US20030223472A1 - Clinical tester wash and method - Google Patents

Clinical tester wash and method Download PDF

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Publication number
US20030223472A1
US20030223472A1 US10/158,495 US15849502A US2003223472A1 US 20030223472 A1 US20030223472 A1 US 20030223472A1 US 15849502 A US15849502 A US 15849502A US 2003223472 A1 US2003223472 A1 US 2003223472A1
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US
United States
Prior art keywords
probe
wash
sample
fluid
predetermined period
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/158,495
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English (en)
Inventor
Patricia Ravalico
Charlie Wilson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to US10/158,495 priority Critical patent/US20030223472A1/en
Assigned to ABBOTT LABORATORIES reassignment ABBOTT LABORATORIES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RAVALICO, PATRICIA H., WILSON, III, CHARLIE W.
Priority to PCT/US2003/016872 priority patent/WO2003102597A2/fr
Priority to EP12150274.4A priority patent/EP2463663A3/fr
Priority to CA2486264A priority patent/CA2486264C/fr
Priority to JP2004514403A priority patent/JP2005527839A/ja
Priority to EP03756244A priority patent/EP1518125A2/fr
Publication of US20030223472A1 publication Critical patent/US20030223472A1/en
Priority to US12/714,601 priority patent/US8759106B2/en
Priority to JP2010046040A priority patent/JP5437115B2/ja
Priority to US14/306,961 priority patent/US9308560B2/en
Priority to US15/095,893 priority patent/US20160223575A1/en
Abandoned legal-status Critical Current

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1004Cleaning sample transfer devices
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B08CLEANING
    • B08BCLEANING IN GENERAL; PREVENTION OF FOULING IN GENERAL
    • B08B3/00Cleaning by methods involving the use or presence of liquid or steam
    • B08B3/04Cleaning involving contact with liquid
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016Control of the volume dispensed or introduced
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B08CLEANING
    • B08BCLEANING IN GENERAL; PREVENTION OF FOULING IN GENERAL
    • B08B3/00Cleaning by methods involving the use or presence of liquid or steam
    • B08B3/02Cleaning by the force of jets or sprays
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178Special arrangements of analysers
    • G01N2035/00277Special precautions to avoid contamination (e.g. enclosures, glove- boxes, sealed sample carriers, disposal of contaminated material)
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1004Cleaning sample transfer devices
    • G01N2035/1006Rinsing only the inside of the tip
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/11Automated chemical analysis
    • Y10T436/113332Automated chemical analysis with conveyance of sample along a test line in a container or rack
    • Y10T436/114998Automated chemical analysis with conveyance of sample along a test line in a container or rack with treatment or replacement of aspirator element [e.g., cleaning, etc.]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/11Automated chemical analysis
    • Y10T436/115831Condition or time responsive
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/12Condition responsive control

