JP7814965B2 - Detection device and blood processing system - Google Patents

Description

The present invention relates to a detection device and a blood processing system.

Hemodialysis and hemodiafiltration, which are used to treat patients with kidney failure, are currently widely used treatments. In these treatments, waste products from the blood that flows into the dialyzer (filter) are filtered and removed by diffusing through the dialysis membrane into fresh dialysate that also flows into the dialyzer.

Many patients with renal failure complain of symptoms such as itching, irritability, and bone and joint pain. To alleviate these symptoms, the indicator substance α1-microglobulin (MG) is actively removed. However, the active removal of α1-MG inevitably results in albumin, which is essential for the body, leaking into the dialysis effluent, as albumin is similar in size to α1-MG. While dialysis treatment is performed three times a week, the current common method for managing albumin is to measure the patient's serum albumin concentration once or twice a month to monitor albumin levels.

In light of 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.

Patent documents 1, 2, and 3 disclose methods for measuring the concentration of target substances such as albumin in dialysis effluent, in which ultraviolet light is irradiated and the concentration of the target substance is measured from the fluorescence intensity.

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).

Patent Document 5 also discloses a method for calculating the concentration of a target substance, which involves irradiating the substance with 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.

Furthermore, Patent Document 6 discloses a method for calculating albumin concentration in which the absorbance of dialysis effluent is measured, albumin is separated from the dialysis effluent using a filter that serves as an albumin separator, 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.

European Patent No. 2579910 European Patent No. 2579911 WO2020/262534 specification Special Publication No. 2014-518517 Special Publication No. 2015-521492 Japanese Patent Application Laid-Open No. 2015-146837

In detection devices such as fluorescence spectrophotometers that measure the intensity of fluorescence obtained by irradiating excitation light, it is advisable to position the irradiation unit and detection unit 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.

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 more likely to become dirty, which could affect the measurement results. Furthermore, if the cross-section of the flow path is square, the weak corners are more likely to break if the internal pressure increases for some reason, and the leakage of medical waste such as dialysis effluent is undesirable from the perspective of infection prevention.

Therefore, when measuring the albumin concentration in dialysis effluent, it is desirable to use a tube with a circular cross section. However, as mentioned above, 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 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.

The present invention was made in consideration of these points, and one of its objectives is to provide a detection device and blood processing system that can detect fluorescence generated by irradiating an irradiation target, such as dialysis effluent in a tube, with excitation light with high accuracy without increasing the complexity of the device.

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 unit in a specified direction from the center of the tube, leading to the completion of the present invention.

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, which is located within a tube, with excitation light, and a detection unit that detects fluorescence generated from the irradiation object located within the tube, wherein the tube has a shape with 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 arranged 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 described in 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) A detection device described in any one of (1) to (7), in which the object to be irradiated flows continuously within the tube. (9) A detection device described in any one of (1) to (8), in which the substance to be detected is albumin contained in dialysis effluent.
(10) A blood processing system comprising the detection device according to any one of (1) to (9).

The present invention provides a detection device and blood processing system that can detect fluorescence generated by irradiating an object inside a tube with excitation light with high accuracy without increasing the complexity of the device.

FIG. 1 is an explanatory diagram showing an example of the configuration of a dialysis system. 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. 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. 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. FIG. 2 is a block diagram showing the configuration of a detection device. FIG. 10 is a diagram showing an example of a fluorescence spectrum. FIG. 1 is an explanatory diagram showing an experimental machine used in an experiment of an embodiment. 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. 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. 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. 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. 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. 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. 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. 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. 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.

An example of a preferred embodiment of the present invention will be described below with reference to the drawings. Note that, unless otherwise specified, the positional relationships, such as up, down, left, and right, of the drawings, are based on the positional relationships shown in the drawings. The dimensional ratios of the drawings are not limited to the ratios shown. 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, the present invention can be modified in various ways without departing from the spirit of the invention.

<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.

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, and a detection device 16.

The dialyzer 10 is, for example, a hollow fiber module incorporating hollow fiber membranes, and is capable of separating unwanted components from blood. The dialyzer 10 has a cylindrical container 20, inside which numerous hollow fiber membranes 21 are arranged along the longitudinal direction. The hollow fiber membranes 21 are capable of separating unwanted components from blood. The top and bottom of the cylindrical container 20 are provided with an inlet 22 and an outlet 23 that lead to the intraluminal space (blood side) of the hollow fiber membranes 21, and the side of the cylindrical container 20 is provided with two inlets 24 and 25 that lead to the extraluminal space (dialysis fluid side) of the hollow fiber membranes 21.

