Detection device and blood processing system

Abstract

To provide a detection device capable of highly accurately detecting fluorescence generated by applying excitation light to dialysis drainage in a tube, without complicating the device.SOLUTION: A detection device 16 includes an irradiation part 80 for applying excitation light to dialysis drainage containing albumin in the tube 60, and a detection part 81 for detecting fluorescence generated from the dialysis drainage in the tube 60. The tube 60 is shaped into a circular cross section. The irradiation part 80 and the detection part 81 are so disposed that an optical axis L1 of the exciting light emitted by the irradiation part 80 and an optical axis L2 of the fluorescence detected by the detection part 81 are perpendicular to each other. The irradiation part 80 is so disposed that a position P1 at which the optical axis L1 of the exciting light comes into contact with a surface of the tube 60 is shifted from a center O of the tube 60 to a non-detection side S2 opposite to the detection side S1 where the detection part 81 is disposed.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] The present invention relates to a detection device and a blood processing system. [Background technology]

[0002] Hemodialysis and hemodiafiltration, which are currently widely used treatments for patients with kidney failure, are performed by diffusing waste products from the blood that flows into a dialyzer (filter) through the dialysis membrane into fresh dialysate that also flows into the dialyzer, where they are filtered and removed.

[0003] Many patients with renal failure complain of symptoms such as pruritus, irritability, and bone and joint pain. To improve these symptoms, active removal of α1-microglobulin (MG) as an indicator substance is performed. However, active removal of α1-MG inevitably leads to leakage of albumin, which is essential for the body, into the dialysis effluent due to its similar size to α1-MG. While dialysis treatment is performed three times a week, the current standard method for managing albumin is to measure the patient's serum albumin concentration once or twice a month to monitor albumin levels.

[0004] Given the above situation, there is a need in dialysis treatment settings for a means to monitor the albumin concentration in dialysis effluent in real time.

[0005] As a method for measuring the concentration of a target substance such as albumin in a dialysis effluent, Patent Documents 1, 2 and 3 disclose a method in which ultraviolet light is irradiated and the concentration of the target substance is measured from the intensity of fluorescence.

[0006] Patent Document 4 discloses a method for calculating the concentration of a target substance in dialysis effluent by irradiating the sample with ultraviolet light and calculating the concentration of the target substance from the fluorescence intensity, while eliminating the influence of contaminants (such as indoxyl sulfate).

[0007] Furthermore, Patent Document 5 discloses a method for calculating the concentration of a target substance, which involves irradiating linearly polarized light, detecting the intensity of the emitted fluorescence in a first polarization plane, detecting the intensity in a second polarization plane different from the first polarization plane, identifying the anisotropy of the fluorescence, and calculating the concentration based on both the anisotropy and the intensity.

[0008] Furthermore, Patent Document 6 discloses a method for calculating the albumin concentration, in which the absorbance of the dialysis effluent is measured, the albumin is separated from the dialysis effluent using a filter that serves as an albumin separation section, the absorbance of the dialysis effluent is measured, and the albumin concentration is calculated from the change in absorbance before and after passing through the filter. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] European Patent No. 2579910 [Patent Document 2] European Patent No. 2579911 [Patent Document 3] WO2020 / 262534 Specification [Patent Document 4] Special Publication No. 2014-518517 [Patent Document 5] Special Publication No. 2015-521492 [Patent Document 6] Japanese Patent Application Laid-Open No. 2015-146837 Summary of the Invention [Problem to be solved by the invention]

[0010] In a detection device such as a fluorescence spectrophotometer that measures the intensity of fluorescence obtained by irradiating excitation light, the irradiation unit and detection unit should be positioned so that the optical axis of the excitation light irradiated by the irradiation unit and the optical axis of the fluorescence detected by the detection unit are perpendicular to each other, in order to avoid the influence of excitation light, which is more intense than fluorescence.

[0011] Furthermore, when measuring the albumin concentration in dialysis effluent flowing through a tube, if the cross-section of the flow path at the measurement site is square, the structure of the connection site with other dialysis tubing with a circular cross-section becomes more complex than if the cross-section of the flow path is circular. Furthermore, if the cross-section of the flow path is square, in an environment where a liquid containing various substances, such as dialysis effluent, flows over a long period of time, the corner areas where the liquid flows slowly are likely to become dirty, which may affect the measurement results. Furthermore, if the cross-section of the flow path is square, if the internal pressure increases for some reason, the weak corners are likely to break, and leakage of medical waste such as dialysis effluent is undesirable from the perspective of infection prevention.

[0012] Therefore, when measuring the albumin concentration in dialysis effluent, it is desirable to use a tube with a circular cross section. However, if the optical axis of the excitation light from the irradiation unit and the optical axis of the fluorescence from the detection unit are perpendicular to each other as described above and a tube with a circular cross section is used, the excitation light may be reflected from the surface or inner surface of the tube and may enter the fluorescence detected by the detection unit. If the excitation light, which is stronger than the fluorescence, enters the fluorescence, it becomes difficult to detect the fluorescence with high accuracy in the detection unit.

[0013] The present invention has been made in consideration of the above points, and one of its objects is to provide a detection device and a blood processing system that can detect fluorescence generated by irradiating an irradiation object, such as dialysis wastewater in a tube, with excitation light with high accuracy without making the device complicated. [Means for solving the problem]

[0014] After extensive research, the inventors discovered that the above problem could be solved by using a tube with a circular cross section and shifting the optical axis of the excitation light from the irradiation section in a predetermined direction from the center of the tube, and thus completed the present invention.

