Patent Application
20220003685
The present disclosure relates to an analyzer that analyzes a specimen and an analysis method for analyzing a specimen.
Typically, in clinical examinations for analyzing protein, sugar, lipid, enzyme, hormone, inorganic ion, disease marker, or the like contained in a biological specimen such as blood or urine, a sample and a reagent are dispensed into a reaction vessel, and analysis for an examination item is made based on a change in optical characteristics such as absorbed light, fluorescent light, emitted light, or scattered light. For example, in an automatic blood analyzer, blood and a reaction reagent are dispensed into a reaction vessel and thoroughly mixed, and measurement of a concentration of an examination item that is a predetermined biological substance such as glucose or cholesterol is performed by measuring absorbance of the solution.
In recent years, as the number of measurement items in clinical examinations has increased, analysis of a small amount of biological specimen with high sensitivity has been required. This is because it is necessary to measure as many analysis items as possible from a limited amount of sample, or analysis items have changed due to the accumulation of knowledge and technological progress, which makes measurement of a trace amount of substance necessary. In response to the need for small-amount and high-sensitive analysis, an amount of a reaction solution to be dispensed into the reaction vessel used in the analyzer is getting smaller.
Typically, an autoanalyzer used in clinical examinations dispenses, while transferring a plurality of reaction vessels one after another, a biological specimen into each reaction vessel, dispenses a reagent, performs stirring on the reaction vessel, performs photometry on the reaction vessel, and then cleans the reaction vessel with a cleaning solution for reuse. After initiating the reaction between the biological specimen and the reagent at a predetermined timing, photometry data such as absorbance is acquired by causing a light source to emit light to and through the reaction vessel, each time the reaction vessel into which the biological specimen and the reagent have been dispensed passes through a photometer until a predetermined timing before cleaning.
Quartz glass or resin, which has low photometry value noise and high optical transparency, is widely used as the material of such reaction vessels. For reaction vessels designed to be repeatedly used, a scratch or foreign matter such as dirt on each reaction vessel is often detected as noise during photometry. To cope with such a situation, typically, a photometry value of an empty reaction vessel or a reaction vessel containing purified water is measured as a baseline, the purified water is removed from the reaction vessel if the purified water exists, a biological specimen and a reagent are dispensed into the same reaction vessel, and then photometry is performed on the reaction vessel.
For example, PTL 1 discloses an autoanalyzer that measures the intensity of light transmitted through a vessel containing purified water and uses the value thus measured as base absorbance (baseline value) for each vessel.
Proposed in PTL 2 is a method for correcting a value that results from measuring, by a photometry sensor, luminous flux transmitted through a reaction vessel containing a liquid in an autoanalyzer capable of measuring optical characteristics of a liquid specimen with high reliability even when a light source that has large output fluctuations is used.
Further, PTL 3 discloses, as a technique for increasing reliability of a measured value through data correction, a method for measuring absorbance A of a reaction liquid based on input light intensity Io measured using a predetermined solution that does not absorb light and transmitted light intensity I measured using a reaction liquid that is kept for a reaction time T after mixing a specimen and a reagent, in which the input light intensity is corrected by Io′=Io*(Ib/Ibo) where Ibo represents light intensity at a portion constant in transmittance that is measured immediately before the Io measurement, and Ib represents light intensity at the portion constant in transmittance that is measured immediately before the I measurement, and the absorbance A of the reaction solution is obtained by A=log(Io′/I).
However, in the optical analysis of a trace amount of reaction solution, when purified water is put into the reaction vessel for measuring the photometry baseline value as in the example in the related art, the purified water cannot be completely removed because the reaction vessel is small in size and thus water remains.
In the method disclosed in PTL 1, when a light source that tends to fluctuate in output for each measurement is used, the base absorbance varies for each vessel, so that it is conceivable that the reliability of the photometry value decreases. Further, in the analyzers disclosed in PTL 2 and 3, there is a possibility that variations in light intensity of the light source increase due to the time difference from the baseline measurement, and the analysis accuracy deteriorates accordingly.
Further, in analysis using a reaction vessel having a small volume of 50 microliters or less, the water residue or photometry time difference as described above has a great impact on analysis accuracy as compared with scratches or molding differences.
The present disclosure therefore provides an analyzer that analyzes a specimen with high accuracy and an analysis method for analyzing a specimen with high accuracy.
