WO2010144859A2 - Dispositifs et procédés de préparation, de dosage et d'analyse automatisés d'échantillon - Google Patents

Dispositifs et procédés de préparation, de dosage et d'analyse automatisés d'échantillon Download PDF

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Publication number
WO2010144859A2
WO2010144859A2 PCT/US2010/038404 US2010038404W WO2010144859A2 WO 2010144859 A2 WO2010144859 A2 WO 2010144859A2 US 2010038404 W US2010038404 W US 2010038404W WO 2010144859 A2 WO2010144859 A2 WO 2010144859A2
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WIPO (PCT)
Prior art keywords
support plate
reaction device
reaction
sensor
assay
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Application number
PCT/US2010/038404
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English (en)
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WO2010144859A8 (fr
WO2010144859A3 (fr
Inventor
Robert Dees
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Life Technologies Corporation
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Publication of WO2010144859A2 publication Critical patent/WO2010144859A2/fr
Publication of WO2010144859A8 publication Critical patent/WO2010144859A8/fr
Publication of WO2010144859A3 publication Critical patent/WO2010144859A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/028—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having reaction cells in the form of microtitration plates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0401—Sample carriers, cuvettes or reaction vessels
    • G01N2035/0418—Plate elements with several rows of samples
    • G01N2035/042—Plate elements with several rows of samples moved independently, e.g. by fork manipulator

Definitions

  • the present teachings relate to devices and methods for automated sample preparation, assay, and analysis useful for various biological, chemical, and/or cytobiological applications. More specifically, the present teachings relate to devices and methods for automated sample preparation, assay, and analysis having high throughput capability.
  • Achieving high throughput is desirable in various biological, chemical, and/or cytobiological assay applications.
  • Automation of as many steps as possible in the overall performance of high throughput assays can reduce the number of manual steps and improve overall efficiency.
  • Automation of various steps in an assay workflow including for example fluid handling and/or other sample preparation steps, also may reduce errors and/or cross-contamination, thereby improving both speed and quality of assay performance.
  • microarray chips in which an array of microscopic probes, such as, for example, nucleic acid or protein probes, are attached (e.g., via spotting or in situ synthesis) to a solid surface, such as glass, plastic, or silicon, may be affixed to or form at least a portion of the bottom of a reaction well into which a sample, reagents, and/or other substances may be delivered for reaction with the probes on the microarray chip.
  • a solid surface such as glass, plastic, or silicon
  • Other flat-bottomed reaction chambers also exist.
  • Flat-bottomed chambers e.g., wells
  • FIG. 1 is a front perspective view of an exemplary embodiment of an automated system for sample preparation, assay, and analysis in accordance with the present teachings: [0012]
  • FIG. 2 is a right, front perspective view of the system of FIG. 1 showing various internal components thereof;
  • FIG. 3 is a left, front perspective view of the system of FIG. 1 showing various internal and external components thereof;
  • FIG. 4 is another left, front perspective view of the system of FIG. 1 showing various internal components thereof;
  • FIG. 5 is a perspective, isolated view of an exemplary embodiment of a mounting panel and various exemplary components mounted thereon of the system of FIG. 1 ;
  • FIG. 6 is a perspective, isolated view of an exemplary embodiment of imaging components of the system of FIG. 1 ;
  • FIG. 7 is a detailed isometric view of an exemplary embodiment of agitator instrumentation of the system of FIG. 1 ;
  • FIG. 8 is a detailed isometric view of an exemplary embodiment of the agitator instrumentation of FIG.7 and cooling components of the system of FIG. 1 ;
  • FIG. 9A is a perspective isolated view of an exemplary embodiment of reservoirs used with the system of FIG. 1 ;
  • FIG. 9B is a view of the components of FIG. 9A from the underside of the components
  • FIG. 10A is a schematic view of an exemplary layout of exemplary components to be received by an upper platform of the system of FIG. 1 ;
  • FIG. 10B is a schematic view of an exemplary layout of exemplary components to be received by a lower platform of the system of FIG. 1 ;
  • FIG. 1 1 is an isolated perspective view of an exemplary embodiment of a level sensor and related components of the system of FIG.1 ;
  • FIG. 12 is a perspective view of an exemplary embodiment of a reaction device support plate of the system of FIG. 1 ;
  • FIG. 12A is an isometric view of the reaction device support plate of FIG. 12;
  • FIG. 13 is a perspective view of an exemplary embodiment of a reaction device of the system of FIG. 1 ;
  • FIG. 13A is an isometric view of the reaction device of FIG. 13;
  • FIG. 14 is a perspective view of the reaction device of FIG. 13 received by the reaction device support plate of FIG. 12;
  • FIG. 15 is a flowchart illustrating exemplary steps to be performed by a user of the system of FIG. 1.
  • sample means any biological substance that contains cells and/or matter contained in cells, e.g., polynucleotides or proteins. Samples also may contain such cellular matter mixed with other substances, such as, for example, buffers, reagents, and other substances that may react with the cellular matter or may be added to support a future reaction with the cellular matter.
  • reagent when reference is made to a "reagent,” it should be understood that a reagent is not necessarily limited to a single active component. Rather, a “reagent” can refer to a composition comprising multiple active components or a single active component. Also, in some instances throughout the specification, “reagent” may be used to refer to substances including buffer solutions and/or other substances added to a sample to prepare the sample, or otherwise react with or support a reaction with the sample.
  • systems and methods in accordance with the present teachings may be useful for performing automated sample preparation, assay, and/or analysis for various biological, chemical, and/or cytobiological applications.
  • systems and methods in accordance with the present teachings may be used to perform high throughput assays, including both nucleic acid and proteomic assays, which may be used, for example, for genotyping and phenotyping in transplant diagnostics applications.
  • high throughput assays including both nucleic acid and proteomic assays, which may be used, for example, for genotyping and phenotyping in transplant diagnostics applications.
  • such assays may be used to determine the identity of alleles of interest, such as HLA alleles for use in transplantation applications.
  • a system in accordance with the present teachings may automatically prepare a sample, such as a nucleic acid (e.g., DNA) sample, react (e.g., through a series of incubation steps) the prepared sample with oligonucleotide probes bound on microarray chips, and analyze the labeled nucleic acid samples that bind to the probes on the chips.