[0015] That is, the present invention includes the following aspects. (1) A detection device comprising an irradiation unit that irradiates an irradiation object containing a substance to be detected within a tube with excitation light, and a detection unit that detects fluorescence generated from the irradiation object within the tube, wherein the tube has a circular cross-section, the irradiation unit and the detection unit are arranged so that the optical axis of the excitation light irradiated by the irradiation unit and the optical axis of the fluorescence detected by the detection unit are perpendicular to each other, and the irradiation unit is arranged so that the position where the optical axis of the excitation light contacts the surface of the tube is shifted to a second side opposite to the first side on which the detection unit is arranged, with respect to the center of the direction of the optical axis of the fluorescence in the tube. (2) A detection device as described in (1), wherein the position at which the optical axis of the excitation light contacts the surface of the tube is set so that the ratio of the length of the optical path of the excitation light formed inside the tube to the inner diameter of the tube is 0.90≦L / D<1. (3) The detection device according to either (1) or (2), wherein the detection unit is positioned so that the optical axis of the fluorescence passes through the center of the tube. (4) A detection device described in any one of (1) to (3), wherein the irradiation unit is configured to irradiate the excitation light onto the irradiation object from below the tube. (5) The detection device according to any one of (1) to (4), wherein the detection unit is a spectroscope. (6) The detection device according to any one of (1) to (5), wherein the irradiation unit is an LED. (7) A detection device according to any one of (1) to (6), further comprising a concentration calculation unit that calculates the concentration of the target substance based on the detection of fluorescence by the detection unit, wherein the concentration calculation unit calculates the concentration of the target substance using a calibration model, and the calibration model is created by multivariate analysis using the spectrum of the fluorescence. (8) The detection device according to any one of (1) to (7), wherein the object to be irradiated flows continuously through the tube. (9) The detection device according to any one of (1) to (8), wherein the substance to be detected is albumin contained in dialysis effluent. (10) A blood processing system equipped with a detection device according to any one of (1) to (9). [Effects of the Invention]

[0016] According to the present invention, it is possible to provide a detection device and a blood processing system that can detect fluorescence generated by irradiating an object to be irradiated in a tube with excitation light with high accuracy without making the device complicated. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is an explanatory diagram showing an example of the configuration of a dialysis system. [Figure 2] 2 is a schematic diagram showing a cross section of the optical monitor taken along a plane perpendicular to the flow path direction of the tube. FIG. [Figure 3] 1 is a schematic diagram showing a cross section of an optical monitor taken along a plane passing through the center of a tube and extending in the flow path direction. FIG. [Figure 4] 4 is an explanatory diagram showing the positional relationship between the optical axis of excitation light from the irradiation unit, and the optical axes of the tube and fluorescence from the detection unit. FIG. [Figure 5] FIG. 2 is a block diagram showing the configuration of a detection device. [Figure 6] FIG. 10 is a diagram showing an example of a fluorescence spectrum. [Figure 7] FIG. 1 is an explanatory diagram showing an experimental machine used in an experiment of an embodiment. [Figure 8] 10 shows the detection results by the detection unit when the excitation light irradiation position is shifted in a direction closer to the detection unit. [Figure 9] 10 shows the detection results by the detection unit when the excitation light irradiation position is shifted in a direction away from the detection unit. [Figure 10] 10 is a graph showing the actual and estimated albumin concentrations when the excitation light irradiation position is aligned with the apex of the tube. [Figure 11] 10 is a graph showing the actual and estimated albumin concentrations when the excitation light irradiation position is shifted in a direction closer to the detection unit. [Figure 12]10 is a graph showing the actual and estimated albumin concentrations when the excitation light irradiation position is shifted by +1 mm in a direction away from the detection unit. [Figure 13] 10 is a graph showing the actual and estimated albumin concentrations when the excitation light irradiation position is shifted by +2 mm in a direction away from the detection unit. [Figure 14] 10A and 10B are diagrams illustrating the amount of deviation of the excitation light irradiation position relative to the tube and the amount of deviation of the detection unit position in an experiment. [Figure 15] 10 is a graph showing the relationship between the deviation amount of the excitation light irradiation position and RMSE, which was created from experimental results. [Figure 16] 10 is a graph showing the relationship between the amount of deviation of the position of the detection unit and RMSE, created from experimental results. DETAILED DESCRIPTION OF THE INVENTION

[0018] An example of a preferred embodiment of the present invention will be described below with reference to the drawings. Positional relationships such as up, down, left, and right in the drawings are based on the positional relationships shown in the drawings unless otherwise specified. Dimensional ratios in the drawings are not limited to the illustrated ratios. Furthermore, the following embodiment is an example for explaining the present invention, and is not intended to limit the present invention to only this embodiment. Furthermore, various modifications of the present invention are possible without departing from the gist of the present invention.

[0019] <Dialysis system> FIG. 1 is an explanatory diagram showing the outline of the configuration of a dialysis system 1 as a blood processing system equipped with a detection device according to this embodiment.

[0020] The dialysis system 1 includes, for example, a dialyzer 10, a blood circuit 11, a dialysate circuit 12, a drainage circuit 13, a replacement fluid circuit 14, a control device 15, a detection device 16, and the like.

