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WO2006056920A1 - Systeme de transfert d'echantillons - Google Patents

Systeme de transfert d'echantillons Download PDF

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Publication number
WO2006056920A1
WO2006056920A1 PCT/IB2005/053825 IB2005053825W WO2006056920A1 WO 2006056920 A1 WO2006056920 A1 WO 2006056920A1 IB 2005053825 W IB2005053825 W IB 2005053825W WO 2006056920 A1 WO2006056920 A1 WO 2006056920A1
Authority
WO
WIPO (PCT)
Prior art keywords
sample
transfer system
liquid
cell
holding means
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.)
Ceased
Application number
PCT/IB2005/053825
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English (en)
Inventor
Ronald Hogg
Reto Hartmann
Reto Stocklin
Daniel Bertrand
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.)
Universite de Geneve
Original Assignee
Universite de Geneve
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 Universite de Geneve filed Critical Universite de Geneve
Priority to CA002589114A priority Critical patent/CA2589114A1/fr
Publication of WO2006056920A1 publication Critical patent/WO2006056920A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C12M33/02—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by impregnation, e.g. using swabs or loops
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads

Definitions

  • the present invention relates to a sample transfer system which, for example, may be used for moving a cell or a group of cells between microwells.
  • Microwells can be on a commecrcally available 'microplate' or can be custom manufactured.
  • a group of cells may for example also include tissues, organs, parasites or other small living organisms.
  • the sample transfer system can also be used to transfer solid substrates or biosensors between different solutions.
  • the sample transfer system may also be used for cell-fusion, cytoplasmic or nuclear transfer from cell to cell.
  • FLIPR Fluorometric Imaging Plate Reader
  • cells expressing the receptor of interest are placed or cultured in a microtiter plate, voltage sensitive channels are opened by depolarization of the cell with KCl or addition of a channel opener such as veratradine for Na + channels (see for example [I]).
  • a channel opener such as veratradine for Na + channels (see for example [I]).
  • Commonly used dyes are sensitive to calcium requiring that the signal is "converted to a calcium readout" the plate is scanned by a scanning laser and changes in the fluorescent readout indicate whether a test compound is affecting an ion channel of interest.
  • VTR Voltage/Ion Probe Reader, Aurora Discovery, San Diego, CA, USA
  • FRET Fluorescence Resonance Energy Transfer
  • the major drawback of with these two systems is that they require identification and cloning of the gene coding for the ion channel of interest and its expression in a host cell line. They also require a single layer of adherent cells in each well of the microtiter plate. Moreover, cells are not voltage clamped and measurements are not possible on channels that display strong voltage dependency (rectification) and difficult on fast activating and inactivating channels. These techniques are also unsuitable for ligand-gated channels that strongly desensitize.
  • Biacore Biacore
  • Detection is done by surface plasmon resonance (see for example [2, 3]).
  • surface plasmon resonance see for example [2, 3]
  • Automated patch clamp machines, perform patch clamp recordings on single cells immobilised on a planar electrode or inside a glass electrode. These electrodes are disposable and are used only once. Many of these machines are able to record from multiple cells in parallel, giving them a high throughput which makes them highly suited to the application of screening multiple compounds on ion channel function. These machines also require the cloning off the gene for the ion channel of interest and it's expression in a host cell line. These cells must be in liquid suspension.
  • OpusXpress (Molecular Devices) is a semi-automated machine capable of making simultaneous recordings from eight Xenopus oocytes in parallel, loading of the oocytes is performed by the operator, impalement and voltage clamping is automated.
  • This system (like the APCs) employs the conventional system of applying liquid to an immobilised cell. Application of liquid to the cells is performed by a modified liquid handling robot. A test compound solution is applied to voltage-clamped cells in a perfusion stream, and is aspirated into the waste at the end of the measurement, to give place to another test compound solution.
  • each volume of test solution can only be used once, which seriously limits the number of teSample transfer system in the case of substances that are not available in large amounts.
  • a purpose of the invention is to develop an automated system for electrophysiological measurements on voltage-clamped cells that are exposed to different test solutions, wherein said test solutions can be retrieved after the measurements to be either reused for other measurements or subjected to further analysis.
  • the present invention describes a sample transfer system that has the ability to insert or extract sample(s) from a medium, e.g. a liquid, while allowing assaying sample or liquid separately or in combination.
  • a medium e.g. a liquid
  • the invention also relates also to a method to transfer a sample from one solution to another while protecting the sample irom forces encountered at the air liquid interface. Moreover, this device can be fully automated and work in an unattended manner.
  • a cell is immobilized and electrodes inserted for electrophysiological recordings.