The analyzer according to the present disclosure include a first reaction vessel which contains a reagent, a second reaction vessel which contains a specimen and the reagent, a detector which detects optical characteristics of the first reaction vessel and optical characteristics of the second reaction vessel, and a controller which analyzes components of the specimen in the second reaction vessel using the optical characteristics of the first reaction vessel as a baseline.
The other features related to the present disclosure will be apparent from the description herein and the accompanying drawings. Further, aspects of the present disclosure are achieved and practiced by the elements, combinations of various elements, and the following detailed description and appended claims.
It should be understood that the description herein is given by way of typical example only and is not intended to limit the scope of claims set forth in the present application or applications in any sense.
As described above, the structure according to the present disclosure allows the specimen to be analyzed with high accuracy.
Problems, configurations, and effects other than those described above will be apparent from the description of the embodiments given below.
The reaction vessel holder 102 holds a plurality of reaction vessels 103 and is movable in a scanning direction 203 along a plane, for example, with the help of an actuator or the like (not shown). The reaction vessel holder 102 may have a disk shape rotatable about its center axis, which allows the plurality of reaction vessels 103 to be arranged in a circumferential direction of the reaction vessel holder 102, for example.
As a material of the reaction vessels 103, an optically transparent material may be used in a manner that depends on a detection light. Specifically, the material of the reaction vessels 103 is, for example, quartz glass, resin, or the like. When each reaction vessel 103 is made of resin, the plurality of reaction vessels 103 can be integrally molded, which has an advantage in that a molding error among the plurality of reaction vessels 103 is small. Examples of the resin used as the material of the reaction vessels 103 include polystyrene and polymethylmethacrylate.
The sample dispenser 106 includes a sample dispensing nozzle 107, and dispenses a sample (specimen) into the reaction vessels 103. Examples of the sample include a biological specimen such as blood or urine and a solution obtained by subjecting such a biological specimen to a predetermined pretreatment. The reagent dispenser 108 includes a reagent dispensing nozzle 109, and dispenses a reagent into the reaction vessels 103.
The light emitter 104 includes a light source that emits light in a photometry direction 301, that is, toward a side surface of each reaction vessel 103. The light receiver 105 includes a photosensor (not shown) such as a photomultiplier tube or a photodiode, and detects optical characteristics such as light transmitted through, light absorbed by, fluorescent light from, light emitted from, light scattered by each reaction vessel 103 to measure a photometry value. The light receiver 105 outputs the photometry value to the controller 101.
The light emission and light detection are made by the light emitter 104 and the light receiver 105 at a predetermined timing and for a predetermined period of time. For example, a configuration may be employed where the light emitter 104 continuously emits light, and the reaction vessel holder 102 is continuously actuated to cause the light receiver 105 to detect a change in intensity of light between the light emitter 104 and the light receiver 105. This allows photometry to be continuously performed on the reaction vessels 103 passing between the light emitter 104 and the light receiver 105. A configuration may be employed where the reaction vessel holder 102 is stopped after each reaction vessel 103 on which photometry is to be performed is moved to a position between the light emitter 104 and the light receiver 105, and photometry is performed on the reaction vessel 103.
The controller 101 is a computer that performs centralized control of the analyzer 100 to control actuation of the reaction vessel holder 102, the light emitter 104, the light receiver 105, the sample dispenser 106, the reagent dispenser 108, and an imaging unit 110. Further, the controller 101 performs, upon receipt of the photometry value from the light receiver 105, various data manipulations to analyze a concentration, characteristics, or the like of a specific component in the sample.
The light receiver 105 may include the imaging unit 110 capable of capturing an image of the plurality of reaction vessels 103. The light receiver 105 may detect light such as light transmitted through, light absorbed by, fluorescent light from, light emitted from, light scattered by each reaction vessel 103 based on image data captured by the imaging unit 110 to measure the photometry value. Further, the imaging unit 110 may output the image data thus captured to the controller 101 to cause the controller 101 to determine the concentration of the specific component from a color tone of each reaction vessel 103 based on the image data.
For example, a color tone part where a color tone serving as a reference for the optical characteristics of each reaction vessel 103 is shown may be provided at a position, such as in a gap between the plurality of reaction vessels 103 or on the reaction vessel holder 102, where the imaging unit 110 can capture an image of the color tone part, so that the imaging unit 110 captures images of the color tone part together with the plurality of reaction vessels 103. This allows the controller 101 to analyze the specific component by comparing the color tone on the color tone part with the color tone of each reaction vessel 103 in the captured image data.