  • a sample such as a nucleic acid (e.g., DNA) sample
  • react e.g., through a series of incubation steps
  • the systems of the present teachings may be loaded with assay reagents, typing test strips comprising microarray chips having sequence specific oligonucleotide (SSO) probes bound thereto, and a nucleic acid sample, such as, for example, a sample that has been amplified via polymerase chain reaction (PCR) to contain a sufficient number of amplicons to perform the desired assay.
  • a nucleic acid sample such as, for example, a sample that has been amplified via polymerase chain reaction (PCR) to contain a sufficient number of amplicons to perform the desired assay.
  • the nucleic acid sample may, in various exemplary embodiments, be provided in one or more well plates, which may be, for example, microtiter plates.
  • sample preparation, assay, including but not limited to, for example, denaturing, hybridization, and/or wash steps, and/or analysis, including but not limited to for example, hybridizations detection (e.g., via fluorescence), are all performed automatically by the system.
  • One exemplary application for which the exemplary systems and methods of the present teachings may be employed includes HLA (human leukocyte antigen) genotyping using SSO probes on microarrays, although those having ordinary skill in the art will appreciate that the systems and methods in accordance with the present teachings may be used for a variety of sample preparation, assay, and analysis applications and the preceding description is nonlimiting and exemplary only.
  • FIGS. 1 -4 an exemplary embodiment of an automated system 100 for performing sample assays is illustrated in the perspective views shown in FIGS. 1 -4.
  • the system 100 is depicted in FIG. 1 with an outer housing, and in FIGS. 2-4 without the outer housing in order to show various internal components of the system 100.
  • FIG. 2 shows a right, front perspective view (based on the orientation of FIG. 1 showing the front view of the system), with portions of the chassis not shown to provide a better view of certain internal components of the system 100.
  • FIGS. 3 and 4 show a front, left side perspective view (based on the orientation of FIG. 1 showing the front view of the system), with FIG. 4 depicting the monitor and electronics panel removed to provide a better view of certain internal components of the system 100.
  • the system 100 may be configured to automate sample preparation and processing, including, for example, performing assays and analysis of the assay results.
  • analysis of the assay results may include, but is not limited to, for example, detection of fluorescently-labeled nucleic acid sequences.
  • Other exemplary embodiments include the colorimetric detection of the binding of the target molecule of interest to the arrayed probes, e.g, via an enzyme that produces a detectable signal.
  • Other techniques for analyzing assay results are known to those having ordinary skill in the art and fluorescent and colorimetric detection should not be understood as limiting the scope of the present teachings.
  • the system 100 is configured to perform high throughput automated sample preparation, assay and/or analysis using microarray chips, although various other formats of multiplexed reaction devices, such as, for example, well plates (e.g., microtiter plates) or centrifuge tubes also may be processed using the system 100.
  • multiplexed reaction devices such as, for example, well plates (e.g., microtiter plates) or centrifuge tubes also may be processed using the system 100.
  • well plates e.g., microtiter plates
  • centrifuge tubes also may be processed using the system 100.
  • the probes may be attached to virtually any surface positioned in a bottom of a reaction chamber, whether the surface forms the bottom or is affixed to another surface forming the bottom of the reaction chamber.
  • the system 100 may be configured so that a sample to be processed can be placed into the system 100 by a user, along with various substances and consumable components (e.g., reagents, buffers, wash solutions, pipette tips, sample plates, reaction devices) needed to prepare the sample, perform the assay and analysis, and wash the components of the system between assays and/or stages of assays, and the user may, after entering various assay parameters required by software designed to operate the system 100, walk away from the system 100.
  • various substances and consumable components e.g., reagents, buffers, wash solutions, pipette tips, sample plates, reaction devices
  • Preparation of the sample for the particular desired assay(s), performance of the assay(s), and analysis of the assay results may then be performed without the need for any additional manual intervention by a user. Exemplary steps that can be performed by a user of the system 100 are described in more detail below with reference to the description of FIG. 15.
  • the system 100 may be configured to be reusable.
  • the system 100 may be configured such that each of its components may be used repeatedly during a run and, consequently, multiple sample assays, including those of the same or different makeup, may be prepared and performed using the system 100.
  • the system 100 and specific components thereof may be configured such that the system may be sufficiently washed and/or decontaminated between different assays and/or differing stages of an assay using the system 100 (e.g., between sample preparation steps and/or assay reactions).
  • the system 100 may be a computer-processor driven system configured for a user to enter desired protocols for performing sample preparation, assay, and analysis through an interface such as, for example, a touch screen display, mouse, keyboard, and/or other interface useful for entering information into a processor with which those ordinarily skilled in the art are familiar.
  • Data generated by the system 100 may be stored on a variety of storage media known to those of ordinary skill in the art, as discussed below.
  • the system 100 may be self-contained in that all of the hardware and software needed to use the system 100 may be contained within the system 100, albeit some of the components for use with the system 100 (e.g., reagents, buffers, pipette tips, sample holders, reaction devices, etc.) may be consumable and loaded (or refilled) into the system 100 by a user.
  • the system 100 may be configured as a table-top (or lab counter) apparatus and may be sized accordingly.
  • the system 100 includes an outer housing 101 and a monitor 1 15 configured to display information regarding the system 100 to a user.
  • monitor 1 15 also may be configured as a touch screen to permit a user to enter information to the system 100.
  • a computer processing unit 130 may be provided to utilize the software provided with the system 100 and to control various functions of the system 100, including but not limited, for example, controlling movement of the various moving components of the system 100 (some of which are described in further detail below), and interpreting and executing software programs that control image processing and/or other data analysis algorithms, and/or interpreting and executing software programs that control various input/output interface devices (e.g., the monitor 1 15, keyboard (not shown), mouse (not shown)).
  • the processing unit 130 may be coupled to various control electronics, as would be familiar to those ordinarily skilled in the art.
  • the system 100 may also include storage media configured to store program instructions which are executable by the processing unit 130 and/or other processors for automating the preparation and processing of a fluid assay, such as, for example, any of a number of genotyping and/or phenotyping assays, including but not limited to HLA assays.
