System and method for handling sample for study in charged particle apparatus, such as transmission electron microscope

Abstract

To provide an improved sample storage and handing system that provides an improved user experience for storing samples, transferring samples, and using these samples in a charged particle apparatus, such as a charged particle microscope.SOLUTION: A system includes a storage apparatus for storing a plurality of samples, and a Charged Particle Apparatus (CPA), such as a cryo-TEM, at a location remote from the storage apparatus. The system further includes a transfer device that is releasably connectable to the storage apparatus, and that is releasably connectable to the CPA as well. As defined in the specification, the transfer device is arranged for acquiring a sample from the plurality of samples when connected to the storage apparatus, and arranged for transferring the sample from the transfer device to the CPA when connected to the CPA.SELECTED DRAWING: Figure 7b

Description

[Technical Field]

[0001] The present invention relates to a storage apparatus, a transfer device, and a transmission electron microscope. Charged Particle Microscope (TEM) and a Charged Particle Apparatus (CPA), such as a Charged Particle Microscope (CPM). [Background technology]

[0002] Biology is the natural science that studies life and living organisms, including their physical structure, chemical processes, molecular interactions, physiological mechanisms, development, and evolution.

[0003] Cell biology is the branch of biology that studies the structure and function of cells, the basic units of life. Cell biology covers the physiological properties, metabolic processes, signaling pathways, life cycle, chemical composition, and interactions of cells with their environment. In cell biology, molecular recognition between macromolecules governs all of the most sophisticated processes within the cell. The most common macromolecules include biopolymers (nucleic acids, proteins, carbohydrates, and lipids) and large non-polymers (such as lipids and macrocycles).

[0004] Many researchers are interested in studying macromolecular complexes in their native environment at high resolution to reveal their structural dynamics and interactions. Charged particle microscopy can be used for this purpose.

[0005] Charged particle microscopy, especially electron microscopy, Electron microscopy (EM) is a well-known and increasingly important technique for imaging microscopic objects. Historically, the basic genus of electron microscopes has evolved into several well-known instrument types, such as transmission electron microscopes (TEM), scanning electron microscopes (SEM), and scanning transmission electron microscopes (STEM), as well as various variants, such as so-called "dual beam" tools (e.g., FIB-SEM) that employ a "mechanical" focused ion beam (FIB) as an adjunct to, for example, ion beam milling or ion-beam-induced deposition (IBID). Those skilled in the art will be familiar with different types of charged particle microscopy.

[0006] In an SEM, a scanning electron beam is irradiated onto a sample, causing the sample to emit "auxiliary" radiation in the form of secondary electrons, backscattered electrons, X-rays, and cathodoluminescence (infrared, visible, and / or ultraviolet photons). One or more components of this emitted radiation can be detected and used for sample analysis.

[0007] In a TEM, a beam of electrons is transmitted through a specimen, creating an image from the interaction of the electrons with the specimen as the beam passes through it. This image is magnified and focused onto an imaging device, such as a fluorescent screen, a layer of photographic film, or a sensor such as a scintillator attached to a charge-coupled device (CCD). The scintillator converts the primary electrons in the microscope into photons that the CCD can detect.

[0008] EM offers multiple methods for studying biological samples, while conventional TEM is used to study the overall morphology of biological samples. Electron crystallography and single particle analysis are dedicated to the study of proteins and macromolecular complexes, while (cryo-)electron tomography and cryo-EM of vitreous sections (CEMOVIS) target cellular organelles and molecular structures. In cryo-EM and CEMOVIS, samples are preserved by rapid freezing using vitrification techniques and then observed in a cryo-TEM. CEMOVIS adds the ability to freeze samples (cryosectioning), which can be performed using cryo-FIB techniques. Summary of the Invention [Problem to be solved by the invention]

[0009] Preparing biological samples for study in analytical devices is often time-consuming and labor-intensive. Cryo-EM specimen preparation, for example, involves taking an aqueous sample of biological material (usually a purified protein complex), applying it to a support structure (grid), reducing it to a layer as thin as possible (100-800 Å depending on the size of the biomolecule), and then freezing this layer quickly enough to prevent water from crystallizing. Many aspects of this process of preparing biological samples are problematic.

[0010] Once a cryo-EM sample has been prepared, it must be stored and handled in the proper conditions for later use in charged particle microscopy. For this purpose, multiple cryo-EM samples can be stored in individual grid boxes. These grid boxes can then be placed in conical Falcon tubes and stored in long-term liquid nitrogen storage dewars.