  • the cell can be transferred from one solution to another, while being continuously maintained in voltage clamp and protected from the mechanical stress that occurs when crossing the air-liquid interface. Exposure to mechanical forces at the liquid-air interface during the transfer from one microwell to another is avoided by keeping the cell surrounded at all times with a thin layer of liquid. This is achieved for example by placing an object, such as a spiral, or a ring around the cell, which can also immobilize the cell and can serve as a ground electrode or by moving the cell through a layer of inert hydrophobic liquid.
  • sample transfer system only requires very small amounts of each test compound. If the automated system is used in combination with microtiter plates, the volume of each test compound solution can be as low as 30 microlitres. Standard well plates can be used (to date test have been realized with 96 and 384 microwells). Moreover, after the sample is removed from the well, the liquid remains in the microwell and can be reused for measurements on another sample. Contamination between wells can be avoided by rinsing the sample in fresh solution either in a perfusion chamber or in a microwell. Reducing the volume that is maintained around the sample minimizes dilution of the test solution. Measurements in the Xenopus oocyte recording example (presented below) indicate that 20 or more cells can be probed in a single well that contains 45 ⁇ l of solution before significant dilution of the test solution (> 10%) is observed.
  • sample transfer system over other presently existing automated systems is that the liquid can be recovered after the measurement and be reused or analysed, for example for molecules secreted by the sample during the experiment.
  • test compounds can be used without contaminating the whole apparatus. This allows combination of electrophysiological measurements with biochemical experiments at the single cell level.
  • Another advantage is that several compounds can be tested on the same sample, allowing direct comparison of the amplitude of the elicited response. Conversely, the system allows measuring the individual response of several different samples in the same liquid, permitting to easily calculate mean responses.
  • sample transfer system can be used in a wide range of applications that require transfer of samples (eg. cells, biological or non-biologic material) into different liquids present in small volume and with minimal mechanical forces applied to the tested sample and allowing testing of the sample or liquid using a wide range of techniques. Examples presented below illustrate, in a non-exhaustive way, the adequacy of this method for delicate measurements such as electrophysiological recording while testing cells in different solutions.
  • samples eg. cells, biological or non-biologic material
  • Examples presented below illustrate, in a non-exhaustive way, the adequacy of this method for delicate measurements such as electrophysiological recording while testing cells in different solutions.
  • the sample transfer system according to the invention may be advantageously used in an automated system for electrophysiological fluorometric or biochemical measurements on cells exposed to different solutions
  • Liquid handling has become a field of large development with liquid handlers that have the capacity of pumping or injecting solutions from single or multiple heads.
  • liquid handlers that have the capacity of pumping or injecting solutions from single or multiple heads.
  • many efforts produced by many companies i.e. Gilson, Tecan, Beckman, ?” liquid handling remains difficult and often sheer forces applied to the tested sample or other mechanical problem related to fluid handling can result in undesired side effects.
  • the sample transfer system is designed to carry out measurement from one or many samples at the same time.
  • the sample transfer system is well suited for low to medium and high throughput analysis. Typically if the measurement requires a minute and assuming continuous work, single head measurement will be limited to about 1400 measures/day. Use of multiple head with 12 or 96 sample holders proportionally extends measurements to respectively 17000 and 138000 measures/day.
  • Ligand fishing using cells, tissue samples or solid substrates Fluorescence measurements using single or multiple samples
  • sample transfer system An important feature of the sample transfer system according to the invention is its capacity of challenging multiple samples with a minimum and reusable volume of test solution. Recovery of the test solution is possible at the end of the experiments. This additional feature opens new strategies such as "ligand fishing".
  • membrane proteins including but not limited to voltage- dependent ion channels, ligand-gated ion channels or metabotropic receptors and their role in physiological processes and disease states has underlined the importance of developing new drugs targeted at these proteins.
  • the effect of individual compounds or mixtures of compounds such as natural extracts or chemical libraries on the electrophysiological properties of cells and/or on specific membrane proteins can be measured in Xenopus oocytes or other cells.
  • Cultured or freshly dissociated cells expressing the channels of interest are manually voltage clamped and the cell is then exposed to a test solution applied in a perfusion stream that is then aspirated to the waste.
  • test solution applied in a perfusion stream that is then aspirated to the waste.
  • APCs The development of APCs has partially automated this process, however, each volume of test solution can be used only once and cannot be conserved for further testing or use.