The analyzer 100 may include a thermoregulation mechanism (not shown) that regulates the temperature of the reaction vessel 103. With thermoregulation mechanism, it is possible to maintain a temperature optimum for the sample that is a biological specimen and, thereby, to increase measurement accuracy.
The analyzer 100 may include a stirring mechanism (not shown) that stirs the solution dispensed into the reaction vessel 103. Note that the solution may be stirred with the sample dispensing nozzle 107 or the reagent dispensing nozzle 109 without providing such a stirring mechanism.
A description will be given below of an example of operation of the controller 101. First, a user causes the reaction vessel holder 102 to hold the reaction vessels 103 before analysis made by the analyzer 100. The controller 101 may actuate a three-axis robot or the like (not shown) capable of moving the reaction vessels 103 to install the reaction vessels 103 into the reaction vessel holder 102.
The controller 101 moves the reaction vessel holder 102 to a predetermined position such that a predetermined reaction vessel 103a (first reaction vessel) is located at a position where the reagent can be dispensed by the reagent dispenser 108 (in a range where the reagent dispenser 108 is movable). The controller 101 actuates the reagent dispenser 108 to dispense a predetermined amount of reagent into the reaction vessel 103a through the reagent dispensing nozzle 109. Note that, when the reagent does not change over time, the reagent may be introduced into the reaction vessel 103 before the reaction vessel 103 is held in the reaction vessel holder 102.
Next, the controller 101 actuates the reaction vessel holder 102 to move the reaction vessel 103a to a position on a line connecting the light emitter 104 and the light receiver 105. Subsequently, the controller 101 actuates the light emitter 104 to emit light to a side surface of the reaction vessel 103a. The light receiver 105 detects light transmitted through or light scattered by the reaction vessel 103a and outputs the result to the controller 101. As will be described later, the photometry value of the reaction vessel 103a into which only the reagent has been dispensed is used as a baseline of the optical characteristics of the specimen.
Next, the controller 101 moves the reaction vessel holder 102 to a predetermined position such that a predetermined reaction vessel 103b (second reaction vessel) is located at a position where the sample can be dispensed by the sample dispenser 106 (in a range where the sample dispensing nozzle 107 is movable). The controller 101 actuates the sample dispenser 106 to dispense a predetermined amount of sample into the reaction vessel 103b through the sample dispensing nozzle 107.
Next, the controller 101 actuates the reagent dispenser 108 to dispense the reagent into the reaction vessel 103b into which the sample has been dispensed to create a reaction solution. The controller 101 stirs the reaction solution in the reaction vessel 103b by, for example, rotating the reagent dispensing nozzle 109 of the reagent dispenser 108 in the reaction vessel 103b. Subsequently, the controller 101 actuates the reaction vessel holder 102 to move the reaction vessel 103b to the position on the line connecting the light emitter 104 and the light receiver 105, and actuates the light emitter 104 to emit light to a side surface of the reaction vessel 103b. The light receiver 105 detects optical characteristics such as absorbance or emission intensity of the reaction vessel 103b and outputs the optical characteristics to the controller 101.
The controller 101 computes a photometry value of the reaction vessel 103b including the sample using the photometry value (reagent blank) of the reaction vessel 103a as the baseline and analyzes a concentration of a specific component in the sample. The controller 101 may display the analysis result on a display (not shown) or store the analysis result in a storage.
Here, the reaction vessel 103b into which the sample is dispensed may be positioned in close proximity to the reaction vessel 103a into which only the reagent is dispensed. The reaction vessels 103a and 103b may be arranged adjacent to each other. For example, in a case where the plurality of reaction vessels 103 are made of resin and integrally molded, if each of the reaction vessels 103 has a small volume, reaction vessels 103 adjacent to each other have almost the same surface scratch or molding difference, so that their respective baseline values of the photometry value are extremely approximate to each other. This allows an increase in analysis accuracy. Note that the small volume corresponds to a solution amount of 50 microliters or less, and more preferably 20 microliters or less.
When the size of the reaction vessel 103 is small, the usage of the reagent becomes the same as or smaller than the usage in the related art, which is economical. When the reaction vessel 103 is disposable, it is conceivable that the number of reaction vessels 103 used in the analyzer 100 according to the present embodiment will increase, but since each of the reaction vessels 103 is small in size, a material cost of the reaction vessels 103 is estimated to be almost the same as the material cost in the related art.
