WO2011068049A1 - 血液凝固分析装置 - Google Patents
血液凝固分析装置 Download PDFInfo
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- WO2011068049A1 WO2011068049A1 PCT/JP2010/070741 JP2010070741W WO2011068049A1 WO 2011068049 A1 WO2011068049 A1 WO 2011068049A1 JP 2010070741 W JP2010070741 W JP 2010070741W WO 2011068049 A1 WO2011068049 A1 WO 2011068049A1
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- blood coagulation
- light intensity
- light
- intensity change
- change data
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Classifications
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/47—Scattering, i.e. diffuse reflection
- G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
- G01N21/51—Scattering, i.e. diffuse reflection within a body or fluid inside a container, e.g. in an ampoule
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/47—Scattering, i.e. diffuse reflection
- G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
- G01N21/53—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke
- G01N21/532—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke with measurement of scattering and transmission
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/82—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a precipitate or turbidity
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
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- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
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Definitions
- the present invention relates to a blood coagulation analyzer that mixes plasma and a blood coagulation reagent to precipitate fibrin and measures the blood coagulation time using optical means.
- Such blood coagulation ability includes an endogenous one that stops bleeding in tissue and an extrinsic one that stops bleeding due to trauma or the like.
- the measurement items related to blood coagulation ability include prothrombin time (PT) in the extrinsic blood coagulation reaction test, activated partial thromboplastin time (APTT) in the intrinsic blood coagulation reaction test, and fibrinogen amount (Fbg). Each of these items is based on detecting fibrin precipitated by adding a reagent that initiates coagulation by an optical, physical, or electrical technique.
- the reaction solution is irradiated with light, and the fibrin deposited in the reaction solution is detected by measuring the intensity change over time of scattered light or transmitted light, so that the time when fibrin starts to precipitate can be increased.
- a method of calculating is known.
- Patent Document 2 there is a technique described in Patent Document 2 that measures a plurality of light scattering intensities at different angles with respect to the optical axis of a single laser light source.
- Patent Document 2 the technology described in Patent Document 2 is optimized for antigen-antibody reaction analysis using blood coagulation analysis or latex reagent, etc., and the blood coagulation analysis and antigen-antibody reaction measurement can be performed with a single device.
- the focus is on realization, and no further effects are mentioned.
- the object of the present invention is to secure a dynamic range in blood coagulation analysis by selecting an appropriate detection angle according to the intensity of scattered light for each specimen without complicating the apparatus.
- An object of the present invention is to provide a blood coagulation analyzer that achieves high sensitivity.
- the configuration of the present invention for achieving the above object is as follows.
- a reaction container for mixing and reacting a sample and a reagent, a light source for irradiating the reaction container with light, and a mixture of a sample and a reagent arranged around the reaction container at different angles with respect to the optical axis of the light source
- a plurality of detectors for detecting scattered light emitted from the storage; a storage unit for capturing and storing a plurality of temporal light intensity change signals obtained from the detector; and light intensity change data stored in the storage unit
- a blood coagulation unit comprising: a determination unit that selects light intensity change data to be used for calculating the blood coagulation time based on the light intensity change amount; and a calculation unit that calculates the blood coagulation time from the light intensity change data selected by the determination unit Analysis equipment.
- the difference in blood coagulation ability between samples and the influence of interfering substances can be alleviated to ensure a dynamic range of signal detection, and a larger signal amount can be obtained even for a sample with a small signal amount.
- a blood coagulation analyzer capable of realizing highly sensitive and reproducible analysis can be provided.
- the figure which shows the outline of the blood coagulation analyzer in this invention The figure which shows the flowchart of the blood coagulation analysis in one Example of this invention.
- FIG. 1 shows an outline of a blood coagulation analyzer for carrying out the present invention.
- a sample is dispensed into an optically transparent reaction vessel 101 by a sample dispensing mechanism (not shown), and then a reagent is dispensed into the reaction vessel 101 by a reagent dispensing mechanism (not shown).
- a single wavelength light source 102 (LED, laser, etc.) irradiates light to the mixed solution of the sample and reagent in the reaction vessel 101, and a plurality of detectors 103a to 103 that are prioritized with the scattered light from the mixed solution.
- Light is received by 103b (photodiode, phototransistor, etc.).