  • the sample transfer system allows to continuously record the electrophysiological activity of a cell while transferring it between different test solutions.
  • the effects of different solutions on cells loaded with ratiometric or non-ratiometric ion or voltage sensitive dyes can be measured using the sample transfer system.
  • Cells loaded with dye are contained in the sample holder and transferred between different wells containing different test compounds.
  • a light-conducting device, such as an optical fiber is held on the sample holder close to the sample and the changes in emitted light in the different solutions are measured by suitable measuring apparatus connected to the other end of the optical fiber.
  • the sample transfer system enables samples loaded with radiolabeled or non radiolabeled substances to be transferred between different microwells filled with desired solutions. Measurement of the substance efflux into the solution can be determined by subsequent analysis of the microwell liquid. Alternatively, samples can be transferred into liquid containing labeled substances, and influx into the sample can be measured by analysis of the solution or the sample content.
  • Fluorescent probes or any adequate reporter molecule can be equally used instead of the radiolabeled substance. d) Studies of efflux or influx of unlabeled substances
  • the incubation chambers Given the small volume size of the incubation chambers (within tens of microliters) it is possible to examine substances released by a sample. For example, brain slices, are known to release neurotransmitters in the extracellular space upon electrical or chemical stimulation. Detection of the neurotransmitters released in the microwells can be done using appropriate detection methods such as voltametry, high pressure liquid chromatography (HPLC), mass spectrometry (MS) spectrophotometry etc.
  • HPLC high pressure liquid chromatography
  • MS mass spectrometry
  • release measurements systems are available, they are often cumbersome and difficultly amenable to automation, especially when in the experimental paradigm requires electrical stimulation or culture conditions.
  • the sample transfer system opens new possibility of challenging the effects of drugs or any chemical on the substance released in response to a given stimulus. Measurements can be done either in singular or multiple mode depending upon the design of the sampler holder.
  • the sample transfer system can be used to detect influx of substances into the sample. Monitoring of the microwell solution content or determination of the substance in the specimen can be used to quantify the substance influx.
  • sample transfer system in placing a sample (or multiple samples) that contains a target (binding protein, ion channel, receptor or equivalent) into a small volume of liquid that contains a mixture of potential ligands. Specific binding of any of these molecules to the sample will cause i) a reduction of the amount of that molecule in the liquid and ii) binding of the molecule on the sample. Detection of the ligands that have been depleted from the original solution or alternatively that are bound to the sample will allow to screen large compound libraries such as those encountered in venom fractionation or testing of chemical libraries .
  • Such detection can for example be performed by differential display analyses using mass spectrometry and proteomic techniques, or any other detection system including but not limited to immunoassays, fluoresence, radioactivity, spectrophotometry, etc.
  • the sample can also be non-living material such as proteins, receptor fragments or antibodies anchored or attached to a solid substrate.
  • a technique analogous to ligand fishing can be designed for labelled compounds.
  • the ligand of interest is tagged, for instance with a fluorescent reporter, binding of a molecule to the ligand of interest can, for instance, be monitored by fluorescence measurement. Monitoring can be done in a continuous or discontinuous way depending upon the type of measurements.
  • FRET Fluorescence Activated Reassisted laser desorption
  • Insertion of light guides in the recording head can allow FRET measurements to be performed either in discrete or continuous way during the sample transfer system operation. Alternatively, given its mechanical stability the sample can be monitored using a more conventional optical set of lenses.
  • Typical example of application could be found in measurements of protein activation by a tagged ligand or if the protein contains both the donor and acceptor of fluorescence such as that found in "chameleon proteins". Binding of the ligand causes a structural change in the protein, which changes the distance between the donor and acceptor groups.
  • the sample transfer system allows to efficiently transfer the sample (or multiple samples) in different test solutions with precision and automatic handling.
  • Such application requires a specific sample holder that has low adsorption coefficients for the ligand of interest and is non-toxic for the sample.
  • the sample-holder serves four purposes: i) mechanical holding of the sample, ie. immobilisation, ii) maintenance of a liquid layer around the sample, iii) protection from the mechanical forces of passing through the liquid-air interface, iv) grounding of the electrical circuit in the case of electrical measurement from the sample.
  • sample transfer system can be used to increase the measurement throughput by enabling measurements to be carried out in parallel.
