand binding.
  • the expression “determining the... binding of a first substance” may e.g.
  • said first substance directly or indirectly influences the amount of a second substance binding to or releasing from the surface may e.g. be interpreted as the two substances being directly bound to each other, that they are able to bind to each other, or that they compete for the same binding sites on the surface.
  • VIS and near-IR wavelength range most substances, and in particular most biochemical substances like e.g. proteins and nucleic acids, exhibit a very slow and monotonous decrease (normal dispersion) of the refractive index with wavelength.
  • the expression "a significant variation of the refractive index within said wavelength interval" is to be interpreted as a substance exhibiting a strong decrease and/or an increase (anomalous dispersion) of the refractive index with wavelength.
  • the substance may also exhibit normal as well as anomalous dispersion within the selected wavelength interval, and may thus exhibit a minimum and/or a maximum of the refractive index.
  • Reflectometric interferometry sensors work like modified Fabry-Perot interferometers, a simplified exemplary sketch of which is shown in Figure 1 .
  • the interferometer is optical fibre based, but other optical configurations are also conceivable as is obvious to the skilled person.
  • Part of the incoming light 1 is reflected off a first optical surface 6 of the sensor, and part of the light passes through this first surface and is reflected off a second optical surface 7 (another part of the incoming light may simply be transmitted 3 through the sensor).
  • the layer between the two optical surfaces, the etalon layer 2 is a solid or semi-solid layer that comprises the chemically selective layer of the sensor and that may consist of a biocompatible matrix.
  • the two backreflected beams 4 and 5 interfere with each other, and the interference will be constructive or destructive depending on the wavelength of the light according to the equation:
  • I is the light intensity of the interferogram
  • 11 and I2 are the light intensities of the beams reflected off the first and second optical surface, respectively
  • ⁇ is the wavelength
  • ⁇ is the optical thickness of the etalon layer, which is equal to the product of the physical thickness of the layer and the refractive index of the layer.
  • the interferogram is simply a modified cosine function of 1/ ⁇ . Any change of the optical thickness ⁇ causes a simple phase change of the cosine function.
  • Figure 2 schematically depicts the interference pattern obtained when the resulting light intensity is registered within a finite wavelength interval.
  • Figure 2 shows two different interferograms obtained by inserting slightly different values of the optical thickness ⁇ in Equation 1 .
  • a change of the optical thickness of the etalon layer results in a phase change of the interference pattern.
  • the change of optical thickness of the etalon layer may be due to substances binding to or releasing from the sensor surface. Such binding (or release) may influence the optical thickness in different ways. For example:
  • a substance may simply bind to the top of the layer, thereby increasing the physical thickness of the layer.
  • the substance may have the same refractive index as the layer, or it may have a different refractive index, thereby also changing the average refractive index of the etalon layer.
  • a substance may penetrate the etalon layer and change the refractive index of the layer. This process may involve displacement of another substance, e.g. bulk liquid, from the layer material.
  • Both these processes may contribute simultaneously to the change of optical thickness upon binding, and it is in general not possible to easily differentiate between refractive index and physical thickness changes, respectively.
  • the binding process may also, e.g., cause swelling or conformational changes of the etalon layer thereby causing changes of the optical thickness.
  • a slight change of the optical thickness simply causes a slight change of the phase of the interference pattern, as is schematically depicted in Figure 2. This is the case when the binding substance has a constant refractive index, within the wavelength interval used. Even if the binding substance shows normal dispersion, i.e.
  • equation 1 changes to:
  • a first step a) of the present invention involves selecting a second substance that shows a significant variation of the refractive index within the used wavelength interval .
  • the expression "significant variation” means that binding of this second substance to the sensor surface should cause a detectable and/or quantifiable change of the shape (and not only the phase) of the interference pattern.
  • this shape change is quantified and the amount of the second substance binding to (or releasing from) the surface is correlated to shape change.
  • the shape change may be quantified by established mathematical methods for pattern recognition and multivariate data analysis.
  • the concentration, amount, or binding of the first substance in the sample solution is correlated to the amount of the second substance binding to (or releasing from) the surface.