[0021] The dialyzer 10 is, for example, a hollow fiber module incorporating hollow fiber membranes, and is capable of separating unnecessary components from blood. The dialyzer 10 has a cylindrical container 20, inside which a number of hollow fiber membranes 21 are arranged along the longitudinal direction. The hollow fiber membranes 21 are capable of separating unnecessary components from blood. An inlet 22 and an outlet 23 that communicate with the intratubular space (blood side) of the hollow fiber membranes 21 are provided at the top and bottom of the cylindrical container 20, and two inlets 24 and 25 that communicate with the extratubular space (dialysate side) of the hollow fiber membranes 21 are provided on the side of the cylindrical container 20.

[0022] The blood circuit 11 includes, for example, a blood removal line 31 that connects the blood removal section 30 and the dialyzer 10, and a blood return line 33 that connects the dialyzer 10 and the blood return section 32. The blood removal line 31 and the blood return line 33 are mainly composed of soft tubes. The blood removal line 31 is connected to the inlet 22 of the dialyzer 10, and the blood return line 33 is connected to the outlet 23 of the dialyzer 10.

[0023] The blood removal line 31 is provided with, for example, a blood pump 40. Furthermore, a drip chamber 41 is connected to the blood removal line 31. In some cases, the drip chamber 41 is not provided.

[0024] The dialysate circuit 12 is connected from a dialysate supply source (not shown) to an inlet / outlet 25 of the dialyzer 10. The drainage circuit 13 is connected from an inlet / outlet 24 of the dialyzer 10 to a drainage section (not shown). The dialysate circuit 12 and the drainage circuit 13 are provided with a supply / drainage pump (not shown) that supplies dialysate to the dialyzer 10 through the dialysate circuit 12 and drains the dialysate from the dialyzer 10 through the drainage circuit 13.

[0025] The fluid replacement circuit 14 is connected, for example, from the dialysate circuit 12 to the drip chamber 41 (blood circuit 11). If there is no drip chamber 41, the fluid replacement circuit 14 is directly connected to the blood removal line 31. The fluid replacement circuit 14 is provided with a fluid replacement pump 50.

[0026] The flow paths of the blood circuit 11, the dialysate circuit 12, and the replacement fluid circuit 14 are mainly composed of tubes with circular cross sections.

[0027] The control device 15 is, for example, a computer, and can control the operation of the blood pump 40 and the replacement fluid pump 50 by executing a program stored in a storage unit on a CPU, for example, to perform a dialysis process for dialysis treatment. Note that communication between the control device 15 and various devices (blood pump 40, replacement fluid pump 50, detection device 16) may be performed by wire, such as a communication cable, or wirelessly, such as Bluetooth (registered trademark).

[0028] In dialysis treatment, the patient's blood is sent from the blood removal unit 30 to the intraluminal space of the hollow fiber membrane 21 of the dialyzer 10 in the blood circuit 11, passes through the dialyzer 10, and is returned to the patient from the blood return unit 32. At this time, the dialysate is sent to the extraluminal space of the hollow fiber membrane 21 of the dialyzer 10 through the dialysate circuit 12 and then drained through the drainage circuit 13. In the dialyzer 10, mainly unnecessary components in the blood flowing through the intraluminal space of the hollow fiber membrane 21 pass through the hollow fiber membrane 21 and flow into the extraluminal space (dialysate side) and are discharged together with the dialysate. A replacement fluid (dialysate) from the dialysate circuit 12 is supplied to the blood circuit 11 through the replacement fluid circuit 14, and predetermined components are replenished in the blood. Note that there are hemodiafiltration, in which replacement fluid is replenished, and hemodialysis, in which replacement fluid is not replenished.

[0029] <Detection device> The detection device 16 includes an optical monitor 70 that irradiates a dialysis effluent, which is an irradiation object (protein solution) containing albumin as a detection target substance, with excitation light and detects fluorescence emitted from the dialysis effluent, a concentration calculation unit 71 that calculates the concentration of albumin contained in the dialysis effluent based on the fluorescence intensity of multiple wavelengths in a predetermined wavelength range of the fluorescence spectrum acquired by the optical monitor 70 and a predetermined calibration model, and a display unit 72. Note that communication between the optical monitor 70, the concentration calculation unit 71, and the display unit 72 may be performed via a wired connection such as a communication cable, or wirelessly via Bluetooth (registered trademark). The detection device 16 may include a control device 15.

[0030] The optical monitor 70 is provided in the drainage circuit 13. Fig. 2 is a schematic diagram showing a cross section of the tube 60 of the optical monitor 70 cut along a plane perpendicular to the flow path direction X, and Fig. 3 is a schematic diagram showing a cross section of the tube 60 of the optical monitor 70 cut along a plane passing through the center of the tube 60 and along the flow path direction X.

[0031] 2 and 3, the optical monitor 70 includes an irradiation unit 80 that irradiates the dialysis effluent flowing through the tube 60 of the drainage circuit 13 with excitation light, a detection unit 81 that detects fluorescence emitted from the dialysis effluent in the tube 60, and a monitor main body 82. The dialysis effluent is an example of an object to be irradiated, and albumin in the dialysis effluent is an example of a substance to be detected.

[0032] The tube 60 has a cylindrical shape with a circular cross section perpendicular to the flow path direction X. The tube 60 has, for example, an outer diameter of about 10 mm to 40 mm and an inner diameter of about 5 mm to 35 mm. The tube 60 is made of, for example, translucent quartz. The tube 60 may be connected to separate tubes on the upstream and downstream sides of the drainage circuit 13. In this case, the tube 60 may be harder than the separate tubes. The tube 60 may also be integrated with the tubes on the upstream and downstream sides of the drainage circuit 13. The tube 60 may or may not be included in the optical monitor 70.

