Measurement system and measurement method

Abstract

This measurement system comprises: a light source that radiates excitation light onto a fluorescent substance in a sample accommodation part in which a sample containing the fluorescent substance is accommodated; a detector that detects, on the basis of the excitation light, emitted light emitted by the fluorescent substance; a measurement device that measures the concentration of the fluorescent substance on the basis of a detection signal from the detector; and a cleaning device that can supply a cleaning liquid for cleaning the sample accommodation part to the sample accommodation part. The measurement device comprises: a first determination unit that executes first determination processing for determining whether or not a first intensity of the detection signal detected under a first condition is within a first range; a first measurement unit that, if the first intensity is within the first range, executes first measurement processing for carrying out analog measurement and measuring the concentration of the fluorescent substance in the sample; a second measurement unit that, once it has been determined that the first intensity is below the lower limit of the first range, executes second measurement processing for carrying out digital measurement and measuring the concentration of the fluorescent substance in the sample; and a first control unit that controls the cleaning device such that the sample accommodation part is cleaned over a first cleaning period if the first measurement processing has been executed, and the sample accommodation part is cleaned over a second cleaning period if the second measurement processing has been executed.

Description

Measurement system and measurement method

[0001] The present invention relates to a measurement system and a measurement method.

[0002] A technique is known in which excitation light is applied to a fluorescent substance of a fluorescent label in a sample in a sample storage section, and the fluorescent label is analyzed based on the emitted light from the fluorescent substance (see, for example, Patent Document 1).

[0003] Special Publication No. 2014-504154

[0004] However, when multiple samples are analyzed sequentially in the same sample container, the sample container needs to be cleaned between successive analyses. However, the cleaning time is generally fixed. Therefore, when analyzing samples with high concentrations of fluorescent substances, the cleaning time may be insufficient, resulting in insufficient cleaning of the sample container.

[0005] The present invention has been made in view of the above-mentioned problems, and aims to provide a measurement system that is capable of cleaning a sample storage section for a cleaning time that corresponds to the concentration of a fluorescent substance.

[0006] One invention for achieving the above object is a measurement system including: a light source that irradiates excitation light onto a fluorescent substance in a sample holding portion that holds a sample containing the fluorescent substance; a detector that detects radiation emitted by the fluorescent substance based on the excitation light; a measurement device that measures the concentration of the fluorescent substance based on a detection signal from the detector; and a cleaning device that can supply a cleaning solution to the sample holding portion for cleaning the sample holding portion, wherein the measurement device includes a first determination unit that executes a first determination process to determine whether a first intensity of the detection signal detected under a first condition is within a first range; is within the first range, a first measurement unit that performs a first measurement process by taking an analog measurement to measure the concentration of the fluorescent substance in the sample; a second measurement unit that performs a second measurement process by taking a digital measurement to measure the concentration of the fluorescent substance in the sample after it is determined that the first intensity is smaller than the lower limit of the first range; and a first control unit that controls the cleaning device so that the sample storage unit is cleaned for a first cleaning period when the first measurement process is performed, and so that the sample storage unit is cleaned for a second cleaning period when the second measurement process is performed.

[0007] a measuring device that measures the concentration of the fluorescent substance based on a detection signal from the detector; and a cleaning device that can supply a cleaning solution to the sample storage unit to clean the sample storage unit, the measuring method including the steps of: executing a first determination process by the measuring device to determine whether a first intensity of the detection signal detected under a first condition is within a first range; executing a first measurement process to perform an analog measurement and measure the concentration of the fluorescent substance in the sample if the first intensity is within the first range; executing a second measurement process to perform a digital measurement and measure the concentration of the fluorescent substance in the sample after it is determined that the first intensity is smaller than the lower limit of the first range; and controlling the cleaning device so that the sample storage unit is cleaned for a first cleaning period when the first measurement process is executed, and so that the sample storage unit is cleaned for a second cleaning period when the second measurement process is executed. Other features of the present invention will become apparent from the description of this specification.

[0008] According to the present invention, it is possible to provide a measurement system that can clean a sample container for a cleaning time that corresponds to the concentration of a fluorescent substance.

[0009] FIG. 1 is a diagram illustrating an example of a measurement system 1a. FIG. 2 is a diagram illustrating analog processing and digital processing. FIG. 3 is a diagram illustrating the hardware configuration of measurement devices 60a, 60b, and 60c. FIG. 4 is a diagram illustrating functional blocks of measurement device 60a. FIG. 5 is a flowchart illustrating processing executed by measurement device 60a. FIG. 6 is a diagram illustrating an example of measurement system 1b. FIG. 7 is a diagram illustrating an example of measurement system 1c. FIG. 8 is a diagram illustrating an example of measurement system 1d.

[0010] 1 is a diagram illustrating a measurement system 1a according to this embodiment. The measurement system 1a is a system for measuring the concentration of a fluorescent substance F in a predetermined sample S.

[0011] The sample S is a material to be measured or analyzed, and is a liquid containing a fluorescent label and a solvent (water, physiological saline, oil, alcohol, buffer solution, etc.). The fluorescent label refers to a substance that serves as a marker when analyzing a test substance, and a fluorescent substance is directly or indirectly bound to an antigen, antibody, nucleic acid, biomolecule, low molecular weight compound, hormone, polypeptide, protein, etc. The sample S is, for example, a fluorescently labeled antibody solution, a fluorescently labeled antigen solution, a fluorescently labeled nucleic acid solution, a fluorescently labeled polypeptide solution, or a fluorescently labeled protein solution.

[0012] Fluorescent substance F is the above-mentioned fluorescent label. Examples of fluorescent substances in fluorescent labels include europium complexes, low molecular weight compounds such as fluorescein isothiocyanate (FITC), rhodamine isothiocyanate (RITC), and sulfonated cyanines, and fluorescent proteins such as allophycocyanin (APC) and phycoerythrin (R-PE). Alternatively, fluorescent substance F may be a fluorescent substance that is not bound to a label.