- the detectors 103a to 103b are arranged on a horizontal plane including the optical axis of the single wavelength light source 102, and the direction coinciding with the optical axis is 0 °.
- 45 ° with respect to the optical axis means that forward scattered light in the 45 ° direction can be detected.
- the light received by the detectors 103a to 103b is converted into a photocurrent, amplified by the amplification unit 104, converted from an analog signal to a digital signal by the A / D conversion unit 105, and passed through the determination unit 106 over time.
- the light intensity fluctuation data is stored in the storage unit 107.
- the determination unit 106 For the stored light intensity fluctuation data from the detectors 103a to 103b, according to a determination procedure to be described later, which light intensity fluctuation data from the detectors 103a to 103b is used by the determination unit 106 to calculate the blood coagulation time.
- the selected light intensity variation data is transmitted to the calculation unit 108 as determined.
- the calculation unit 108 calculates the blood coagulation time from the light intensity fluctuation data, and the result is transmitted to the control unit 109, and the control unit 109 outputs the result to the output unit 110.
- the blood coagulation time is calculated by a method in which the time until the light intensity fluctuation data reaches a certain amount is set as the coagulation time, and the differential value of the light intensity fluctuation data that changes with time by differentiating the light intensity fluctuation data is There are known a method in which the time at which the maximum time is reached is used as the blood coagulation time, and a method in which the time until the time corresponding to 1 / N of the time at which the differential value of the light intensity fluctuation data is maximum is used as the coagulation time. In either case, the coagulation time is calculated by capturing the change in light intensity, and the absolute amount of light intensity does not directly affect the coagulation time.
- the blood coagulation time is assumed to be practically the same as long as the light intensity fluctuation data is obtained appropriately. Can be handled.
- FIG. 2 shows a flowchart of blood coagulation analysis in this example.
- the two-direction detectors 103a and 103b will be described.
- the first detector with a high priority is the detector 103a with a 90 ° direction with respect to the optical axis
- the second detector with a low priority Is set to a detector 103b in the direction of 45 ° with respect to the optical axis.
- the signal of the first detector having the higher priority is (1) the signal is more stable (less noise) and (2) the signal base level is lower than the signal of the second detector having the lower priority. It is set according to the judgment standard (reagent blank signal level is low).
- the reaction vessel 101 into which the sample and the reagent are dispensed is irradiated with light from the light source 102 having a single wavelength, and the scattered light emitted from the mixed solution of the sample and the reagent is caused by the first detector 103a and the second detector 103b.
- Light is received, converted into photocurrent, and sent to the amplifying unit 104.
- the photocurrent is amplified by the amplification unit 104, converted into a digital signal by the A / D conversion unit 105, and stored in the storage unit 107 via the determination unit 106 as scattered light intensity fluctuation data.
- the determination unit 106 transmits the signal from the first detector 103a and the second detector 103b to the storage unit 107 while confirming that the signal is not more than the set signal strength upper limit value Smax.
- the reaction saturates after detecting the start of fibrin deposition, and the blood coagulation reaction ends when the signal from any detector falls below a preset signal change rate ⁇ Sfin for a predetermined time (for example, 10 seconds) Then, the scattered light measurement is finished.
- the determination unit 106 checks whether the signal change amount from the signal base level of the signal from the first detector 103a is greater than or equal to a preset minimum signal intensity change amount ⁇ Smin. When it is equal to or greater than the minimum signal intensity change amount ⁇ Smin, the scattered light intensity fluctuation data is transmitted to the calculation unit 108 to calculate the blood coagulation time. Further, when the signal from the first detector 103a is equal to or less than the minimum signal intensity change amount ⁇ Smin, the process proceeds to checking the signal of the second detector.
- the scattered light intensity fluctuation data is transmitted to the calculation unit 108, and the blood coagulation time is calculated.
- the determination unit 106 transmits a non-measurable flag to the control unit 109.
- the blood coagulation time, the dilution retest request flag, and the measurement impossible flag are transmitted from the control unit 109 to the output unit 110 and output.
- FIG. 3 shows light intensity fluctuation data obtained by measuring the prothrombin time of a specimen having a standard level of clotting ability actually obtained.
- the signal of the second detector 103b exceeds the signal intensity upper limit value Smax, it can be seen that the signal of the first detector 103a has a margin for an increase in the signal base level due to interference substances such as chyle.