[0033] The irradiation unit 80 can irradiate the dialysis effluent in the tube 60 with light of a wavelength that excites the fluorescence of albumin. The light source of the irradiation unit 80 is not particularly limited, but may be, for example, a halogen lamp, a xenon lamp, a deuterium lamp, or an LED, with an LED being preferred. The excitation light irradiated from the irradiation unit 80 may have a continuous wavelength, or may have a wavelength of a certain value (e.g., 340 nm).

[0034] The detection unit 81 is, for example, a spectroscope. The detection unit 81 detects fluorescence emitted from the dialysis effluent in the tube 60 to obtain a fluorescence spectrum. The irradiation unit 80 and the detection unit 81 are arranged, for example, in directions perpendicular to each other with respect to the tube 60 of the drainage circuit 13, and the detection unit 81 acquires fluorescence at an angle perpendicular to the excitation light.

[0035] For example, the monitor main body 82 includes a first holding portion 85 that holds the tube 60, a second holding portion 86 that holds the irradiation portion 80, and a conduit portion 87 that collects fluorescence generated from the dialysis effluent in the tube 60 and guides it to the detection portion 81.

[0036] The first holding unit 85 holds the circular tube 60 at multiple locations, for example, three locations. For example, the first holding unit 85 has a first portion 85a that holds the tube 60 at one location and a second portion 85b that holds the tube 60 at two locations. The first portion 85a holds the lower portion of the tube 60 on the side opposite the detection unit 81. The second portion 85b holds the lower and upper portions of the tube 60 on the detection unit 81 side. An opening 85c is formed between the first portion 85a and the second portion 85b, through which the tube 60 is exposed to the outside. The second holding unit 86 holds and fixes the irradiation unit 80 on the first holding unit 85. The irradiation unit 80 is located above the tube 60 and is fixed so that the optical axis L1 of the excitation light faces vertically downward. The vertical relationship between the excitation light (irradiation unit 80) and the tube 60 can be selected as desired. On the other hand, when bubbles pass through the tube 60, the excitation light may be scattered, which may have a negative effect on detection. However, by configuring the irradiation unit 80 to irradiate the excitation light from below the tube 60, the bubbles will move near the wall of the tube 60 on the opposite side to the excitation light (irradiation unit 80), thereby suppressing this effect.

[0037] The conduit 87 has, for example, a cylindrical shape. A first holder 85 is fixed to the tip of the conduit 87. The central axis of the conduit 87 is perpendicular to the optical axis L1 of the excitation light, passes through the center O of the tube 60, and is directed outward in a horizontal direction Y perpendicular to the flow direction X of the tube 60. A condenser lens 88 is disposed inside the conduit 87, which condenses fluorescence generated from the dialysis effluent in the tube 60. A detector 81 is fixed on the central axis of the rear end of the conduit 87. The detector 81 is fixed so that the optical axis L2 of the fluorescence to be detected coincides with the central axis of the conduit 87.

[0038] 2, the irradiation unit 80 and the detection unit 81 are arranged so that the optical axis L1 of the excitation light irradiated by the irradiation unit 80 and the optical axis L2 of the fluorescence detected by the detection unit 81 are perpendicular to each other. The optical axis L1 of the excitation light and the optical axis L2 of the fluorescence are perpendicular to the flow path direction X of the tube 60.

[0039] FIG. 4 is an explanatory diagram showing the positional relationship between the optical axis L1 of the excitation light from the irradiator 80 and the optical axis L2 of the fluorescence from the tube 60 and the detector 81. As shown in FIG. 4 , in a cross section of the tube 60 viewed from the flow path direction X (a longitudinal cross section of the tube 60 cut along a plane perpendicular to the flow path direction X), the irradiator 80 irradiates the excitation light vertically downward. The irradiator 80 is positioned such that a position P1 (excitation light irradiation position) where the optical axis L1 of the excitation light contacts the surface of the tube 60 is shifted from the center O of the tube 60 in the horizontal direction Y (a central axis C passing through the center O and parallel to the optical axis L1) to a second side (non-detection side S2 in FIG. 4 ) opposite the first side where the detector 81 is positioned (detection side S1 in FIG. 4 ). For example, the excitation light irradiation position P1 is shifted a predetermined distance Y1 from the center O of the tube 60 toward the non-detection side S2. For example, if the tube outer diameter is 14 mm and the inner diameter is 11 mm, the predetermined deviation amount Y1 is preferably 0.5 mm or more and 3 mm or less, and more preferably 1 mm or more and 2 mm or less.

[0040] Furthermore, the excitation light irradiation position P1 is set so that the ratio of the length L of the optical path E of the excitation light formed inside the tube 60 to the inner diameter D of the tube 60 is 0.90≦L / D<1. The ratio of the length L of the optical path E of the excitation light inside the tube 60 to the inner diameter D of the tube 60 is preferably 0.950≦L / D≦0.995. The excitation light incident on the tube 60 is refracted at the surface and inner surfaces of the tube 60. For this reason, the optical path E of the excitation light inside the tube 60 may be inclined with respect to the optical axis L1 of the excitation light.

[0041] The detection unit 81 receives the fluorescence from a direction perpendicular to the optical axis L1 of the excitation light in the horizontal direction Y with respect to the tube 60. The detection unit 81 is disposed so that the optical axis L2 of the fluorescence is perpendicular to the optical axis L1 of the excitation light and passes through the center O of the tube 60.