Further, the reaction vessel 103a into which only the reagent is dispensed and the reaction vessel 103b into which the reagent and the specimen are dispensed may be arranged in a range where the imaging unit 110 can capture images of both the reaction vessel 103a and the reaction vessel 103b at the same time. This eliminates a difference in photometry time between the reaction vessels 103a and 103b and, in turn, prevents variations in intensity of light emitted from the light emitter 104, which allows an increase in analysis accuracy.
Each time the light emitter 104 emits light, the controller 101 may stop the actuation of the reaction vessel holder 102, or alternatively the controller 101 may cause the light emitter 104 to emit light while actuating the reaction vessel holder 102.
Such an arrangement of the reaction vessel 103a into which only the reagent is dispensed and the reaction vessel 103b into which the specimen and the reagent are dispensed in the photometry area 302b allows photometry to be performed on the reaction vessels 103a and 103b at the same time. This eliminates a time difference in photometry timing between the reaction vessel 103a serving as the baseline and the reaction vessel 103b containing the specimen, which allows a reduction in influence of fluctuations and variations in output of the light source as well as an increase in analysis accuracy.
Note that the number of the reaction vessels 103 located in the photometry area 302b where the light emitter 104 can emit light is not limited to two and may be any number. Further, a set of the light emitter 104 and the light receiver 105 may be provided for each reaction vessel 103, and as many sets of the light emitters 104 and the light receivers 105 as the number of the reaction vessels 103 on which measurement is performed at the same time may be provided.
When light is emitted to the plurality of reaction vessels 103 at the same time for photometry as in the example shown in
First, the user causes the reaction vessel holder 102 to hold the reaction vessels 103 before analysis made by the analyzer 100 and causes a power source or the like (not shown) to bring the analyzer 100 into operation.
In step S1, the controller 101 verifies that the reaction vessels 103 are installed in the reaction vessel holder 102 and then starts the operation. At this time, the controller 101 stores the number and position of each of the reaction vessels 103 into the storage. Note that the number and position of each of the reaction vessels 103 may be stored in advance.
In step S2, the controller 101 actuates the reaction vessel holder 102 to position an even-numbered reaction vessel 103b in the range where the sample dispenser 106 is movable and then actuates the sample dispenser 106 to dispense a predetermined amount of biological specimen into the even-numbered reaction vessel 103b.
In step S3, the controller 101 actuates the reaction vessel holder 102 to position an odd-numbered reaction vessel 103a in the range where the reagent dispenser 108 is movable and then actuates the reagent dispenser 108 to dispense a predetermined amount of reagent into the odd-numbered reaction vessel 103a.
In step S4, the controller 101 actuates the reaction vessel holder 102 to position the even-numbered reaction vessel 103b in the range where the reagent dispenser 108 is movable and then actuates the reagent dispenser 108 to dispense the predetermined amount of reagent into the even-numbered reaction vessel 103b.
In step S5, the controller 101 actuates the reagent dispenser 108 to perform stirring on the even-numbered reaction vessel 103b to cause the biological specimen and the reagent to react with each other. In this step, the reaction solution may be stirred by being drawn in and out of the reagent dispensing nozzle 109. The reaction solution may be stirred by rotation of the reagent dispensing nozzle 109 in the reaction vessel 103b. Further, a stirring means rather than the reagent dispensing nozzle 109 may be actuated to stir the reaction solution.
In step S6, the controller 101 determines whether stirring on the reaction vessel 103b is sufficient. In this step, the controller 101 may actuate the light emitter 104 and the light receiver 105 to perform photometry on the reaction vessel 103b and determine whether stirring is sufficient based on the photometry value. Further, the controller 101 may actuate the imaging unit 110 to capture the image of the reaction vessel 103b, receive the image data, and determine whether stirring is sufficient based on the color tone of the image data.
When stirring is not sufficient (No), the process returns to step S5, and the controller 101 actuates the reagent dispenser 108 to perform stirring on the reaction vessel 103b again.
When stirring is sufficient (Yes), the process proceeds to step S7, and the controller 101 actuates the light emitter 104 and the light receiver 105. The light emitter 104 emits light to the odd-numbered reaction vessel 103a and the even-numbered reaction vessel 103b at the same time, and the light receiver 105 detects the optical characteristics of these reaction vessels 103a and 103b. The light receiver 105 outputs the detection result to the controller 101.
