WO2022131167A1 - 検体前処理装置の制御方法 - Google Patents
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- WO2022131167A1 WO2022131167A1 PCT/JP2021/045656 JP2021045656W WO2022131167A1 WO 2022131167 A1 WO2022131167 A1 WO 2022131167A1 JP 2021045656 W JP2021045656 W JP 2021045656W WO 2022131167 A1 WO2022131167 A1 WO 2022131167A1
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- G—PHYSICS
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- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
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- G—PHYSICS
- G01—MEASURING; TESTING
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation
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Definitions
- the present invention is a sample pretreatment apparatus for automating a pretreatment step in a sample inspection automation system for the purpose of analyzing the concentration of a predetermined component in a biological sample (hereinafter referred to as a sample) such as blood or urine. Regarding the control method.
- Patent Document 1 describes hemolysis that measures the presence or absence of hemorrhage, milkiness, and jaundice in serum in a sample test automation system having a dispensing device and an automatic analyzer.
- a sample test automation system having a serum and sedation measuring device, characterized in that measurement results of hemolysis, sprouting and sedation and selection of test items for an automated analyzer are described.
- Phosphorlipids contained in biological samples such as serum and plasma cause inhibition of ionization of the target component (hereinafter referred to as ion suppression) in measurement with a liquid chromatograph mass spectrometer (LC / MS), and in particular, phospholipids. It occurs remarkably in a high-lipid-containing sample containing a high value of.
- ion suppression does not occur only in phospholipids, and in an analyzer using the electrospray ionization method (ESI method), the ESI method has the characteristic of preferentially ionizing molecules that are easily ionized.
- the device will be contaminated and the detector of the mass spectrometer will be contaminated, resulting in malfunction or damage to the device. Alternatively, it may accelerate the deterioration of the device.
- the pretreatment step of the injected sample is also very important to prevent contamination of the mass spectrometer and detector.
- the sample pretreatment process for high lipid-containing specimens is important to prevent contamination of columns used in liquid chromatographs (LCs). Injecting a sample containing more lipid than usual may degrade the performance of the column and shorten the life of the column.
- LCs liquid chromatographs
- a cleaning method for removing lipids there are known methods such as using a cleaning process using hydrophobic interaction, but when the polarity of the target component is low, the component to be measured is retained together with the phospholipid. Both are removed by the cleaning process, which can reduce the sensitivity of the object to be measured in mass spectrometry.
- the blood collection tube to which a separating agent, a coagulation promoter, an anticoagulant and the like having various properties are added is transported.
- a separating agent, a coagulation promoter, an anticoagulant and the like having various properties are added is transported.
- those that affect the spectrum of the mass spectrometer and those that may cause ion suppression may be included.
- Patent Document 1 It is described in Patent Document 1 that the sample test automation system does not flag the measurement result or perform the subsequent measurement with an automatic analyzer for the sample in which hemolysis, milkiness, and jaundice in serum are observed. However, interrupting the measurement itself may lead to a delay in reporting the measurement results.
- An object of the present invention is to provide a sample pretreatment device capable of maintaining the measurement accuracy of a mass spectrometer without installing new components and without significantly changing the measurement process of the automatic analyzer. It is to provide a control method.
- the present application includes a plurality of means for solving the above problems, and one example thereof is a sample pretreatment device for performing pretreatment of a sample used in mass analysis, a mass analyzer, and another automated analyzer.
- a control method of the sample pretreatment device of the sample test automation system to which is connected and the serum information is determined by referring to the measurement result or the previous value information of the sample by the other automated analyzer, and the serum information is described.
- the conditions of the washing process for removing impurities contained in the sample during the sample pretreatment are determined, and the washing solution is dispensed into the reaction vessel in which the sample and the reagent are mixed based on the above conditions. And.
- a sample pretreatment device capable of maintaining the measurement accuracy of a mass spectrometer without installing new components and without significantly changing the measurement process of the automatic analyzer.
- a control method can be provided.
- FIG. 1 is a diagram showing an overall configuration of a sample pretreatment device of this embodiment.
- the sample pretreatment device 1 shown in FIG. 1 is a device that reacts a sample with a reagent and performs sample pretreatment using a device for measuring the reaction solution, and is a transfer line 100 and a sample dispensing mechanism 101. , Reagent disk 102, Incubator 103, Magazine 104, Transfer mechanism 105, Reagent dispensing mechanism 106, Magnetic particle stirring mechanism 107, Cleaning unit 110, Cleaning liquid storage 111, Cleaning liquid supply mechanism 112, Cleaning liquid nozzle 113, Chamber 114, Magnetic separator It includes 115, a mixer 116, an elution unit 117, a supernatant separation unit 118, a liquidity adjusting unit 119, a calculation unit 130, a control unit 131, a recording device 132, a display device 133, an input device 134, and an LC transfer 140.