[0042] The concentration calculation unit 71 is a computer. As shown in Fig. 5, the concentration calculation unit 71 includes a concentration calculation unit 90 that calculates the concentration of albumin in the dialysis effluent using information on the fluorescence intensity of multiple wavelengths in a predetermined wavelength range of the fluorescence spectrum acquired by the optical monitor 70 and a calibration model obtained by multivariate analysis, a storage unit 91 that stores the albumin concentration obtained by the concentration calculation unit 90, and a calibration model creation unit 92 that creates a calibration model in advance.

[0043] The calibration model creation unit 92 acquires, for example, from the optical monitor 70, fluorescence spectra of simulated dialysis effluents having known albumin concentrations and different albumin concentrations, and creates a calibration model M in advance by multivariate analysis. The multivariate analysis for creating the calibration model M may be any of partial least squares (PLS) regression analysis, principal component regression analysis, multiple regression analysis, support vector machine regression analysis, and machine learning analysis. The created calibration model M is stored, for example, in the memory unit 91, and used as a parameter in the calculation process in the concentration calculation unit 90. Note that a calibration model M obtained in advance may be stored in the memory unit 91 and used.

[0044] An example of the calibration model M is shown below. The calibration model M can be expressed as an equation for calculating the calculated albumin concentration C by multiplying the fluorescence intensity at each wavelength of the obtained fluorescence spectrum by a coefficient and then summing them. Specifically, the calibration model M is expressed as in equation (1). C=a1×I1+a2×I2++a n ×I n +K···(1) C: calculated albumin concentration, a n : coefficient, I n : Fluorescence intensity, K: Constant, Subscript n: Natural number representing each wavelength at which the fluorescence spectrum was acquired, starting from the shortest (e.g., for wavelengths of 300 nm, 310 nm, 320 nm, . . ., 400 nm, the subscripts would be 1, 2, 3, . . ., 11).

[0045] The concentration calculation unit 90 acquires the fluorescence spectrum of the dialysis effluent from the optical monitor 70 in real time during dialysis treatment, and calculates the albumin concentration from the fluorescence intensity of multiple wavelengths in a predetermined wavelength range of the fluorescence spectrum and a calibration model M created in advance.

[0046] The display unit 72 is, for example, a panel display, and displays the albumin concentration calculated by the concentration calculation unit 90. The control device 15, concentration calculation unit 71, and display unit 72 may be means or functions realized by the same computer.

[0047] Next, an example of the operation of the detection device 16 configured as above will be described.

[0048] During dialysis treatment, the detector 16 continuously or intermittently calculates in real time the albumin concentration in the dialysis effluent in the drainage circuit 13. The dialysis effluent flows continuously at a flow rate of 10 mL / min or more and 1000 mL / min or less.

[0049] Specifically, the irradiating unit 80 of the optical monitor 70 emits excitation light, which is irradiated onto the dialysis effluent in the tube 60. The detecting unit 81 detects the fluorescence emitted from the dialysis effluent in the tube 60.

[0050] At this time, the excitation light irradiation position P1 of the irradiation unit 80 on the tube 60 is shifted by a predetermined amount Y1 from the center O of the tube 60 to the non-detection side S2 opposite the detection unit 81. The detection unit 81 receives fluorescence from a direction perpendicular to the optical axis L1 of the excitation light.

[0051] The excitation light emitted from the irradiation unit 80 includes light with a wavelength between 300 nm and 400 nm, which excites the fluorescence that forms the sub-peak of albumin. Note that the excitation light may also include light with a wavelength between 310 nm and 380 nm, light with a wavelength between 320 nm and 350 nm, light with a wavelength between 330 nm and 350 nm, and light with a wavelength between 340 nm and 350 nm.

[0052] The detection unit 81 detects a fluorescence spectrum as shown in FIG. 6. The fluorescence spectrum detected by the detection unit 81 may be in a range from the lower wavelength limit of the excitation light plus 10 nm to the upper wavelength limit of the excitation light plus 450 nm, or may be in a range from the lower wavelength limit of the excitation light plus 10 nm to the upper wavelength limit of the excitation light plus 400 nm. The wavelength range of the fluorescence detected by the detection unit 81 is, for example, from 310 nm to 850 nm. The detection unit 81 adjusts measurement-related parameters based on the numerical value of the maximum intensity in the wavelength range of 380 nm to 480 nm of the obtained fluorescence spectrum, so that the measurement is within the upper measurement limit of the sensor of the detection unit 81.

[0053] The concentration calculation unit 90 of the concentration calculation unit 71 calculates the albumin concentration contained in the dialysis effluent based on the fluorescence intensity of multiple wavelengths in a predetermined wavelength range of the fluorescence spectrum detected by the detection unit 81 and the calibration model M. The concentration calculation unit 90 calculates the albumin concentration in the dialysis effluent continuously or intermittently in real time during dialysis treatment. The albumin concentration calculated by the concentration calculation unit 90 is stored in the memory unit 91 each time. This albumin concentration is displayed on the display unit 72, for example, in real time.

[0054] The calibration model M is created in advance by the calibration model creation unit 92 before the start of dialysis treatment and stored in the memory unit 91. The calibration model M is created by, for example, acquiring fluorescence spectra of simulated dialysis effluents with different albumin concentrations from the optical monitor 70 and performing multivariate analysis. For example, partial least squares (PLS) regression analysis, principal component regression analysis, multiple regression analysis, support vector machine regression analysis, or machine learning analysis is used for the multivariate analysis.