  • Storage media may be integral with the system 100 (e.g., as part of the processing unit 130) and/or may be removably and configured to be electronically coupled thereto.
  • Storage media may include but is not limited to a readonly memory, a random access memory, a magnetic or optical disk, or a magnetic tape.
  • the program instructions may be implemented in any of various ways, including procedure-based techniques, component-based techniques, and/or object-oriented techniques, among others.
  • the program instructions may be implemented using ActiveX controls, C++ objects, JavaBeans, Microsoft Foundation Classes ("MFC"), or other technologies or methodologies, as desired.
  • MFC Microsoft Foundation Classes
  • the processing unit 130 may take various forms, including a personal computer system, mainframe computer system, workstation, network appliance, Internet appliance, personal digital assistant (PDA), a digital signal processor (DSP), field programmable gate array (FPGA), or other device.
  • PDA personal digital assistant
  • DSP digital signal processor
  • FPGA field programmable gate array
  • processing unit and variants thereof may be broadly defined to encompass any component or components having one or more processors to execute program instructions from a memory medium.
  • the system 100 may also include a chassis 133 (shown in FIGS. 3 and 4) configured to support various working components of the system 100; the chassis 133 being surrounded by the housing 101.
  • the chassis 133 may include a bottom platform 1 10, described in further detail below, and a mounting panel 135 configured to mount various electronics and circuitry for operating the system 100.
  • a bottom platform 1 described in further detail below
  • a mounting panel 135 configured to mount various electronics and circuitry for operating the system 100.
  • the mounting panel 135 may support processing unit 130, various central processing units or other processors and input and output modules 131 , one or more printed circuit boards 132, one or more electrical connectors (e.g., cable connectors) 133 that can provide an electrical interface with various components such as a monitor, keyboard, printer, mouse, or the like, and a fan 134 configured to cool the electronic components.
  • the fan 134 may be positioned and configured to draw air into the housing 101 of the system 100 via a filtered inlet 136 (shown in FIG. 2 in dotted) provided in the housing 101.
  • the system 100 also includes a mechanized and programmable pipettor 140 and imaging instrumentation (shown generally as 150 in FIGS. 2 and 4 and in more detail in FIG. 6), both of which are configured to move in the x-direction shown in FIGS. 2-4. Movement of the pipettor 140 and imaging instrumentation 150 in the x-direction, coupled with movement of the system platform 120 holding various components, such as, for example, sample holders, a reaction device, pipette cartridges, and/or various reservoirs, in the y-direction, as will be explained in further detail below, enables the system 100 to control the placement of the pipettor 140 and imaging instrumentation 150 relative to the aforementioned components to perform automated sample preparation, assay, and/or analysis.
  • various components such as, for example, sample holders, a reaction device, pipette cartridges, and/or various reservoirs
  • the pipettor 140 may include an eight-channel pipettor 140, although other pipettor configurations (e.g., number of channels) may be used depending on the particular application, including a single channel (i.e., single pipette) format.
  • Using an eight-channel pipettor configuration may be desirable for some commonly used sample holder and/or reaction device configurations that have an array of reaction and/or sample chambers or locations that are in rows of 8, such as, for example, 8 X 12, 8 X 48, etc. array formats, with which those having ordinary skill in the art are familiar.
  • the pipettor 140 may be configured such that each pipette can deliver and/or aspirate volumes of liquid on the order of from about 1 microliter to about 1200 microliters.
  • the pipettor 140 may be motor-driven and configured to be supported on and move in the x-direction, for example, via bearings 143 that receive and move along an upper rail 142 and lower rail 154.
  • the pipettor 140 can move in the z- direction shown in FIGS. 2-4 to permit the pipettor 140 to move toward and away from various reservoirs, and sample and/or reaction chambers, positioned proximate a bottom portion of the system housing.
  • the pipettor 140 also may be configured to automatically eject pipette tips therefrom, for example into waste pipette cartridges, and to pick up new pipette tips from various pipette tip cartridges.
  • Those having ordinary skill in the art are familiar with various types of robotic pipettors that can be used with the system 100.
  • imaging instrumentation 150 includes a camera 152 associated with a lens 153 that is configured to be adjusted as needed.
  • the camera 152 may be a CMOS (complimentary metal-oxide semiconductor) camera, a CCD (charge coupled device) camera, or other photodiode array.
  • the imaging instrumentation 150 further includes an illumination source 157, which in one exemplary embodiment may include a fluorescent source of illumination.
  • Various optical components such as, for example, beam splitters, diffusers, lenses, etc.
  • the illumination source 157 may be provided in the path of the illumination source 157 between an object to be imaged and the lens 153, to achieve the desired illumination and image capture of the object.
  • Those ordinarily skilled in the art are familiar with various optical components that may be included in the imaging instrumentation 150 and the details of such components are thus not described herein.
  • the camera 152, along with lens 153, and the illumination source 157 may be mounted on a support bracket 155 that is configured to cooperate with and move along upper and lower rails 154 (shown in FIGS. 2 and 4) in the x-direction, as shown by the arrow labeled x in FIG. 6.
  • the support bracket 155 is provided at opposite ends with bearing and lead screw mechanisms 159 that allow movement of the bracket 155 along the rails 154.
  • the direction of motion of an object (shown in dotted line in FIG. 6) to be imaged, such as, for example reaction chambers in a reaction device, is shown by the arrow labeled y in FIG. 6 and by the y-axis in FIGS. 2-4.
  • a roller 156 may be coupled to the support bracket 155 and configured to interact with agitator/cooler components of the system, as will be described in further detail below.
  • a cam follower 151 may be provided proximate a right front edge of the illumination source 157 in order to control the height of imaging instrumentation 150 (e.g. the height of the illumination source 157) relative to a frame of a reaction device to ensure that a sufficient and known distance is maintained relative thereto.
  • a ring of LEDs may be provided around the lens 153 of the camera 152 to provide illumination to an object being imaged.
  • LED illumination sources an example of which includes SpecBrightTM LED Ringlights.
  • Other illumination sources are also considered within the scope of the present teachings and those ordinarily skilled in the art would understand how to modify the imaging instrumentation to utilize a variety of illumination sources as may be desired for a particular application.