  • sample holder can also supply oxygenation to the tissue. Negative pressure can also be applied through the sample holder to maintain strong contact between the sample and the sample holder, eg. In the case of extracellular electrophysiological recording from tissue slices and samples.
  • the sample-holder serves three purposes: i) mechanical holding of the cell, ii) maintenance of a liquid layer around the oocyte, and protection from the mechanical forces of passing through the liquid-air interface iii) grounding of the electrical circuit.
  • Specific sample holders can be designed for cell culture of adherent or non-adherent cells, tissue slices, brain slices that can be stimulated during or recorded during solution exposure etc.
  • Figure 1 shows a picture and a corresponding drawing of a sample holder and microelectrodes for electrophysiological recording.
  • Figure 2 shows a picture and a corresponding drawing of a sample holder containing a
  • Xenopus oocyte with microelectrodes for electrophysiological recording Xenopus oocyte with microelectrodes for electrophysiological recording.
  • Figure 3 shows a picture and a corresponding drawing of a Xenopus oocyte in a sample holder in the recording configuration, with glass microelectrodes inserted in a perfusion stream.
  • Figure 4 represents a sequence of events involved in an automated oocyte loading.
  • Figure 5 shows an example of a concentration response curve for inhibition of human alpha 7 nicotinic acetylcholine receptors by methyllycaconitine (MLA).
  • the sample transfer system is preferably based on a three X-Y-Z movement that is controlled by a computer. This positional system displaces the microwells in relation to the sample or vice versa to incubate the sample in a given liquid.
  • the sample transfer system is controlled by a proprietary software.
  • a Xenopus oocyte 2 is placed in a small basket or appropriately shaped support 1.
  • the support is made from a spiral of coated metal wire, however this can be any shape and can also be uncoated. The coating minimises the interaction of the metal with the sample 2.
  • This support also forms the ground electrode for the recording circuit through the open extremity of the wire.
  • This support immobilizes the oocyte 2 and allows penetration by electrodes 3,4.
  • the spiral has a conical shape with the larger opening at the top and a 5 degree angle.
  • the spiral support also protects the oocyte 2 from the mechanical forces of passing through the liquid-air interface and the support allows liquid exchange around the cell.
  • cells are aspirated using a standard 10 ⁇ l pipette tip with microelectrodes positioned on either side.
  • a syringe pump under computer control aspirates the cell and holds it firmly at the pipette tip.
  • the ground electrode is shaped into a spiral or a ring with a diameter slightly larger than that of the cell, and is positioned around the cell, causing the formation, by capillary forces, of a thin layer of aqueous solution around the oocytes.
  • microelectrodes Penetration of the cell from above by microelectrodes, allows electrophysiological measurements to be made using standard configurations (current clamp or voltage clamp). Voltage clamping is performed by an amplifier also under computer control (i.e. Geneclamp 500 from Axon instrument). Ground electrodes are placed in the vicinity of the cell. Test solutions are deposited in microwells and the cell, which is firmly held by the pipette tip, is moved between wells using an X-Y-Z positioner controlled by a computer. In another embodiment the microplate is moved relative to the sample holder in the X, Y and Z directions. The sample holder remains stationary, thus minimising possible vibration of the sample holder.
  • a layer of an inert, hydrophobic biocompatible fluid for example mineral oil, is disposed on top of the test compound solution baths and the cell is moved through this fluid from one bath to another without passing the liquid/air interface.
  • the transfer of the oocyte from a microplate with conical wells into the sample holder is automated and controlled by the software. Loading of the oocyte can be started by the user or can be triggered by pre-determined criteria in the experimental protocol.
  • the sequence of events for oocyte loading is shown in fig. 4. Unloading is also automated and is the reverse of the loading procedure.
  • the sequence illustrated in figure 4 comprises the following steps :
  • Microelectrodes are positioned above the empty sample holder.
  • Oocyte is aspirated into loading tube and loading tube moves up. 5.) Sample holder moves horizontally into position below loading tube. 6.) Loading tube descends above sample holder and the oocyte is expelled from loading tube into the sample holder by gentle pressure. 7.) Loading tube moves up and sample holder moves horizontally into position below electrodes.
  • the impaled oocyte and the sample holder are illustrated iin the configuration for electrophysiological recording.
  • the assembly can now be moved through the liquid air interface without damage or movement of the sample or disturbance of the recording configuration.
  • a Xenopus oocyte expressing human ⁇ 7 nicotinic acetylcholine receptors was placed in the sample holder and impaled with two electrode to establish voltage clamp.
  • the cell was then briefly challenged with an acetylcholine test pulse in a perfusion chamber and its response recorded.
  • the test pulse and recording lasted 10 s and the cell was then automatically transferred into a microwell from a 96 microtiter plate containing the competitive inhibitor methyllycaconitine.
  • the cell was incubated for 10 s in a given concentration of methyllycaconitine and its response to acetylcholine was tested upon return into the perfusion chamber.
  • MLA methyllycaconitine