[0055] According to this embodiment, the detection device 16 includes an irradiation unit 80 that irradiates excitation light onto the dialysis effluent containing albumin in the tube 60, and a detection unit 81 that detects fluorescence emitted from the dialysis effluent in the tube 60, the tube 60 having a circular cross section, the irradiation unit 80 and the detection unit 81 being arranged so that the optical axis L1 of the excitation light and the optical axis L2 of the fluorescence are perpendicular to each other, and the irradiation unit 80 is arranged so that a position P1 at which the optical axis L1 of the excitation light contacts the surface of the tube 60 is shifted to a second side opposite to the first side on which the detection unit 81 is arranged, with respect to the center O of the tube 60 in the direction of the optical axis L2 of the fluorescence. With this detection device 16, the use of the tube 60 having a circular cross section simplifies connection to, for example, other tubes, thereby simplifying the structure of the device. Furthermore, position P1 where optical axis L1 of the excitation light contacts the surface of tube 60 is shifted to the non-detection side S2 opposite detection unit 81 with respect to center O of tube 60, which prevents excitation light from being reflected by the surface or inner surface of tube 60, leaking into the fluorescence, and being detected by detection unit 81. As a result, fluorescence can be detected with high accuracy.

[0056] The position P1 where the optical axis L1 of the excitation light contacts the surface of the tube 60 is set so that the ratio of the length L of the optical path E of the excitation light formed inside the tube 60 to the inner diameter D of the tube 60 is 0.90≦L / D<1. This ensures a sufficient optical path E of the excitation light inside the tube 60, and a sufficient irradiation area of ​​the excitation light on the dialysis effluent. As a result, the intensity of the fluorescence generated from the dialysis effluent is ensured, allowing the detection unit 81 to detect high-intensity fluorescence.

[0057] The detection unit 81 is disposed so that the optical axis L2 of the fluorescence passes through the center O of the tube 60. This allows the detection unit 81 to detect high-intensity fluorescence. Note that the optical axis L2 of the fluorescence may be offset from the center O of the tube 60.

[0058] The dialysis system 1 includes a concentration calculation unit 71 that calculates the concentration of the target substance based on the detection of fluorescence by the detection unit 81, and the concentration calculation unit 71 calculates the albumin concentration using a calibration model M. This allows the albumin concentration to be calculated with high accuracy.

[0059] The object to be irradiated is the dialysis effluent, which flows continuously inside the tube 60. In this case, the intensity of the fluorescence is affected by the flow of the dialysis effluent, but by suppressing leakage of the excitation light into the fluorescence, the fluorescence can be detected with high accuracy. As a result, the concentration of albumin, for example, can also be calculated with high accuracy.

[0060] When used in a medical setting, the detection device 16 installed in the dialysis system 1 is desirably small. For this reason, it is desirable to use an LED as the light source of the irradiation unit 80. However, the wavelength of light emitted by an LED is not uniform, but also includes wavelengths surrounding the peak wavelength. Therefore, when the detection unit 81 detects fluorescence that may include a wavelength range close to the wavelength of the excitation light, leakage of excitation light, which has a higher light intensity than the fluorescence, into the fluorescence can deteriorate the detection accuracy of the detection unit 81. According to the present embodiment, leakage of excitation light into the fluorescence is suppressed, so that the detection device 16 can be downsized by using an LED as the light source of the irradiation unit 80, while still allowing for highly accurate detection of fluorescence.

[0061] While the preferred embodiments of the present invention have been described above with reference to the accompanying drawings, the present invention is not limited to these examples. It is clear that those skilled in the art can conceive of various modifications and alterations within the scope of the ideas described in the claims, and it is understood that these modifications and alterations also fall within the technical scope of the present invention.

[0062] For example, in the above embodiment, the object to be irradiated with excitation light was the dialysis effluent in the drainage circuit 13, but it may also be a liquid flowing through another circuit in the dialysis system 1. The substance to be detected was albumin, but it may also be another substance. While the detection device 16 calculates the concentration of albumin contained in the dialysis effluent, the detection device according to the present invention may calculate the concentration of a substance other than albumin contained in the dialysis effluent, or may calculate the concentration of albumin or another substance contained in an object to be irradiated other than the dialysis effluent. Note that the wavelength of the excitation light that is most suitable may vary depending on the substance, so it is desirable to select an appropriate wavelength.

[0063] Furthermore, the configuration of the dialysis system 1 is not limited to that of performing hemodiafiltration as in the above embodiment. For example, when performing hemodialysis in the dialysis system 1, the fluid replacement pump 50 and fluid replacement circuit 14 do not need to be used. The fluid replacement circuit 14 may be connected to the blood return line 33 instead of the blood removal line 31. Furthermore, the present invention is not limited to dialysis systems and can be applied to blood processing systems that perform other blood processes. For example, the present invention can be applied to blood processing systems that perform plasma exchange therapy, leukopheresis therapy, continuous slow hemofiltration therapy, etc. The present invention can also be applied to systems other than blood processing systems that require fluorescence detection. [Example]

[0064] (Experiment 1) The difference in the amount of excitation light leaking into the detection unit depending on the position of the optical axis of the excitation light irradiating the tube was measured.

