WO2014046156A1 - Procédé de mesure d'interaction intermoléculaire, procédé de mesure d'épaisseur de film optique, système de mesure et programme de mesure - Google Patents

Procédé de mesure d'interaction intermoléculaire, procédé de mesure d'épaisseur de film optique, système de mesure et programme de mesure Download PDF

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WO2014046156A1
WO2014046156A1 PCT/JP2013/075237 JP2013075237W WO2014046156A1 WO 2014046156 A1 WO2014046156 A1 WO 2014046156A1 JP 2013075237 W JP2013075237 W JP 2013075237W WO 2014046156 A1 WO2014046156 A1 WO 2014046156A1
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spectral intensity
measurement system
intensity
wavelength
measurement
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PCT/JP2013/075237
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English (en)
Japanese (ja)
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泉谷　直幹
由佳 吉原
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コニカミノルタ株式会社
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Priority to JP2014536890A priority Critical patent/JPWO2014046156A1/ja
Publication of WO2014046156A1 publication Critical patent/WO2014046156A1/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
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/05—Flow-through 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
    • 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
    • G01N21/41—Refractivity; Phase-affecting properties, e.g. optical path length
    • G01N21/45—Refractivity; Phase-affecting properties, e.g. optical path length using interferometric methods; using Schlieren methods
    • 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
    • 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
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/05—Flow-through cuvettes
    • G01N2021/058—Flat flow cell

Definitions

  • the present invention relates to an intermolecular interaction measurement method, a measurement system thereof, and a measurement program thereof, and more particularly to an intermolecular interaction capable of generating a value indicating the progress of intermolecular interactions such as biomolecules and organic polymers.
  • the present invention relates to an action measurement method, a measurement system thereof, and a program for causing a computer to perform a process for performing the measurement.
  • the present invention also relates to an optical film thickness measurement method, an optical film thickness measurement system, and an optical film thickness measurement program using reflection interference spectroscopy.
  • a substrate 102 provided with an optical thin film 104 is used.
  • the optical thin film 104 on the substrate 102 is irradiated with white light as shown in FIG. 34a
  • the spectral intensity of the white light itself is represented by a solid line 106 as shown in a typical example of FIG. Is represented by a solid line 108.
  • a reflection spectrum 110 having a bottom peak (minimum portion in the spectrum curve) represented by a solid line is obtained as shown in FIG.
  • the ligand 120 is provided on the optical thin film 104 as shown in FIG. 34b.
  • the optical thickness 112 at the site where the ligand 120 is provided changes, the optical path length changes, and the interference wavelength also changes due to the reflection interference effect. That is, the peak position of the spectral intensity distribution of the reflected light is shifted, and as a result, as shown in FIG. 36, the reflection spectrum 110 is shifted to the reflection spectrum 122 (see the dotted line portion).
  • the ligand 120 and the analyte 130 in the sample solution are bonded as shown in FIG. 34c.
  • the optical thickness 112 at the site where the analyte 130 is bonded further changes.
  • the analyte 130 partially adheres to the ligand 120 to generate a heterogeneous layer.
  • This macroscopic layer is macroscopically determined to have a predetermined optical thickness corresponding to the amount of the analyte 130 deposited. It is replaced with a homogeneous layer having a thickness. Accordingly, the optical thickness of the homogeneous layer through which incident light passes changes depending on the amount of the analyte 130 attached. As a result, as shown in FIG. 36, the reflection spectrum 122 is shifted to the reflection spectrum 132 (see the chain line portion).
  • the presence or absence of the intermolecular interaction can be detected. Further, by detecting the amount of change in the bottom peak wavelength of the reflection spectrum 132 with respect to the bottom peak wavelength of the reflection spectrum 122, the progress of the intermolecular interaction can be detected.
  • the change in the bottom peak wavelength due to the ligand 120 can be confirmed at the time point 140, which is the first shoulder portion on the curve, as shown in FIG.
  • the time 142 which is the second shoulder portion above, a change in the bottom peak wavelength due to the binding between the ligand 120 and the analyte 130 can be confirmed.
  • the method of observing the transition of the bottom peak wavelength over time has a limit in measurement accuracy due to the measurement principle, and the progress of intermolecular interaction is more accurately determined.
  • the overall rate of binding Increases uniformly, that is, the progress of intermolecular interaction increases with time as shown in FIG. 38A.
  • the data that is actually output by the detection device that detects the spectral intensity of the reflected light repeatedly fluctuates, for example, as reflectance data 151 shown in FIG.
  • An operation such as fitting the approximate curve 152 to the reflectance data 151 to calculate the approximate curve 152 and obtaining the minimum value of the approximate curve as the above-described bottom peak position is required.
  • the change in reflectance is small near the bottom peak, the method of determining the bottom peak position using the approximate curve as described above tends to cause the bottom peak position to be inaccurate in principle. This is disadvantageous when it is required to calculate the progress of the interaction with higher accuracy.
  • the change amount ⁇ of the bottom peak wavelength may change differently from the progress of the intermolecular interaction, as shown in FIG. 38B. In such a case, the change amount ⁇ of the bottom peak wavelength. Is not suitable as a value for accurately determining the progress of intermolecular interaction.
  • the method of tracking the change amount ⁇ of the bottom peak wavelength tracks only one point on the graph of the spectral characteristic of reflected light, does not capture the overall shift of the graph, and accurately changes There is a limit to catching it.
  • a high-performance calculation device or a complicated calculation is required, or the calculation cannot catch up in a case where the intermolecular interaction proceeds rapidly. There is also a concern.
  • Patent Documents 2 and 3 Patents have already been filed for inventions that solve the above problems (Patent Documents 2 and 3).
  • a change ⁇ R in the spectral reflectance of reflected light before and after the start of intermolecular interaction at a predetermined wavelength is adopted as a value indicating the degree of progress of intermolecular interaction.
  • it is possible to accurately and efficiently generate a value indicating the degree of progress of intermolecular interactions such as biomolecules and organic polymers.
  • Patent Document 3 paying attention to the extreme value of the spectral characteristic of the detected light, it is found that this extreme value shows a constant change tendency according to the thickness of the interference film, and the relationship is specified in advance.
  • the optical film thickness of the interference film has been found.
  • the invention described in Patent Document 3 not only the film formed by the intermolecular interaction but also the The film thickness can be measured, and if there is a change in the optical film thickness over time, such as intermolecular interaction, this can be detected and the optical film thickness corresponding to the change can be measured. That is, in the measurement of the intermolecular interaction, when the ligand and the analyte are bonded, the amount of change in the optical film thickness at the site where the analyte is bonded can be measured.
  • the present invention has been made in view of the above circumstances, and can accurately and efficiently generate a value indicating the degree of progress of an intermolecular interaction such as a biomolecule or an organic polymer, and includes detection including a light source It is an object of the present invention to provide a method for measuring an intermolecular interaction capable of calculating a measurement result that eliminates the influence caused by the attribute of the means, a measurement system thereof, and a program for causing a computer to perform processing for performing the measurement.
  • the present invention can measure the optical film thickness of the interference film by reflection interference spectroscopy, if there is a change in the optical film thickness of the interference film, can measure the optical film thickness of the change, and It is an object of the present invention to provide an optical film thickness measurement method, an optical film thickness measurement system, and an optical film thickness measurement program capable of calculating a measurement result in which an influence caused by an attribute of a detection unit including a light source is removed.
  • the invention according to claim 1 for solving the above problems is a measurement method for optically measuring the intermolecular interaction between a plurality of substances on a thin film,
  • a measurement system reference spectral intensity creating step of creating a measurement system reference spectral intensity in advance and registering it, Detecting the intensity at the first wavelength of the reflected light before the start of intermolecular interaction by means of detecting the reflected light from the thin film; Detecting the intensity at the first wavelength of the reflected light after the start of intermolecular interaction by the detection means; Calculating a change in intensity of the reflected light before and after the start of intermolecular interaction at the first wavelength divided by the measurement system reference spectral intensity with respect to the first wavelength;
  • the measurement system reference spectral intensity creating step divides the spectral intensity of the reflected light detected by the detection means with respect to the reference interference film by the spectral reflectance of the reference interference film calculated by simulation, and this is measured. It is a method for measuring an intermolecular interaction, characterized in that it
  • the step of calculating the change in intensity of the reflected light by dividing the second wavelength different from the first wavelength by the measurement system reference spectral intensity with respect to the second wavelength.
  • the invention according to claim 3 measures a plurality of changes in the intensity of the reflected light by dividing the measurement wavelength by the measurement system reference spectral intensity for each measurement wavelength within a predetermined wavelength band.