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Abstract

La présente invention concerne un système de transfert d'échantillons convenant pour des mesures électrophysiologiques sur des cellules mises sous tension, des fragments de membrane, des tissus, des embryons, des petits organismes vivants ou des échantillons inorganiques pouvant être exposés à différentes solutions composées, lesdites solutions composées pouvant être récupérées après les mesures. L'invention concerne également une méthodes de transfert d'une cellule ou d'un échantillon biologique, notamment d'un bain de solution aqueuse à un autre bain de solution aqueuse, tout en le protégeant contre une exposition à des forces mécaniques au niveau de l'interface air-liquide.
PCT/IB2005/053825 2004-11-26 2005-11-19 Systeme de transfert d'echantillons Ceased WO2006056920A1 (fr)

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Application Number Priority Date Filing Date Title
CA002589114A CA2589114A1 (fr) 2004-11-26 2005-11-19 Systeme de transfert d'echantillons

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CHPCT/CH2004/000712 2004-11-26

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008055612A1 (fr) * 2006-11-06 2008-05-15 Universität Wien Dispositifs et procédés pour analyses électrophysiologiques de cellules
WO2011015864A1 (fr) * 2009-08-07 2011-02-10 Isis Innovation Limited Essai
US8293532B2 (en) 2009-03-26 2012-10-23 Dow AgroSciences, L.L.C. Method and apparatus for tissue transfer
US20230039753A1 (en) * 2021-08-03 2023-02-09 Leica Mikrosysteme Gmbh Sample transfer device

Citations (7)

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Publication number Priority date Publication date Assignee Title
US1482966A (en) * 1922-06-24 1924-02-05 Llewellyn E W Bevan Bacteriological test apparatus
US4613573A (en) * 1982-05-20 1986-09-23 Hitachi, Ltd. Automatic bacterial colony transfer apparatus
US6159199A (en) * 1997-09-13 2000-12-12 Eppendorf-Netheler-Hinz Gmbh Device for the manipulation of cytotechnical instruments
WO2003048786A2 (fr) * 2001-11-30 2003-06-12 Bristol-Myers Squibb Company Configurations de pipettes et jeux de pipettes pour mesurer des proprietes electriques cellulaires
WO2003101586A1 (fr) * 2002-05-31 2003-12-11 Apollo Life Sciences Pty Limited Recuperation de cellules
US6664044B1 (en) * 1997-06-19 2003-12-16 Toyota Jidosha Kabushiki Kaisha Method for conducting PCR protected from evaporation
WO2004011937A1 (fr) * 2002-07-30 2004-02-05 Amersham Biosiciences Uk Limited Dispositif d'examen de cellules utilisant une methode patch clamp

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1482966A (en) * 1922-06-24 1924-02-05 Llewellyn E W Bevan Bacteriological test apparatus
US4613573A (en) * 1982-05-20 1986-09-23 Hitachi, Ltd. Automatic bacterial colony transfer apparatus
US6664044B1 (en) * 1997-06-19 2003-12-16 Toyota Jidosha Kabushiki Kaisha Method for conducting PCR protected from evaporation
US6159199A (en) * 1997-09-13 2000-12-12 Eppendorf-Netheler-Hinz Gmbh Device for the manipulation of cytotechnical instruments
WO2003048786A2 (fr) * 2001-11-30 2003-06-12 Bristol-Myers Squibb Company Configurations de pipettes et jeux de pipettes pour mesurer des proprietes electriques cellulaires
WO2003101586A1 (fr) * 2002-05-31 2003-12-11 Apollo Life Sciences Pty Limited Recuperation de cellules
WO2004011937A1 (fr) * 2002-07-30 2004-02-05 Amersham Biosiciences Uk Limited Dispositif d'examen de cellules utilisant une methode patch clamp

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008055612A1 (fr) * 2006-11-06 2008-05-15 Universität Wien Dispositifs et procédés pour analyses électrophysiologiques de cellules
US8293532B2 (en) 2009-03-26 2012-10-23 Dow AgroSciences, L.L.C. Method and apparatus for tissue transfer
US8409860B2 (en) 2009-03-26 2013-04-02 Dow Agrosciences, Llc. Method and apparatus for tissue transfer
US8722407B2 (en) 2009-03-26 2014-05-13 Dow Agrosciences, Llc. Method and apparatus for tissue transfer
US9500570B2 (en) 2009-03-26 2016-11-22 Dow Agrosciences Llc Apparatus for tissue transfer
WO2011015864A1 (fr) * 2009-08-07 2011-02-10 Isis Innovation Limited Essai
US20230039753A1 (en) * 2021-08-03 2023-02-09 Leica Mikrosysteme Gmbh Sample transfer device
US12429403B2 (en) * 2021-08-03 2025-09-30 Leica Mikrosysteme Gmbh Sample transfer device

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