[0013] The measurement system 1 a includes a sample storage unit 10 , a light source 20 , a detector 30 , an adjustment device 40 , a dispensing device 50 , a measurement device 60 a , and a cleaning device 70 .

[0014] <Sample storage section 10> The sample storage section 10 is a member that stores the sample S to be measured (hereinafter, sometimes simply referred to as "sample S") when measuring the concentration of fluorescent substance F (hereinafter, sometimes simply referred to as "concentration").

[0015] The sample holding portion 10 of this embodiment is a container-shaped member. The sample holding portion 10 receives excitation light from a light source 20 at a position 100, which is at least a part of the interior of the sample holding portion 10 (described later).

[0016] The shape of the sample container 10 is not limited to this. The sample container 10 may have any shape as long as it can irradiate at least a part of the contained sample S with excitation light from the light source 20. Other examples of the sample container 10 include a cell-like shape and a flow channel-like shape (described later).

[0017] <Light Source 20> The light source 20 is a device that irradiates excitation light onto the fluorescent substance F (hereinafter, sometimes simply referred to as "fluorescent substance F") in the sample S accommodated in the sample accommodation unit 10. The light source 20 includes an oscillator 201 that oscillates the excitation light, and an irradiation port 200 for emitting the excitation light.

[0018] A portion of the excitation light that reaches the sample holding portion 10 is absorbed by the fluorescent substance F. When the fluorescent substance F in the ground state absorbs the excitation light, it transitions to an excited state. The fluorescent substance F that transitioned to the excited state emits light (radiated light) and returns to the ground state. The radiation light at this time is detected by the detector 30, which will be described later.

[0019] The light source 20 does not need to irradiate all of the fluorescent material F in the sample S contained in the sample container 10 with excitation light, but only needs to irradiate at least a portion of the fluorescent material F with excitation light.

[0020] In this embodiment, the excitation light from the light source 20 reaches a position 100, which is a part of the sample holding portion 10. Then, a part of the excitation light that reaches the position 100, which is a part of the sample holding portion 10, is absorbed by the fluorescent material F in the vicinity of the position 100.

[0021] <Detector 30> The detector 30 is a device that detects the radiation emitted by the fluorescent substance F in response to the excitation light. As the detector 30, a photomultiplier tube, a silicon photodiode, an avalanche photodiode, or the like is used. As the detector 30 in this embodiment, a photomultiplier tube is used.

[0022] The radiation entering the photomultiplier tube is gradually amplified by the multiple dynodes arranged inside the tube through repeated secondary electron emission, and is then output as charge pulses from the anode. A signal containing these charge pulses (detection signal D1) is detected, and the intensity of the detection signal D1 is measured.

[0023] The position where the detector 30 is placed is not particularly limited as long as it is not a position where the excitation light may be detected. In other words, the position where the detector 30 is placed may be any position that is not on the path along which the excitation light propagates or on an extension of the path.

[0024] <Adjusting device 40> The adjusting device 40 is a device that adjusts the intensity of the radiant light emitted by the fluorescent substance F. The adjusting device 40 is located on the path along which the radiant light travels from the sample storage section 10 to the detector 30. The adjusting device 40 includes an attenuator 400 and a control device 401.

[0025] The attenuator 400 is provided to attenuate the intensity of the emitted light. The attenuator 400 is located on the path (optical path) along which the emitted light travels from the sample container to the detector 30. In other words, the detector 30 detects the emitted light that has passed through the attenuator 400.

[0026] In this embodiment, the dimmer 400 is one dimmer filter selected from a plurality of dimmer filters having a predetermined optical density (details of the dimmer filters will be described later).

[0027] The control device 401 controls the attenuator 400 so as to change the intensity of the emitted light transmitted through the attenuator 400. In this embodiment, the control device 401 performs control to apply a predetermined attenuation filter from a plurality of attenuation filters having different optical densities.

[0028] The attenuator 400 of this embodiment uses one of two neutral density filters F0 and F1, each having an optical density of 4 and 2. The control device 401 controls to apply either of these two neutral density filters or to apply neither neutral density filter.

[0029] Although a neutral density filter is used as the attenuator 400 in this embodiment, the attenuator is not limited to a neutral density filter as long as it can attenuate the intensity of the emitted light.

[0030] Another example of the attenuator 400 is a plurality of dichroic mirrors that reflect or transmit light in different wavelength ranges. In this case, the control device 401 controls the application of one of the plurality of dichroic mirrors, thereby controlling the amount of radiation light that passes through the dichroic mirrors.

[0031] The dichroic mirror in this example is placed in the same position as the above-mentioned neutral density filter. The intensity of the emitted light can also be attenuated by using such an attenuator 400.

[0032] Another example of the attenuator 400 is a diaphragm having an opening. In this case, the control device 401 controls the diameter of the opening, thereby controlling the amount of emitted light passing through the opening.

[0033] The diaphragm in this example is placed in the same position as the above-mentioned neutral density filter. The intensity of the emitted light can also be attenuated by using such an attenuator 400.

[0034] Furthermore, another example of the attenuator 400 is a lens for defocusing. In this case, the control device 401 controls the shifting of the focus of the emitted light, thereby controlling the amount of emitted light incident on the detector 30.

[0035] The lens in this example is placed in the same position as the above-mentioned neutral density filter. The intensity of the emitted light can also be attenuated by using such an attenuator 400.

[0036] <Dispenser 50 > The dispenser 50 is a device for supplying the sample S to the sample storage section 10 so that the sample S is stored in the sample storage section 10 .

[0037] The dispensing device 50 has a nozzle (not shown) and supplies the sample S to the sample storage section 10 by injecting the sample S into the sample storage section 10 through the nozzle.

[0038] <Measuring device 60a> The measuring device 60a is a device that measures the concentration of the fluorescent substance F based on the detection signal D1 of the detector 30. The measuring device 60a of this embodiment controls the above-mentioned adjusting device 40, dispensing device 50, and cleaning device 70. Details of the measuring device 60a will be described separately later.