  • a substance with a significant variation of the refractive index within the used wavelength interval causes a deterministic change of the shape of the interferogram, and that shape change depends in a unique and specific way on the pattern of the refractive index variation, or, in other words, the refractive index spectrum. It is obvious from Equation 2 that the interferogram is no longer simply a modified cosine function of 1/ ⁇ , but that the shape of the refractive index spectrum will directly influence the shape of the interferogram. Thus, by analysing and quantifying the shape change, it is possible to very specifically determine the amount of the substance with the significant refractive index variation binding to the surface. Consequently, the present invention provides a method to improve the specificity of reflectometric sensors.
  • the present invention also provides a method to improve the sensitivity of reflectometric sensors.
  • a substance having anomalous dispersion of the refractive index within at least part of the wavelength range 500-800 nm is used in the method of the invention defined in a broad sense, including any or all of the different aspects and embodiments specifically described below.
  • a substance showing this anomalous behaviour of the refractive index causes a particularly large change of the shape of the interferogram according to Equation 2, which is
  • step b) of the invention is advantageous for the correlation in step b) of the invention.
  • a second substance is used for improving the sensitivity and/or specificity of a method of determining the concentration, amount, or binding of a first substance by reflectometric light interferometry within a finite wavelength interval, wherein the concentration, amount, or binding, respectively, of said first substance directly or indirectly influences the amount of said second substance binding to or releasing from a sensor surface of said sensor, and wherein said second substance shows a significant variation of the refractive index within said wavelength interval.
  • the variation of the refractive index increment of the second substance should be as high as possible: for example, at least 2 ml/g, or more preferably at least 3 ml/g, within the wavelength range 450-850 nm.
  • the method may comprise the steps of:
  • a substance with a maximum absorptivity of at least 50 000 M “1 cm “1 , or more preferably at least 100 000 M “1 cm “1 , within the wavelength range 500-800 nm is used in the method of the invention defined in a broad sense, including any or all of the different aspects and embodiments
  • Substances with a strong light absorption are especially well suited for use in the methods of the invention, since they cause a large change of the shape of the interferogram. Since most reflectometric sensors work in the visible and near-IR wavelength range, the use of a substance with strong absorption in the range 500-800 nm is especially advantageous.
  • the substance may be e.g. a natural or synthetic dye molecule, a reactive dye molecule, a dye molecule coupled to another species, a coloured particle or bead, or a coloured protein.
  • Yet another variant of the invention comprises a computer program product comprising computer-executable components for causing a device to perform any one or all of the steps of the method of the invention defined in a broad sense, including any or all of the different aspects and embodiments specifically described below, when the computer-executable components are run on a processing unit included in the device.
  • the computer program product may include a software for performing at least step b/ of the invention, but may additionally also include software for performing step c).
  • Yet another variant of the invention comprises a reagent kit comprising at least one substance with a maximum absorptivity of at least 50 000 M “1 cm “1 , or more preferably at least 100 000 M “1 cm “1 , within the wavelength range 500-800 nm and instructions on how to use it in the method of the invention defined in a broad sense, including any or all of the different aspects and embodiments specifically described below. It may prove valuable to combine such a substance with e.g. instructions on how to use it according to the methods and uses of the present disclosure, in a single kit.
  • the kit may also contain various auxiliary compounds and solutions other than said substance to enable the kit to be used easily and efficiently.
  • auxiliary compounds and solutions include solvents for dissolving the substance and wash buffers.
  • FIGURE 1 is a simplified sketch of an optical fibre based Fabry-Perot interferometer.
  • FIGURE 2 is a simplified sketch of two exemplary interferograms with a slight difference in the optical thickness in the wavelength interval 400-800 nm according to Equation 1 .
  • FIGURE 3 shows parts of three different interferograms theoretically calculated from Equations 1 and 2. For simplicity, 11 and I2 are supposed to be equal, and the interferograms are normalized to maximum intensity 1 .
  • the refractive index is set to 1 .4, except in the wavelength interval 520-600 nm where it is set to vary according to a simplified but realistic representation of the refractive index spectrum of a dye with an absorption maximum at 560 nm.