  • the system 100 also may include agitator instrumentation 170 configured to agitate, for example, gently vibrate (e.g., via orbital horizontal movement) or otherwise impart motion to, the reaction device support plate and a reaction device supported by the support plate, exemplary embodiments of which are described in further detail below. Agitation of the reaction device before and/or during an assay may facilitate the assay reaction.
  • agitator instrumentation 170 configured to agitate, for example, gently vibrate (e.g., via orbital horizontal movement) or otherwise impart motion to, the reaction device support plate and a reaction device supported by the support plate, exemplary embodiments of which are described in further detail below. Agitation of the reaction device before and/or during an assay may facilitate the assay reaction.
  • agitation may facilitate mixing and/or flow of the sample reaction mixture relative to the probed surfaces, thereby enhancing the ability of the components in the sample reaction mixture to come interact and ultimately bind (e.g., including hybridizing in nucleic acid assay applications) with the probes.
  • the agitator instrumentation 170 may comprise speed-controlled, motor-driven cams configured to be placed in operable connection with a reaction device to impart a gentle orbital horizontal motion to the reaction device. The operation, including the speed of the motor driving the cams, of the agitator 170 may be controlled via software and the processing and electronic circuitry of the system 100.
  • the agitator instrumentation 170 is shown in detail in an isometric perspective view.
  • the agitator instrumentation 170 includes a motor 171 which drives a belt connected to eccentric cams 172.
  • the cams 172 through drive pins 173 drive an engagement plate 174 in orbital motion.
  • the engagement plate 174 in turn is provided with another set of drive pins 175 that are placed into and out of operable connection with the a reaction device support plate 270 (shown in FIGS. 2-4 and described in more detail below with reference to FIGS. 12, 12A and 14), by the movement of the camera frame 155, as will be described below.
  • Counterweights 176 also may be provided to counterbalance forces associated with movement of the reaction device support plate during agitation.
  • the agitator instrumentation 170 further includes a bushing 177 to guide z axis motion of agitator and a cooler assembly, which will be described next.
  • Cooling components such as, for example, a cooling device 180 (shown in FIG. 2) and a heat sink 182 (shown in FIG. 4) may be positioned underneath and spaced from the agitator 170.
  • the cooling components 180, 182 may be spaced from but in operable connection with the agitator instrumentation 170 so as to permit the reaction device support plate and a reaction device thereon to be sandwiched between the heat sink 182 and the agitator instrumentation 170 during incubation of the sample in the reaction device.
  • the cooling device 180 may be a Peltier module and the heat sink 182 may be a metal (e.g., Aluminum) block.
  • the cooling device 180 may be programmable and controlled via the software and processing and electronic circuitry associated with the system 100.
  • the bottom of the reaction device support plate (labeled as 270 in FIGS. 2-4) may be placed in contact with the block 182 to cool the reaction device held by the support plate 270.
  • thermal cyclers and other temperature cycling devices are familiar with the use of metal blocks and Peltier modules to achieve cooling during various biological, chemical, and cyctobiological assays. It should be understood however that numerous cooling devices, such as, for example, water and/or other circulating cooling fluid devices, may also be used instead of or in addition to cooling components 180 and 182.
  • heat sinks in various other assay devices that perform incubation and/or thermal cycling of reactions.
  • heating may be achieved using heater elements associated with the reaction device support plate.
  • a user may enter the desired assay and/or assay parameters to be performed to cycle the Peltier module 180 or other cooling device and/or the heaters of the system 100 through various thermal cycles during incubation of the sample reaction in the reaction device.
  • the agitator instrumentation 170 and the cooling components 180, 182 may be operably connected as an entire assembly and may be driven into differing positions/operating conditions using the motion of the imaging instrumentation support bracket 155.
  • the agitator instrumentation 170 and the cooling components 180, 182 are depicted.
  • a frame 177 attaches the various elements of the agitator instrumentation 170 and the cooling components 180, 182 such that the entire assembly depicted in FIG. 8 moves in unison up and down in the z-direction of FIGS. 2-4.
  • a track member 178 is provided as part of the overall assembly and cooperates with the with the roller 156 on the imaging instrumentation support bracket 155 to place the agitator/cooler assembly into various operating positions during the operation of the system 100. More specifically, the track member 178 defines a recessed track 179 configured to receive the roller 156.
  • the track 179 includes three different levels 179a, 179b, 179c as the roller 156 moves in the x- direction of FIGS. 2-4 along the track 179.
  • the system 100 may include a lower platform 1 10 and an upper platform 120 configured to hold various components for performing sample preparation, assay, and analysis.
  • the lower platform 110 may be configured to receive and hold one or more reservoirs 210 for containing reagents, buffers, wash solutions and/or other substances used to prepare a sample for a desired assay and/or wash sample holders, pipettes, and/or reaction devices and the like between assays and/or steps of an assay.
  • the lower platform 1 10 also may be configured to receive one or more reservoirs 220 used to dispense waste, for example, fluid waste. As depicted in FIGS.
  • the reservoirs 210 and 220 may be defined by individual containers, which may be placed on a tray 212 or directly on the surface of the lower platform 110. It should be understood that FIGS. 2-4 schematically depict the various reservoirs 210 and 220, and that those reservoirs can have numerous arrangements, shapes, and sizes without departing from the scope of the present teachings.
  • the reservoirs 210 may be color-coded or otherwise include differing indicia to indicate what type of substance should be placed in which reservoir 210.
  • a user may input into the system 100 the applicable information regarding the type of substance that each reservoir 210 contains prior to running the system 100 to perform a particular assay.
  • the colors and/or other indicia of the reservoirs 210 may be associated with colors and/or other indicia provided on the bottles and/or other containers containing substances and used to fill the reservoirs 210.
  • one or more reservoirs 210 may remain empty during an assay.
  • the reservoirs 210 may respectively contain a hybridization buffer, a denaturation solution, a wash solution, a conjugate solution, and a substrate solution.
  • the substances may be sufficient to perform human leukocyte antigen (HLA) genotyping or antibody analysis using sequence specific oligonucleotide or protein spotted microarray chips, although other assays may also be performed using the system 100 as would be understood by those ordinarily skilled in the art.
  • One or more of the reservoirs 210 may be empty, depending on the particular assay application for which the system 100 will be used.