[0039] <Washing Device 70> The washing device 70 is provided to wash the sample holding portion 10 after the concentration measurement. The washing device 70 is a device that can supply a washing liquid to the sample holding portion 10 for washing the sample holding portion 10.

[0040] Although not shown, the cleaning device 70 has a tank for storing the cleaning liquid and a pump for injecting or discharging the cleaning liquid.

[0041] <<Analog Processing and Digital Processing>> The processing for measuring the concentration of the fluorescent substance F based on the detection signal D1 of the detector 30 includes analog processing and digital processing.

[0042] As will be described later, the measurement device 60a of this embodiment performs measurement processing using both analog processing and digital processing. Before providing a detailed description of the measurement device 60a, these processes will be described.

[0043] Analog processing treats the detection signal D1 as an analog current signal. Based on the analog current signal over a predetermined measurement period, the total amount of fluorescence within the measurement period is measured. Furthermore, based on the measured total amount of fluorescence, the concentration of the fluorescent substance F is determined from a calibration curve for analog measurement that has been prepared in advance using standard samples of known concentrations.

[0044] Analog processing is effective when the detection signal D1 contains a huge number of charge pulses or when a plurality of charge pulses are superimposed, that is, when measuring a fluorescent substance F at a high concentration.

[0045] Digital processing treats the charge pulses as individual discrete pulses. The charge pulses are counted by a counter circuit. Based on the counted charge pulses, the concentration of fluorescent substance F is determined from a calibration curve for digital measurement, which is prepared in advance using standard samples of known concentrations.

[0046] Digital processing is effective when the charge pulses contained in the detection signal D1 are discrete and the detection signal is weak, that is, when measuring a fluorescent substance F at a low concentration.

[0047] 2 is a diagram illustrating analog processing and digital processing. Graphs (a) to (e) are shown in FIG. 2, which show the time progression of the detection signal D1 from the detector 30. These graphs show the detection signal D1 for each of five types of samples S with different concentrations of fluorescent substance F, under the condition that the intensity of the excitation light is constant.

[0048] Graph (a) corresponds to the case of the highest concentration of fluorescent substance F, and graph (e) corresponds to the case of the lowest concentration of fluorescent substance F. As can be seen from these graphs, the higher the concentration of fluorescent substance F, the greater the number of charge pulses included in the detection signal D1.

[0049] In graph (e), which corresponds to the lowest concentration of fluorescent substance F, the detection signal D1 contains one charge pulse, while in graph (d), the detection signal D1 contains multiple charge pulses, but these are discrete.

[0050] When the charge pulses are discrete and do not overlap, as in graphs (e) and (d), measurement by digital processing is possible, but in these cases, analog processing is not suitable for analog measurement because the analog current signal is weak and may fall below the lower limit of detectability.

[0051] Furthermore, in graph (c), the number of charge pulses included in the detection signal D1 is increased and the charge pulses are spaced closer together than in graph (d). Although some of the charge pulses overlap, they are generally discrete.

[0052] In cases such as graph (c), analog processing can provide analog measurements with a certain degree of accuracy, provided there are enough charge pulses so that the analog current signal is within a detectable range.

[0053] In such a case, the digital processing allows digital measurement with a certain degree of accuracy because the multiple charge pulses are almost discrete and each charge pulse is counted as one charge pulse.

[0054] Furthermore, the number of charge pulses included in the detection signal D1 in graph (b) is greater than that in graph (c). Furthermore, the intervals between the charge pulses are closer, and multiple charge pulses overlap each other.

[0055] When multiple charge pulses are superimposed as in graph (b), digital processing may count the superimposed multiple charge pulses as a single charge pulse, making digital measurement impossible.

[0056] Furthermore, in graph (a), the number of charge pulses included in the detection signal D1 is greater than in graph (b), and the number of superimposed charge pulses is further increased, causing the absolute value of the detection signal D1 to increase over the detection time.

[0057] In the case of graph (a), analog processing is not suitable for analog measurement because the analog current signal may exceed the upper limit of what can be detected.

[0058] <Details of the Measuring Device 60a> The measuring device 60a will be described in detail below. The hardware configuration of the measuring device 60a will be described below, followed by a description of the functional blocks realized by the measuring device 60a.

[0059] 3 is a diagram illustrating the hardware configuration of the measurement device of this embodiment. The measurement device 60a is a computer having a CPU (Central Processing Unit) 600, a memory 601, a communication device 602, a storage device 603, an input device 604, an output device 605, and a recording medium reader 606.

[0060] [CPU 600] The CPU 600 executes information processing programs stored in the memory 601 and the storage device 603 to realize various functions of the measuring device 60a.

[0061] [Memory 601] The memory 601 is, for example, a RAM (Random-Access Memory) and is used as a temporary storage area for various programs, data, and the like.

[0062] [Communication Device 602] The communication device 602 exchanges various programs and data with other computers via a network.

[0063] [Storage Device 603] The storage device 603 is a non-transitory (for example, non-volatile) storage device that stores various data to be executed or processed by the CPU 600.

[0064] [Input Device 604] The input device 604 is a device that accepts commands and data input by the user, and includes an input interface such as a keyboard and a touch sensor that detects a touch position on a touch panel display.

[0065] [Output Device 605] The output device 605 is, for example, a display, a printer, or the like.

[0066] [Recording Medium Reader 606 ] The recording medium reader 606 reads various data such as information processing programs recorded on recording media such as SD cards, DVDs, and CD-ROMs, and stores the data in the storage device 603 .

[0067] Functional Blocks of the Measuring Device 60a Next, the functional blocks of the measuring device 60a will be described.

[0068] 4 is a diagram illustrating the functional blocks of a measurement device 60a according to this embodiment. The measurement device 60a includes determination units 610, 611, and 612, measurement units 613 and 614, control units 615 and 616a, and a warning unit 617. Each of these units will be described below.

[0069] The determination unit 610 executes a determination process to determine whether the intensity I0 of the detection signal D1 detected under a predetermined condition C0 is within a predetermined range R0. The process by the determination unit 610, the condition C0, and the range R0 will be described in detail later.