  • the invention according to claim 4 is a measuring method for optically measuring the intermolecular interaction between a plurality of substances on a thin film
  • a measurement system reference spectral intensity creating step of creating a measurement system reference spectral intensity in advance and registering it, Detecting the intensity at the first wavelength of the transmitted light before the start of intermolecular interaction by a detection means for detecting the transmitted light transmitted through the thin film; Detecting the intensity of the transmitted light at the first wavelength after initiation of intermolecular interaction by the detection means; Calculating a change in intensity of the transmitted light before and after the start of intermolecular interaction at the first wavelength divided by the measurement system reference spectral intensity with respect to the first wavelength;
  • the measurement system reference spectral intensity creating step divides the spectral intensity of the transmitted light detected by the detection means with respect to the reference interference film by the spectral transmittance of the reference interference film calculated by simulation, and this is measured. It is a method for measuring an intermolecular interaction, characterized in that it includes a process of setting
  • the invention according to claim 5 is a step of calculating a change in intensity of the transmitted light by dividing the second wavelength different from the first wavelength by the measurement system reference spectral intensity with respect to the second wavelength.
  • the invention according to claim 6 measures a plurality of changes in the intensity of the transmitted light by a value obtained by dividing the change in the intensity of the transmitted light by the measurement system reference spectral intensity for each measurement wavelength by changing the measurement wavelength. 5.
  • the invention according to claim 7 compares the already registered measurement system reference spectral intensity with the measurement system reference spectral intensity created later when the measurement system reference spectral intensity creation step is further executed at least once.
  • the invention according to claim 8 reduces the driving power of the light source included in the detection means when the intensity obtained by measuring the intermolecular interaction by the detection means exceeds the maximum value of the measurable range. Re-measure the intensity above, The measurement system reference spectral intensity to be applied to the remeasured intensity, and the measurement system reference spectral intensity registered by driving the light source with the corresponding driving power after the reduction and executing the measurement system reference spectral intensity creation step.
  • the method for measuring an intermolecular interaction according to any one of claims 1 to 6, wherein:
  • the invention according to claim 9 is a measurement system for optically measuring intermolecular interactions between a plurality of substances on a thin film,
  • a measurement system reference spectral intensity creating means for creating a measurement system reference spectral intensity in advance and registering it, The reflected light from the thin film can be detected, the intensity of the reflected light at the first wavelength before the start of the intermolecular interaction is detected, and the first of the reflected light after the start of the intermolecular interaction is detected.
  • the measurement system reference spectral intensity creating means divides the spectral intensity of the reflected light detected by the detection means with respect to a reference interference film by the spectral reflectance of the reference interference film calculated by simulation, and this is measured.
  • An intermolecular interaction measurement system comprising a calculation means for setting a system reference spectral intensity.
  • the calculation means divides the change in the intensity of the reflected light by the measurement system reference spectral intensity with respect to the second wavelength for a second wavelength different from the first wavelength.
  • the calculation means includes a plurality of values obtained by dividing the change in intensity of the reflected light by the measurement system reference spectral intensity for each measurement wavelength by changing the measurement wavelength within a predetermined wavelength band. 10.
  • the invention according to claim 12 is a measurement system for optically measuring an intermolecular interaction between a plurality of substances on a thin film, A measurement system reference spectral intensity creating means for creating a measurement system reference spectral intensity in advance and registering it,
  • the transmitted light transmitted through the thin film can be detected, the intensity of the transmitted light at the first wavelength before the start of the intermolecular interaction is detected, and the transmitted light after the start of the intermolecular interaction is detected.
  • Detecting means for detecting intensity at a wavelength of 1;
  • a calculating means for calculating a value obtained by dividing a change in intensity of the transmitted light before and after the start of intermolecular interaction at the first wavelength by the measurement system reference spectral intensity with respect to the first wavelength;
  • the measurement system reference spectral intensity creating means divides the spectral intensity of the transmitted light detected by the detection means with respect to a reference interference film by the spectral transmittance of the reference interference film calculated by simulation, and this is measured.
  • An intermolecular interaction measurement system comprising a calculation means for setting a system reference spectral intensity.
  • the invention according to claim 13 is a value obtained by dividing the intensity change of the transmitted light by the measurement system reference spectral intensity with respect to the second wavelength for a second wavelength different from the first wavelength.
  • the calculation means is configured to calculate a plurality of values obtained by dividing a change in the intensity of the transmitted light by the measurement system reference spectral intensity for each measurement wavelength by changing the measurement wavelength within a predetermined wavelength band.
  • the measurement system reference spectral intensity when the measurement system reference spectral intensity is created by the measurement system reference spectral intensity creation means and further created after registration, the measurement system reference spectral intensity already registered and the measurement created later.
  • the intermolecular interaction measurement system according to any one of claims 9 to 14, further comprising means for calculating a temporal change amount of the light source light amount by comparing with a system reference spectral intensity. is there.
  • the invention according to claim 16 is a judging means for judging whether or not the intensity obtained by measuring the intermolecular interaction by the detecting means exceeds the maximum value of the measurable range; Re-measurement means for re-measuring the intensity after reducing the driving power of the light source included in the detection means when the determination means determines that it exceeds
  • the calculation means applies a measurement system reference spectral intensity to be applied to the intensity re-measured by the re-measurement means by the measurement system reference spectral intensity creation means in a state where the light source is driven in advance with the corresponding driving power after the reduction.
  • the intermolecular interaction measurement system according to any one of claims 9 to 14, wherein the measurement system reference spectral intensity is created and registered.
  • the invention according to claim 17 is a program for causing a computer to perform a process for optically measuring an intermolecular interaction between a plurality of substances on a thin film, A measurement system reference spectral intensity creation process for creating a measurement system reference spectral intensity in advance and registering it, A process for detecting the intensity at the first wavelength of the reflected light before the start of intermolecular interaction by a detection means for detecting the reflected light from the thin film; Processing for detecting the intensity of the reflected light at the first wavelength after the start of intermolecular interaction by the detection means; A process of calculating a change in intensity of the reflected light before and after the start of intermolecular interaction at the first wavelength divided by the measurement system reference spectral intensity with respect to the first wavelength; A program for causing the computer to The measurement system reference spectral intensity creating process divides the spectral intensity of the reflected light detected by the detection means with respect to a reference interference film by the spectral reflectance of the reference interference film calculated by simulation, and this is measured.
  • a process of calculating a change in the intensity of the reflected light by a value obtained by dividing the change in the intensity of the reflected light by the measurement system reference spectral intensity with respect to the second wavelength for a second wavelength different from the first wavelength is a process of calculating a change in the intensity of the reflected light by a value obtained by dividing the change in the intensity of the reflected light by the measurement system reference spectral intensity with respect to the second wavelength for a second wavelength different from the first wavelength.
  • the invention according to claim 19 measures a plurality of changes in the intensity of the reflected light within a predetermined wavelength band by dividing the measurement wavelength by the measurement system reference spectral intensity for each measurement wavelength.
  • the invention according to claim 20 is a program for causing a computer to perform a process for optically measuring an intermolecular interaction between a plurality of substances on a thin film, A measurement system reference spectral intensity creation process for creating a measurement system reference spectral intensity in advance and registering it, A process for detecting the intensity at the first wavelength of the reflected light before the start of the intermolecular interaction by a detection means for detecting transmission transmitted through the thin film; A process for detecting the intensity of the transmitted light at the first wavelength after the start of intermolecular interaction by the detection means; A process of calculating a change in intensity of the transmitted light before and after the start of intermolecular interaction at the first wavelength divided by the measurement system reference spectral intensity with respect to the first wavelength; A program for causing the computer to The measurement system reference spectral intensity creating process divides the spectral intensity of the transmitted light detected by the detection means with respect to the reference interference film by the spectral transmittance of the reference interference film calculated by simulation, and this is measured. This is
  • a process of calculating a change in the intensity of the transmitted light by a value obtained by dividing the change of the transmitted light by the measurement system reference spectral intensity with respect to the second wavelength for a second wavelength different from the first wavelength 21.
  • the invention according to claim 22 measures a plurality of changes in the intensity of the transmitted light by a value obtained by dividing a change in the intensity of the transmitted light by the measurement system reference spectral intensity for each measurement wavelength within a predetermined wavelength band, 21.
  • the invention according to claim 23 compares the already registered measurement system reference spectral intensity with the measurement system reference spectral intensity created later when the measurement system reference spectral intensity creation process is executed at least once after the execution. 23.
  • the invention according to claim 24 reduces the driving power of the light source included in the detection means when the intensity obtained by measuring the intermolecular interaction by the detection means exceeds the maximum value of the measurable range.
  • Processing to re-measure the intensity above The measurement system reference spectral intensity to be applied to the remeasured intensity is registered in advance by driving the light source with the corresponding driving power after the reduction and executing the measurement system reference spectral intensity creation process.