[0011] If necessary, remove the Falcon tube from the Dewar and remove the correct grid box corresponding to the desired sample from the Falcon tube.

[0012] A variety of methods can be applied to get the desired sample into the cryo-EM.

[0013] In a first embodiment, a cryo-transfer holder can be used. This is a liquid nitrogen holder designed for frost-free transfer of samples to a transmission electron microscope (TEM) at liquid nitrogen temperatures. The sample is removed from the grid box and manually placed in the cryo-transfer holder. The cryo-transfer holder can then be connected to the TEM. The cryo-transfer holder holds the sample in place within the TEM during acquisition. Because of a relatively high failure rate of cryo-holder insertion into the microscope, placing the cryo-transfer holder within the TEM has proven cumbersome. A significant amount of sample drift occurs within the first 20 minutes after connecting the cryo-transfer holder. Furthermore, the cryo-transfer holder requires manual refilling of liquid nitrogen every 12 hours, and the microscope's cryo-cycle, required after 4-5 insertions, is long, at 4 hours. Therefore, the cryo-transfer holder limits the throughput of samples within the TEM.

[0014] In a second embodiment, samples are loaded into a TEM using a cryogenic sample handling robot. Such a sample handling robot is known, for example, as the AutoLoader product sold by Thermo Scientific™. The AutoLoader is a module installed as part of a TEM. Samples are manually placed into AutoLoader Cartridges. These AutoLoader Cartridges are stored in a cryogenic storage chamber, such as a Dewar. When needed, the Cartridges are removed from the Dewar and placed into the AutoLoader Module. The desired sample is then removed from the cartridge by the handling robot, which transfers the sample to a sample holder in the TEM. The sample can then be imaged using the TEM. While this known system provides excellent results, particularly in terms of sample transfer quality and screening throughput, there is room for improvement on other levels, such as improvements in sample loading into the cartridge, complexity, ease of installation and maintenance, and associated costs.

[0015] One or more of these embodiments may require the user to perform steps to latch the cryogenic transfer holder and / or cartridge, or perform other tasks, including connecting cables, opening and / or closing transition chambers, opening and / or closing valves, and / or inserting samples.

[0016] It follows from the above that an improved sample storage and handling system is desired that provides improved security and an improved user experience for storing, transporting, and studying cryogenic samples within a charged particle microscope or similar device.

[0017] Generally, there is a need for improved sample storage and handling systems that provide an improved user experience for storing samples, transporting samples, and using those samples in charged particle instruments such as charged particle microscopes. Thus, the present disclosure is not limited to cryo-EM samples, but can also be used for non-cryo-EM samples. [Means for solving the problem]

[0018] With the above in mind, the present disclosure provides a sample handling and storage system.

[0019] The sample handling and storage system includes a storage device for storing a plurality of samples. The storage device is configured to store samples, which may be cryo-EM samples. The storage device may be configured to store the samples under cryogenic conditions.

[0020] The sample handling and storage system further comprises a charged particle apparatus (CPA) located remotely from the storage apparatus, the distance between the CPA and the storage apparatus being such that direct transfer of samples between the storage apparatus and the CPA is difficult or substantially impossible, and therefore the system further comprises a transfer device configured to be movable between the storage apparatus and the CPA.

[0021] The transfer device is releasably connectable to the storage apparatus and the CPA. This means that the transfer device can be connected and disconnected to the storage apparatus. The transfer device is further releasably connectable to the CPA, and thus the transfer device can be connected and disconnected to the CPA. In the disconnected state of the transfer device, the transfer device is movable between the storage apparatus and the CPA, specifically by a human operator carrying the transfer device from and to the storage apparatus and the CPA, respectively, or vice versa. In the connected state of the transfer device, sample transfer is possible between the transfer device and the apparatus to which it is connected. Thus, the system is configured to transfer a sample from the storage apparatus to the transfer device when the transfer device is connected to the storage apparatus, and to transfer the sample from the transfer device to the CPA when the transfer device is connected to the CPA. Reverse transfer from a CPA to a storage apparatus by the transfer device is also conceivable. In other words, the transfer device is configured to acquire a sample at a CPA and transfer the sample from the transfer device to the storage apparatus. This increases the versatility of the storage and handling system as defined herein.