[0070] [Determination Unit 611] When the determination unit 610 determines that the intensity I0 is smaller than the lower limit L0 of the range R0, the determination unit 611 executes a determination process to determine whether the intensity I1 of the detection signal D1 detected under a predetermined condition C1 is within a predetermined range R1. Details of the process by the determination unit 611, the condition C1, and the range R1 will be described later.

[0071] [Determination Unit 612] When the determination unit 611 determines that the intensity I1 is smaller than the lower limit L1 of the range R1, the determination unit 612 executes a determination process to determine whether the intensity I2 of the detection signal D1 detected under a predetermined condition C2 is within a predetermined range R2. Details of the process by the determination unit 612, the condition C2, and the range R2 will be described later.

[0072] [Measurement Unit 613] The measurement unit 613 measures the concentration using analog processing when it is determined that analog processing is to be used as a result of processing by the determination units 610 to 612. The processing by the measurement unit 613 will be described in detail later.

[0073] [Measurement Unit 614] The measurement unit 614 measures the concentration using digital processing when it is determined that digital processing is to be used as a result of processing by the determination unit 612. Details of the processing by the measurement unit 614 will be described later.

[0074] If the determination unit 612 determines that the intensity I2 is smaller than the lower limit L2 of the range R2 in the determination process, the measurement unit 614 performs digital measurement and executes a measurement process to measure the concentration.

[0075] [Control Unit 615] The control unit 615 controls the cleaning device 70. This control is performed depending on whether analog processing or digital processing is performed in measuring the concentration.

[0076] When analog processing is performed in the concentration measurement, the control unit 615 controls the washing device 70 so that the sample storage portion 10 is washed for a predetermined washing time Tw1.

[0077] When digital processing is performed in the concentration measurement, the control unit 615 controls the washing device 70 so that the sample storage portion 10 is washed for a predetermined washing time Tw2.

[0078] Here, the cleaning time Tw1 is set to be longer than the cleaning time Tw2. The reason why such a setting is effective will be explained.

[0079] Generally, the higher the concentration of the fluorescent substance F in the sample S, the longer it will take to clean the sample receptacle 10 after a concentration measurement has been carried out.

[0080] According to the processing of the above-mentioned determination units 610 to 612, when digital processing is performed, the intensity of the radiation emitted directly from the sample S (radiation before passing through the neutral density filter) is lower than when analog processing is performed.

[0081] That is, when digital processing is performed, the concentration of the fluorescent material F in the sample S is lower than when analog processing is performed.

[0082] Therefore, when analog processing is performed, a longer cleaning time (cleaning time Tw1) is required compared to when digital processing is performed. In other words, when digital processing is performed, a shorter cleaning time (cleaning time Tw2) is sufficient compared to when analog processing is performed.

[0083] [Control Unit 616a] The control unit 616a controls the adjustment device 40 to apply or switch between conditions C0, C1, and C2 in accordance with the processing of the above-described determination units 610 to 612. Details of the processing by the control unit 616a will be described later.

[0084] The control unit 616a controls the adjustment device 40 so that the condition C0 is satisfied in the determination process of the determination unit 610. In this case, in this embodiment, the adjustment device 40 applies a neutral density filter F0 with an optical density of 4. As a result, the intensity of the detection signal D1 becomes intensity I0.

[0085] Furthermore, the control unit 616a controls the adjustment device 40 so that condition C1 is met in the determination process of the determination unit 611. In this case, in this embodiment, the adjustment device 40 applies a neutral density filter F1 with an optical density of 2. As a result, the intensity of the detection signal D1 becomes intensity I1.

[0086] Furthermore, the control unit 616a controls the adjustment device 40 so that condition C2 is met in the determination process of the determination unit 612. In this case, in this embodiment, the adjustment device 40 does not apply the neutral density filter, so that the intensity of the detection signal D1 becomes intensity I2.

[0087] [Warning Unit 617] The warning unit 617 issues a warning when it is determined that neither analog processing nor digital processing is possible in the concentration measurement. Details of the processing by the warning unit 617 will be described later.

[0088] 5 is a flowchart illustrating the process performed by the measurement device 60a according to this embodiment. The process from measuring the concentration of the fluorescent substance F in the sample S to cleaning the sample storage unit 10 after the measurement will be described below using the flowchart.

[0089] [Step S101] First, in step S101, the dispensing device 50 (FIG. 1) dispenses the sample S. At this time, the dispensing device 50 ejects the sample S from a nozzle (not shown) into the sample storage portion 10, and injects the sample S into the sample storage portion 10.

[0090] [Step S102] Next, in step S102, the adjustment device 40 applies the neutral density filter F0. The neutral density filter F0 is a neutral density filter with an optical density of 4.

[0091] [Step S103] Next, in step S103, the determination unit 610 executes a first determination process. At this time, the determination unit 610 determines whether the intensity I0 of the detection signal D1 detected under the condition in which the neutral density filter F0 is applied (condition C0) is less than the lower limit L0 of a predetermined range R0, is within the range R0, or is greater than the upper limit U0 of the range R0.

[0092] In this embodiment, the period Td during which this determination process is performed (the period during which the detection signal is detected) is 0.5 seconds. Note that the period Td is not particularly limited and may be freely set by the operator.

[0093] Here, the condition C0 may be any condition in which the intensity of the detection signal D1 is smaller than when the attenuator 400 is not provided (that is, when the detector 30 directly detects the emitted light).

[0094] The lower limit L0 of the range R0 may be set to a value equal to or greater than the lower limit La of the intensity at which analog processing is possible, and the upper limit U0 may be set to a value equal to or less than the upper limit Ua of the intensity at which analog processing is possible but close to the upper limit Ua.

[0095] [Step S104] If the determination unit determines in step S103 that the value is within the range R0, the process proceeds to step S104. In step S104, the measurement unit 613 performs analog measurement while maintaining the condition under which the filter F0 is applied (condition C0), and executes a measurement process to measure the concentration.