- the transport line 100 is a line for transporting a rack 100B on which a plurality of sample containers 100A containing a sample can be placed to a sample dispensing position or the like.
- the sample dispensing mechanism 101 is a nozzle for sucking the sample contained in the sample container 100A and discharging it to the reaction container 108 on the incubator 103.
- the incubator 103 is a disk for performing the reaction between the sample and the reagent at a constant temperature, and by keeping the temperature at a predetermined temperature by a heater (not shown), the reaction between the sample and the reagent is promoted.
- a plurality of reaction vessels 108 are held in the incubator 103, and serve as a place for mixing and reacting a sample and a reagent.
- the magazine 104 stores the reaction container 108 in which the sample and the reagent separated by the sample dispensing mechanism 101 are put and reacted when the sample is sorted and dispensed.
- the transport mechanism 105 transports the unused reaction vessel 108 held in the magazine 104 to the incubator 103, and transports the used reaction vessel 108 to the reaction vessel disposal unit (not shown).
- the reagent disk 102 is a disk for storing a reagent container 121 for storing magnetic particles and reagents used for sample pretreatment and analysis, and is kept cold in order to suppress deterioration of the reagents.
- the reagent dispensing mechanism 106 is a nozzle for sucking the reagent stored in the reagent container 121 in the reagent disk 102 and discharging it to the reaction container 108.
- the magnetic particle stirring mechanism 107 stirs the magnetic particle solution among the reagents in the reagent disk 102.
- the calculation unit 130 checks and determines the serum information of the sample by referring to the information based on either the measurement result of the sample by another automatic analyzer, the previous value information, or both of them. You may refer to the information stored in the recording device 132.
- the control unit 131 determines the conditions of the cleaning process performed in the cleaning unit 110 based on the determination of the serum information of the sample in the calculation unit 130.
- the control unit 131 determines the conditions of the cleaning process and controls various operations of each unit.
- the control of the operation of each device by the control unit 131 is executed by various programs. This program is stored in a recording device 132 or the like, is read by a CPU, and is executed.
- the operation control process executed by the control unit 131 may be integrated into one program, may be divided into a plurality of programs, or may be a combination thereof. Further, a part or all of the program may be realized by dedicated hardware or may be modularized.
- the recording device 132 records various computer programs for executing control of the operation of each connected device such as a sample preprocessing device and a mass spectrometer, and has various display functions and analysis results by the mass spectrometer. Also recorded. It is composed of a recording medium such as a flash memory or a magnetic disk such as an HDD.
- the recording device 132 records each condition of the cleaning process performed by the cleaning unit, such as the type of cleaning liquid, the mixing ratio of the cleaning liquid, the number of cleanings, and the cleaning temperature, and the cleaning pattern in which each is combined is also recorded.
- the display device 133 is a display device such as a liquid crystal display that displays information related to the analysis result and the progress of the analysis.
- the input device 134 is composed of a keyboard, a mouse, etc. for inputting data.
- the cleaning unit 110 executes a cleaning process in the sample pretreatment for removing impurities in the sample based on the cleaning process determined by the control unit 131.
- the cleaning liquid storage 111 is an area for storing necessary and selectable cleaning liquid, and is connected to the cleaning liquid supply mechanism 112. Based on the conditions determined by the control unit 131, the required cleaning liquid is supplied to the chamber 114 in the required amount by the cleaning liquid supply mechanism 112.
- the cleaning liquid nozzle 113 is provided with two nozzles, a cleaning liquid suction nozzle and a cleaning liquid discharge nozzle (not shown), and it is possible to perform both drainage after cleaning and supply of cleaning liquid.
- the cleaning liquid supplied to the chamber 114 is dispensed into the reaction vessel 108 by the cleaning liquid discharge nozzle.
- the mixer 116 stirs the dispensed cleaning liquid and the sample by a rotary operation. Each unit of the reaction vessel 108 is transferred by the transfer mechanism 105.
- the magnetic separator 115 performs a magnetic separation process on the reaction vessel 108 into which the magnetic particle solution and the cleaning liquid are dispensed.
- the cleaning step performed in the magnetic separator 115 is performed to remove impurities derived from the biological sample remaining in the mixed solution of the sample, the reagent, and the magnetic particles. After a certain period of time has elapsed and after the magnetic separation is completed, drainage after cleaning is performed by the cleaning liquid suction nozzle.