- the dynamic range of signal detection can be secured by using the signal of the first detector 103a for measurement.
- FIG. 4 shows light intensity fluctuation data of prothrombin time measurement of a sample obtained by diluting a specimen having a standard level of clotting ability by 16 times.
- the signal intensity change amount of the first detector 103a is small and it is difficult to calculate the blood coagulation time
- the signal intensity of the second detector 103b is about twice that of the first detector 103a, and the calculation of the blood coagulation time is easy. It can be seen that it is.
- the optical path of the first detector having a high priority is obstructed by bubbles generated by the ejection of the reagent, or a signal cannot be normally obtained due to the influence of electrical noise or the like, and the blood coagulation time
- the blood clotting time may be calculated using the signal from the second detector.
- FIG. 5 shows another embodiment of the present invention.
- a plurality of single wavelength light sources 502a to 502b which are given priorities in advance, are arranged around the reaction vessel 101, and each single wavelength light source flashes alternately at a sufficiently short flashing interval (for example, 100 ms).
- the single wavelength light sources 502a to 502b are arranged on a horizontal plane including the optical axis, and the direction connecting the detector 503 and the center of the reaction vessel 101 is set to 0 °.
- the forward scattered light in the 45 ° direction can be detected by the scattered light from the single wavelength light source 502b in the 45 ° direction.
- the scattered light from the single-wavelength light sources 502a to 502b flashing alternately is received by the single detector 503, and the received light is converted into a photocurrent, amplified by the amplifier 104, and A / D converted.
- An analog signal is converted into a digital signal by the unit 105, and is stored in the storage unit 107 through the determination unit 106 as temporal light intensity fluctuation data.
- FIG. 6 shows a schematic diagram of the light intensity fluctuation data in this example.
- the stored light intensity variation data is divided into signals for each light source by the determination unit 106, and the light intensity variation data by any light source is calculated by the determination unit 106 according to the same determination procedure as in the above embodiment.
- the selected light intensity fluctuation data is transmitted to the calculation unit 108.
- the calculation unit calculates the blood coagulation time from the light intensity fluctuation data, the result is transmitted to the control unit 109, and the control unit 109 outputs the result to the output unit 110.
- a single wavelength light source by selecting an appropriate wavelength from 320 nm to 1000 nm.
- a wavelength of 600 nm to 1000 nm may be selected. It is known that when the size of particles to be detected is equal to the number density of particles, the shorter the light source wavelength, the easier it is to scatter.
- 502a as the long wavelength light source
- 502b as the short wavelength light source