[0096] In this embodiment, the period Tam during which this measurement process is performed (the period during which the detection signal is detected) is 2.0 seconds. Note that the period Tam is not particularly limited and may be freely set by the operator.

[0097] [Step S105] If it is determined in step S103 that the concentration is greater than the upper limit U0, the process proceeds to step S105. In step S105, the warning unit 617 issues a warning that neither analog processing nor digital processing is possible. At this time, the warning unit 617 causes the output device 605 (FIG. 3) to display a message on the display screen, such as "Measurement is impossible because the concentration exceeds the measurement upper limit."

[0098] [Step S106] If the determining unit 610 determines in step S103 that the value is less than the lower limit L0, the process proceeds to step S106. In step S106, the adjustment device 40 applies the neutral density filter F1. The neutral density filter F1 is a neutral density filter with an optical density of 2.

[0099] That is, the neutral density filter F1 is a neutral density filter that increases the intensity of the detection signal D1 more than the neutral density filter F0, which has an optical density of 4 and was used in the determination process of step S103.

[0100] [Step S107] In step S107, the determination unit 611 performs a second determination process. At this time, the determination unit 611 determines whether the intensity I1 of the detection signal D1 detected under the condition in which the neutral density filter F1 is applied (condition C1) is less than the lower limit L1 of the range R1, is within the range R1, or is greater than the upper limit U1 of the range R1.

[0101] Here, condition C1 is a condition in which the intensity of the detection signal D1 is greater than that of the above-mentioned condition C0. Furthermore, in this embodiment, range R1 is the same as the above-mentioned range R0. However, the present invention is not limited to this, and range R1 may be set to a range different from range R0.

[0102] In this embodiment, the period Td during which this determination process is performed (the period during which the excitation light is irradiated) is 0.5 seconds.

[0103] [Step S108] If the determination unit 611 determines in step S107 that the concentration is within range R1, the process proceeds to step S108. In step S108, the measurement unit 613 executes a measurement process to measure the concentration of the fluorescent substance F in the sample S by performing analog processing on the detection signal D1 of intensity I1 while maintaining the condition (condition C1) in which the neutral density filter F1 is applied.

[0104] In this embodiment, the period Tam during which this measurement process is performed (the period during which the excitation light is irradiated) is 2.0 seconds.

[0105] [Step S109] If the determination unit 611 determines in step S107 that the value is greater than the upper limit U1, the process proceeds to step S109. In step S109, the warning unit 617 issues a warning that neither analog processing nor digital processing is possible. In other words, the warning unit 617 executes the same process as in step S105.

[0106] [Step S110] If the determining unit 611 determines in step S107 that the value is less than the lower limit L1, the process proceeds to step S110. In step S110, the adjustment device 40 removes the neutral density filter F1, thereby setting the adjustment device 40 in a state where no neutral density filter is applied.

[0107] [Step S111] In step S111, the determination unit 612 performs a third determination process. At this time, the determination unit 612 determines whether the intensity I2 of the detection signal D1 detected under the condition in which the neutral density filter is not applied (condition C2) is less than the lower limit L2 of the range R2, is within the range R2, or is greater than the upper limit U2 of the range R2.

[0108] Here, condition C2 is a condition in which the intensity of the detection signal D1 is greater than that of condition C1. Furthermore, the lower limit L2 of range R2 may be set to a value that is equal to or greater than the lower limit of the intensity that can be processed analogically and equal to or less than the upper limit of the intensity that can be processed digitally. The upper limit U2 may be set to the same value as upper limit U2.

[0109] In this embodiment, the period Td during which this determination process is performed (the period during which the excitation light is irradiated) is 0.5 seconds.

[0110] [Step S112] If the determination unit 612 determines in step S111 that the concentration is within range R2, the process proceeds to step S112. In step S112, the measurement unit 613 executes a measurement process to measure the concentration of the fluorescent substance F in the sample S by performing analog processing on the detection signal D1 with intensity I2, while maintaining the condition (condition C2) in which the neutral density filter is not applied.

[0111] In this embodiment, the period Tam during which this measurement process is performed (the period during which the excitation light is irradiated) is 2.0 seconds.

[0112] [Step S113] If the determination unit 612 determines in step S111 that the value is greater than the upper limit U2, the process proceeds to step S113, where the warning unit 617 issues a warning that neither analog processing nor digital processing is possible.

[0113] [Step S114] If the determination unit 612 determines in step S111 that the concentration is less than the lower limit L2, the process proceeds to step S114. In step S114, the measurement unit 614 performs digital measurement while maintaining the condition (condition C2) in which the neutral density filter is not applied, and executes a measurement process to measure the concentration of the fluorescent substance F in the sample S.

[0114] In this embodiment, the period Tdm during which this measurement process is performed (the period during which the excitation light is irradiated) is 18 seconds.

[0115] [Step S115] After the above-described steps S104, S105, S108, S109, S112, and S113, the process proceeds to step S115. These steps S104, S105, S108, S109, S112, and S113 are steps in which either measurement using analog processing is performed or a warning is issued to the effect that measurement is not possible.

[0116] In step S115, the control unit 615 controls the washing device 70 so that the washing liquid flows into the sample storage portion 10 for the washing time Tw1.

[0117] [Step S116] After step S114, the process proceeds to step S116. In step S114, measurement using digital processing is performed.

[0118] In step S116, the control unit 615 controls the washing device 70 so that the washing liquid flows into the sample storage portion 10 for the washing time Tw2. As described above, the washing time Tw1 is set to be longer than the washing time Tw2.

[0119] The above is the process of measuring the sample S and then cleaning the sample storage portion 10. When step S115 or step S116 is completed, the process returns to step S101, and processing is performed on another sample to be measured.

[0120] According to the process of the measuring device 60a described above, it is possible to clean the sample container 10 for a cleaning time according to the concentration of the fluorescent substance F.

[0121] Furthermore, in this embodiment, the cleaning time Tw1 when analog processing is used is longer than the cleaning time Tw2 when digital processing is used, so that a more sufficient cleaning time for the sample storage section 10 can be ensured.