  • the reservoirs 210 and 220 may have a configuration as shown in FIGS. 9A and 9B.
  • the reservoirs 210 may be formed as individual containers 21 1 held in a tray 212 that is configured to be removably received in the lower platform 1 10.
  • the reservoir 220 may also be formed by an individual partially covered container 213. As shown in FIG. 9A and 9B.
  • the lower platform 1 10 also may provide space between edges of the platform 1 10 and the reservoirs 210, 220 so as to collect any substances that may spill during operation of the system 100, thereby serving as a drip tray.
  • the tray 212 can be provided with temperature control devices 217 and 219 configured to respectively provide thermal exchange with the two containers 21 1 situated at the far right and the two containers 21 1 situated at the far left of the tray 212, respectively.
  • the temperature control device 217 may be a heating element and the temperature control device 219 may be a cooling element, although any arrangement as desired may be used.
  • the central portion of the tray 212 may not be provided with any temperature control device, and thus the three central reservoirs 21 1 of FIGS. 9A may remain at ambient temperature.
  • the waste reservoir container 213 may be maintained at ambient temperature and may comprise a container configured to be directly received in the lower platform 1 10.
  • FIG. 9A also depicts how the pipettor 140 interacts with the reservoirs 210, 220 to pipette substance to and from those reservoirs 210, 220.
  • the upper platform 120 may be configured to receive and hold one or more cartridges configured to hold pipette tips, a reaction device (to be described in further detail later), and one or more sample holders, such as microtiter plates. As shown in the exemplary embodiment in FIGS. 3 and 4, the upper platform 120 may hold four cartridges 230, 240, and 250 each configured to hold a plurality of pipette tips; such cartridges for holding pipette tips having a configuration known to those ordinarily skilled in the art.
  • the cartridge 230 may be configured to hold pipette tips used for pipetting reagent, buffer, and/or wash solutions (e.g., from reservoirs 210), the cartridge 240 may be configured to hold pipette tips used for pipetting sample (e.g., from sample holder(s) 260), and the cartridges 250 may be configured to hold the used pipette tips ejected from pipettor 140 after the pipetting of reagent and/or sample is completed.
  • the pipette tips may be filtered or unfiltered depending upon the desired use of the pipette tips.
  • cartridge 240 may hold filtered pipette tips while cartridge 230 holds unfiltered pipette tips.
  • the upper platform 120 also may be configured to receive and hold one or more sample holders 260 and to mount a reaction device support plate 270 configured to receive a removable reaction device, as will be described in more detail below.
  • the support plate 270 may be hingedly mounted to the upper platform 120 via support brackets 290, while the cartridges 230, 240, and 250 and the sample plates 260 may be removably received by the upper platform 120.
  • the upper platform 120 may be moveable in the y-direction, as shown best in FIGS. 3 and 4 in which the upper platform 120 is shown in two differing positions within the system 100. In the position illustrated in FIG. 3, the upper platform 120 is disposed toward a rear of the system 100 (in the orientation depicted in FIGS. 1 -4). The upper platform 120 in the rearward position permits exposure of at least a portion of the bottom platform 1 10 so as to provide access to the bottom platform 1 10 to enable a user to load and unload the reservoirs 210 and 220 through the open doors 102 and 103. Moreover, when the upper platform 120 is placed in the rearward position shown in FIGS. 2 and 3, the reaction device support plate 270 is placed into position between the cooling components 180, 182 and the agitator 170 to permit incubation and/or agitation of the reaction device plate 270 and a reaction device held by the support plate 270.
  • Movement of the upper platform 120 in the y-direction also helps to align the appropriate cartridges 230, 240, 250, sample holder(s) 260, and support plate 270, with other components of the system 100, such as, for example, the pipettor 140 and the imaging instrumentation 150.
  • the upper platform 120 may be supported on and configured to move along rails 122 via a motor controlled by the processing and electronic circuitry and software associated with the system 100. Those having ordinary skill in the art are familiar with various controls and motor-driven assemblies to achieve translation of the upper platform 120 in the y-direction shown in FIGS. 2-4.
  • movement of the upper platform 120 may control movement of the reaction device support plate 270 into a desirable position for pipetting fluid into and out of a reaction device supported on the support plate 270, which will be described in more detail below. Movement of the upper platform 120 may be accomplished through the use of a motor controlled by the processing and electronics circuitry and corresponding software of the system 100. A manual override also may be provided to permit a user to move the upper platform 120 along the y-axis.
  • FIGS. 10A and 10B are schematic representations of an exemplary arrangement of the various components to be received and held by the upper and lower platforms 120 and 1 10, respectively.
  • the arrangement, number, and relative sizes of the various reservoirs, cartridges, and other components shown on the lower platform 1 10 and the upper platform 120 in FIGS. 10A and 10B are exemplary and nonlimiting of the present teachings, and that other arrangements, numbers, and sizes may be chosen as desired to achieve a desired assay workflow with corresponding modifications made to the software programs controlling the overall system.
  • a graphical user interface (GUI) displayed on the monitor 1 15 may aid a user in where and/or in what orientation to place the various components on the lower and upper platforms 1 10 and 120 by depicting the various component positions and orientations.
  • labels and/or other indicia may be provided on the upper and lower platforms to indicate to a user the proper positioning of the components on the lower and upper platforms 110 and 120.
  • reservoirs 210 may be configured for single or multiple use operations.
  • reservoirs 210 may come in a pack and may be configured to be disposable (i.e., thrown away after a single fluid assay has been prepared) or may be reusable (i.e., include reagents and other solutions in amounts sufficient to prepare multiple assays and to decontaminate the various system components after each assay).
  • the containers of a pack may be configured to be disposed after one or more of the reagents and/or other solutions are consumed or may be configured to be refilled.
  • a pack may facilitate replacement and may be generally inexpensive to maintain and produce.
  • the system 100 may include a level sensor used to detect the levels of the substances, such as, for example, reagents, wash solutions, buffer solutions, etc. provided in the various reservoirs, as well as sensing that pipette tip cartridges are appropriately filled with pipette tips and that the waste reservoirs are empty or at least not at risk of overflowing during use of the system 100 for an automated sample preparation, assay, and analysis run.