  • the program for measuring an intermolecular interaction according to any one of claims 17 to 22, further causing the computer to perform a process of:
  • the invention according to claim 25 is an optical film thickness measuring method for measuring an optical film thickness of an interference film in a laminate in which one or two or more interference films are stacked on a substrate by reflection interference spectroscopy.
  • the spectral intensity in the laminate to be measured is divided by the measurement system reference spectral intensity to obtain the spectral reflectance, and the wavelength that gives the extreme value of the spectral reflectance is applied to the relationship, and the wavelength that gives the extreme value is Identifying the optical film thickness to be approximated to obtain the optical film thickness in the laminate to be measured; and
  • the measurement system reference spectral intensity creating step divides the spectral intensity of the reflected light detected by the detection means with respect to the reference interference film by the spectral reflectance of the reference interference film calculated by simulation, and this is measured. It is an optical film thickness measuring method characterized by including the process of setting it as system standard spectral intensity.
  • the optical film thickness of the molecules adsorbed on the interference film is reduced by the intermolecular interaction performed on the interference film of the laminate in which one or more interference films are laminated on the substrate.
  • the spectral reflectance of the second laminate, the wavelength giving the extreme value of the change in the spectral reflectance of the second laminate relative to the spectral reflectance of the first laminate, and the optical thickness of the second interference film The step of creating the relationship for the optical film thickness of the different second interference film, The intermolecular interaction of the laminate of the measurement target with respect to the spectral reflectance obtained by dividing the spectral intensity in the laminate of the measurement target obtained by the detection means before the start of the intermolecular interaction by the reference spectral intensity of the measurement system By applying the wavelength that gives the extreme value of the amount of change in the spectral reflectance after the start of the above to the above relationship and identifying the optical film thickness of the second interference film that approximates the wavelength that gives the extreme value, Obtaining an optical film thickness of molecules adsorbed on the interference film by intermolecular interaction in the laminate of With
  • the measurement system reference spectral intensity creating step divides the spectral intensity of the reflected light detected by the detection means with respect to the reference interference film by the
  • the invention according to claim 28 is the optical film thickness measuring method according to any one of claims 25 to 27, wherein the relationship is created by a function.
  • the identification is performed by specifying an optical film thickness that approximates the wavelength that gives the extreme value, and the optical film thickness to be obtained is estimated from the optical film thickness that is most approximated.
  • the optical film thickness measuring method according to any one of claims 1 to 29.
  • the invention according to claim 31 is any one of claims 25 to 30 in which the detection means irradiates the laminate to be measured with white light to obtain the spectral intensity of the reflected light from the laminate. It is an optical film thickness measuring method as described in one.
  • the invention according to claim 32 is the optical film thickness measuring method according to any one of claims 25 to 31, wherein the measurement is performed in a state in which the liquid layer covers the interference film.
  • the already registered measurement system reference spectral intensity is compared with the measurement system reference spectral intensity created later.
  • the optical film thickness measuring method according to any one of claims 25 to 32, further comprising a step of calculating a temporal change amount of the light source light amount.
  • the driving power of the light source included in the detection unit is reduced.
  • the measurement system reference spectral intensity obtained by dividing the remeasured spectral intensity is previously measured by driving the light source with the corresponding driving power after the reduction and executing the measurement system reference spectral intensity creation step. It is an intensity
  • the invention according to claim 35 is an optical film thickness measurement system for measuring an optical film thickness of an interference film in a laminate in which one or more interference films are laminated on a substrate by reflection interference spectroscopy.
  • a light source Irradiating means for irradiating the laminate with light from the light source;
  • a light receiving means for receiving reflected light from the laminate;
  • Spectral detection means for detecting the spectral intensity of the reflected light received by the light receiving means;
  • a measurement system reference spectral intensity creating means for creating a measurement system reference spectral intensity in advance and registering it, Data constructed by creating in advance a relationship between the optical film thickness and the wavelength that gives the extreme value of the spectral reflectance in the laminated body whose optical film thickness of the interference film is known by simulation for different optical film thicknesses
  • Storage means for storing For the spectral reflectance obtained by dividing the spectral intensity of the laminate to be measured detected by the spectral detection means by the measurement system reference spectral intensity, the wavelength that gives the extreme value
  • the invention according to claim 36 is the optical film thickness of the molecules adsorbed on the interference film by the intermolecular interaction performed on the interference film of the laminate in which one or more interference films are laminated on the substrate.
  • An optical film thickness measurement system for measuring by reflection interference spectroscopy, A light source; Irradiating means for irradiating the laminate with light from the light source; A light receiving means for receiving reflected light from the laminate; Spectral detection means for detecting the spectral intensity of the reflected light received by the light receiving means; A measurement system reference spectral intensity creating means for creating a measurement system reference spectral intensity in advance and registering it, Spectral reflectance in the first laminated body in which a first interference film with a known optical film thickness is laminated in advance by simulation, and a second interference film with a known optical film thickness are laminated on the interference film of the first laminated body.
  • the optical film of the second interference film that specifies the wavelength that gives the extreme value of the change amount of the spectral reflectance after the start of the action, is applied to the data stored in the storage means, and approximates the wavelength that gives the extreme value
  • the measurement system reference spectral intensity creating means divides the spectral intensity of the reflected light detected by the detection means with respect to the reference interference film by the spectral reflectance of the reference interference film calculated by simulation, and this is measured.
  • An optical film thickness measuring system including a calculation means for setting a system reference spectral intensity.
  • the invention according to claim 38 is the optical film thickness measurement system according to any one of claims 35 to 37, wherein the light source is a light source that emits white light.
  • the invention according to claim 39 is a member that forms a flow path on the interference film, and a liquid containing molecules that interact with the molecules connected to the flow path and provided on the interference film. It is an optical film thickness measuring system as described in any one of Claim 35 to 38 provided with the liquid feeding means to flow.
  • the measurement system reference spectral intensity when the measurement system reference spectral intensity is created by the measurement system reference spectral intensity creation means and registered, the measurement system reference spectral intensity and the measurement created later are created.
  • the optical film thickness measuring system according to any one of claims 35 to 39, further comprising means for comparing the system reference spectral intensity and calculating a temporal change amount of the light source light amount.
  • the invention according to claim 41 is a judging means for judging whether or not the spectral intensity of the measuring object obtained by the detecting means exceeds a maximum value of a measurable range;
  • a re-measuring means for re-measuring the spectral intensity after reducing the driving power of the light source included in the detecting means when it is judged by the judging means that
  • the calculation means measures the spectral intensity re-measured by the re-measurement means, drives the light source with the corresponding driving power after the reduction, and creates and registers the measurement-system reference spectral intensity by the measurement-system reference spectral intensity creation means.
  • the optical film thickness measurement system according to any one of claims 35 to 39, wherein the identification is performed on the spectral reflectance divided by the intensity.
  • the invention according to claim 42 is an optical film thickness for causing a computer to execute a process for measuring the optical film thickness of the interference film by reflection interference spectroscopy in a laminate in which one or more interference films are laminated on a substrate.
  • a measurement program A measurement system reference spectral intensity creation process for creating a measurement system reference spectral intensity in advance and registering it, Data constructed by creating in advance a relationship between the optical film thickness and the wavelength that gives the extreme value of the spectral reflectance in the laminate having a known optical film thickness of the interference film, by simulation, for different optical film thicknesses
  • the process of reading Divide the spectral intensity in the laminate of the measurement target obtained by the detection means by the measurement system standard spectral intensity to obtain the spectral reflectance, specify the wavelength that gives the extreme value of the spectral reflectance, and apply it to the data , By calculating the optical film thickness that approximates the wavelength that gives the extreme value, A program for causing the computer to The measurement system reference spectral intensity creating process divides the spectral intensity
  • the invention according to claim 43 provides an optical film thickness of molecules adsorbed on the interference film by intermolecular interaction performed on the interference film of the laminate in which one or more interference films are laminated on the substrate.
  • An optical film thickness measurement program for causing a computer to execute processing to measure by reflection interference spectroscopy, A measurement system reference spectral intensity creation process for creating a measurement system reference spectral intensity in advance and registering it, Spectral reflectance in the first laminated body in which a first interference film with a known optical film thickness is laminated by simulation and a second interference film with a known optical film thickness are laminated on the interference film of the first laminated body in advance.
  • the spectral reflectance of the second laminated body, the wavelength giving the extreme value of the amount of change in the spectral reflectance of the second laminated body relative to the spectral reflectance of the first laminated body, and the optical film thickness of the second interference film The process of reading the data configured by creating the relationship for the optical film thickness of the different second interference film, The intermolecular interaction of the laminate of the measurement object with respect to the spectral reflectance obtained by dividing the spectral intensity of the laminate of the measurement object obtained by the detection means before the start of the intermolecular interaction by the reference spectral intensity of the measurement system.
  • the optical film thickness of the second interference film that approximates the wavelength that gives the extreme value is identified.