[0122] In the above process, the period Td (0.5 seconds) during which the determination processes are performed in steps S103, S107, and S111 is shorter than the period Tam (2.0 seconds) during which the analog processes are performed in steps S104, S108, and S112.

[0123] In this embodiment, the process executed by the measurement device 60a includes three determination processes (steps S103, S107, and S111). However, the number of determination processes is not limited to three.

[0124] For example, steps S102 to S104 may be omitted, and the determination process (steps S107 and S111) may be executed twice.

[0125] Alternatively, the determination process may be performed four or more times. In this case, if the attenuator 400 is a neutral density filter, n (n is an integer equal to or greater than 4) neutral density filters F0 to Fn-1 with different optical densities are used.

[0126] Then, starting with the neutral density filter F0 having the highest optical density, the determination process is performed n times in descending order of optical density using the same procedure as in this embodiment.

[0127] By increasing the number of times the determination process is performed in this way, the boundary between the density when analog processing is used and when digital processing is used becomes a more appropriate value.

[0128] <<Regarding Correspondence>> The judgment unit 611 corresponds to a "first judgment unit," the condition C1 corresponds to a "first condition," the intensity I1 corresponds to a "first intensity," the range R1 corresponds to a "first range," and the judgment process performed by the judgment unit 611 corresponds to a "first judgment process."

[0129] The judgment unit 612 corresponds to the "second judgment unit," the condition C2 corresponds to the "second condition," the intensity I2 corresponds to the "second intensity," the range R2 corresponds to the "second range," and the judgment process performed by the judgment unit 612 corresponds to the "second judgment process."

[0130] The measurement unit 613 corresponds to a "first measurement unit," and the measurement process (analog process) executed by the measurement unit 613 corresponds to a "first measurement process."

[0131] The measurement unit 614 corresponds to a "second measurement unit," and the measurement process (digital process) executed by the measurement unit 614 corresponds to a "second measurement process."

[0132] The control unit 615 corresponds to the "first control unit," the cleaning time Tw1 corresponds to the "first cleaning period," and the cleaning time Tw2 corresponds to the "second cleaning period." The control unit 616a corresponds to the "second control unit." The period Td corresponds to the "first period," and the period Tam corresponds to the "second period."

[0133] ==Second Embodiment== In the measurement system 1a of the first embodiment, an adjustment device 40 is used to set the respective conditions (conditions C0, C1, C2) when the judgment process is performed by the judgment units 610 to 612.

[0134] Specifically, the adjustment device 40 adjusts the detected intensity of the emitted light by controlling whether to apply the neutral density filter F0 or F1 or to apply no neutral density filter.

[0135] However, the control for setting the conditions C0, C1, and C2 is not limited to this example. In this embodiment, another example for setting the conditions C0, C1, and C2 will be described.

[0136] 6 is a diagram illustrating a measurement system 1b of this embodiment. The measurement system 1b differs from the first embodiment in that a measurement device 60b controls the output of a light source 20.

[0137] In the measurement system 1b, a measurement device 60b includes a control unit 616b (corresponding to a "third control unit") instead of the control unit 616a of the first embodiment.

[0138] For example, instead of the process of the control unit 616a in step S106 in Fig. 5, the control unit 616b controls the light source 20 so that the intensity of the detection signal D1 becomes intensity I2. The same applies to the determination process of the control unit 616a in steps S102 and S110.

[0139] Even with such control by the control unit 616b, it is possible to set the predetermined conditions C0, C1, and C2.

[0140] ==Third Embodiment== In this embodiment, another aspect for setting the above-mentioned conditions C0, C1, and C2 will be described.

[0141] 7 is a diagram illustrating a measurement system 1c of this embodiment. The measurement system 1c differs from the first embodiment in that a measurement device 60c controls the detector 30.

[0142] In a measurement system 1c of this embodiment, a measurement device 60c includes a control unit 616c (corresponding to a "fourth control unit") instead of the control unit 616a of the first embodiment.

[0143] For example, instead of the processing of the control unit 616a in step S106 of Fig. 5, the control unit 616c controls the detector 30 so that the intensity of the detection signal D1 becomes intensity I2. Specifically, the control unit 616c increases the sensitivity of the detector 30 so that the intensity of the detection signal D1 becomes I2.

[0144] The same applies to the determination processing by the control unit 616a in steps S102 and S110.

[0145] Even with such control by the control unit 616c, it is possible to set the predetermined conditions C0, C1, and C2.

[0146] ==Fourth Embodiment== In this embodiment, a measurement system 1d having a sample receptacle 801 different in configuration from that of the first embodiment will be described.

[0147] 8 is a diagram illustrating a measurement system 1d of this embodiment. The measurement system 1d differs from the first embodiment in that it has a chip 80 instead of the sample container 10 (FIG. 1).

[0148] The chip 80 of this embodiment is formed of a silicon substrate 800. On one surface of the silicon substrate 800, a sample storage section 801, an inlet 802, an outlet 803, and an optical waveguide 804 are provided.

[0149] The sample storage section 801 of this embodiment is a hollow space through which the sample S can pass when the concentration is measured.

[0150] In this embodiment, the sample storage portion 801 is a hollow channel that is formed so that the sample S can flow therethrough when measuring the concentration.

[0151] The inlet 802 is provided to supply the sample S or a cleaning solution to the sample storage portion 801 from one end of the sample storage portion 801. The inlet 802 is provided on one end side of the sample storage portion 801. The inlet 802 in this embodiment is cylindrical and communicates with one end of the sample storage portion 801 at the bottom.

[0152] In this embodiment, the dispensing device 50 supplies the sample S to the sample storage section 10 by injecting the sample S into the injection port 802 via a nozzle.

[0153] The washing device 70 also supplies the washing liquid to the sample storage section 801 by injecting the washing liquid into the inlet 802 .

[0154] The outlet 803 is provided for discharging the sample S or the cleaning solution from the other end of the sample storage portion 801. The outlet 803 is provided on the other end side of the sample storage portion 801. The outlet 803 in this embodiment is cylindrical and communicates with the other end of the sample storage portion 801 at the bottom portion.