  • the refractive index spectrum in the region 520-600 nm is shown in Figure 4.
  • FIGURE 4 is a schematic and simplified but realistic representation of the refractive index spectrum of a dye with an absorption maximum at 560 nm.
  • FIGURE 5 shows parts of three different interferograms theoretically calculated from Equations 1 and 2.
  • 11 and I2 are supposed to be equal, and the interferograms are normalized to maximum intensity 1 .
  • the refractive index is set to 1 .4, except in the wavelength interval 520-600 nm where it is set to vary according to a simplified but realistic representation of the refractive index spectrum of a dye with an absorption maximum at 560 nm.
  • the refractive index spectrum in the region 520-600 nm is shown in Figure 4.
  • FIGURE 6 shows details of three different interferograms theoretically calculated from Equations 1 and 2. For simplicity, 11 and I2 are supposed to be equal, and the interferograms are normalized to maximum intensity 1 .
  • the second interferogrann, Int2 is calculated with the same thickness but with 0.64 mg/ml of a substance with a wavelength-independent refractive index increment 0.185 g/ml absorbed into and bound by the etalon layer.
  • the third interferogrann, Int3, is calculated with the same thickness but with the same concentration 0.64 mg/ml of a substance with a maximum refractive index increment 4.7 g/ml at 580 nm absorbed into and bound by the etalon layer.
  • a representative refractive index spectrum in the region 520-600 nm is shown in Figure 4.
  • FIGURE 7 shows differential interferograms based on the same data as Figure 5.
  • the intensity differences Int2-lnt1 and Int3-lnt1 are calculated at each single wavelength.
  • the first substance is labelled with the second substance, and the method is a direct binding assay.
  • the term "labelled" is to be interpreted as the presence of a stable chemical link between the two substances. This link may e.g. be a covalent bond.
  • one of the substances may e.g. be linked to a streptavidin molecule and the other to a biotin molecule, and the two substances linked together by a streptavidin/biotin bond.
  • the direct binding assay is a very simple assay format, where both substances bind to the surface in a
  • an analogue of the first substance is labelled with the second substance, and the method is a competitive binding assay.
  • the term "analogue” is to be interpreted as a chemically more or less similar substance that is able to bind to the same binding site as the first substance.
  • a competitive assay [J. Homola, Chem. Rev. 2008, 108, 462-493]
  • the first substance and the labelled analogue compete for the same binding sites on the surface. In this way, the concentration and binding equilibrium and kinetic behaviour of the first substance may be indirectly studied by studying the binding of the labelled analogue.
  • the advantage of this assay format is that the first substance as such need not be labelled.
  • the competitive format is especially advantageous in screening experiments, e.g. in drug screening or fragment screening.
  • the "analogue” is a substance with known binding to a defined binding site or binding molecule, e.g. a drug substance with known binding to a receptor. A number of other substances are then screened for their ability to compete with the binding of the "analogue" to the defined site.
  • the "analogue” may not be chemically similar to the screened substances, and the screened substances are only potentially able to compete for the same binding site, so in this case the term "analogue” is rather to be interpreted as a known binder or a reference binder to a defined site or molecule.
  • the second substance is a binder of the first substance, or, by definition, vice versa.
  • the second substance may e.g. comprise an antibody to which the first substance is an antigen.
  • Other conceivable binding mechanisms are e.g. nucleic acid hybridization, receptor/I igand, or avidin/biotin binding. This aspect enables the practice of several different useful and well established assay formats.
  • the method is an inhibition assay [J. Homola, Chem. Rev. 2008, 108, 462-493].
  • the sample containing the first substance is pre-mixed with the second substance, being a binder of the first substance.
  • the mixture is then contacted with the sensor surface, to which an analogue of the first substance, able to bind the second substance, has been immobilized.
  • This format may be used to measure concentration and to study molecular interactions without labelling of the first substance per se.
  • the inhibition assay may also be especially advantageous in screening experiments [S. Geschwindner et al. Sensors, 2012, 12, 431 1 -4323].