Definitions

  • the present invention relates generally to clinical test equipment and in particular the present invention relates to reduction of sample carryover in clinical test equipment.
  • analysis of a test sample involves the reaction of test samples with one or more reagents with respect to one or more analytes wherein it is frequently desired that the analysis be performed on a selective basis with respect to each test sample.
  • Automated clinical analysis systems analyze a test sample for one or more characteristics. Automated clinical analyzers also provide results much more rapidly while frequently avoiding operator or technician error, thus placing emphasis on accuracy and repeatability of a variety of tests. Automated clinical analyzers presently available for routine laboratory tests include a transport or conveyor system designed to transport containers of sample liquids between various operating stations.
  • a robotic arm automatically processes the test samples with a probe and a carousel, or robotic track, that positions the samples for processing.
  • a typical tester has a sample probe arm to sample fluids and deposit the samples in a reaction vessel.
  • One or more reagents are added to the vessel using reagent probe arms.
  • the sample and reagent probe arms include a probe that can be moved between sample or reagent locations, the reagent vessel and wash stations.
  • Clinical chemistry and immunoassay testers have traditionally been standalone systems. These systems can be combined using a common transport system to provide a more efficient integrated system.
  • Previous standalone chemistry analyzers did not require sample-to-sample carryover performance requirements of an integrated clinical chemistry and immunoassay system. As laboratories integrate automated analytical systems, between-sample carryover becomes a critical goal. Many companies have elected to overcome this problem through use of disposable probe tips, but this approach is costly, wasteful and less reliable.
  • Another safeguard is to prioritize test sequencing such that immunoassay sampling is done prior to all chemistry tests. This approach impacts chemistry turnaround time and lowers total workflow throughput.
  • Yet another method to reduce sample carryover is to flush the system with large amounts of fluids (buffer, water, detergents).
  • a fluid tester comprises a probe having an interior region and an exterior surface. The probe is used to selectively aspirate a fluid into the interior region.
  • a first wash mechanism is coupled to the probe to dispense a wash fluid through the interior region of the probe for a first predetermined period.
  • a second wash mechanism is located to dispense the wash fluid on the exterior surface of the probe for a second predetermined period. The second predetermined period extends beyond the first predetermined period.
  • a method of cleaning a probe comprises flushing an interior region of the probe with a wash fluid for X seconds, and simultaneously flushing an exterior surface of the probe with the wash fluid for Y seconds, wherein Y is greater than X.
  • a method of sample carryover in an integrated chemistry and immunoassay analyzer comprises aspirating a first test sample from a first sample container using a probe, depositing the first test sample into a reaction vessel and performing a chemical analysis of the test sample.
  • the probe is washed by pumping a wash fluid through an interior region of the probe and pumping the wash fluid on the exterior of the probe. The pumping of the wash fluid is terminated from the interior region prior to terminating the pumping of the exterior.
  • a second test sample is then aspirated from a second sample container using the probe.
  • FIG. 1A is a perspective view of a clinical tester of an embodiment of the present invention.
  • FIG. 1B is a clinical chemistry analyzer of the tester of FIG. 1A;
  • FIG. 1C is an immunoassay analyzer of the tester of FIG. 1A;
  • FIG. 2 illustrates a probe arm of the clinical tester of FIG. 1
  • FIG. 3 is a simplified cross-section of a probe in a wash station.
  • test sample refers to a test material that can be used directly as obtained from a source or following a pretreatment to modify the character of the sample.
  • the test sample can be derived from any biological source, such as physiological fluid, including, whole blood, serum, plasma, saliva, ocular lens fluid, cerebral spinal fluid, sweat, urine, milk, ascites fluid, raucous, synovial fluid, peritoneal fluid, amniotic fluid or the like.
  • Carryover refers to cross-contamination or contact transfer between test samples. Carryover is a byproduct of using a common sample probe for multiple test samples.
  • HbsAg hepatitis surface-antigen
  • a probe wash protocol of an embodiment of the invention passes the between-sample carryover limit of 0.1 ppm without sample pre-aliquoting, use of additional consumables, test prioritization, or significant impact to system specimen throughput.
  • Critical variables include clinical chemistry sampling/aspiration volumes and external sample probe wash duration, sequencing relative to the internal sample probe wash. Other variables include positioning of the sample probe within the sample wash cup, sample wash cup design and external sample wash flow volumes/rates.