[0155] In this embodiment, the washing device 70 discharges the washing liquid from the outlet 803. This causes the washing liquid to flow through the sample holding portion 801, thereby cleaning the sample holding portion 801.

[0156] The optical waveguide 804 is formed so as to guide excitation light (described later) from the light source 20 to the sample holding portion 801. The optical waveguide 804 is filled with a transparent medium. The optical waveguide 804 is disposed so as to intersect with the sample holding portion 801.

[0157] The optical waveguide 804 of this embodiment has a linear shape and is arranged so as to be perpendicular to the sample holding portion 801 at a position 805 where it intersects with the sample holding portion 801 .

[0158] The excitation light from the light source 20 enters the transparent medium of the optical waveguide 804 from one end thereof and propagates through the optical waveguide 804. Then, the excitation light is irradiated onto the fluorescent material F in the vicinity of a position 805 in the sample holding portion 801.

[0159] Even with such a configuration of the sample container 801, it is possible to clean the sample container for a cleaning time that corresponds to the concentration of the fluorescent substance.

[0160] Summary The measurement systems 1a, 1b, 1c, and 1d of the above-described embodiments are measurement systems including a light source 20 that irradiates excitation light onto a fluorescent substance F in a sample storage portion 10, 801 that stores a sample S containing a fluorescent substance, a detector 30 that detects radiation emitted from the fluorescent substance F based on the excitation light, measurement devices 60a, 60b, and 60c that measure the concentration of the fluorescent substance F based on a detection signal D1 of the detector 30, and a cleaning device 70 that can supply a cleaning liquid to the sample storage portion to clean the sample storage portion, and the measurement devices 60a, 60b, and 60c determine whether an intensity I1 of the detection signal D1 detected under condition C1 is within a range R1. a measurement unit 613 that performs a measurement process by performing analog measurement to measure the concentration of the fluorescent substance F in the sample S if the intensity I1 is within the range R1; a measurement unit 614 that performs a measurement process by performing digital measurement to measure the concentration of the fluorescent substance F in the sample S after it has been determined that the intensity I1 is smaller than the lower limit L1 of the range R1; and a control unit 615 that controls the cleaning device 70 so that the sample storage unit 10, 801 is cleaned over a cleaning period Tw1 if the analog measurement has been performed, and so that the sample storage unit 10, 801 is cleaned over a cleaning period Tw2 if the digital measurement has been performed.

[0161] With this configuration, the determining unit 611 selects an appropriate process, either analog or digital, depending on the concentration of the fluorescent substance F. Then, the sample holding unit 10, 801 is cleaned for a cleaning time depending on the process used to measure the concentration. In other words, it is possible to clean the sample holding unit 10, 801 for a cleaning time depending on the concentration of the fluorescent substance F.

[0162] Furthermore, in the measurement systems 1a, 1b, 1c, and 1d, the measurement devices 60a, 60b, and 60c include a determination unit 612 that performs a determination process to determine whether the intensity I2 of the detection signal D1 detected under condition C2, in which the intensity of the detection signal D1 is greater than that under condition C1, is within range R2, and performs digital measurement if it is determined that the intensity I2 is smaller than the lower limit L2 of range R2. With this configuration, the determination unit 612 selects the most appropriate processing, either analog processing or digital processing, depending on the concentration of the fluorescent substance F, thereby improving the accuracy of the measurement.

[0163] Furthermore, in the measurement systems 1a, 1b, 1c, and 1d, the cleaning period Tw2 is shorter than the cleaning period Tw1. With this configuration, the measurement and cleaning processes performed by the measurement systems 1a, 1b, 1c, and 1d are made more efficient, and the overall processing time is shortened.

[0164] The measurement systems 1a and 1d of the first and fourth embodiments include an adjustment device 40 that is located on the path of light traveling from the sample container 10, 801 to the detector 30 and adjusts the intensity of the emitted light, and the measurement device 60a includes a control unit 616a that controls the adjustment device 40 so that the intensity of the detection signal D1 becomes intensity I2 when it is determined that the intensity I1 is smaller than the lower limit L1 of the range R1. With this configuration, variation in the intensity I2 is suppressed, thereby improving measurement accuracy.

[0165] In the measurement systems 1a and 1d of the first and fourth embodiments, the adjustment device 40 includes an attenuator 400 located between the sample container 10, 801 and the detector 30, and a control device 401 that controls the attenuator 400 so as to change the intensity of the emitted light passing through the attenuator 400. With this configuration, the variation in intensity I2 is further suppressed, thereby improving the measurement accuracy.

[0166] In the measurement system 1b of the second embodiment, the measurement device 60b includes a control unit 616b that controls the light source 20 so that the intensity of the detection signal D1 becomes intensity I2 when it is determined that the intensity I1 is smaller than the lower limit L1 of the range R1. With this configuration, it is sufficient to control the output of the light source 20, and the configuration of the measurement system 1b is simplified.

[0167] In the measurement system 1c of the third embodiment, the measurement device 60c includes a control unit 616c that controls the detector 30 so that the intensity of the detection signal D1 becomes intensity I2 when it is determined that the intensity I1 is smaller than the lower limit of the range R1. With this configuration, it is sufficient to control the sensitivity of the detector 30, and the configuration of the measurement system 1c is simplified.

[0168] In the measurement systems 1a, 1b, 1c, and 1d of the embodiments, the period Td during which the determination process is performed is shorter than the period Tam during which the analog process is performed. With this configuration, the overall processing time is shortened while maintaining the measurement accuracy.

[0169] The measurement systems 1a, 1b, 1c, and 1d of the embodiments each include a warning unit 617 that issues a warning when it is determined that the intensity I1 is greater than the upper limit U1 of the range R1. With this configuration, the operator can recognize that the concentration of the fluorescent substance F is a concentration that cannot be measured by either analog processing or digital processing.