  • a program for causing the computer to The measurement system reference spectral intensity creating process divides the spectral intensity of the reflected light detected by the detection means with respect to a reference interference film by the spectral reflectance of the reference interference film calculated by simulation, and this is measured.
  • An optical film thickness measurement program including a process for setting a system reference spectral intensity.
  • the intensity of the reflected light or transmitted light before the start of the intermolecular interaction at the first wavelength and the reflected light or transmitted light after the start of the intermolecular interaction are increased. Since the change with the intensity at one wavelength is calculated, an accurate value indicating the degree of progress of the intermolecular interaction can be efficiently obtained by using the amount of change as the value indicating the degree of progress of the intermolecular interaction. Can do.
  • the optical film thickness of the interference film can be measured.
  • the interference film is caused by intermolecular interaction.
  • the spectral intensity of the reflected light detected by the detecting means with respect to the reference interference film is divided by the spectral reflectance of the reference interference film calculated by simulation, and this is measured.
  • the measurement result that eliminates the influence caused by the attributes of the detection means including the light source can be calculated. There is an effect.
  • FIG. 1 It is a schematic diagram which shows schematic structure of the measurement system of the intermolecular interaction which concerns on one Embodiment of this invention. It is a perspective view showing a schematic structure of a measuring member concerning one embodiment of the present invention. It is a schematic diagram which shows the mode of a measurement of the measuring system of intermolecular interaction. It is a circuit block diagram of the measurement system of intermolecular interaction. It is sectional drawing which represented typically the mode of the coupling
  • FIG. 7 is a graph of an example reference interference film spectral intensity (measured value), a reference interference film spectral reflectance (simulation) graph b, and a measurement system reference spectral intensity graph c processed in the flow of FIG. 6; It is a flowchart which shows the whole flow including calculation of the absolute spectral reflectance using the measurement system reference
  • FIG. 8 shows an example of measurement target spectral intensity graph a, measurement system reference spectral intensity graph b, absolute spectral reflectance graph c, and absolute spectral reflectance change amount
  • 2 is a graph d and a graph e showing a change with time in optical film thickness.
  • FIG. 10 is a diagram for explaining calculation of a sum of absolute values of change amounts ⁇ R within a predetermined wavelength band according to an embodiment of the present invention, and is a graph showing an example of a spectral reflectance distribution. It is a flowchart which shows the process for calculating the variation
  • FIG. 25 is a graph which shows the relationship between the sample film thickness d obtained by simulation, and the extreme position wavelength of spectral reflectance change amount (DELTA) R.
  • 27 is a graph created from the graph of FIG. 27 by converting the horizontal axis to the optical path length (optical film thickness) nd and the vertical axis to 1000 / ⁇ .
  • DELTA spectral reflectance change amount
  • 31 is a graph a of reference interference film spectral intensity (measured value), a graph b of reference interference film spectral reflectance (simulation), and a graph c of measurement system reference spectral intensity processed in the flow of FIG. 30; It is a flowchart which shows the whole flow including calculation of the absolute spectral reflectivity using the measurement system reference
  • 33 is a graph a of a measurement target spectral intensity, a measurement system reference spectral intensity graph b, and an absolute spectral reflectance graph c of an example processed in the flow of FIG. It is a schematic diagram for demonstrating the outline of a RIfS system.
  • DELTA change_quantity
  • the measurement system which is an embodiment for implementing the intermolecular interaction measurement system and optical film thickness measurement system of the present invention
  • the outline of 1 will be described.
  • the measurement system 1 executes the intermolecular interaction measurement method and the optical film thickness measurement method of the present invention, and includes the various means described above.
  • the computer included in the system configuration includes the present invention.
  • a program reflecting the intermolecular interaction measurement program and the optical film thickness measurement program is stored in an executable manner.
  • the use of this invention which concerns on an optical film thickness measurement is not limited to the measurement of an intermolecular interaction.
  • the measurement system 1 is connected to a measurement device 80 that includes a measurement member 10 that holds a sample to be measured and a measurement mechanism that includes a light source and a spectroscope described later, and the measurement device 80.
  • the computer includes a control arithmetic device 50 which is a computer, a display 91 and an input / output device 92 connected to the control arithmetic device 50.
  • the control arithmetic device 50 includes a control unit for a measurement mechanism such as a light source and a spectroscope built in the measurement device 80, a calculation unit for detection information, and an input / output unit for inputting / outputting control commands and detection information. Functions as (interface).
  • the measuring device 80 includes a lower housing 82 and an upper housing 81 that is rotatably attached to the lower housing 82.
  • the lower housing 82 is provided with a table 83 for holding the measuring member 10.
  • a connection portion 84 having an injection port 85 and a suction port 87 for connecting the measurement member 10 and circulating the sample and a detection window 86 is provided inside the upper housing 81.
  • a white light source 20, a spectroscope 30, and optical fibers 40 and 41 are provided in the upper casing 81, and light is irradiated from the detection window 86 and light incident from the detection window 86 is received. Is configured to do.
  • the upper casing 81 When performing measurement, first, the upper casing 81 is rotated upward to open the table 83 on the lower casing 82, and the measuring member 10 is set on the table 83. Thereafter, the upper casing 81 is rotated downward and closed, whereby the injection port 85 and the suction port 87 are connected to the measurement member 10, and the detection window 86 faces the measurement member 10 to complete the measurement preparation.
  • the measurement member 10 includes a sensor chip 12 provided with an optical thin film and a flow cell 14 that forms a flow path together with the sensor chip 12.
  • the sensor chip 12 has a silicon substrate 12a.
  • a SiN film 12b (silicon nitride) is deposited on the silicon substrate 12a.
  • the SiN film 12b is an example of an optical thin film.
  • the flow cell 14 is a transparent member made of silicone rubber.
  • a groove 14 a is formed in the flow cell 14. When brought into close contact with the flow cell 14 sensor chip 12, a sealed channel 14b is formed as shown in FIG. Both ends of the groove 14a are exposed from the surface of the flow cell 14, and one end functions as a sample solution inlet 14c and the other end functions as an outlet 14d.
  • a ligand 16 is previously bonded to the bottom of the groove 14a (see FIG. 3).
  • the flow cell 14 can be replaced with the sensor chip 12, and the flow cell 14 can be used in a disposable manner.
  • the surface of the sensor chip 12 may be modified with a silane coupling agent or the like. In this case, the flow cell 14 can be easily replaced.
  • the upper casing 81 is rotated downward and closed, so that the detection window 86 faces the flow cell 14 as shown in FIG.
  • the optical fiber 40 is installed above the path 14b.
  • the white light source 20 is connected to one end of the optical fiber 40.
  • a halogen light source is used as the white light source 20.
  • the other end of the optical fiber 40 faces the detection window 86.
  • the spectroscope 30 is connected to one end of the optical fiber 41, and the other end faces the detection window 86.
  • the white light source 20 and the spectroscope 30 are connected to a control arithmetic device 50, and the control arithmetic device 50 controls the operation of these modules.
  • the white light source 20, the spectroscope 30, the optical fibers 40 and 41, etc. constitute detection means for detecting the intensity of the reflected light of the optical thin film in which the intermolecular interaction proceeds.
  • the optical fiber for guiding the light from the light source and the optical fiber connected to the spectroscope are arranged on the opposite side with the measurement member interposed therebetween.
  • control arithmetic device 50 obtains input of data representing the spectral characteristics of reflected light through an interface at a predetermined timing linked to detection operation control by executing a program stored in a storage device described later. It functions as a calculation means (including the above-described measurement system reference spectral intensity creation means and calculation means) that calculates various values described below based on the obtained data.
  • FIG. 4 is a schematic circuit block diagram of the measurement system 1.
  • the control arithmetic device 50 includes a CPU 500, a ROM 501, a RAM 502, a storage device 503 such as a hard disk, a communication device 504, a reader / writer 505 of a storage medium such as a memory card, and each part and display of the measurement device 80.
  • An interface 506 is provided for exchanging signals with the input device.
  • the measurement program of the present invention is stored in the storage device 503, and the CPU 500 is controlled by this program so as to execute various operations and processes.
  • the sample solution 60 containing the analyte 62 is circulated from the inlet 14c to the outlet 14d through the sealed channel 14b.
  • the control arithmetic device 50 controls the liquid feeding device 35 (see FIG. 4) for feeding the sample solution 60.
  • the analyte 62 is a substance that specifically binds to the ligand 16 and is a target molecule to be detected.
  • biomolecules such as proteins, nucleic acids, lipids, and sugars, and foreign substances that bind to biomolecules such as drug substances and endocrine confusion chemical substances are used.
  • the control arithmetic device 50 turns on the white light source 20 at a timing before the sample solution 60 flows into the measurement member 10, and the reflected light of the optical thin film (SiN film 12 b) before the start of the intermolecular interaction from the spectroscope 30.