In step S8, the controller 101 computes, upon receipt of the detection result from the light receiver 105, the photometry value of the even-numbered reaction vessel 103b using the odd-numbered reaction vessel 103a as the baseline.
In step S8, the controller 101 analyzes the concentration of the specific component in the biological specimen based on the photometry value of the even-numbered reaction vessel 103b and brings the operation to an end. At this time, the analysis result may be output to the display (not shown).
In the example described above, the reaction vessel 103a into which only the reagent is dispensed is assigned an odd number, the reaction vessel 103b into which the reagent and the biological specimen are dispensed is assigned an even number, and the reaction vessel 103a and the reaction vessel 103b are arranged adjacent to each other. However, the arrangement of the reaction vessel 103a and the reaction vessel 103b is not limited to the example. For example, the empty reaction vessel 104c may be provided every third reaction vessels.
As described above, in the analyzer and analysis method according to the present embodiment, the first reaction vessel containing only the reagent and the second reaction vessel containing the reagent and the specimen are held in close proximity to each other, the photometry value of the second reaction vessel is obtained using the first reaction vessel as the baseline value, and the components in the biological specimen are analyzed. Such a configuration can almost completely eliminates a time difference in photometry timing between the baseline and the specimen, as compared with a method in the related art in which the baseline is measured with a liquid such as purified water, the liquid is removed, the specimen is dispensed, and then photometry is performed; therefore, the configuration allows a reduction in influence of fluctuations and variations in output of the light source and allows the component concentration in the specimen to be computed with high accuracy.
Further, according to the present embodiment, unlike the method in the related art, neither the specimen nor the reagent is diluted with a residue of the liquid used for the baseline, which makes it possible to suppress variations in the analysis value.
A description will be given below of a comparative example and example according to the present embodiment.
First, 18 reaction vessels 103 were made of resin optically transparent in a visible light wavelength range and were integrally molded to be arranged in a row. The amount of solution to be contained in each reaction vessel 103 was 30 μL, and an optical path length of each reaction vessel 103 was designed to be 2 mm. The reaction vessels 103 are numbered 1 through 18 in the order of arrangement.
In the comparative example 1, in order to measure the baseline value, an orange G aqueous solution obtained by adding a dye (orange G) to purified water was dispensed into each reaction vessel 103, and photometry was performed using the light emitter 104 and the light receiver 105. Then, the orange G aqueous solution was removed from each reaction vessel 103, an absorption solution (sample) to be measured was dispensed, and photometry was performed using the light emitter 104 and the light receiver 105. The photometry was performed by emitting, to each reaction vessel 103, light having a wavelength of 470 nm and light having a wavelength of 600 nm. The controller 101 computed absorbance of the absorption solution for each of the wavelengths of 470 nm and 600 nm of the emitted light using the baseline value based on the orange G aqueous solution and computed a difference in absorbance between the above-described two wavelengths.
In the example 1, reaction vessels 103 numbered 1 through 18 were prepared in the same manner as in the comparative example 1, and a liquid (purified water) used to resemble the reagent was dispensed into odd-numbered reaction vessels 103, and the absorption solution was dispensed into even-numbered reaction vessels 103. The reaction vessel holder 102 was actuated to pass between the light emitter 104 and the light receiver 105 in the order of the reaction vessels 103 numbered 1 through 18, and photometry was continuously performed.
The absorbance of each of the even-numbered reaction vessels 103 was computed using the photometry value of the immediately preceding odd-numbered reaction vessel 103 as the baseline. The above-described photometry was performed for each of the wavelengths of 470 nm and 600 nm of the emitted light to compute a difference in absorbance between the above-described two wavelengths.
As described above, it was found that performing photometry using the photometry value of the adjacent reaction vessel 103 as the baseline reduces the photometry variation as compared with the comparative example 1, and the absorption solution can be analyzed with high accuracy.
The present disclosure is not limited to the above-described embodiments, and various modifications fall within the scope of the present disclosure. For example, the above-described embodiments have been described in detail to facilitate the understanding of the present disclosure, and the present disclosure is not necessarily limited to an embodiment having all the components described above. Further, some components of one embodiment may be replaced with components of another embodiment. Further, the components of one embodiment may additionally include components of another embodiment. Further, it is possible to add, to some components of each embodiment, some components of another embodiment, delete some components of each embodiment, or replace some components of each embodiment with some components of another embodiment.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2018-228229 | Dec 2018 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2019/042733 | 10/31/2019 | WO | 00 |