- short-wave light source 502a and the long-wave light source 502b are used to compensate for each weak point.
- first light source and the second light source by using a single light source in the embodiment shown in FIG.
- the detector and the light source are arranged in the horizontal direction, but can be arranged in the vertical direction.
- Example is related with the blood coagulation analyzer, it is applicable also to antigen antibody reaction analysis, such as a latex agglutination method and an immunoturbidimetric method.
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Abstract
Description
たとえば特許文献1記載の技術によると、複数の波長の光を照射し、被測定検体に応じ干渉物質の影響の少ない波長のデータを選択して凝固時間の算出に用いる技術が開示されている。
応が終了したとして、散乱光測定を終了する。このとき、測定終了までに第1検出器103aおよび第2検出器103bからの信号が、ともに信号強度上限値Smaxを予め設定された一定時間(例えば3秒間)連続で超えたことを判断部106が検出した場合、即時、測定を終了し、制御部109に希釈再検依頼のフラグを送信する。
102…単一波長光源
103a~103b…検出器
104…増幅部
105…A/D変換部
106…判断部
107…記憶部
108…演算部
109…制御部
110…出力部
502a~502b…単一波長光源
503…検出器
Claims (11)
- 試料と試薬を混合し反応させるための反応容器(101)と、前記反応容器(101)に光を照射するための単一波長の光源(102)と、前記反応容器(101)周辺に前記光源(102)の光軸に対し異なる角度で配置され試料と試薬の混合液から発せられる散乱光を検出する複数の検出器(103a、103b)と、前記検出器(103a、103b)から得られる複数の経時的な光強度変化データを取り込み記憶する記憶部(107)と、前記記憶部(107)に保管された各々の光強度変化データから光強度変化量に基づき血液凝固時間の算出に用いる光強度変化データを選択する判断部(106)と、前記判断部(106)により選択された光強度変化データから血液凝固時間を算出する演算部(108)を備えた血液凝固分析装置において、
前記検出器(103a、103b)に予め優先順位が設定されており、前記検出器(103a、103b)で優先順位の高い検出器(103a、103b)からの光強度変化データの変化量が予め設定された閾値以下の場合、次の優先順位の検出器(103a、103b)からの光強度データを血液凝固時間の算出に用いることを特徴とする血液凝固分析装置。 - 請求項1記載の血液凝固分析装置において、
前記検出器(103a、103b)で優先順位の高い検出器からの光強度変化データがノイズ等の影響で血液凝固時間の算出が困難な場合に、次の優先順位の検出器からのデータを血液凝固時間の算出に用いることを特徴とする血液凝固分析装置。 - 試料と試薬を混合し反応させるための反応容器(101)と、前記反応容器(101)に光を照射するための互いに異なる角度で配置される複数の単一波長の点滅光源(502a、502b)と、前記反応容器(101)周辺に配置され試料と試薬の混合液から発せられる散乱光を検出する単一の検出器(503)と、前記検出器(503)から得られる経時的な光強度変化データを取り込み記憶する記憶部(107)と、前記記憶部(107)に保管された光強度変化データから血液凝固時間を算出する演算部(108)を備えた血液凝固分析装置において、
前記複数の点滅光源(502a、502b)が互いに発光タイミングが重ならないように点滅することを特徴とする血液凝固分析装置。 - 請求項3記載の血液凝固分析装置において、
前記記憶部(107)に保管された光強度変化データから前記点滅光源(502a、502b)ごとのデータを分離し、光強度変化量に基づき血液凝固時間の算出に用いる光強度変化データを選択する判断部(106)を備えることを特徴とする血液凝固分析装置。 - 請求項4記載の血液凝固分析装置において、
前記点滅光源(502a、502b)に予め優先順位が設定されており、優先順位の高い点滅光源(502a、502b)の光強度変化データの変化量が予め設定された閾値以下の場合、次の優先順位の点滅光源(502a、502b)の光強度データを血液凝固時間の算出に用いることを特徴とする血液凝固分析装置。 - 請求項5記載の血液凝固分析装置において、
前記優先順位の高い点滅光源(502a、502b)の波長が、前記次の優先順位の点滅光源(502a、502b)の波長より長波長であることを特徴とする血液凝固分析装置。 - 請求項5記載の血液凝固分析装置において、
前記優先順位の高い点滅光源(502a、502b)の波長が、前記次の優先順位の点滅光源(502a、502b)の波長より短波長であることを特徴とする血液凝固分析装置。 - 請求項5記載の血液凝固分析装置において、
前記点滅光源(502a、502b)で優先順位の高い点滅光源(502a、502b)の光強度変化データがノイズ等の影響で血液凝固時間の算出が困難な場合に、次の優先順位の検出器からのデータを血液凝固時間の算出に用いることを特徴とする血液凝固分析装置。 - 請求項6記載の血液凝固分析装置において、
前記点滅光源(502a、502b)で優先順位の高い点滅光源(502a、502b)の光強度変化データがノイズ等の影響で血液凝固時間の算出が困難な場合に、次の優先順位の検出器からのデータを血液凝固時間の算出に用いることを特徴とする血液凝固分析装置。 - 請求項7記載の血液凝固分析装置において、
前記点滅光源(502a、502b)で優先順位の高い点滅光源(502a、502b)の光強度変化データがノイズ等の影響で血液凝固時間の算出が困難な場合に、次の優先順位の検出器からのデータを血液凝固時間の算出に用いることを特徴とする血液凝固分析装置。 - 試料と試薬の混合液を反応させる反応容器(101)と、前記反応容器(101)に単一波長光を照射する光源(102)と、照射した前記反応容器(101)から散乱する散乱光を検出する検出器(103a、103b)とを備え、前記検出器(103a、103b)により検出される経時的な光強度変化データより血液凝固時間を算出する血液凝固分析装置において、
前記検出器(103a、103b)を前記光源(102)の光軸に対し異なる角度で複数配置して複数の光強度変化データを取得し、前記複数の光強度変化データより血液凝固分析におけるダイナミックレンジ確保と高感度化に適する方を択一することを特徴とする血液凝固分析装置。
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