[0022] This allows a single transfer device to be connected to a storage device to retrieve a sample, transport the transfer device with the sample to a CPA such as a TEM, and load the sample into the CPA. The transfer from the transfer device to the CPA may include transfer of a sample holder (i.e., sample stage) that is part of the CPA. The transfer from the storage device to the CPA can be performed manually, i.e., by a human operator carrying the transfer device from the storage device to the CPA.

[0023] As defined herein, a sample handling and storage system comprises at least one suction disk mechanism for securing the connection between the transfer device and at least one of the storage apparatus and the CPA.

[0024] By using a suction disk mechanism, a reliable connection can be established between the transfer device and at least one of the storage device and the CPA. This allows the transfer device to be easily and quickly connected to the storage device and / or CPA. The connection is reliable and reproducible, allowing safe transfer of samples between the various devices that are established. Thus, the objectives as defined herein are achieved.

[0025] As previously mentioned, the transfer device can be connected to a storage device and a charged particle device. For simplicity, this will be referred to as a "desired device." Thus, the transfer device can be connected to a desired device, including a storage device and / or a CPA.

[0026] The suction disk mechanism can include at least a first seal ring. When the transfer device is connected to the desired device, the first seal ring contacts the transfer device and the desired device. The first seal ring, at least a portion of the transfer device, and at least a portion of the desired device (i.e., storage device or CPA) define a suction disk volume. By reducing the pressure within this suction disk volume, the resulting reduced pressure ensures a more secure connection between the transfer device and the desired device. Reducing the pressure within the suction disk volume can be accomplished in multiple ways, including reducing the pressure with a pump element and expanding the volume of the suction disk volume while keeping the housing airtight. Expanding the volume can be accomplished, for example, by using flexible or movable wall elements.

[0027] Advantageous embodiments are described below.

[0028] In one embodiment, the transfer device comprises an elongated housing. The storage apparatus may comprise a receiving recess adapted to receive at least a portion of the elongated housing of the transfer device. Similarly, the CPA may comprise a corresponding receiving recess for receiving at least a portion of the elongated housing of the transfer device. The receiving recess of the CPA may generally correspond to the receiving recess of the storage apparatus, although variations may of course exist. The use of an elongated housing and a corresponding recess may make the initial connection of the transfer device to the CPA and / or storage apparatus quick and easy. Once the elongated transfer device is inserted into the recess, a suction disk mechanism may be activated to secure the connection so that sample transfer may occur.

[0029] In one embodiment, the side walls of the receiving recess provide guide surfaces for the housing of the transport device. Furthermore, the recess may comprise a bottom wall providing an abutment surface for the housing. By inserting the elongate housing of the transport device into the receiving recess and continuing the insertion movement until the top surface of the transport device reaches the bottom wall of the recess, it is ensured that the transport device is connected to the corresponding apparatus in a predictable manner, in particular with its reproducible position.

[0030] In one embodiment, the elongate housing comprises a connection surface that, in a connected state, faces the bottom wall of the recess and at least partially contacts the bottom wall.

[0031] It may be advantageous to provide a suction disk mechanism on the transfer device. In other embodiments, suction disk mechanisms may be provided on the storage device and the CPA. In further embodiments, the storage device, the CPA and the transfer device each have their own suction disk mechanism. However, from the standpoint of cost and connectability, it may be advantageous to only provide a transfer device with a suction disk mechanism. In that case, in one embodiment, it is preferred that the suction disk mechanism is provided on the connecting surface of the transfer device, so that it can be brought into contact with the bottom wall of the recess to temporarily establish a fixed connection.

[0032] In one embodiment, the transfer device comprises a transfer port provided on the connection surface, and the bottom wall of the recess comprises a transfer opening. The transfer device can comprise a transfer vault provided within the elongate housing. The transfer port can be used to gain access to the transfer vault. The transfer vault can be configured to maintain the sample in a desired environment. If cryo-EM samples are used, for example, the transfer vault can be configured to keep the cryo-EM at or near cryogenic conditions. This can include active and / or passive cooling elements.

[0033] In one embodiment, the suction disk mechanism surrounds the transfer port when the transfer device is connected to a desired device. To this end, the suction disk mechanism can include a first seal ring and a second seal ring. The second seal ring has smaller dimensions than the first seal ring. The first seal ring completely surrounds the second seal ring. The first seal ring and the second seal ring, together with the transfer device and the desired device, define a suction disk volume. Thus, the first seal ring defines the outermost contour of the suction disk volume, and the second seal ring defines the innermost contour of the suction disk volume. The second seal ring surrounds the transfer port.