[0065] Figure 7 shows the experimental optical monitor (fluorescence spectrophotometer) used in this experiment. The experimental device in Figure 7 has the same basic structure as the optical monitor 70 described above, but furthermore, the optical axis L1 of the excitation light from the irradiation unit 80 can be moved in the horizontal direction Y perpendicular to the flow path direction X of the tube 60. An LED was used as the light source of the excitation light for the irradiation unit 80. A CA12880MA (manufactured by Hamamatsu Photonics KK) was used as the detection unit 81 for acquiring fluorescence. Here, the direction in which the position of the optical axis L1 of the excitation light from the irradiation unit 80, i.e., the position where the optical axis L1 of the excitation light strikes the tube 60 (excitation light irradiation position P1), moves away from the detection unit 81 with respect to the apex (center O) of the tube 60, is defined as a positive direction, and the direction in which it moves closer to the detection unit 81 is defined as a negative direction.

[0066] In addition, the experimental device in Figure 7 has a detachable diaphragm 130 attached to the optical axis L2 of the fluorescence from the detection unit 81. The diaphragm 130 prevents leakage of excitation light into the detection unit 81. The difference between the amount of light received with the diaphragm 130 and the amount of light received without the diaphragm 130 corresponds to the amount of leakage of excitation light into the detection unit 81. A phosphate buffer solution that emits almost no fluorescence was used as the sample to be irradiated inside the tube in order to measure leakage of excitation light. The LED drive current was set to 200 mA and the detector integration time to 0.5 s so that the maximum value of the fluorescence spectrum from 380 nm to 480 nm would be within the upper measurement limit of the detection unit sensor.

[0067] 8 shows the detection results by the detection unit 81 when the excitation light irradiation position P1 is shifted by −2 mm, that is, in the direction closer to the detection unit 81. It can be seen that the amount of received light changes significantly depending on whether or not the diaphragm 130 is present, and that a large amount of light originating from the excitation light is detected by the detection unit 81.

[0068] 9 shows the detection results by the detection unit 81 when the excitation light irradiation position P1 is shifted by +2 mm, that is, in the direction away from the detection unit 81. It can be seen that the amount of received light does not change with or without the diaphragm 130, and almost no light originating from the excitation light is detected by the detection unit 81.

[0069] Since fluorescence is weaker than excitation light, leakage of a large amount of excitation light will affect fluorescence detection. In particular, when an LED is used as the light source for excitation light, LED light has a range of emission wavelengths by nature, and the wavelength difference between the excitation light and fluorescence is not large, so leakage of this light into the detection unit will have a significant effect on fluorescence detection. Based on these results, in order to reduce the effect of excitation light on the detection unit, it is effective to shift the irradiation position of the excitation light away from the detection unit.

[0070] (Experiment 2) This shows an example of calculating the albumin concentration at multiple excitation light irradiation positions P1 using a detection device. The experimental device shown in Figure 7 was used as the optical monitor.

[0071] The components of the simulated dialysis solution used in the experiment are shown in Table 1. Phosphate buffer solution (pH 7.4) was used as the solvent.

[0072] [Table 1]

[0073] The simulated dialysis effluent was passed through a tube at a flow rate of 600 mL / min. The simulated dialysis effluent was irradiated with LED light as excitation light with a peak wavelength of 340 nm (half-width 10 nm) in an optical monitor to obtain a fluorescence spectrum. The LED drive current was set to 200 mA, and the detector integration time was set to 0.5 s so that the maximum value of the fluorescence spectrum from 380 nm to 480 nm was within the upper measurement limit of the sensor in the detection unit. A calibration model was created in advance from the obtained fluorescence spectrum using multivariate analysis. Using the calibration model, albumin concentrations were calculated using the detection device of the present invention using simulated dialysis effluents with known albumin concentrations. The compatibility of the estimated concentrations with the actual concentrations was verified, and the accuracy of the calibration model was also verified.

[0074] The tube used in the detection section is a quartz tube with an inner diameter of 11 mm and an outer diameter of 14 mm.

[0075] The root mean square error (RMSE) obtained from the difference between the actual and estimated concentrations was used as an index of the fit between the estimated and actual concentrations and the accuracy of the calibration model, calculated from the following equation (2). RMSE = {[Σ((Ce i -Ck i )^2)] / n}^0.5 (2) RMSE: root mean square error, Ce: estimated concentration, Ck: actual concentration, subscript i: ith sample, n: number of samples.

[0076] Figure 10 is a graph showing the actual and estimated albumin concentrations when the excitation light irradiation position P1 was set to 0 mm, i.e., aligned with the apex (center O) of the tube. Figure 11 is a graph showing the actual and estimated albumin concentrations when the excitation light irradiation position P1 was shifted to -2 mm, i.e., toward the detection unit. Figures 10 and 11 show that the results when the excitation light irradiation position P1 was set to 0 mm and when it was set to -2 mm were nearly identical, but the RMSE values ​​for both were greater than 1 mg / dL. In Figures 10 to 13, the solid lines in the graphs indicate a perfect match between the actual and estimated concentrations calculated from the model. The plots in the graphs show the relationship between the actual and estimated concentrations calculated from the model for various albumins used in the experiments. Even when the albumin concentration is the same, the estimated concentration varies slightly due to the influence of different concentrations of other substances contained in the albumin.

[0077] Figures 12 and 13 are graphs showing the actual and estimated albumin concentrations when the excitation light irradiation position P1 was shifted +1 mm and +2 mm, respectively, i.e., away from the detection unit. The RMSE value was less than 1 mg / dL, a better value than when the excitation light irradiation position P1 was zero or a negative value. The correlation coefficient R also showed a better value when the excitation light irradiation position P1 was a positive value, i.e., when it was shifted away from the detection unit, than when the excitation light irradiation position P1 was zero or a negative value.