The blood circuit 11 includes, for example, a blood removal line 31 connecting the blood removal section 30 and the dialyzer 10, and a blood return line 33 connecting the dialyzer 10 and the blood return section 32. The blood removal line 31 and the blood return line 33 are mainly composed of flexible tubing. 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.

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

The dialysate circuit 12 is connected from a dialysate supply source (not shown) to the inlet/outlet 25 of the dialyzer 10. The drainage circuit 13 is connected from the 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 via the dialysate circuit 12 and drains dialysate from the dialyzer 10 via the drainage circuit 13.

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

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

The control device 15 is, for example, a computer, and can control the operation of the blood pump 40 and the fluid replacement pump 50 and perform dialysis treatment for dialysis therapy by, for example, executing a program stored in the memory unit using a CPU. Communication between the control device 15 and various devices (blood pump 40, fluid replacement pump 50, detection device 16) can be wired, such as via a communication cable, or wirelessly, such as via Bluetooth (registered trademark).

During dialysis treatment, the patient's blood is sent from the blood removal section 30 to the intraluminal space of the hollow fiber membrane 21 of the dialyzer 10 in the blood circuit 11. After passing through the dialyzer 10, the blood is returned to the patient through the blood return section 32. At this time, 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, primarily unwanted components in the blood flowing through the intraluminal space of the hollow fiber membrane 21 pass through the hollow fiber membrane 21 into the extraluminal space (dialysate side) and are discharged along with the dialysate. Replacement fluid (dialysate) from the dialysate circuit 12 is supplied to the blood circuit 11 through the replacement fluid circuit 14, replenishing the blood with specific components. There is hemodiafiltration, in which replacement fluid is replenished, and hemodialysis, in which replacement fluid is not replenished.

<Detection device>
The detection device 16 includes an optical monitor 70 that irradiates a dialysis effluent, which is an irradiation target (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 intensities 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.

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

As shown in Figures 2 and 3, the optical monitor 70 includes an irradiation unit 80 that irradiates excitation light onto the dialysis effluent flowing through the tube 60 of the drainage circuit 13, 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.

The tube 60 has a cylindrical shape with a circular cross section perpendicular to the flow path direction X. The tube 60 has an outer diameter of, for example, approximately 10 mm to 40 mm and an inner diameter of, for example, approximately 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.

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, xenon lamp, deuterium lamp, or LED, with LED being preferred. The excitation light irradiated from the irradiation unit 80 may have a continuous wavelength range, or may have a wavelength of a specific value (e.g., 340 nm).

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

For example, the monitor main body 82 includes a first holder 85 that holds the tube 60, a second holder 86 that holds the irradiation unit 80, and a conduit 87 that collects fluorescence emitted from the dialysis effluent in the tube 60 and guides it to the detection unit 81.

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, exposing the tube 60 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 tube 60 with excitation light from below, the bubbles move near the wall of the tube 60 on the side opposite the excitation light (irradiation unit 80), which can mitigate this effect.

The conduit section 87 has, for example, a cylindrical shape. A first holding section 85 is fixed to the tip of the conduit section 87. The central axis of the conduit section 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 the horizontal direction Y perpendicular to the flow direction X of the tube 60. A focusing lens 88 is disposed inside the conduit section 87, which focuses fluorescence generated from the dialysis effluent in the tube 60. A detection section 81 is fixed on the central axis of the rear end of the conduit section 87. The detection section 81 is fixed so that the optical axis L2 of the fluorescence to be detected coincides with the central axis of the conduit section 87.

As shown in Figure 2, the irradiation unit 80 and the detection unit 81 are arranged so that the optical axis L1 of the excitation light emitted 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 direction X of the tube 60.

Figure 4 is an explanatory diagram showing the positional relationship between the optical axis L1 of the excitation light from the irradiation unit 80 and the optical axis L2 of the fluorescence from the tube 60 and the detection unit 81. As shown in Figure 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 irradiation unit 80 irradiates the excitation light vertically downward. The irradiation unit 80 is positioned so that the position P1 (excitation light irradiation position) where the optical axis L1 of the excitation light contacts the surface of the tube 60 is offset from the center O of the tube 60 in the horizontal direction Y (the central axis C passing through the center O and parallel to the optical axis L1) to the second side (non-detection side S2 in Figure 4 ) opposite the first side (detection side S1 in Figure 4 ) where the detection unit 81 is located. For example, the excitation light irradiation position P1 is offset 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.

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.

The detection unit 81 receives fluorescence from a direction horizontal to the tube 60, Y, perpendicular to the optical axis L1 of the excitation light. The detection unit 81 is positioned 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.

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 memory 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.