  • a large number of potential binders (first substances) may be rapidly screened for potential binding to the second substance, without labelling of the potential binders.
  • the potential binders may e.g. be drug candidates while the second substance is a soluble receptor protein.
  • the method is a sandwich assay [J. Homola, Chem. Rev. 2008, 108, 462-493].
  • a first binder of the first substance is immobilized onto the sensor surface, and the first substance in the sample is allowed to bind to the surface.
  • the second substance in solution is contacted with the surface, and allowed to act as a second binder to the first substance.
  • the sandwich format may be used for both concentration analysis and for interaction studies including the study of different binding epitopes on the first substance.
  • the second substance comprises a dye entity.
  • Dye substances show a strong absorption of light at some wavelength interval, and as a corollary of the Kramer-Kronig relations of fundamental optical physics, show a strong variation of the refractive index, including anomalous dispersion, within and in the vicinity of that wavelength interval. Consequently, dye substances are especially well suited for use in the methods of the invention. Since most reflectometric sensors work in the visible and near-IR wavelength range, the dye is most often selected to be a visible dye.
  • the dye entity may be e.g. a natural or synthetic dye molecule, a reactive dye molecule, a dye molecule coupled to another species, a coloured particle or bead, or a coloured protein. In one embodiment of this aspect, the dye entity has a maximum absorptivity of at least 50 000 M "1 cm “1 , or more preferably at least 100 000 M "1 cm “1 , within the wavelength range 500-800 nm.
  • the finite wavelength interval, within which an interferogram is generated comprises an absorption maximum of the dye entity.
  • the dye In the vicinity of the absorption maximum, the dye exhibits anomalous dispersion, i.e. an increase of the refractive index with wavelength. This anomalous behaviour of the refractive index causes a particularly large change of the shape of the interferogram according to Equation 2, which is advantageous for the correlation in step b) of the invention.
  • interferometer comprises at least one wavelength within 60 nm, or preferably within 30 nm, from an absorption maximum of the dye entity.
  • a large refractive index variation normal or anomalous dispersion
  • the embodiment may e.g. be used in cases where it is impractical to exactly match the maximum absorption wavelength of the dye with the working wavelength of the interferometer.
  • the second substance is selected to show anomalous dispersion of the refractive index within at least part of the working wavelength interval.
  • This anomalous behaviour of the refractive index causes a particularly large change of the shape of the interferogram according to Equation 2, which is advantageous for the correlation in step b/ of the invention.
  • the second substance shows a variation of the refractive index increment of, for example, at least 2 ml/g, or more preferably at least 3 ml/g, within the wavelength range 450-850 nm.
  • the refractive index increment is a measure of how much the refractive index of a liquid is increased when a certain concentration of a substance is added to the liquid.
  • the refractive index increment also depends on the optical properties of the liquid as such; in the present case, the figures refer to water or a dilute aqueous solution.
  • the working wavelength interval of the interferometer comprises at least two, or preferably at least 10, or more preferably at least 100, discrete wavelengths.
  • it is, in principle, enough to track the light intensity at one single wavelength.
  • at least one additional shape parameter in step b) of the invention e.g. the width of an interference fringe in the interferogram
  • at least two measurement wavelengths are required. It is advantageous to use several measurement wavelengths in order to obtain more information, e.g. to extract more shape parameters. Also, an overdetermined system with more measured values than calculated parameters generally yields a more robust and less noisy result.
  • the detection of light intensities may e.g. be performed by a diode array or a CCD light detector, with each pixel corresponding to a discrete wavelength or a small wavelength interval.
  • the correlation of step b) involves taking the difference between at least two different interferograms recorded at different times.
  • Interaction or binding studies most often involve following a process as a function of time, and simple concentration determinations often involve taking the different between a baseline at a first point of time and a sample at a second point of time.
  • First forming the difference between two or several raw interferograms and then calculating shape parameters of the differential interferograms has the advantage that the shape differences are highlighted when the difference is formed. This may be especially advantageous e.g. in cases where relatively small shape changes due to anomalous dispersion are overlaid onto relatively large phase changes.