[0078] (Experiment 3) To investigate the effect of excitation light irradiation position P1 in more detail, an optical stage capable of precisely positioning optical components was used to investigate the effect of excitation light irradiation position P1 on albumin detection accuracy, as in Experiment 2. At the same time, the effect of the position of detection unit 81 relative to tube 60 on albumin detection accuracy was also investigated. The simulated dialysis effluent used was that shown in Table 1, but in creating the calibration model used to calculate the albumin concentration, the two concentration combinations A and B shown in Table 2 were used, taking into account the effect of the combination of albumin concentrations in the simulated dialysis effluent used.

[0079] [Table 2]

[0080] The positive and negative relationship indicating the excitation light irradiation position P1 and the position of the detection unit 81 relative to the tube 60 in the experiment is as shown in Figure 14. The amount of deviation of the excitation light irradiation position P1 from the center (O) of the tube 60 is represented by Y1, and the amount of deviation of the detection unit 81 from the center (O) of the tube 60 is represented by Z1.

[0081] FIG. 15 is a graph showing the relationship between the deviation Y1 of the excitation light irradiation position P1 and RMSE, created from experimental results. The deviation Z1 of the position of the detection unit 81 was set to 0 mm. As a result, it was found that the RMSE was smallest when the excitation light irradiation position P1 was +1 mm. According to the results of Experiment 2 shown in FIGS. 10 to 13, the RMSE was smallest when the excitation light irradiation position P1 was +2 mm. Taking into account differences in the samples selected when creating a calibration model for multivariate analysis, it was found that the RMSE was smallest when the excitation light irradiation position P1 was approximately +1 to +2 mm. FIG. 16 is a graph showing the relationship between the deviation Z1 of the position of the detection unit 81 and RMSE, created from experimental results. The deviation Y1 of the excitation light irradiation position P1 was set to +1 mm. It was found that the RMSE was smallest when the detection unit 81 was positioned at 0 mm, that is, when the optical axis L2 of the light receiving unit 81 was positioned so as to pass through the center of the tube 60.

[0082] The length of the optical path formed by the excitation light inside the tube (optical path length inside the tube) was determined by changing the excitation light irradiation position P1. The optical path length inside the tube was determined from the inner and outer diameters of the tube, the refractive index of air, the refractive index of the tube, and the refractive index of the liquid inside the tube.

[0083] Table 3 shows the ratio of the optical path length L in the tube to the inner diameter D of the tube when the shift amount Y1 of the excitation light irradiation position P1 is changed.

[0084] [Table 3]

[0085] Considering the values ​​in Table 3, the results obtained in Experiment 3, and variations in the refractive index of the substance to be detected, as well as errors due to assembly, it is desirable that the excitation light irradiation position P1 be set so that the ratio of the optical path length L within the tube to the tube inner diameter D is 0.90≦L / D<1, and more preferably 0.950≦L / D≦0.995. [Industrial Applicability]

[0086] The present invention is useful in providing a detection device and a blood processing system that can detect fluorescence generated by irradiating an irradiation object in a tube with excitation light with high accuracy without making the device complicated. [Explanation of symbols]

[0087] 1. Dialysis system 16. Detection Device 60 tubes 70 Optical Monitor 71 Concentration calculation section 80 Irradiation unit 81 Detector L1 Optical axis of excitation light L2 Fluorescence optical axis P1 Excitation light irradiation position O center S1 Detection side S2 Non-detection side

Claims

1. an irradiation unit that irradiates an irradiation object containing a detection target substance with excitation light, the irradiation unit being located within the tube; a detection unit that detects fluorescence generated from the irradiation object located within the tube, The tube has a circular cross section, the irradiation unit and the detection unit are arranged such that an optical axis of the excitation light irradiated by the irradiation unit and an optical axis of the fluorescence detected by the detection unit are perpendicular to each other; A detection device in which the irradiation unit is positioned so that the position where the optical axis of the excitation light contacts the surface of the tube is shifted to a second side opposite to the first side on which the detection unit is positioned, with respect to the center of the direction of the optical axis of the fluorescence in the tube.

2. The detection device described in claim 1, wherein the position where the optical axis of the excitation light contacts the surface of the tube is set so that the ratio of the length of the optical path of the excitation light formed inside the tube to the inner diameter of the tube is 0.90≦L / D<1.

3. 3. The detection device according to claim 1, wherein the detection unit is disposed so that an optical axis of the fluorescence passes through a center of the tube.

4. The detection device according to any one of claims 1 to 3, wherein the irradiation unit is configured to irradiate the excitation light onto the irradiation object from below the tube when the tube is positioned so that the flow path direction is horizontal.

5. The detection device according to claim 1 , wherein the detection unit is a spectroscope.

6. The detection device according to claim 1 , wherein the irradiating unit is an LED.

7. a concentration calculation unit that calculates the concentration of the target substance based on the detection of fluorescence by the detection unit; the concentration calculation unit calculates the concentration of the target substance using a calibration model; The detection device according to claim 1 , wherein the calibration model is created by multivariate analysis using a spectrum of the fluorescence.

8. The detection device according to claim 1 , wherein the object to be irradiated flows continuously through the tube.

9. The detection device according to claim 1 , wherein the substance to be detected is albumin contained in dialysis effluent.

10. A blood processing system comprising a detection device according to any one of claims 1 to 9.

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