The calibration model creation unit 92 acquires, for example, from the optical monitor 70, fluorescence spectra of simulated dialysis effluents with known albumin concentrations and different albumin concentrations, and creates a calibration model M in advance by multivariate analysis. The multivariate analysis used to create the calibration model M may be partial least squares (PLS) regression analysis, principal component regression analysis, multiple regression analysis, support vector machine regression analysis, or 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 previously calculated calibration model M may also be stored in the memory unit 91 and used.

An example of the calibration model M is shown below. The calibration model M can be expressed as an equation for determining 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=a ₁ ×I ₁ +a ₂ ×I ₂ +...+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).

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 pre-created calibration model M.

The display unit 72 is, for example, a panel display, and displays the albumin concentration calculated by the concentration calculation unit 90. Note that the control device 15, concentration calculation unit 71, and display unit 72 may be implemented as means and functions on the same computer.

Next, we will explain an example of the operation of the detection device 16 configured as described above.

The detection device 16 continuously or intermittently calculates the albumin concentration in the dialysis effluent in the drainage circuit 13 in real time during dialysis treatment. The dialysis effluent flows continuously at a flow rate of 10 mL/min or more and 1000 mL/min or less.

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

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.

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. 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.

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 wavelength obtained by adding 10 nm to the lower wavelength limit of the excitation light to the wavelength obtained by adding 450 nm to the upper wavelength limit of the excitation light, or may be in a range from the wavelength obtained by adding 10 nm to the lower wavelength limit of the excitation light to the wavelength obtained by adding 400 nm to the upper wavelength limit of the excitation light. 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 maximum intensity value 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.

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.

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, for example, by acquiring fluorescence spectra of simulated dialysis effluents with different albumin concentrations from the optical monitor 70 and performing multivariate analysis. Multivariate analysis may use, for example, partial least squares (PLS) regression analysis, principal component regression analysis, multiple regression analysis, support vector machine regression analysis, or machine learning analysis.

According to this embodiment, the detection device 16 includes an irradiation unit 80 that irradiates excitation light onto the dialysis effluent containing albumin within the tube 60, and a detection unit 81 that detects fluorescence emitted from the dialysis effluent within the tube 60. The tube 60 has a circular cross-section, and the irradiation unit 80 and detection unit 81 are arranged so that the optical axis L1 of the excitation light and the optical axis L2 of the fluorescence are perpendicular to each other. The irradiation unit 80 is arranged so that the 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 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 a tube 60 with a circular cross-section simplifies connection to, for example, other tubes, thereby simplifying the device structure. Furthermore, because the position P1 where the optical axis L1 of the excitation light contacts the surface of the tube 60 is shifted toward the non-detection side S2 opposite the detection unit 81 with respect to the center O of the tube 60, the excitation light is prevented from reflecting off the surface or inner surface of the tube 60, leaking into the fluorescence, and being detected by the detection unit 81. As a result, the fluorescence can be detected with high accuracy.

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 that the optical path E of the excitation light inside the tube 60 is sufficiently secured, and the area irradiated with the excitation light on the dialysis effluent is sufficiently secured. As a result, the intensity of the fluorescence generated from the dialysis effluent is secured, allowing the detection unit 81 to detect high-intensity fluorescence.

The detection unit 81 is positioned 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.

The dialysis system 1 is equipped with a concentration calculation unit 71 that calculates the concentration of the target substance based on the fluorescence detected by the detection unit 81, and the concentration calculation unit 71 calculates the albumin concentration using a calibration model M. This allows for highly accurate calculation of the albumin concentration.

The object to be irradiated is the dialysis effluent, which flows continuously within 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, for example, the concentration of albumin can also be calculated with high accuracy.

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 single, 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 fluorescence, into the fluorescence can deteriorate the detection accuracy of the detection unit 81. According to this embodiment, leakage of excitation light into fluorescence is suppressed, so by using an LED as the light source of the irradiation unit 80, the detection device 16 can be miniaturized while still allowing for highly accurate detection of fluorescence.

The above describes preferred embodiments of the present invention with reference to the accompanying drawings, but the present invention is not limited to such examples. It is clear that those skilled in the art will be able to conceive of various modifications and alterations within the scope of the ideas set forth in the claims, and it is understood that these also naturally fall within the technical scope of the present invention.

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 of 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.

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, leukocyte removal therapy, continuous slow hemofiltration therapy, etc. The present invention can also be applied to systems other than blood processing systems that require fluorescence detection.

(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.

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 it can also move the optical axis L1 of the excitation light from the irradiation unit 80 in the horizontal direction Y, perpendicular to the flow 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, which acquires the 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 relative 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.