- the organic solvent is discharged to elute the substance to be measured that has been adsorbed on the magnetic particles.
- the separated substance to be measured is dispensed into a new reaction vessel 108 transported by the transport mechanism 105.
- liquid property adjusting unit 119 in order to adjust the liquid property suitable for separation by LC, a diluted solution or the like is adjusted and stirred.
- the LC transfer 140 transfers a sample for which a series of sample pretreatments has been completed to the LC.
- the overall flow of sample pretreatment in the sample pretreatment device 1 of the present embodiment shown in FIG. 1 will be outlined with reference to FIGS. 2 and 3.
- a cleaning process using magnetic particles will be described.
- the user installs necessary assay reagents and consumables such as the reaction vessel 108 on the reagent disk 102 and the magazine 104 in the analyzer, respectively.
- the user puts the rack 100B into the mass spectrometer and the automatic analyzer with the sample such as blood or urine to be analyzed put in the sample container 100A (S1).
- the calculation unit 130 checks whether or not the sample checker module is connected in addition to the sample pretreatment device and the mass spectrometer that perform the pretreatment of the sample used in the mass spectrometry (S2), and the sample checker module is used. If connected, the existing technique detects serum information (S2A).
- the calculation unit 130 checks whether other modules such as an automatic biochemical analyzer, an automatic immunoanalyzer, an electrolyte analyzer, and a sample checker module are connected (S3). If other modules are connected, their existing techniques will detect serum information (S3A).
- the arithmetic unit 130 checks the electronic medical record and recording device, and checks the patient information such as the previous value information and the medical history.
- the calculation unit 130 refers to the information from S2 to S4 or the measurement results of other connection modules, and the sample information is a high-lipid sample or a sample suspected of having a high phospholipid level in other related items, or it affects other measurements. It is determined whether or not there is serum information to be given (S5).
- Serum information transmitted from the calculation unit 130 is transmitted to the control unit 131, and the cleaning conditions are determined in the control unit 131 (S6).
- cleaning is performed using two types of cleaning solutions in sequence.
- the cleaning liquid A uses an aqueous solution and mainly removes coexisting substances such as inorganic salts.
- As the cleaning liquid B a solution containing an organic solvent is used, and coexisting substances such as lipids and proteins are mainly removed. If no abnormalities are found in the normal lipid range and other serum information, for example, 100% acetonitrile and one wash are selected as the wash solution, and the wash conditions are transmitted to the wash unit (S7).
- the transport mechanism 105 transports the unused reaction vessel 108 to the incubator 103.
- the sample is dispensed into the reaction vessel 108 by the sample dispensing mechanism 101.
- the internal standard solution containing the isotope of the measurement target at a predetermined concentration is dispensed.
- the reaction vessel 108 is kept at a constant temperature of 37 ° C. in the incubator 103.
- the reagent dispensing mechanism 106 accesses the reagent disk 102, the assay reagent stored in the reagent container 121 and used for mass spectrometry is dispensed into the reaction vessel 108 on the incubator 103, and the sample and the sample are dispensed.
- the reagent reaction begins.
- reaction vessel 108 After the reaction between the sample and the assay reagent starts, magnetic particles having the antibody bound to the surface are further added to the reaction vessel 108 at a specific timing. Also at this time, the reaction vessel 108 is kept at a constant temperature of 37 ° C. in the incubator 103. The reaction vessel 108 placed in the incubator 103 for a predetermined time is transferred to the cleaning unit 110 by the transfer mechanism 105.
- Cleaning is performed based on the cleaning process determined by the control unit 131 (S9).
- the cleaning liquid matching the cleaning conditions is discharged from the cleaning liquid supply mechanism 112 to the chamber 114.
- the reaction vessel 108 is transported to the mixer 116 by the transport mechanism 105, and the cleaning liquid and the sample are stirred.
- reaction vessel 108 is conveyed to the magnetic separator 115 by the transfer mechanism 105, and the magnetic separation in the reaction vessel 108 is performed. After that, unnecessary cleaning liquid is discharged by the cleaning liquid nozzle 113.
- the reaction vessel 108 is transported to the elution unit 117 by the transfer mechanism 105.
- the eluate using an organic solvent such as acetonitrile is dispensed into the reaction vessel 108 and stirred by the mixer 116. It is eluted at 37 ° C. for a predetermined time, and the substance to be measured that has been bound to the magnetic particles is eluted in the eluate (S10).
- the reaction vessel 108 in which the substance to be measured is eluted in the elution unit 117 is transported to the supernatant separation unit 118 by the transfer mechanism 105.