[0034] It should be noted that in the above embodiments, the suction disk mechanism can be provided on the transfer device. It is also contemplated that the suction disk mechanism can be provided on the desired apparatus. In embodiments using two seal rings, the seal rings can be provided on the desired apparatus such that when the transfer device is connected to the desired apparatus, the second seal ring surrounds the transfer port of the transfer device.

[0035] In one embodiment, the transfer device and at least one of the storage device and the CPA include electrical contact elements. The electrical contact elements may be provided on the transfer device and the desired device. The electrical contact elements are configured to contact each other when the transfer device is connected to the at least one of the storage device and the CPA. The electrical contact elements may be provided on the elongated housing of the transfer device and on a recess in the desired device.

[0036] As mentioned above, the elongate housing may have a connection surface that, in the connected state, faces the bottom wall of the recess. The suction disk mechanism may be configured to act on the bottom wall of the recess and on the connection surface. In particular, the suction disk mechanism may be provided on the connection surface of the transfer device. Furthermore, it is also conceivable that electrical contact elements are provided on the connection surface and on the bottom wall.

[0037] In one embodiment, the transfer device includes a transfer mechanism configured to retrieve the sample from the storage device when connected to the storage device and deliver the sample to the CPA when connected to the CPA. The transfer mechanism can be disposed within the elongated housing and configured to store the sample in the transfer storage chamber. The transfer mechanism can be configured to move the sample from the transfer storage chamber through the transfer port to the desired device. The transfer mechanism ensures safe and reliable transfer between devices of the system and the transfer device. No manual labor or manual sample handling is required to transfer the sample from the storage device to the transfer device. Additionally, no manual labor or manual sample handling is required to transfer the sample from the transfer device to the CPA.

[0038] The transfer mechanism may, for example, comprise a gripper, which may be configured to grip the sample.

[0039] The samples used in the system can include EM grids. These grids themselves are known to those skilled in the art and may comprise small (a few millimeters) copper disks with a fine mesh with carbon foil on top. The grids may also be composed of other materials. The samples may be materials science samples that are applied to the sample grids. The samples may be stored in a storage device. A human operator can manually load the samples into the storage device. In one embodiment, that is the only direct human sample handling required for use with the system.

[0040] Manually loading samples into the storage device may include manually loading individual samples into sample cassettes. The storage device may include at least one cassette for storing at least a portion of the plurality of samples. A human operator may place desired samples into such a cassette and then place the cassette into the storage device. Of course, in that case, a transfer device is configured to retrieve the samples from the cassette.

[0041] The storage device can be part of a first work station. The first work station includes a human operator desk where a human operator can sit or stand. The human operator can manually store or retrieve multiple samples from the storage device. The human operator can additionally or alternatively connect a transfer device to the storage device. The transfer device can be docked to part of the first work station for that purpose.

[0042] In one embodiment, the storage device and the CPA each include a first docking member, and the transfer device includes a further (second) docking member configured to mate with the first docking member. The first docking member may include a recess as described herein. The second docking member may include (a portion of) an elongated housing as described herein. At least one of the first and second docking members may include part of a suction disk mechanism, and preferably, the second docking member includes the suction disk mechanism. The first and second docking members may include electrical contact elements. The use of the first and second docking members ensures that it is relatively easy to establish a connection between the transfer device and the storage device, disconnect the transfer device from the storage device, and move the transfer device to the CPA, after which the transfer device is connected to the CPA to transfer a sample from the transfer device to the CPA. In particular, the suction disk mechanism allows for easy connection and release during transfer of a sample from the storage device to the CPA and vice versa.

[0043] In one embodiment, each of the first docking members includes a first valve configured to be closed in a detached state and openable in a docked state. The second docking member can include a transfer port. The transfer port can be opened in a docked state and closed in a detached state. In this manner, preferred sample conditions (e.g., temperature, humidity, pressure, etc.) can be maintained within the storage apparatus, transfer device, and CPA. The transfer device can be connected to the storage apparatus by the docking member, and the valve and / or transfer port can be opened so that the transfer chamber of the transfer device is fluidly connected to the storage chamber of the storage apparatus. Sample transfer can then occur via the fluid connection between the storage apparatus and the transfer device.

[0044] The storage apparatus may comprise an operator input device and a control unit. In such an embodiment, the input device may be part of the first workstation. The operator input device may be configured for selecting a cryogenic sample to be transferred by a human operator. The control unit is configured to control the storage apparatus and the transfer device for transferring the selected cryogenic sample from the storage apparatus to the transfer device, in particular automatically. This improves the reliability of the system by allowing correct labeling and subsequent handling of samples.