  • An embodiment of a wash protocol dictates the between sample wash mechanism based on clinical chemistry sampling volume.
  • the wash includes an external wash and an internal wash of the sample probe. All specimens with a maximum chemistry sampling volume below a predetermined threshold (such as 15 ⁇ L or less) are effectively washed using an extended single cycle wash mechanism. It is noted that a ‘dummy’ fluid volume may be aspirated in addition to the fluid sample volume. The dummy volume provides a buffer between the sample fluid and residual fluid in the probe. The dummy volume is not included in the sample volume levels described herein.
  • the extended single cycle wash mechanism utilizes a one second external probe wash that ends 100 ms after the internal probe wash. This timing relationship between the internal and external wash sequencing is particularly crucial for acceptable carryover performance.
  • Specimens that are processed with chemistry sampling volumes exceeding the threshold (15.1 ⁇ L or more) are washed using the same extended single cycle wash mechanism but also undergo an additional 3.2 seconds of supplemental external wash.
  • the wash protocol of the present invention is not limited to a specific timing duration or over-lap time between the termination of internal and external washes.
  • the magnitude of the failure was calculated by converting the reported concentration of the serum diluents into units of ppm from the reference dilution. Test conditions were created to represent worst-case performance and test result confidence.
  • the clinical chemistry sample volume was defined at 35 ⁇ L, a typical maximum sample volume for a chemistry application. HbsAg samples were processed in duplicate to ensure result integrity.
  • Results demonstrated a sample carryover performance trend associated with sample probe aspiration volume. As the clinical chemistry sample volume increases, between-sample carryover failures also increase. Most systems fail between-sample carryover with a frequency higher than 50% (without optimization critical parameters) at the maximum clinical chemistry sampling volume of 35 ⁇ L. The relationship between sample volume and sample-to-sample carryover performance is significant to understanding the mode of failure. This is because trending demonstrates that internal contamination of the sample probe has an impact on sample-to-sample carryover.
  • the sample probe aspirates a test sample from a sample tube and immediately dispenses the sample volume into a reaction vessel prior to entrance into a wash station.
  • a second variable to carryover performance is wash sequencing at the sample wash station. Further analysis of wash conditions at the sample wash station lead to a study evaluating external wash sequencing relative to the internal wash. Success of the probe wash was less dependent on the external wash duration than it was on the stop sequencing of the external wash relative to the internal wash. If the internal wash stops after the external wash, carryover performance is significantly worse than if the external wash if ends after the internal wash. This relationship supports a theory that internal contamination of the probe is a source for the external between-sample carryover.
  • One wash protocol utilizes a one second external probe wash that extends beyond the stop time of the internal wash to improve carryover performance at low sample volumes. A supplemental washing that would have required an additional instrument cycle is not required to meet carryover performance criteria.
  • FIG. 1A a perspective view of a simplified integrated clinical test system 100 of an embodiment of the present invention.
  • the test system includes a clinical chemistry tester 102 and an immunoassay tester 104 , see FIGS. 1B and 1C for more detail.
  • the two testers share a common sample transporter 106 that allows linear movement of test sample tubes 108 between the two testers.
  • Each tester has a sample probe arm 110 / 112 that includes a probe 114 (see FIG. 2).
  • the arms can move in both a horizontal arc and vertical directions.
  • the probe aspirates a test sample from tube 108 located on the transporter 106 .
  • the probe arm then moves to a sample vessel (not shown) and deposits the aspirated sample.
  • the arm moves to a wash station 120 where the probe is washed.
  • the sample vessel is moved to a location where a reagent is added to the sample by a reagent arm 122 .
  • the reagent arm is movable between a reagent location, the sample vessel and the wash station.
  • the sample vessel may receive additional reagents and is then subjected to chemistry testing, as know to those skilled in the art.
  • a second reagent arm 123 can be included to provide a second reagent to the sample vessel.
  • the sample tube 108 located on the transporter 106 is then moved to a location near the immunoassay tester 104 , FIG. 1C.
  • the immunoassay tester is similar in operation to the clinical chemistry tester in that a test sample from the sample tube is aspirated using sample probe 114 of sample probe arm 112 .