[0170] The measurement method of the embodiment is a measurement method performed by measurement systems 1a, 1b, 1c, 1d including a light source 20 that irradiates excitation light onto a fluorescent substance F in a sample storage section 10, 801 that stores a sample containing a fluorescent substance, a detector 30 that detects radiation emitted from the fluorescent substance F based on the excitation light, measurement devices 60a, 60b, 60c that measure the concentration of the fluorescent substance F based on a detection signal D1 of the detector 30, and a cleaning device 70 that can supply a cleaning solution to the sample storage section 10, 801 to clean the sample storage section 10, 801, and the measurement devices 60a, 60b, 60c detect an intensity I1 of a detection signal D1 detected under condition C1 within a range R1 the step of executing a determination process to determine whether intensity I1 is within range R1 or not; the step of executing a measurement process to perform an analog measurement and measure the concentration of fluorescent substance F in sample S if intensity I1 is within range R1; the step of executing a measurement process to perform a digital measurement and measure the concentration of fluorescent substance F in sample S after it has been determined that intensity I1 is smaller than lower limit L1 of range R1; and the step of controlling the cleaning device 70 so that the sample holding portion 10, 801 is cleaned over a cleaning period Tw1 if analog processing has been executed, and so that the sample holding portion 10, 801 is cleaned over a cleaning period Tw2 if digital processing has been executed.

[0171] According to this method, the determining units 611 and 612 select an appropriate process, either analog or digital, depending on the concentration of the fluorescent substance F. Then, the sample holding unit 10, 801 is cleaned for a cleaning time depending on the process used to measure the concentration. In other words, it is possible to clean the sample holding unit 10, 801 for a cleaning time depending on the concentration of the fluorescent substance F.

[0172] Measurement system 1a, 1b, 1c, 1d Sample storage section 10, 801 Silicon substrate 800 Inlet 802 Outlet 803 Optical waveguide 804 Light source 20 Detector 30 Adjustment device 40 Attenuator 400 Control device 401 Dispensing device 50 Measuring device 60a, 60b, 60c CPU 600 Memory 601 Communication device 602 Storage device 603 Input device 604 Output device 605 Recording medium reading device 606 Determination section 610, 611, 612 Measuring section 613, 614 Control section 615, 616a, 616b, 616c Warning section 617 Cleaning device 70

Claims

1. A measurement system comprising: a light source that irradiates excitation light onto a fluorescent substance in a sample holding unit that holds a sample containing the fluorescent substance; a detector that detects radiation emitted by the fluorescent substance based on the excitation light; a measurement device that measures the concentration of the fluorescent substance based on a detection signal from the detector; and a cleaning device that can supply a cleaning solution to the sample holding unit to clean the sample holding unit, wherein the measurement device comprises: a first determination unit that executes a first determination process to determine whether a first intensity of the detection signal detected under a first condition is within a first range; a first measurement unit that executes a first measurement process to perform an analog measurement and measure the concentration of the fluorescent substance in the sample if the first intensity is within the first range; and a second measurement unit that executes a second measurement process to perform a digital measurement and measure the concentration of the fluorescent substance in the sample after it is determined that the first intensity is smaller than the lower limit of the first range; and when the first measurement process has been executed, the sample holding unit is cleaned for a first cleaning period, a first control unit that controls the cleaning device so that the sample storage unit is cleaned over a second cleaning period when the second measurement process is executed.

2. A measurement system as described in claim 1, wherein the measurement device includes a second determination unit that, when it is determined that the first intensity is smaller than the lower limit of the first range, executes a second determination process to determine whether a second intensity of the detection signal detected under a second condition in which the intensity of the detection signal is greater than the first condition is within a second range, and the second measurement unit performs the digital measurement and executes the second measurement process when it is determined that the second intensity is smaller than the lower limit of the second range.

3. The measurement system according to claim 1, wherein the second cleaning period is shorter than the first cleaning period.

4. A measurement system as claimed in claim 2, comprising an adjustment device located on a path of light traveling from the light source to the detector, for adjusting the intensity of the emitted light, and the measurement device further comprising a second control unit that controls the adjustment device so that the intensity of the detection signal becomes the second intensity when it is determined that the first intensity is smaller than the lower limit of the first range.

5. A measurement system according to claim 4, wherein the adjustment device comprises: an attenuator located between the light source and the detector; and a control device that controls the attenuator so that the intensity of the emitted light passing through the attenuator is changed.

6. A measurement system according to claim 2, wherein the measurement device includes a third control unit that controls the light source so that the intensity of the detection signal becomes the second intensity when it is determined that the first intensity is smaller than the lower limit of the first range.

7. A measurement system according to claim 2, wherein the measurement device includes a fourth control unit that controls the detector so that the intensity of the detection signal becomes the second intensity when it is determined that the first intensity is smaller than the lower limit of the first range.

8. A measurement system according to any one of claims 1 to 7, wherein a first period during which the first determination process is performed is shorter than a second period during which the first measurement process is performed.

9. The measurement system according to claim 8, further comprising a warning unit that issues a warning when it is determined that the first intensity is greater than the upper limit of the first range.

10. A measurement method performed by a measurement system including: a light source that irradiates excitation light onto a fluorescent substance in a sample holding section that holds a sample containing the fluorescent substance; a detector that detects radiation light emitted by the fluorescent substance based on the excitation light; a measurement device that measures the concentration of the fluorescent substance based on a detection signal from the detector; and a cleaning device that can supply a cleaning solution to the sample holding section for cleaning the sample holding section, the method including the steps of: the measurement device performing a first determination process that determines whether a first intensity of the detection signal detected under a first condition is within a first range; performing a first measurement process that performs analog measurement and measures the concentration of the fluorescent substance in the sample if the first intensity is within the first range; and performing a second measurement process that performs digital measurement and measures the concentration of the fluorescent substance in the sample after it is determined that the first intensity is smaller than the lower limit of the first range; and controlling the cleaning device so that the sample holding section is cleaned for a first cleaning period when the first measurement process is performed, and so that the sample holding section is cleaned for a second cleaning period when the second measurement process is performed. Measurement method.

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