- the supernatant separation unit 118 the remaining magnetic particles are again aggregated by magnetic separation, and the supernatant is collected during that time (S11).
- a diluted solution for adjusting the supernatant to a liquid property suitable for separation by LC is dispensed (S12).
- the sample subjected to a series of pretreatments is finally transferred to LC by LC transfer 140 (S13).
- LC transfer 140 After separation by LC, it is transferred to the mass spectrometry (MS) module, measured by the detector of the MS module, the concentration of the substance to be measured in the sample is obtained, and the result is displayed on the display device 133 and notified to the user. At the same time, it is recorded in the recording device 132 (S14).
- MS mass spectrometry
- reaction vessel 108 is transported to the reaction vessel disposal section (not shown) by the LC transfer 140 and discarded.
- the calculation unit 130 refers to the information from S2 to S4 or the measurement results of other connection modules, and the sample information is a high-lipid sample or a sample suspected of having a high phospholipid level in other related items, or other. It is determined whether there is any serum information that affects the measurement of (S5). Judgment criteria are stored in the calculation unit, and as an example, according to the guidelines for dyslipidemia, judgment is made by applying the criteria of LDL cholesterol ⁇ 140 mg / dL, HDL cholesterol ⁇ 40 mg / dL, and triglyceride ⁇ 150 mg / dL. Determine if the sample is out of the standard.
- apoprotein (apolipoprotein) AI apo Calculations for test items such as protein (apolipoprotein) A-II, apoprotein (apolipoprotein) B, apoprotein (apolipoprotein) C-II, apoprotein (apolipoprotein) C-III, apoprotein (apolipoprotein) It may be determined whether the measurement result exceeds the reference range in the unit.
- the previous value information of the above-mentioned item may be determined by the calculation unit 130.
- the calculation department determined whether or not there was a history of hyperlipidemia, diabetes, nephrosis syndrome, hypothyroidism, acute pancreatitis, chronic pancreatitis, obesity, Cushing's syndrome, etc. in the past, and there was a corresponding history. In some cases, it is also possible to determine that the high lipid content sample is likely.
- the cleaning solution in the cleaning process is washed in the washing unit with 5% water, 95% acetonitrile, and two washings as an example. Select the conditions and transmit the cleaning conditions to the cleaning unit. If the number of washes is set multiple times, transfer the reaction vessel to another wash unit and repeat the wash process.
- the cleaning process is usually carried out at room temperature, but when a temperature such as 37 ° C. or higher is set, a temperature control mechanism (not shown) is installed in the magnetic separator 115 and the cleaning process is carried out at a specified temperature. be able to.
- This cleaning condition has some patterned combinations in the control unit 131.
- pattern 1 As an example, when sample information of triglyceride of 150 to 200 mg / dL is obtained, pattern 1. As the above-mentioned "water 5%, acetonitrile 95%, washing frequency 2 times" is selected. When the triglyceride content is 200 mg / dL or more, the ratio of the hydrophobic cleaning solution is further reduced. "Water 8%, acetonitrile 92%, washing frequency 2 times, temperature setting 37 ° C.” may be selected.
- the cleaning conditions are displayed in the maintenance item column of the analysis screen of the display device 133, and the user can manually select and set each condition.
- the user can confirm under what conditions the current cleaning process is being carried out. Alternatively, when the user confirms the analysis result, it is possible to add the conditions of the cleaning process performed to the measurement result.
- the washing conditions for the high-lipid sample were described, but in the above pattern, the serum information refers to hemolysis, jaundice, information on the blood collection tube used, etc. in the calculation unit, and the control unit. It is also possible to select a cleaning pattern suitable for each.
- the sample pretreatment device for pretreating the sample used in mass spectrometry other biochemical automatic analyzers, immunological automatic analyzers, electrolyte analyzers, sample checker modules, etc.
- connection module Using the information of the connection module and the measurement results, for high-lipid samples, samples with suspected high phospholipid levels, or samples judged to be serum other than milk such as hemolysis and jaundice, before the sample. It is possible to change the type and ratio of the cleaning liquid used for the cleaning performed in the cleaning unit at the time of processing, the number of cleanings, and the cleaning temperature.
- the sample pretreatment device 1 of the present embodiment described above can identify a high-lipid-containing sample that is likely to be overlooked by automating the sample pretreatment that has been performed by a conventional method by a user. Will be. It is an effective method in the mass spectrometer that can be connected to other biochemical automatic analyzers, immunological automatic analyzers, electrolyte analyzers, sample checker modules, etc. and can use the information of other modules.