  • the sample arm then moves to a sample vessel (not shown) and deposits the aspirated sample. After the sample has been discharged from the probe, the arm moves to a wash station (not shown) where the probe is washed.
  • the sample vessel is moved to a location where a reagent is added to the sample by a reagent probe arm 115 .
  • the reagent arm is movable between a reagent location, the sample vessel and the wash station.
  • the sample vessel may receive additional reagents and is then subjected to testing, as know to those skilled in the art. It is clear that sample carryover, or contamination, can occur if the sample probes are not cleaned between aspirations of different
  • FIG. 2 illustrates an example probe arm 110 .
  • the arm includes a probe 114 that can be moved about a horizontal arc and in a vertical direction.
  • the probe has a hollow center that allows aspiration of a fluid and the subsequent introduction of a wash fluid.
  • the mechanics of the probe arm are not described in detail herein, but are generally know to those skilled in the art.
  • the arm is controllable to regulate the amount of sample aspirated and the amount and duration of wash fluid that flows through the probe.
  • the probe is substantially tube-shaped and includes an exterior surface 132 and an interior surface 130 .
  • An interior wash dispenser 136 is located to discharge a wash fluid into the interior region of the probe.
  • the wash cup includes one or more exterior wash dispensers 138 , or nozzles, positioned to spray a wash fluid toward a center region of the cup and onto the exterior of the probe.
  • the wash fluid pumped through the probe and on its exterior is the same fluid and depends upon the material that is to be removed from the probe.
  • the wash fluid can be located in a common reservoir 140 and pumped to the nozzles using separate pumps 142 and 144 . Alternately, a single pump and controllable valves can be used to pump the wash fluid to the nozzles.
  • the present invention is not limited to a specific pump design, provided the termination of the internal fluid and the external fluid can be separately controlled by pump(s) controller 150 .
  • the term ‘pump’ is intended to include any mechanism that allows for controlled movement of a liquid, such as the wash fluid.
  • the probe needs to be sufficiently cleaned between sample aspirations to reduce sample carryover.
  • the sample carryover can be a test sample or reagent depending upon the probe.
  • the internal wash is terminated prior to terminating the external wash. This termination overlap significantly reduces sample carryover and allows clinical chemistry testers to meet restrictive specifications of immunoassay testers.
  • One example wash for chemistry sampling volume below a predetermined threshold includes a one second external sample probe wash that ends 100 ms after the internal sample probe wash. The external wash can begin prior to the internal wash without departing from the present invention.
  • the present invention is not limited to an integrated clinical chemistry/immunoassay tester, and other analytical systems can utilize the relationship of between-sample carryover performance to improve sample wash parameters. This includes other clinical chemistry and immunoassay systems as well as hematology and other methodologies.
  • the wash method can also be used utilized for reagent carryover washing, sample pretreatment instrumentation, and with laboratory automation systems.
  • a clinical tester has been described that includes a probe to aspirate a fluid.
  • the probe is washed between aspirations to reduce carryover.
  • the wash operation includes both an internal and an external wash, where the internal wash operation is terminated prior to terminating the external wash.
  • the probe wash can be implemented on an integrated clinical chemistry/immunoassay tester.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
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US10/158,495 2002-05-29 2002-05-29 Clinical tester wash and method Abandoned US20030223472A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US10/158,495 US20030223472A1 (en) 2002-05-29 2002-05-29 Clinical tester wash and method
EP03756244A EP1518125A2 (fr) 2002-05-29 2003-05-29 Lavage d'un appareil d'essais et procede associe
JP2004514403A JP2005527839A (ja) 2002-05-29 2003-05-29 臨床試験装置におけるプローブ洗浄方法
EP12150274.4A EP2463663A3 (fr) 2002-05-29 2003-05-29 Nettoyage de testeur clinique et procédé
CA2486264A CA2486264C (fr) 2002-05-29 2003-05-29 Lavage d'un appareil d'essais et procede associe
PCT/US2003/016872 WO2003102597A2 (fr) 2002-05-29 2003-05-29 Lavage d'un appareil d'essais et procede associe
US12/714,601 US8759106B2 (en) 2002-05-29 2010-03-01 Clinical analyzer wash and method
JP2010046040A JP5437115B2 (ja) 2002-05-29 2010-03-03 臨床試験装置におけるプローブ洗浄方法
US14/306,961 US9308560B2 (en) 2002-05-29 2014-06-17 Clinical analyzer wash and method
US15/095,893 US20160223575A1 (en) 2002-05-29 2016-04-11 Clinical analyzer wash and method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10/158,495 US20030223472A1 (en) 2002-05-29 2002-05-29 Clinical tester wash and method