  • An input of spectral characteristic data including data indicating the intensity of light is obtained.
  • the control arithmetic device 50 turns on the white light source 20 while the sample solution 60 is circulating in the closed flow path 14b.
  • the white light passes through the flow cell 14 and is irradiated to the sensor chip 12, and the reflected light is detected by the spectroscope 30.
  • the detected intensity of the reflected light detected by the spectroscope 30 is transmitted to the control arithmetic device 50.
  • the optical thickness that is, the optical film thickness 70 changes, and the characteristics of the reflected light (for example, the spectroscope 30).
  • the wavelength at which the detection intensity due to (1) becomes the smallest) changes.
  • the control arithmetic device 50 obtains from the spectroscope 30 input of spectral characteristic data including data indicating the intensity of reflected light during or after the progress of the intermolecular interaction.
  • the control arithmetic device 50 creates a measurement system reference spectral intensity prior to measurement.
  • the measurement system reference spectral intensity is created for the reference interference film.
  • the reference interference film is the center chip 12.
  • the measurement system reference spectral intensity creation step is executed as shown in the flowchart of FIG.
  • the spectral reflectance of the reference interference film, that is, the center chip 12 (referred to as “reference interference film spectral reflectance”) is calculated by simulation and stored in the RAM 502 (FIG. 6, step S101).
  • the control arithmetic unit 50 may be used as the simulation execution means, or another computer may be used.
  • the reference interference film spectral reflectance is calculated, for example, as shown in FIG. 7b.
  • the control arithmetic device 50 causes the measurement device 80 to perform a measurement operation without causing the sample solution 60 to flow into the measurement member 10, and spectrally reflects the spectral intensity (referred to as “reference interference film spectral intensity”) of the reflected light from the center chip 12. Received from the container 30 (FIG. 6, step S102). The reference interference film spectral intensity is measured, for example, as shown in FIG. 7a.
  • the control arithmetic unit 50 divides the reference interference film spectral intensity by the reference interference film spectral reflectance (FIG. 6, step S103), and registers this as the measurement system reference spectral intensity (FIG. 6, step S104). This registration information is stored in the RAM 502. When the data shown in FIGS. 7a and 7b is used, the measurement system reference spectral intensity is calculated as shown in FIG. 7c.
  • the measurement object is the measurement member 10, and the sample solution 60 is also introduced, and a plurality of measurements are performed at a predetermined time rate before the start, during and after the intermolecular interaction.
  • the control arithmetic device 50 controls the measurement apparatus 80 to measure the spectral intensity of the measurement target (FIG. 8, step S202). The spectral intensity to be measured is measured and input to the control arithmetic device 50 as shown in FIG.
  • the control arithmetic device 50 divides the obtained spectral intensity of the measurement object by the measurement system reference spectral intensity to obtain the spectral reflectance of the measurement object (FIG. 8, step S203).
  • This spectral reflectance is referred to as “absolute spectral reflectance”.
  • the measurement system reference spectral intensity shown in FIG. 9b is the same as FIG. 7c.
  • the absolute spectral reflectance is calculated as shown in FIG. 9c.
  • a measurement method (FIG. 8, step S204) for calculating ⁇ R described in Patent Document 2 by applying absolute spectral reflectance, or an optical film thickness described in Patent Document 3 by applying absolute spectral reflectance.
  • the measurement method to be calculated (FIG. 8, step S205) is executed.
  • ⁇ R and the optical thin film change with time.
  • ⁇ R is measured as shown in FIG. 9d
  • the optical thin film is measured as shown in FIG. 9e.
  • a measurement method for calculating ⁇ R described in Patent Document 2 to which the absolute spectral reflectance is applied will be described in (2-3) below.
  • the measurement method for calculating the optical film thickness described in Patent Document 3 to which the absolute spectral reflectance is applied is described in (2-5) below.
  • the control arithmetic device 50 outputs the calculated value as a value indicating the degree of progress of the intermolecular interaction, and displays it on the display 91 or records it on the storage medium by the reader / writer 505.
  • the absolute spectral reflectance used in this calculation is obtained in the above (2-2), and the change in absolute spectral reflectance before and after the start of the intermolecular interaction at a predetermined wavelength is ⁇ R.
  • ⁇ R at the wavelength is calculated as a value indicating the degree of progress.
  • an appropriate wavelength can be selected as long as the spectral intensity changes depending on the progress of the intermolecular interaction, but the spectral intensity depends on the progress of the intermolecular interaction.
  • ⁇ R can be easily obtained by selecting a wavelength at which the change is large, particularly a wavelength at which the change in absolute spectral reflectance is maximized.
  • substance I (corresponding to the above-mentioned analyte 62), substance II (corresponding to the above-mentioned ligand 16), optical thin film III (corresponding to the above-mentioned SiN film 12b), substrate IV (the above-mentioned silicon substrate) 12a) is considered.
  • the interference film is composed of the substance I, the substance II, and the optical thin film III, and the heterogeneous layer composed of the substance I and the substance II is replaced with an effective homogeneous layer as shown in FIG. 15B. Think.
  • the thickness of this virtual homogeneous layer corresponds to the optical thickness at the time of calculation.
  • R ( ⁇ , ⁇ ) (1 ⁇ ) A ( ⁇ ) + ⁇ B ( ⁇ ) (1)
  • a ( ⁇ ) is the reflectance curve in state A
  • B ( ⁇ ) is the reflectance curve in state B
  • ⁇ is the degree of progress of the intermolecular interaction.
  • the reflectance value R ( ⁇ 1, 0.6) at the wavelength ⁇ 1 is 0.4 ⁇ A ( ⁇ 1) + 0.6B ( ⁇ 1) from the equation (1). Desired.
  • ⁇ R indicates a change characteristic that changes linearly with respect to the progress degree ⁇ of the intermolecular interaction, and these can be handled as an accurate value that indicates the progress degree of the intermolecular interaction.
  • ⁇ R it is not necessary to calculate an approximate curve in order to determine the position of the bottom peak, and the value can be calculated without going through such calculation, and the calculation of the value is facilitated.
  • ⁇ R captures the overall shift of the spectral characteristics of the reflected light, the change can be accurately captured.
  • the wavelength for calculating ⁇ R may be only one predetermined wavelength as shown in FIG. 10, or two or more different wavelengths.
  • ⁇ R is calculated for two or more different wavelengths in the wavelength band.
  • the most accurate value may be adopted as the measurement value, or the measurement value may be obtained using a plurality of measurement values.
  • measurement may be performed at a plurality of wavelengths within a predetermined wavelength band, and the sum of each measured ⁇ R or the sum of absolute values may be calculated.
  • a monochromatic light source can be applied, so that an expensive spectroscope for detecting the spectral intensity is not necessary. Furthermore, since a monochromatic light source with a simple configuration can be used, the measurement system can be configured at low cost.
  • FIG. 14 shows an example of a flowchart of a measurement program for causing the control arithmetic device 50, which is a computer, to perform processing.
  • the control arithmetic device 50 turns on the white light source 20, starts the detection operation of the spectrometer 30, and obtains data indicating the spectral characteristics of the reflected light before the start of the intermolecular interaction from the spectrometer 30 (step) S1) is executed.
  • the control arithmetic device 50 executes a process (step S2) for determining a wavelength (measurement wavelength) for measuring the amount of change in the spectral intensity of the reflected light based on the obtained spectral characteristic data of the reflected light.
  • the measurement wavelength corresponds to a portion having a steep gradient in the spectral spectrum curve, such as a wavelength between two adjacent extreme values, so that a large change occurs in the spectral intensity depending on the progress of the intermolecular interaction. Select the wavelength. If the measurement wavelength is determined in advance, step S2 is not necessary. Further, after obtaining spectral characteristic data after the start of intermolecular interaction, the measurement wavelength may be determined based on the spectral characteristics before and after the start of intermolecular interaction.
  • the control arithmetic device 50 controls the liquid delivery device 35 of the sample solution 60 to cause the sample solution 60 to flow through the closed flow path 14b, and the reflected light from the spectroscope 30 during the progress and / or after the completion of the intermolecular interaction.
  • the process (step S3) which acquires the data which show the intensity of is performed. At least when the intensity of the reflected light after the start of the intermolecular interaction is obtained, the control arithmetic device 50 determines the intensity of the reflected light before the start of the intermolecular interaction and the obtained reflection during or after the progress. Based on the light intensity and the measurement system reference spectral intensity, a process (step S4) of calculating an absolute spectral reflectance change amount ⁇ R is executed.
  • control arithmetic device 50 outputs the calculated value as a value indicating the degree of progress of the intermolecular interaction, and displays the value on the display 91 or records it in the storage medium (step S5).