- the cleaning process in this embodiment prevents contamination of the sample pretreatment device, LC piping, MS main body, MS detector, etc. with lipids, thereby causing deterioration or malfunction of the device or malfunction of the MS detector. And damage can be prevented.
- the cleaning process in this embodiment prevents contamination of the column used in LC, it can be used without shortening the life as a consumable item.
- connection modules may be connected to each other. Also, the order is not specified.
- the present invention is not limited to the above-described embodiment, but includes various modifications.
- the above-described embodiment has been described in detail in order to explain the present invention in an easy-to-understand manner, and is not necessarily limited to the one including all the described configurations.
- Specimen pretreatment device 100: Transfer line, 100A: Specimen container, 100B: Rack, 101: Specimen dispensing mechanism, 102: Reagent disk, 103: Incubator, 104: Magazine, 105: Transfer mechanism, 106: Reagent component Note mechanism, 107: Magnetic particle stirring mechanism, 108: Reaction vessel, 110: Cleaning unit, 111: Cleaning liquid storage, 112: Cleaning liquid supply mechanism, 113: Cleaning liquid nozzle, 114: Chamber, 115: Magnetic separator, 116: Mixer, 117: Elution unit, 118: Supernatant separation unit, 119: Liquid property adjustment unit, 130: Calculation unit, 131: Control unit, 132: Recording device, 133: Display device, 134: Input device, 140: LC transfer
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Abstract
Description
Claims (5)
- 質量分析で使用する検体の前処理を実施する検体前処理装置と、質量分析装置と、他の自動分析装置とが接続されている検体検査自動化システムの検体前処理装置の制御方法であって、
前記他の自動分析装置による前記検体の測定結果または前回値情報を参照して血清情報を判断し、
前記血清情報に基づいて、検体前処理時に検体に含まれた夾雑物を排除する洗浄プロセスの条件を決定し、
前記検体と試薬を混合する反応容器に、前記条件に基づいて洗浄液を分注する、
検体前処理装置の制御方法。 - 請求項1に記載の検体前処理装置の制御方法であって、
前記他の自動分析装置での検体の測定結果または前記前回値情報を参照し、前記検体が質量分析においてイオン化抑制を生じる可能性のある検体かどうかを判断する、
検体前処理装置の制御方法。 - 請求項2に記載の検体前処理装置の制御方法であって、
前記血清情報に基づいて、前記洗浄液の種類または前記洗浄液の混合比率を変更する、
検体前処理装置の制御方法。 - 請求項3に記載の検体前処理装置の制御方法であって、
前記血清情報に基づいて、前記洗浄プロセスにおける洗浄回数または洗浄温度を変更する、
検体前処理装置の制御方法。 - 請求項1乃至4のいずれか1項に記載の検体前処理装置の制御方法において、
前記反応容器中に磁性粒子を含む試薬を分注し、前記反応容器中の磁性成分と非磁性成分とを分離し、前記洗浄プロセスを実施する、
検体前処理装置の制御方法。
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CN202180080011.3A CN116670514A (zh) | 2020-12-16 | 2021-12-10 | 检体预处理装置的控制方法 |
US18/036,956 US20230417784A1 (en) | 2020-12-16 | 2021-12-10 | Control method of sample pretreatment apparatus |
EP21906529.9A EP4266059A1 (en) | 2020-12-16 | 2021-12-10 | Method for controlling sample pretreatment device |
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Citations (4)
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JPS62146963U (ja) * | 1986-03-11 | 1987-09-17 | ||
WO2013099660A1 (ja) * | 2011-12-26 | 2013-07-04 | 株式会社日立ハイテクノロジーズ | 自動分析装置及び試料分注プローブ洗浄方法 |
WO2016194825A1 (ja) * | 2015-05-29 | 2016-12-08 | シスメックス株式会社 | リポタンパク質のコレステロール取り込み能を測定する方法及び試薬キット |
JP2018109520A (ja) * | 2016-12-28 | 2018-07-12 | シスメックス株式会社 | 分析方法および分析装置 |
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JPS62146963U (ja) * | 1986-03-11 | 1987-09-17 | ||
WO2013099660A1 (ja) * | 2011-12-26 | 2013-07-04 | 株式会社日立ハイテクノロジーズ | 自動分析装置及び試料分注プローブ洗浄方法 |
WO2016194825A1 (ja) * | 2015-05-29 | 2016-12-08 | シスメックス株式会社 | リポタンパク質のコレステロール取り込み能を測定する方法及び試薬キット |
JP2018109520A (ja) * | 2016-12-28 | 2018-07-12 | シスメックス株式会社 | 分析方法および分析装置 |
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