The experimental device in Figure 7 also has a detachable diaphragm 130 attached to the optical axis L2 of the fluorescence from the detection unit 81. The diaphragm 130 prevents excitation light from leaking 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 excitation light leaking 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 the leakage of excitation light. The LED drive current was set to 200 mA and the detector integration time to 0.5 seconds so that the maximum value of the fluorescence spectrum from 380 nm to 480 nm was within the measurement limit of the detection unit sensor.

Figure 8 shows the detection results by the detection unit 81 when the excitation light irradiation position P1 is shifted by -2 mm, i.e., in the direction closer to the detection unit 81. It can be seen that the amount of light received 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.

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

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 excitation light and fluorescence is not large, so leakage of this light into the detection unit will have a significant impact on fluorescence detection. Based on these results, in order to reduce the impact of excitation light on the detection unit, it is effective to shift the irradiation position of the excitation light away from the detection unit.

(Experiment 2)
An example is shown in which the albumin concentration was calculated at a plurality of excitation light irradiation positions P1 using a detection device. The experimental device shown in Figure 7 was used as the optical monitor.

The components of the simulated dialysis fluid used in the experiment are shown in Table 1 below. The solvent used was phosphate buffer (pH 7.4).

The prepared simulated dialysis effluent was passed through a tube at a flow rate of 600 mL/min, and 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 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 detection sensor. A calibration model was created in advance from the obtained fluorescence spectrum using multivariate analysis. From the calibration model, albumin concentrations were calculated using the detection device of the present invention using simulated dialysis effluents with multiple known albumin concentrations, and the compatibility of the estimated concentrations with the actual concentrations was verified, as well as the accuracy of the calibration model.

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.

As an index of the compatibility between the estimated concentration and the actual concentration and the accuracy of the calibration model, the root mean square error (RMSE) obtained from the difference between the actual concentration and the estimated concentration was calculated using the following formula (2) and used.

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.

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 were nearly identical when the excitation light irradiation position P1 was set to 0 mm and -2 mm, but the RMSE values for both were greater than 1 mg/dl. In Figures 10 to 13, the solid lines in the graphs are the lines where the actual concentration and the estimated concentration calculated from the model are in perfect agreement. The plots in the graphs show the relationship between the actual concentration and the estimated concentration calculated from the model for various albumins used in the experiments. Note that even when the albumin concentration is the same, the estimated concentration varies slightly due to the influence of different concentrations of other substances contained.

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 shifted away from the detection unit, than when the excitation light irradiation position P1 was zero or a negative value.

(Experiment 3)
To investigate the effect of excitation light irradiation position P1 in more detail, an optical stage capable of precisely determining the position of optical components was used to investigate the effect of excitation light irradiation position P1 on the accuracy of albumin detection, as in Experiment 2. At the same time, the effect of the position of detection unit 81 relative to tube 60 on the accuracy of albumin detection 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.

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.

Figure 15 is a graph created from experimental results showing the relationship between the deviation Y1 of the excitation light irradiation position P1 and RMSE. 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 Figures 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 the calibration model for multivariate analysis, it was found that the RMSE was smallest when the excitation light irradiation position P1 was around +1 mm to +2 mm, which is preferable. Figure 16 is a graph created from experimental results showing the relationship between the deviation Z1 of the position of the detection unit 81 and RMSE. 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 that it passed through the center of the tube 60.

The length of the optical path formed by the excitation light inside the tube (intratube optical path length) was determined when the excitation light irradiation position P1 was changed. The intratube optical path length 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.

Table 3 summarizes the ratio of the optical path length L within the tube to the tube inner diameter D when the deviation Y1 of the excitation light irradiation position P1 is changed.

Taking into account the values in Table 3, the results obtained in Experiment 3, variations in the refractive index of the substance to be detected, and assembly-related errors, it is recommended 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.

The present invention is useful in providing a detection device and blood processing system that can detect fluorescence generated by irradiating an object inside a tube with excitation light with high accuracy without increasing the complexity of the device.

1 Dialysis system 16 Detector 60 Tube 70 Optical monitor 71 Concentration calculation unit 80 Irradiation unit 81 Detection unit L1 Optical axis of excitation light L2 Optical axis of fluorescence P1 Excitation light irradiation position O Center S1 Detection side S2 Non-detection side

Claims (10)

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. 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. The detection device described in either claim 1 or 2, wherein the detection unit is positioned so that the optical axis of the fluorescence passes through the center of the tube. 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 . The detection device described in any one of claims 1 to 4, wherein the detection unit is a spectroscope. The detection device described in any one of claims 1 to 5, wherein the illumination unit is an LED. 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. The detection device described in any one of claims 1 to 7, wherein the object to be irradiated flows continuously through the tube. The detection device described in any one of claims 1 to 8, wherein the substance to be detected is albumin contained in dialysis effluent. A blood processing system equipped with a detection device according to any one of claims 1 to 9.