  • a level sensor may be mounted proximate the pipettor 140 (e.g., behind the pipettor 140 in the view of FIG.
  • FIG. 1 1 depicts an isolated detail perspective view of the level sensor 148 mounted to the supporting structure 145 to which the pipettor 148 is mounted, with the pipettor 148 removed from the view of FIG. 1 1 in order to make the level sensor 148 visible.
  • the level sensor 148 can move via the motor that drives the pipettor 140 in the x-direction of FIGS. 2-4.
  • the level sensor 148 may be configured to detect the levels of the various substances in the reservoirs 210 and the pipette tips in the pipette cartridges 230 and 240 and, in conjunction with information input by the user regarding the number and kind of assays to be performed, sense whether there is sufficient solution in each reservoir 210 and sufficient number of pipette tips in the cartridges 230, 240 to perform the desired automated run.
  • the level sensor 148 may also detect the state of the waste reservoirs 220 and waste cartridges 250, for fluid waste and used pipette tips, respectively, to determine whether or not they are empty prior to starting an automated process. Detecting that the waste pipette tip cartridge is empty prior to beginning an automated procedure can help ensure that ejection of used pipette tips from the pipettor 140 occurs properly and without potential damage to the system 100. Ensuring that the waste fluid reservoir 220 is empty or has sufficient room to add more waste solution can help ensure that the waste reservoir does not overflow through the addition of more waste fluid occurring during an automated process.
  • the level sensor 148 can detect that the reaction device is fully inserted into the reaction device support plate.
  • the reaction device includes a cover and other mechanical features which prevent the reaction device from being fully inserted unless the cover is closed and the reaction device is oriented properly.
  • the reaction chamber locations within the system 100 are important when, for example, matching patient samples with the data collected from the assays and analysis.
  • the reaction device includes mechanical features to ensure that the reaction chambers can be placed in only a precise location, and the interaction of the support plate and the reaction device is such that the reaction device may only be inserted in a preferred orientation.
  • the monitor 1 15 may display a GUI to guide a user as to proper placement of both reaction chambers in a reaction device and of the reaction device within the system 100.
  • the level sensor 148 helps to ensure that prior to beginning any automated process using the system 100, the system 100 will complete the desired sample preparation, assay, and/or analysis without risk of not having enough solutions or pipette tips for performing the same or of having undesired waste overflow and/or malfunctioning of the system 100 due to hindrance of pipette ejection.
  • the level sensor 140 can help ensure that a reaction device is appropriately positioned prior to beginning an automated run. Such a system check by the level sensor 148 can save valuable time that may otherwise result in the system 100 malfunctioning or failing to accurately complete a desired assay after a user has loaded the system 100 and walked away.
  • the level sensor 148 may be an ultrasonic proximity sensor such as a UNAM series ultrasonic proximity sensor made by Baumer Ltd., although such configuration is nonlimiting and exemplary only.
  • a reaction device support plate 270 in accordance with an exemplary embodiment of the present teachings may be configured to removably receive various differing reaction device configurations.
  • the support plate 270 includes a lower frame 272 defining an opening 273 that may have a generally rectangular configuration.
  • a plate 274 supporting a planar heater element 275 may rest in the opening 273.
  • the heater element 275 may, in an exemplary embodiment, include a Kapton/copper track heating element and the plate 274 may be an aluminum plate. Control of the heater element 275 may be provided via software and the processing and electronic circuitry of the system 100.
  • the support plate 270 may further include an upper flanged support tray 276 defining a recess 277 configured to receive a reaction device.
  • the dimensions of the recess 277 may be selected so as to be able to receive various reaction device configurations, such as, for example, microtiter plates and/or other reaction devices having similar configurations, including but not limited to a test strip holder as will be described further below with reference to the exemplary embodiment of FIGS. 13 and FIG. 14.
  • the recess 277 may be sized so as to receive a reaction device in a contacting relationship with the bottom surface of the recess 277 in order to achieve good thermal contact between the reaction device and the bottom surface of the recess 277.
  • the flange 278 surrounding the recess 277 may rest on the upper surface of the frame 272 when the support plate 270 is in an assembled configuration.
  • a cutout portion 279 may be provided at an end of the recess 277 to facilitate grasping and removal of a reaction device received in the recess 277.
  • the tray 276 may comprise holes 375 configured to receive the drive pins 175 of the agitator instrumentation 170 when the agitator instrumentation 170 is in the engaged position with the support plate 270, as described above.
  • the tray 276 may be attached to four L-shaped springs 278.
  • the springs 278 may permit orbital, horizontal motion of the tray 276 during interaction with the agitator 170 as described above.
  • the springs 278 may be formed of materials that minimize corrosion that can occur from the use of solutions containing salt in the system 100; for example, the springs 278 may be made from stainless steel.
  • the support plate 270 also may include a bearing roller 271 which is coupled to and protrudes outwardly from an end of the upper flanged support tray 276 that is opposite to the end at which the recess 279 is disposed.
  • the frame 272 may include an indented or cutout region 272 to permit pivotably (e.g., via a hinge) connecting the support plate 270 to the brackets 290 mounted on the upper platform 120, that connection being shown best in FIG. 4.
  • the end of the support plate 270 opposite to the end which hingedly connects to the brackets 290 may rest on a support wall 291 provided on the upper platform 120.
  • the support wall 291 may be at a height that permits support of the support plate 270 so that the support plate 270 is substantially horizontal and parallel to the x-y plane of the system 100 shown in FIGS. 1 -4.
  • the hinged connection of the support plate 270 to the brackets 290 mounted to the upper platform 120 permits the support plate 270 to rotate about the hinge axis relative to the upper platform 120, thereby permitting the plane of the support plate 270 to be positioned at an angle relative to the plane of the upper platform 120 (i.e., relative to the horizontal x-y plane in the orientation of the system shown in FIGS. 1 -4).
  • the ramped track 310 guides the support plate 270 into an angled position when the platform 120 is moved in the Y direction.
  • FIG. 12A The various components depicted in FIG. 12A may be assembled together via use of various pins, brackets and other connection mechanisms known to those having ordinary skill in the art.