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/714,601 Division US8759106B2 (en) 2002-05-29 2010-03-01 Clinical analyzer wash and method

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US20030223472A1 true US20030223472A1 (en) 2003-12-04

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Family Applications (4)

Application Number Title Priority Date Filing Date
US10/158,495 Abandoned US20030223472A1 (en) 2002-05-29 2002-05-29 Clinical tester wash and method
US12/714,601 Expired - Fee Related US8759106B2 (en) 2002-05-29 2010-03-01 Clinical analyzer wash and method
US14/306,961 Expired - Fee Related US9308560B2 (en) 2002-05-29 2014-06-17 Clinical analyzer wash and method
US15/095,893 Abandoned US20160223575A1 (en) 2002-05-29 2016-04-11 Clinical analyzer wash and method

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US12/714,601 Expired - Fee Related US8759106B2 (en) 2002-05-29 2010-03-01 Clinical analyzer wash and method
US14/306,961 Expired - Fee Related US9308560B2 (en) 2002-05-29 2014-06-17 Clinical analyzer wash and method
US15/095,893 Abandoned US20160223575A1 (en) 2002-05-29 2016-04-11 Clinical analyzer wash and method

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US (4) US20030223472A1 (fr)
EP (2) EP2463663A3 (fr)
JP (2) JP2005527839A (fr)
CA (1) CA2486264C (fr)
WO (1) WO2003102597A2 (fr)

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CN109374913A (zh) * 2018-09-06 2019-02-22 迪瑞医疗科技股份有限公司 一种液路系统装置及控制方法
US10456786B2 (en) 2013-03-12 2019-10-29 Abbott Laboratories Septums and related methods
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JP4976870B2 (ja) * 2006-01-30 2012-07-18 株式会社東芝 自動分析装置及びプローブ洗浄方法
JP2008209339A (ja) * 2007-02-28 2008-09-11 Hitachi High-Technologies Corp 自動分析装置
JP2009293939A (ja) * 2008-06-02 2009-12-17 Olympus Corp 検体分注装置のプローブ洗浄方法、検体分注装置及び自動分析装置
US7932826B2 (en) * 2008-06-12 2011-04-26 Abbott Laboratories Inc. System for tracking the location of components, assemblies, and subassemblies in an automated diagnostic analyzer
JP5028350B2 (ja) * 2008-07-11 2012-09-19 株式会社日立ハイテクノロジーズ 自動分析装置
WO2013016034A1 (fr) 2011-07-22 2013-01-31 Constitution Medical, Inc. Systèmes et procédés de préparation d'échantillon fluide
JP5453375B2 (ja) * 2011-11-07 2014-03-26 株式会社東芝 自動分析装置
US20140271369A1 (en) * 2013-03-15 2014-09-18 Abbott Laboratories System and Method for Processing Both Clinical Chemistry and Immunoassay Tests
JP1521782S (fr) * 2014-09-03 2015-04-20
CN104690044B (zh) * 2015-03-09 2016-08-24 北京普立泰科仪器有限公司 一种防止交叉污染的主动型取样针清洗装置及清洗方法
US9829498B2 (en) * 2015-04-22 2017-11-28 Shimadzu Corporation Sampling device
JP7456719B2 (ja) 2017-12-28 2024-03-27 シスメックス株式会社 検体測定装置および検体測定方法

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US20140290706A1 (en) 2014-10-02
WO2003102597A3 (fr) 2004-05-13
EP2463663A2 (fr) 2012-06-13
EP2463663A3 (fr) 2017-11-29
EP1518125A2 (fr) 2005-03-30
US20160223575A1 (en) 2016-08-04
CA2486264C (fr) 2014-02-18
WO2003102597A2 (fr) 2003-12-11
US20100151578A1 (en) 2010-06-17
CA2486264A1 (fr) 2003-12-11
JP2010117378A (ja) 2010-05-27
JP2005527839A (ja) 2005-09-15
US8759106B2 (en) 2014-06-24

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