[0045] According to one aspect, there is provided a transfer device for transferring samples for use in a sample handling and storage system as defined herein. The transfer device is releasably connectable to a storage apparatus for storing a plurality of samples, and samples can be transferred from the storage apparatus to the transfer device when the transfer device is connected to the storage apparatus. The transfer device is further releasably connectable to a charged particle apparatus (CPA), and samples can be transferred to the CPA when the transfer device is connected to the CPA. As defined herein, the transfer device comprises at least one suction disk mechanism for ensuring the connection between the transfer device, the sample handling and storage system, and the CPA. The suction disk mechanism may be embodied as described herein above in relation to a suction disk mechanism that is part of the transfer device.

[0046] In one embodiment, the transfer device comprises an elongate housing having at least one connecting surface, and a suction disk mechanism may be provided on said transfer device, in particular on said connecting surface.

[0047] The transfer device may include a transfer port provided on the connection surface.

[0048] In one embodiment, a suction disk mechanism surrounds the transfer port.

[0049] According to one aspect, the present disclosure relates to a sample handling and storage system configured to store and handle samples for use in charged particle instruments, where the samples are handled under cryogenic conditions. One example of this is cryo-electron microscopy (cryo-EM), which is a cryo-microscopy technique applied to samples that are cryogenically cooled and embedded in a vitreous water environment. These types of samples are often referred to as cryo-EM samples, although typically these samples can be used in other charged particle instruments as well. Hereinafter, this type of sample will be referred to as a cryogenic sample (CS).

[0050] Thus, in one embodiment, the present disclosure may relate to a cryogenic sample handling and storage system. The handling and storage system may be configured to handle and store cryo-EM samples.

[0051] The cryogenic sample storage and handling system defined herein allows samples stored under cryogenic conditions to be quickly and easily collected into a charged particle instrument, such as a TEM, for study. Sample collection (i.e., retrieval from the storage device) and sample drop-off (i.e., transfer to the CPA) can be performed semi-automatically, i.e., without a human operator actually handling the sample. Transfer from the storage device to the CPA can be performed manually, i.e., by a human operator carrying a transfer device from the storage device to the CPA.

[0052] This embodiment provides an improved cryogenic sample storage and handling system that can be used to easily and safely store, transport, and store such cryo-EM samples to a charged particle instrument such as a cryo-TEM, and return the sample to a storage device where it can be stored under cryogenic conditions. Thus, an improved cryogenic sample storage and handling system is provided.

[0053] In one embodiment, the cryogenic sample storage device comprises a cryogenic storage chamber. The storage chamber may be fluidly connected to the transfer device, in particular to the transfer chamber. The storage chamber may be directly connected to the transfer chamber with the transfer device connected. An intermediate chamber may also be provided. In this case, samples may be transferred from the storage chamber to the intermediate chamber and then from the intermediate chamber to the transfer chamber of the transfer device. The storage device may also comprise a transfer mechanism. The storage device transfer mechanism may be configured to cooperate with the transfer mechanism of the transfer device, so that efficient sample transfer between the storage device and the transfer device may be performed.

[0054] It should be noted that the general system described herein may include at least one additional CPA. In that case, the transfer device may be configured to be releasably connectable to the additional CPA, and thus the transfer device may also be connected and disconnected to the additional CPA. In the disconnected state of the transfer device, the transfer device is movable between the storage apparatus and the CPA and at least one additional CPA. In the connected state of the transfer device, sample transfer between the transfer device and an apparatus to which the transfer device is connected, such as an additional CPA, is possible. Thus, the transfer device may be configured to transfer the sample from the transfer device to the additional CPA when connected to the additional CPA. Thus, a single transfer device can be used in a system where multiple CPAs are present. This central approach to the storage and handling system ensures that multiple CPAs do not each require a specific, dedicated transfer mechanism, as would be the case if each CPA were equipped with an AutoLoader module. In this way, the system may be simple in construction and therefore relatively inexpensive.

[0055] The systems, apparatus, and devices described herein enable a method for transferring a sample to be carried out, the method comprising the steps of providing a sample handling and storage system as defined herein, the method comprising: - storing at least one sample in said storage device; - connecting said transport device to said storage device; - transferring said sample from said storage apparatus to said transfer device; - removing said transport device from said storage apparatus; - moving the transfer device to the charged particle apparatus (CPA), the CPA being located away from the storage apparatus; - connecting said transport device to said CPA; - transferring the sample from the transfer device to the CPA.