  • control arithmetic unit 50 executes a step of calculating a sum of change amounts ⁇ R or a sum of absolute values ⁇
  • FIG. 18 shows a spectroscopic analysis of an optical thin film model in which a SiN thin film having a thickness of 66.5 nm is provided on a silicon substrate having a thickness of 725 ⁇ m, and a substance having a refractive index of 1.5 adheres to the SiN thin film with a thickness of 650 nm. It is the simulation result which observed the reflectance.
  • FIG. 19 is a graph showing the relationship between the degree of progress and the change amount ⁇ of the bottom peak wavelength. ⁇ represents the amount of change with reference to the bottom peak wavelength when the degree of progress is 0%.
  • ⁇ R indicates the amount of change in reflectance at a wavelength of 600 nm.
  • ⁇ R represents the amount of change based on the reflectance when the degree of progress is 0%.
  • the amount of change ⁇ of the bottom peak wavelength does not change linearly with respect to the degree of progress.
  • the reflectance change amount ⁇ R changes linearly with respect to the degree of progress, as shown in FIG. Therefore, it can be said that the reflectance change amount ⁇ R accurately indicates the progress of the intermolecular interaction.
  • ⁇ R is obtained by applying absolute spectral reflectance. That is, after the required absolute spectral reflectance is calculated in step S203 shown in FIG. 8, the ⁇ R calculation step in step S204 is performed. An outline of the ⁇ R calculation process is shown in the flowchart of FIG. Here, a case where an average value
  • the absolute spectral reflectance is calculated as shown in FIG. Curve R0 is before the start of the intermolecular interaction, and curve R1 is at any time after the start of the intermolecular interaction.
  • the absolute value of the change in reflectance at each of N different wavelengths is calculated (FIG.
  • ⁇ R represents the change in the intensity of the reflected light before and after the start of the intermolecular interaction, and includes the measurement wavelength (including the first wavelength and the second wavelength described above) in the measurement system reference spectral intensity distribution.
  • the sensor chip 12 has one or more interference films (SiN film 12b) on the substrate (silicon substrate 12a).
  • the measurement system 1 can measure the optical film thickness (such as the optical film thickness 70) of the interference film in the stacked body by reflection interference spectroscopy.
  • the optical fiber 40 receives irradiation light that irradiates light from the light source (white light source 20) to the laminate (sensor chip 12), and the optical fiber 41 receives reflected light from the laminate (sensor chip 12).
  • the spectroscope 30 corresponds to a spectroscopic detector that detects the spectral characteristics of the reflected light.
  • the RAM 502 functions as a data storage unit that is referred to when the control arithmetic device 50 calculates the optical film thickness.
  • the data can be read from any of a storage device 503, a server connected via the communication device 504, an external storage device connected via the interface 506, a memory card read by the reader / writer 505, and the like. Good.
  • a hardware configuration in which another computer that has received spectral characteristic data necessary for measuring the optical film thickness of the interference film via the communication device 504 performs calculations for measuring the optical film thickness of the interference film Does not matter.
  • the other computer is a computer in which the optical film thickness measurement program of the present invention is installed while being incorporated in the optical film thickness measurement system of the present invention.
  • the flow cell 14 corresponds to a member that forms a flow path on the interference film. As described above, the flow cell 14 is connected to the flow path formed by the flow cell 14 in the measuring device 80 and is provided on the interference film.
  • a liquid feeding means is configured to flow a liquid containing molecules that interact with the molecules through the flow path.
  • the measurement principle 1 will be described as follows. (Create reference data) When performing measurement based on this measurement principle, the data to be referred to when calculating the optical film thickness is the wavelength that gives the extreme value of the spectral reflectance in the laminate whose optical film thickness of the interference film is known by simulation and the optical It is data configured by creating a relationship with film thickness for different optical film thicknesses. This will be described in detail below.
  • FIG. 23 is a schematic model diagram for explaining the principle of reflection interference spectroscopy.
  • the laminate is configured by a substrate a1 and an interference film a2 having a film thickness d laminated thereon, and the liquid layer a3 covers the interference film a2.
  • the liquid layer a3, the interference film a2, and the substrate a1 have refractive indexes n1, n2, and n3, respectively.
  • reflected light a5 that reflects off the surface of the interference film a2 and reflected light a6 that passes through the interference film a2 and reflects at the interface with the substrate a1. Interfere as shown by part a7.
  • the optical path of the reflected light a6 is longer than the reflected light a5 by 2n2d.
  • the optical path difference 2n2d causes a half-wavelength shift between the reflected light a5 and the reflected light a6, it interferes so as to weaken the reflection intensity most, as shown by a7.
  • the reflection intensity varies depending on the wavelength of the light to be irradiated.
  • the optical film thickness n2d of the interference film a2 can be specified by analyzing the spectral characteristics of the reflected light. This is the basic principle of the present invention using reflection interference spectroscopy. The following description will clarify how the reflected light is analyzed to determine the optical film thickness.
  • the silicon substrate 12a described above corresponds to the substrate a1
  • the SiN film 12b corresponds to the interference film a2. As shown in FIG.
  • the portion corresponding to the optical film thickness 70 added to the SiN film 12b is the interference film. It corresponds to a2.
  • the curve of the spectral reflectance and the amount of change due to reflection interference changes as if it moves in the longer wavelength direction as the thickness of the interference film increases.
  • An example is shown in FIG.
  • the curve b1, b2, b3, b4 of the spectral reflectance change amount shown in FIG. 24 is obtained from the thicker interference film than the curve b1, the curve b2, the curve b2, the curve b3, and the curve b4. It is.
  • the spectral reflectance change amount ⁇ R is a change amount based on the spectral reflectance in an interference film having a certain film thickness. As shown in FIG. 24, the peak position moves to the long wavelength side in the order of curve b1, curve b2, curve b3, and curve b4.
  • This change characteristic depends on the optical film thickness of the interference film. Therefore, by extracting features from the spectral reflectance curve and its variation curve, focusing on the wavelength that gives the extreme value, the optical properties depending on the optical film thickness of the interference film are extracted regardless of the physical properties of the interference film. be able to. And it can expand
  • a curve of spectral reflectance R is calculated for samples having different film thicknesses by simulation, and the wavelength ⁇ at the extreme position is obtained in the curve, and the relationship between the sample film thickness d and the extreme position wavelength ⁇ is shown in the graph of FIG. .
  • This is obtained by examining the substrate a1 as a silicon substrate and changing the SiN film as the interference film a2 thereon in the range of 66.5 nm to 2000 nm.
  • the solid line indicates the wavelength at the maximum value position with respect to the sample film thickness
  • the broken line indicates the wavelength at the minimum value position with respect to the sample film thickness.
  • each of the curves B1 to P24 is approximated by a quadratic function, and the approximate quadratic function is expressed by a mathematical expression.
  • the coefficients a and b and the constant c corresponding to each of the curve B1 to the curve P24 are shown in Table 1 below.
  • the above-mentioned function data is the data that is referred to when calculating the optical film thickness according to this measurement principle, that is, the wavelength ⁇ that gives the extreme value of the spectral reflectance in a laminate in which the optical film thickness of the interference film is known in advance by simulation. And the relationship between the optical film thickness and the optical film thickness.
  • Such function data is stored so that it can be used by a computer (control arithmetic device 50) for calculating the optical film thickness.
  • an absolute value of the absolute spectral reflectance is given to the absolute spectral reflectance in the laminate to be measured. Specify the wavelength. The extreme value is specified including the maximum value and the minimum value.
  • a line parallel to the vertical axis y is drawn at an arbitrary value of the optical film thickness (horizontal axis x), it intersects one of the curves B1 to P24.
  • the y coordinate of the intersection is a value of 1000 / ⁇ giving an extreme value to the spectral reflectance curve at the optical film thickness.
  • the control arithmetic device 50 obtains the y value by converting the wavelength ⁇ giving the extreme value of the absolute spectral reflectance obtained from the measurement object into 1000 / ⁇ , and obtains the maximum value and the minimum value.
  • the solution x that is, the optical film thickness nd value is identified.
  • the control arithmetic unit 50 estimates and outputs the optical film thickness of the interference film in the measurement target laminate from the identified optical film thickness nd value.
  • the identification is performed by specifying those that approximate each other in the narrowest range. Then, for example, the average value of the distributed solution x is output as an estimated measurement value.
  • the reliability of the measurement is ensured to be constant by providing a threshold value of the approximation that may be output as a measurement value and the approximation that is output as a measurement error. The degree of approximation may also be output. Possible fitting patterns are the maximum value of the absolute spectral reflectance curve obtained from the object to be measured as SP1, SP2...
  • the measurement system 1 measures the optical film thickness of the interference film a2 according to the measurement principle 1.
  • the measurement system 1 is based on the measurement principle 1, regardless of whether the interference film a2 includes a layer formed by intermolecular interaction or not, by using reflection interference spectroscopy. Can be measured.