  • a reaction device 280 may include a bottom plate 281 on which layers 282, 283 formed with an array of recesses rest.
  • Layer 282 is a thermally conductive compliant sheet to aid in thermal contact pressure against the reaction chambers described below, and layer 283 is a white film to provide a good imaging background.
  • a frame 284 may be provided and may define a central opening.
  • the frame 284 may include opposing lateral sides 287, 288 including respective features 286 and 296 on each side 287, 288 that are aligned with each other and configured to ensure accurate placement of the test strips 289. More specifically, the features 286 are openings configured to receive the cylindrical chambers at an end of the test strip 289 and the features 296 are small protrusions configured to engage with a small opening 289' on a gripping portion of the test strip 289.
  • the test strips 289 may be formed using spotted microarray chips secured to the bottoms cylindrical wells, for example, to the bottom of plastic disposable test strips.
  • CLONDIAG GmbH under the product name AssayStrips.
  • reaction chamber configurations are envisioned and fall within the scope of the present teachings.
  • a plurality of test strips 289 may be positioned along the lateral edges of the frame 284 and the bottom of each chamber of the test strip 289 may be placed in thermal contact with layer 283.
  • a cover 285, which is hingedly attached to the frame 284 may be closed to secure the test strips 289 within the reaction device 280.
  • the reaction device 280 may then be inserted into the recess 277 of the support plate 270 in the system 100. Removal of the reaction device 280 from the support plate 270 may be accomplished by grasping a holding area 297 provided on the frame 284 that rests proximate the cutout portion 279 of the tray 276. To minimize evaporation of the contents of the test strip wells during incubation, the reaction device 280 is pressed against a conformal layer on the agitator drive plate 174 to seal the reaction area.
  • the reaction device may be have a 96-chamber array format, which is a format used in many biological, chemical, and/or cytobiological applications.
  • the exemplary embodiment of FIGS. 13, 13A, and 14 is configured to receive twelve 8-well test strips.
  • the number and arrangement of the array of reaction chambers may vary and various other formats may be utilized, including, but not limited to, for example, 384 and other high density array formats.
  • the reaction device configuration shown in the exemplary embodiment of FIGS. 13, 13A, and 14 is exemplary only and the system 100 may be used with other reaction device configurations, including, but not limited to, for example, microtiter plates, etc.
  • the support plate 270 is hingedly connected to the support brackets 290 at one end to permit the support plate 270 to rotate about the hinged connection and be placed at an angle relative to horizontal.
  • the tilting of the support plate 270 is performed in conjunction with movement of the upper platform 120.
  • FIGS. 2 and 3 when the upper platform 120 is in a rearward position, the end of the support plate 270 opposite to the hingedly connected end rests on the support wall 291. In this position of the upper platform 120, the plane of the support plate 270 is substantially horizontal and parallel to the x-y plane of the system 100 in the orientation of the system 100 shown. As the upper platform 120 moves in the y-direction from the rearward position of FIGS. 2 and 3 to a frontward position shown in FIG. 4, the support plate 270 moves along with the platform 120, as do the brackets 290 and support wall 291.
  • a ramp structure 310 Mounted on or proximate to an inside surface of the right side of the chassis 133 (in the orientation shown in FIGS. 1 -4) is a ramp structure 310, the lower surface of which rests just above the upper surface of the support wall 291 as the upper platform 120 moves into the frontward position shown in FIG. 4. More specifically, as best shown in FIG. 2, the ramp structure 310 comprises a block-like structure with a cutout portion 315 leading from an opening 316 at an end of the block-like structure facing the rear of the system 100. The cutout portion 315 forms a ramp surface within the block that rises in a direction from the rear of the system 100 toward a front of the system 100. As the upper platform 120 moves from the rearward position (FIGS.
  • the bearing roller 271 enters the opening 316 of the ramp structure 310 and rides along the ramp surface within the cutout portion 315, causing the support plate 270 to rotate about its hinged connection to the brackets 290.
  • the bearing roller 271 rests at approximately the apex of the ramp surface thereby tilting the support plate 270 at an angle relative to the horizontal x-y plane of the system 100.
  • the support plate 270 may be configured to interact with the ramp structure 310 to tilt the support plate 270 at an angle ranging from 5° to about 20°, for example, at an angle of about 7° relative to horizontal.
  • the pipettor 140 When the upper platform 120 is in the frontward position of FIG. 4, the pipettor 140 also is aligned along the y-axis with the support plate 270 and any assay reaction device supported by the support plate 270. In this manner, the pipettor 140 can move in the x-direction shown in FIGS. 2-4 to a position above the reaction device in the support plate 270. To pipette fluid into and out of the reaction chambers of a reaction device supported by the support plate 270, the pipettor 140 may be moved in the z-direction.
  • tilting the support plate 270 may facilitate the pipetting process by permitting the pipette tips to access an edge region of the reaction chambers (wells) of a reaction device where the bottom surface of the reaction chambers meets a side wall of the chambers and by causing fluid in the reaction chambers to pool near that edge region.
  • tilting of the reaction device support plate 270 may be desirable when the reaction device held by the support plate has a flat-bottomed well configuration.
  • the pipette tip may be positioned in the reaction chambers toward an edge of the chamber where the fluid pools as a result of the tilted position.
  • the pipette tips may also be able to access a regions between the edge of the chip and the sides and bottom surfaces of the chamber.
  • Providing a tiltable reaction device support plate 270 may also be desirable when using a reaction device that comprises surfaces comprising a microarray of probes, such as, for example, spotted or in situ synthesized microarray chips (e.g., like test strips 289 described with reference to FIGS. 13 and 13A, or other reaction device configurations having well bottoms that include attached probes.
  • a reaction device that comprises surfaces comprising a microarray of probes, such as, for example, spotted or in situ synthesized microarray chips (e.g., like test strips 289 described with reference to FIGS. 13 and 13A, or other reaction device configurations having well bottoms that include attached probes.
  • the pipetting may wash away the probes.
  • Tilting the support plate and reaction device may permit the pipette tips to be positioned toward respective edges of the arrayed chambers to deliver substance into the chambers (wells) regions of the microarray chips so as to not disrupt the probes.