  • the correlation of step b) involves evaluating the phase and width of an interference fringe of at least two different interferograms recorded at different times. Evaluation of the phase or relative phase of a defined interference fringe is ordinarily performed in reflectometric interferometers, either by monitoring the intensity at one specific wavelength or by monitoring a local maximum, minimum, or inflection point of the fringe. In addition, evaluation of the width of an inference fringe provides a very simple shape parameter. This aspect constitutes a simple method to obtain the improved specificity with respect to a substance with a variable refractive index as discussed above.
  • the correlation of step b) involves multiple linear regression, principal component analysis, factor analysis, principal component regression, partial least squares or any method of linear algebra or multivariate data analysis.
  • linear algebra or multivariate including bivariate, data analysis.
  • spectral analysis e.g., factor analysis or principal component analysis
  • the correlation of step b) involves Fourier transformation. Fourier methods provide an alternative way to efficiently calculate shape parameters of mathematical functions, e.g. interferograms.
  • the refractive index is set to 1 .4, except in the wavelength interval 520-600 nm where it is set to vary according to a simplified but realistic representation of the refractive index spectrum of a dye with an absorption maximum at 560 nm.
  • this Example 1 shows how, by utilizing a substance with a significant variation of the refractive index and by evaluating the shape of the interferogram, the specificity is improved so that a change of the geometrical thickness can be clearly discriminated from absorption of dye into the etalon layer at constant thickness.
  • the resulting phase shift is about 1 nm, while the general shape of the interferogram is unaffected.
  • the refractive index is set to 1 .4, except in the wavelength interval 520-600 nm where it is set to vary according to a simplified but realistic representation of the refractive index spectrum of a dye with an absorption maximum at 560 nm.
  • this Example 2 shows how, by utilizing a substance with a significant variation of the refractive index and by evaluating the shape of the interferogram, the specificity is improved so that a absorption of a substance with constant refractive index, e.g. a biomolecule like a protein or a nucleic acid, can be clearly discriminated from absorption of a dye into the etalon layer.
  • a substance with constant refractive index e.g. a biomolecule like a protein or a nucleic acid
  • the second interferogram, Int2, in Figure 6 is calculated with the same thickness but with 0.64 mg/ml of a substance with a wavelength-independent refractive index increment 0.185 g/ml, which is a realistic value for e.g. a protein, absorbed into and bound by the etalon layer.
  • the third interferogram, Int3, in Figure 6 is calculated with the same thickness but with the same concentration 0.64 mg/ml of a substance with a maximum refractive index increment 4.7 ml/g at 580 nm, which is a realistic value for a dye absorbing in this region [WO 93/04357], absorbed into and bound by the etalon layer.

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Abstract

La présente invention concerne un procédé de détermination de la concentration, de la quantité, ou de la liaison d'une première substance dans une solution d'échantillon à l'aide d'un capteur sur la base d'une interférométrie en lumière réflectométrique, de génération d'un interférogramme à l'intérieur d'un intervalle de longueur d'onde fini, la concentration, la quantité, ou la liaison, respectivement, de ladite première substance influençant directement ou indirectement sur la quantité d'une seconde substance se liant à une surface de capteur dudit capteur ou libérée à partir de celle-ci, caractérisé en ce que ledit procédé comprend les étapes consistant à : sélectionner ladite seconde substance de sorte à présenter une variation significative de l'indice de réfraction à l'intérieur dudit intervalle de longueur d'onde, mettre en corrélation la quantité de ladite seconde substance se liant à la surface ou libérée à partir de celle-ci avec la forme de l'interférogramme à l'intérieur dudit intervalle de longueur d'onde, et mettre en corrélation la concentration, la quantité, ou la liaison, respectivement, de ladite première substance avec la quantité de ladite seconde substance se liant à la surface ou libérée à partir de celle-ci.
PCT/EP2014/068308 2013-08-29 2014-08-28 Procédé amélioré de mesure de capteur WO2015028571A1 (fr)

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Cited By (1)

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US11604140B2 (en) * 2016-10-11 2023-03-14 Access Medical Systems, Ltd. Optical sensor of bio-molecules using interferometer

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