  • the measurement principle 2 will be described as follows.
  • the data to be referred to when calculating the optical film thickness is the spectral reflectance in the first laminate in which the first interference film having a known optical film thickness is previously laminated by simulation, Spectral reflectance in a second laminate in which a second interference film having a known optical thickness is laminated on the interference film of the first laminate, and in the second laminate relative to the spectral reflectance in the first laminate.
  • This measurement principle also presupposes the matters referring to FIG. 23 and FIG. 24 in the above measurement principle 1.
  • the curve of the change amount ⁇ R of the spectral reflectance with respect to the wavelength shows changes in peak movement and increase as the interference film becomes thicker as described above.
  • the curve of the spectral reflectance change ⁇ R is calculated for samples having different film thicknesses by simulation, the wavelength ⁇ at the extreme position is obtained in the curve, and the relationship between the sample film thickness d and the extreme position wavelength is shown in the graph of FIG. Described.
  • the substrate a1 is a silicon substrate
  • the first interference film laminated thereon is a 66.5 nm SiN film.
  • the second interference film laminated on the first interference film is BK7, and the second interference film (BK7) is examined by changing in the range of 0 nm to 1000 nm.
  • the sample film thickness d on the horizontal axis in the graph of FIG. 27 is for the second interference film (BK7).
  • BK7 is a virtual sample for simulation in which properties such as a refractive index are specified, corresponds to a typical kind of glass, and has a refractive index close to that of a biomaterial or a polymer material.
  • the solid line indicates the wavelength at the maximum value position with respect to the sample film thickness
  • the broken line indicates the wavelength at the minimum value position with respect to the sample film thickness.
  • FIG. 27 is a graph created by converting the sample film thickness d on the horizontal axis of the graph in FIG. 27 to the optical path length (optical film thickness) nd by multiplying the refractive index n, and converting the wavelength ⁇ on the vertical axis into 1000 / ⁇ . It is shown in FIG. In the graph of FIG. 28, a curve indicating the wavelength at the local maximum position appears on the leftmost side. This is a curve P1. When going to the right from the curve P1, a curve showing the wavelength of the minimum value position appears. This is a curve B1. When going further to the right from the curve B1, a curve indicating the wavelength at the maximum value position and a curve indicating the wavelength at the minimum value position appear alternately.
  • curves P2, B2, P3, B3... B7, P8 are sequentially designated as curves P2, B2, P3, B3... B7, P8.
  • Each of the curves P1 to P8 is approximated by a quadratic function, and the approximate quadratic function is expressed by a mathematical expression.
  • the coefficients a and b and the constant c corresponding to each of the curves P1 to P8 are shown in Table 2 below.
  • the above function data refers to the data that is referred to when calculating the optical film thickness according to the present measurement principle, that is, the spectral reflectance in the first laminated body in which the first interference film whose optical film thickness is known is previously laminated by simulation. And obtaining a spectral reflectance in a second laminated body in which a second interference film having a known optical thickness is laminated on the interference film of the first laminated body, and obtaining a second laminated layer with respect to the spectral reflectance in the first laminated body. It is data configured by creating the relationship between the wavelength that gives the extreme value of the amount of change in spectral reflectance in the body and the optical film thickness of the second interference film for different optical film thicknesses of the second interference film. . Such function data is stored so that it can be used by a computer (control arithmetic device 50) for calculating the optical film thickness.
  • the control arithmetic device 50 receives the input from the spectroscope 30 before the start of the intermolecular interaction. Obtain absolute spectral reflectance. After the start of the intermolecular interaction, the control arithmetic unit 50 obtains the absolute spectral reflectance after the start of the intermolecular interaction in the measurement target laminate based on the spectral characteristic data input from the spectroscope 30. When the absolute spectral reflectance after the start is obtained, the control arithmetic device 50 starts the intermolecular interaction of the measurement target laminate with respect to the absolute spectral reflectance before the start of the intermolecular interaction of the measurement target stack.
  • the wavelength that gives the extreme value of the change amount ⁇ R of the absolute spectral reflectance later is specified.
  • the extreme value is specified including the maximum value and the minimum value.
  • a line parallel to the vertical axis y is drawn at an arbitrary value of the optical film thickness (horizontal axis x), it intersects one of the curves P1, B1,.
  • the y coordinate of the intersection is a value of 1000 / ⁇ that gives an extreme value to the spectral reflectance change amount curve at the optical film thickness. If the intersection intersects the curves P1-P8, the extreme value is the maximum value, and the curve B1- If it crosses B7, the extreme value is a minimum value.
  • the control arithmetic unit 50 converts the wavelength ⁇ giving the extreme value of the absolute spectral reflectance change amount obtained from the measurement object into 1000 / ⁇ to obtain the y value, and obtains the maximum value and the minimum value.
  • the common solution x that is, the optical film thickness nd value is identified.
  • the control arithmetic device 50 estimates and outputs the optical film thickness of the interference film in the laminate to be measured from the identified optical film thickness nd value.
  • the measurement system 1 can measure the optical film thickness increased by the intermolecular interaction of the interference film a2 according to the measurement principle 2. That is, the measurement system 1 can measure the optical film thickness corresponding to the analyte 62 bound to the ligand 16 as shown in FIG. Due to the progress of the intermolecular interaction, the ligand 16 to which the analyte 62 is bound gradually increases. Even if the analyte 62 is combined even partly, there is a change in the wavelength of reflection interference, so that a curve of the absolute spectral reflectance change amount can be obtained even at the initial stage of the intermolecular interaction.
  • the optical film thickness of the portion where the analyte 62 is bonded is constant regardless of the progress of the intermolecular interaction. Can be specified. That is, the extreme value of the absolute spectral reflectance change amount specified at the initial stage of the intermolecular interaction is not different from that specified thereafter. Therefore, the measurement system 1 can calculate and output the measured value of the optical film thickness from the stage where the wavelength that gives the extreme value of the absolute spectral reflectance change amount can be specified first, and can notify the user at an early stage.
  • the optical film thickness is obtained by applying the absolute spectral reflectance as described above. That is, after the necessary absolute spectral reflectance is calculated in step S203 shown in FIG. 8, the optical film thickness calculation step in step S205 is performed.
  • the outline of the optical film thickness calculation process is shown in the flowchart of FIG. Reference data is created in advance according to measurement principle 1 or 2 as described above (FIG. 29, step S401).
  • the wavelength that gives the extreme value of the absolute spectral reflectance curve is searched (FIG. 29, step S402), this is compared with the reference data (FIG. 29, step S403), and the optical film thickness to be measured is calculated (FIG. 29). Step S404).
  • the measurement system reference spectral intensity is obtained by dividing the reference interference film spectral intensity by the reference interference film spectral reflectance.
  • the reference interference film spectral reflectance is obtained by dividing the spectral intensity of the reflected light of the reference interference film by the simulation by the spectral intensity of the light source light (incident light to the reference interference film) by the simulation.
  • the reference interference film spectral intensity and the reference interference film spectral reflectance are for a common reference interference film.
  • the former is a real object (sensor chip 12), and the latter is a theoretical one by simulation (virtual sensor chip 12).
  • the measurement system reference spectral intensity is the light source light (incident on the reference interference film by simulation). Equal to the spectral intensity of light).
  • the measurement system reference spectral intensity is not the same.
  • the absolute spectral reflectance is obtained by dividing the spectral intensity to be measured by the measurement system reference spectral intensity. Therefore, the absolute spectral reflectance is obtained by multiplying the spectral intensity (measured value) of the object to be measured by the reciprocal of the above ratio, that is, (theoretical value / measured value) and converting the spectral intensity equivalent to the theoretical value by simulation, This corresponds to the spectral reflectance obtained by dividing by the spectral intensity of the light source light (incident light on the reference interference film) by simulation.
  • the measurement target is an arbitrary one different from the reference interference film.
  • the measurement system 1 is calibrated by executing creation and registration of the measurement system reference spectral intensity. This has the effect of being able to calculate a measurement result that also eliminates the influence of the change in.
  • the optical film thickness measurement described in (2-5) above since the measurement result is identified in comparison with reference data based on a curve generated by simulation, there is an effect that the identification accuracy is improved.
  • a reference interference film having a stable and high identity between a simulation object and an actual object.
  • the reproducibility of reproducing the theoretical one by simulation into a real thing is high.
  • the SiN film 12b of the sensor chip 12 is used as the reference interference film.
  • the measurement system reference spectral intensity creation process shown in FIG. 30 creates and registers a measurement system reference spectral intensity for each display output process of the light source light quantity change over time and for each light source drive power setting (drive power 10 to 100%). Processing to include.