  • the pipette tips may be positioned relative to the tilted reaction device such that fluid is dispensed into the reaction chamber substantially along the side wall of the chamber and moves toward the bottom as the chamber is filled with fluid.
  • the risk of the pipetting of the substance interfering with (e.g., washing away) and/or of the pipette tip itself otherwise interfering with the probes on the surface of a microarray chip or other surface can be minimized by permitting tilting of the reaction device during pipetting of substance into the reaction device.
  • tilting the support plate 270 also may facilitate a user in positioning a reaction device into the recessed tray 276 of the support plate 270.
  • the upper platform 120 may be moved into the frontward position of FIG. 4 to provide access to the support plate 270 in a tilted position.
  • the user may utilize electronic controls and/or a manual control to move the upper platform 120 from the rearward position to the frontward position to facilitate loading of the various components received by the upper platform 120, including, for example, a reaction device into the support plate 270.
  • nucleic acid samples e.g., DNA samples
  • probes e.g., sequence- specific oligonucleotide probes, such as, for example, HLA allele-specific oligonucleotide probes, or proteins
  • exemplary steps may in some cases be performed in a different order and/or that some steps may be eliminated altogether depending on the particular application.
  • the general workflow of steps to be performed by a user using the system 100 in an exemplary embodiment includes at block 1001 entering an assay program desired to be performed by the system 100 via an input mechanism, such as, for example the touch screen monitor 1 15 or other interface.
  • an input mechanism such as, for example the touch screen monitor 1 15 or other interface.
  • the desired number and kind of test strips may be inserted into tray of the reaction device 280.
  • any number from one to twelve 8-well test strips may be inserted.
  • the reaction device may next be placed into the support plate 270 as indicated at block 1003.
  • Cartridges 230 and 240 may then be filled with the appropriate number and kind of pipette tips and/or pre-filled cartridges 230 and 240 may be placed in position on the upper platform 120 at block 1004.
  • Cartridges 250 may be emptied and/or replaced with empty cartridges if needed in the next step indicated at block 1005 to ensure that waste pipette tips are removed, if necessary, from the system 100 prior to use.
  • the user may load a sufficient amount of the various reagents, buffers, and wash solutions needed to perform a particular assay into reservoirs 210 and/or load pre-filled reservoirs 210 onto the lower platform 1 10.
  • one or more sample holders 260 (which may be, e.g., microtiter plates) containing, in an exemplary embodiment, nucleic acid sample amplicons that have been amplified via polymerase chain reaction (PCR) outside the system 100 may be placed on the upper platform 120. In this step, it may be desirable to move the upper platform 120 to the frontward position again.
  • the waste reservoir 220 may be emptied if needed, and finally, the doors 102 and 103 may be closed and the system 100 may be run.
  • a graphical user interface on the monitor 115 may prompt a user of the system 100 at each step, including providing information about the type of reagents and other solutions to be placed in the reservoirs 210 and the proper placement of the various components 210, 220, 230, 240, 250, 260 and 270 on the lower and upper platforms 110 and 120.
  • the system 100 will automatically perform the necessary sample preparation, assay, and analysis processes based on the entered assay protocol.
  • the automated process may include the level sensor 148 scanning the various components, as described above, to ensure that the system 100 is ready to perform the programmed assay, including that sufficient amount of substances are in reservoirs 210, that the waste reservoir is empty, that the pipette tips cartridges are stocked with a sufficient number of pipette tips, that the pipette waste cartridge is empty, and that the reaction device is properly loaded in the support plate.
  • the system 100 will prompt the user to let the system begin a run, such as by depicting a prompt on the monitor 1 15 to press a start button. If the level sensor 148 detects that the system 100 is not ready, the user will be prompted regarding the same, which may include, for example, depicting via a GUI on the monitor 1 15 which locations of the system 100 are not ready.
  • the GUI may display a schematic representation of the layouts of the upper and lower platforms, for example, as depicted in FIGS.
  • 10A and 10B may indicate which of the components 210, 220, 230, 240, 250, 260, and/or 270 (for example, by highlighting or flashing of that componenet) were detected by the level sensor to be not ready for the automated process.
  • the upper platform 120 will move according to program instructions in the y-direction and the pipettor 140 will move according to program instructions in the x- and z-directions to fill and remove fluids, including reagents, buffers, sample, and wash solution, or pipette tips as needed from the various components provided on the upper and lower platforms in accordance with the entered assay program.
  • the heaters and coolers of the system 100 will automatically cycle through the appropriate thermal cycles for a particular assay program during incubation of the reaction taking place in the reaction device, and the agitator will engage to agitate the reaction device.
  • the imaging system 150 After completion of the desired assay reaction and/or during the reaction if real-time detection is part of the programmed assay, the imaging system 150 will move in the x- direction and the upper platform 120 in the y-direction to move the reaction device 280 into the view of the camera to be imaged. Data collection useful to analyze the results of the assay may also be performed based on conversion of the images captured by the imaging instrumentation.
  • the system 100 also may include software configured to convert the data into meaningful information to a user, for example, to perform genotyping and/or proteomic assays.

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Abstract

L'invention porte sur un appareil destiné à exécuter des procédures automatisées de dosage d'échantillon, lequel appareil peut comprendre une plaque support configurée de façon à porter un dispositif de réaction comprenant un réseau de chambres de réaction, la plaque support étant inclinable entre une position horizontale et une position inclinée par rapport à l'horizontale. L'appareil peut en outre comprendre une pipette configurée de façon à se déplacer par rapport à la plaque support afin de pipeter du fluide dans les chambres de réaction et hors de celles-ci lorsque la plaque support est en position inclinée.
PCT/US2010/038404 2009-06-12 2010-06-11 Dispositifs et procédés de préparation, de dosage et d'analyse automatisés d'échantillon WO2010144859A2 (fr)

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CN114341613A (zh) * 2019-09-04 2022-04-12 平田机工株式会社 标本制作装置
CN114341613B (zh) * 2019-09-04 2024-02-02 平田机工株式会社 标本制作装置
WO2024115025A1 (fr) * 2022-11-29 2024-06-06 Resolve Biosciences Gmbh Élément de puits, ensemble coulissant d'échantillon, appareil de traitement et procédé de traitement d'un ensemble coulissant d'échantillon

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