  • the measurement system reference shown in FIG. 6 in the state where the light source 20 is driven with the reference drive power (here, 100%) as the initial registration
  • the spectral intensity creation step is executed, and the measurement system reference spectral intensity at the initial driving power of 100% is registered. This registration information is stored in the RAM 502.
  • the light source 20 shown in FIG. Use a light output that can be adjusted.
  • the control arithmetic unit 50 outputs a driving power setting command of 100 to 10% to the light source 20, and the light source 20 receives this and adjusts the light output by changing the setting of the driving power.
  • the measurement system reference spectral intensity is created in units of 10% drive power.
  • the spectral reflectance of the reference interference film is calculated by simulation and stored in the RAM 502 (FIG. 30, step S501).
  • the control arithmetic device 50 causes the measurement device 80 to perform a measurement operation without causing the sample solution 60 to flow into the measurement member 10 in a state where the drive power is initially set to 100%.
  • the spectral intensity of the reflected light of the center chip 12 (“reference interference film spectral intensity”) is received from the spectroscope 30 (FIG. 30, step S502).
  • the reference interference film spectral intensity is measured, for example, as shown by a solid line graph in FIG. 31a.
  • the control arithmetic unit 50 divides the reference interference film spectral intensity by the reference interference film spectral reflectance (FIG. 30, step S503), and registers this as the measurement system reference spectral intensity at the current driving power of 100% (FIG. 30,). Step S507). However, since the drive power is initially set to 100%, YES is determined in branching step S504, and the control arithmetic device 50 determines that the measurement system reference spectral intensity at the current drive power of 100% is the initial drive power of 100%. The percentage of light intensity that has been reduced with respect to the measurement system reference spectral intensity is calculated (FIG. 30, step S505) and displayed on the display 91 (FIG. 30, step S506).
  • the drive power is 10% (FIG. 30, NO in step S508)
  • the drive power is decreased by 10% (FIG. 30, step S509)
  • NO and S507 are repeated in steps S502, S503, and S504 described above.
  • the measurement system reference spectral intensities at the current driving power of 10 to 100% in 10% increments are registered (FIG. 30, step S507). This registration information is stored in the RAM 502.
  • the measurement system reference spectral intensity is calculated as shown in FIG. 31c. If “YES” is determined in the step S508, the driving power of the light source 20 is returned to 100% (FIG. 30, step S510), the measurement system reference spectral intensity creating step is ended, and the measurement is prepared.
  • the measurement object is the measurement member 10, and the sample solution 60 is also introduced, and a plurality of measurements are performed at a predetermined time rate before the start, during and after the intermolecular interaction.
  • the control arithmetic unit 50 controls the measuring apparatus 80 to measure the spectral intensity of the measurement target (FIG. 32, step S601). S602).
  • the spectral intensity to be measured is measured as shown in the broken line graph of FIG.
  • the control arithmetic unit 50 determines whether or not the obtained spectral intensity of the measurement object exceeds the maximum value (MAX) (FIG. 32, step S603).
  • the power is reduced by 10% (FIG. 32, step S604), the process returns to step S602, and the spectral intensity is measured again.
  • the control arithmetic device 50 repeats this as long as the obtained spectral intensity of the measurement object exceeds the maximum value (MAX) of the measurable range, and if not, the process proceeds to step S605.
  • the reflection intensity is too high and saturates, that is, as shown in the broken line graph of FIG. 33a, the portion exceeding the maximum value (MAX) of the measured spectral intensity profile is prevented from being lost and accurate measurement is performed. It can be performed.
  • step S605 the control arithmetic device 50 divides the obtained spectral intensity of the measurement target by the measurement system reference spectral intensity to obtain the absolute spectral reflectance of the measurement target.
  • the measurement system reference spectral intensity at the same drive power as that of the light source 20 at the time of measurement is applied. For example, if the spectral intensity is measured while the light source 20 is driven at a driving power of 80%, this is divided by the measurement system reference spectral intensity at the driving power of 80% registered in step S507 in FIG. Spectral reflectance.
  • the data shown in FIG. 31 is used, one having the same drive power as that at the time of measurement is selected from the measurement system reference spectral intensity shown in FIG. 31c.
  • the measurement system reference spectral intensity is selected according to the driving power at the time of measurement as described above, so that an accurate measurement result can be obtained.
  • FIG. 33a in the measurement of the spectral intensity of the measurement target, when there is a setting of several percent reduction in the driving power of the light source, it is created and registered in advance with the driving power of the same reduction rate as shown in FIG. By dividing by the measured measurement system reference spectral intensity, an accurate absolute spectral reflectance measurement result can be obtained as shown in FIG. 33c.
  • step S204 the absolute spectral reflectance is applied to calculate ⁇ R described in Patent Document 2 (common in FIGS. 8 and 32, step S204), or the absolute spectral reflectance is calculated.
  • the measurement method (common to FIG. 8 and FIG. 32, step S205) for calculating the optical film thickness described in Patent Document 3 is applied.
  • the contents of step S204 are as described in (2-3) and (2-4) above, and the contents of step S205 are as described in (2-5) and (2-6) above.
  • the above program can be updated to the latest one through the communication device 504 connected to a public line such as the Internet through a LAN or the like.
  • the present invention can be used for measurement of bonds such as intermolecular interactions between biomolecules such as antigen-antibody reaction and intermolecular interactions between organic polymers.
  • Measurement member 12 Sensor chip 12a Silicon substrate 12b SiN film 14 Flow cell 14a Groove 14b Sealed flow path 14c Inlet 14d Outlet 16 Ligand 20
  • White light source 30 Spectroscope 40, 41 Optical fiber 50 Control arithmetic unit 60
  • Sample solution 62 Analyte 80 Measuring device R Spectral reflectance ⁇ R Change amount of spectral reflectance ⁇ Progress of intermolecular interaction ⁇ Reflected light wavelength a1 Substrate a2 Interference film a3 Liquid layer

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Abstract

Selon la présente invention, un résultat de mesure obtenu par élimination de l'impact dû à un attribut d'un moyen de détection comprenant une source lumineuse et similaire dans une mesure d'une épaisseur de film optique ou d'un degré de progrès d'une interaction intermoléculaire optique est calculé. A cette fin, une intensité spectrale standard de système de mesure est créée à l'avance et enregistrée. L'intensité spectrale standard de système de mesure est obtenue par division de l'intensité spectrale d'une lumière réfléchie détectée par le moyen de détection, par rapport à un film d'interférence standard, par la réflectivité spectrale du film d'interférence standard telle que calculée par une simulation. L'intensité spectrale d'une lumière réfléchie soumise à la mesure est divisée par l'intensité spectrale standard de système de mesure pour arriver à une réflectivité spectrale absolue, et une quantité de changement (ΔR) dans une longueur d'onde prédéterminée de la réflectivité spectrale absolue avant le début et après le début d'une interaction intermoléculaire est calculée en tant que valeur indicatrice du degré de progrès de l'interaction intermoléculaire. La relation entre une épaisseur de film optique d'un film d'interférence et la longueur d'onde à laquelle l'épaisseur de film optique donne une valeur extrême pour la réflectivité spectrale (quantité de changement) dans un stratifié connu est créée par rapport à différentes épaisseurs de film optique et les longueurs d'onde résultantes donnant une valeur extrême pour la réflectivité spectrale (quantité de changement) dans un stratifié soumis à la mesure sont appliquées à la relation pour identifier une épaisseur de film optique.
PCT/JP2013/075237 2012-09-24 2013-09-19 Procédé de mesure d'interaction intermoléculaire, procédé de mesure d'épaisseur de film optique, système de mesure et programme de mesure WO2014046156A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112334731A (zh) * 2018-06-27 2021-02-05 东京毅力科创株式会社 膜厚测定装置及校正方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001165628A (ja) * 1999-12-13 2001-06-22 Sharp Corp 膜厚測定装置
JP3786073B2 (ja) * 2002-10-10 2006-06-14 株式会社日立製作所 生化学センサ用キットおよび測定装置
WO2012096037A1 (fr) * 2011-01-12 2012-07-19 コニカミノルタオプト株式会社 Procédé de détection d'une interaction intermoléculaire et coffret pour une utilisation dans ce procédé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001165628A (ja) * 1999-12-13 2001-06-22 Sharp Corp 膜厚測定装置
JP3786073B2 (ja) * 2002-10-10 2006-06-14 株式会社日立製作所 生化学センサ用キットおよび測定装置
WO2012096037A1 (fr) * 2011-01-12 2012-07-19 コニカミノルタオプト株式会社 Procédé de détection d'une interaction intermoléculaire et coffret pour une utilisation dans ce procédé

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112334731A (zh) * 2018-06-27 2021-02-05 东京毅力科创株式会社 膜厚测定装置及校正方法
CN112334731B (zh) * 2018-06-27 2022-09-02 东京毅力科创株式会社 膜厚测定装置及校正方法

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