[0056] The step of transferring the sample from the desired apparatus to the transfer device and vice versa may be performed mechanically. A mechanical transfer mechanism can be used to establish the transfer.

[0057] The step of transferring the sample may be performed automatically, meaning that no manual sample handling and / or manipulation from a human operator is required. However, it is conceivable that the human operator may initiate sample transfer, for example, by using a button, dial, knob, etc., or by entering a corresponding command into a user interface, such as a graphical user interface (GUI).

[0058] The steps of connecting and / or disconnecting can be performed by a human operator who physically connects the transfer device to the storage device or CPA. Portions of the connecting and / or disconnecting may, in one embodiment, require the use of a docking mechanism, such as opening and closing a valve.

[0059] The step of moving the transfer device may be performed by a human operator physically moving the transfer device to or from the storage device and / or CPA. [Effects of the Invention]

[0060] The methods and systems defined herein enable safe and effective sample transfer, where a human operator is used to transfer samples between associated apparatus, and where more specialized transfer mechanisms enable safe and reliable transfer from transfer device to apparatus, thus achieving the objectives as defined herein. [Brief explanation of the drawings]

[0061] The invention will now be elucidated in detail on the basis of exemplary embodiments and the accompanying schematic drawings. [Figure 1] 1 shows a longitudinal cross section of a charged particle microscope according to a first embodiment of the invention; [Figure 2] 2 shows a longitudinal cross section of a charged particle microscope according to a second embodiment of the invention; [Figure 3] 1 illustrates prior art sample handling and storage methods. [Figure 4] FIG. 1 illustrates one embodiment of the sample handling and storage method and apparatus defined herein. [Figure 5] FIG. 1 shows one embodiment of a transfer device for use in the sample handling and storage methods and apparatus defined herein. [Figure 6] FIG. 1 illustrates one embodiment of a transfer device and charged particle apparatus for use in the sample handling and storage methods and apparatus defined herein. [Figure 7a] 1 illustrates various steps of a method for transferring a sample within a cryogenic sample handling system as defined herein. [Figure 7b] 1 illustrates various steps of a method for transferring a sample within a cryogenic sample handling system as defined herein. [Figure 7c] 1 illustrates various steps of a method for transferring a sample within a cryogenic sample handling system as defined herein. [Figure 7d] 1 illustrates various steps of a method for transferring a sample within a cryogenic sample handling system as defined herein. [Figure 7e] 1 illustrates various steps of a method for transferring a sample within a cryogenic sample handling system as defined herein. [Figure 7f] 1 illustrates various steps of a method for transferring a sample within a cryogenic sample handling system as defined herein. [Figure 8a] 1 shows an embodiment of a suction disc mechanism as described herein. [Figure 8b] 1 shows an embodiment of a suction disc mechanism as described herein. [Figure 8c] 1 shows an embodiment of a suction disc mechanism as described herein. [Figure 8d] 1 shows an embodiment of a suction disc mechanism as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0062] FIG. 1 (not to scale) is a highly schematic depiction of one embodiment of a charged particle microscope M. More specifically, FIG. 1 shows one embodiment of a transmission microscope M, which in this case is a TEM / STEM (although in the context of the present invention, the transmission microscope M could equally usefully be, for example, an SEM (see FIG. 2) or an ion-based microscope). In FIG. 1, within a vacuum housing 2, an electron source 4 generates a beam B of electrons propagating along an electron-optical axis B′ and traversing an electron-optical illuminator 6, which serves to direct / focus the electrons onto a selected portion of a specimen S (e.g., which may be (locally) thinned / flattened). Also shown is a deflector 8, which (among other things) may be used to effect a scanning movement of the beam B.

[0063] The specimen S is held on a specimen holder H, which can be positioned with multiple degrees of freedom by a positioning device / stage A, which moves a cradle A' to which the holder H is (removably) fixed. For example, the specimen holder H can be equipped with (among other things) fingers movable in the XY plane (see the illustrated Cartesian coordinate system). Typically, movement parallel to Z and tilting about X / Y are also possible). Such movement allows various portions of the specimen S to be illuminated / imaged / inspected by an electron beam B moving along axis B' (in the Z direction) (and / or allows a scanning movement to be performed as an alternative to electron beam scanning). If desired, an optional cooling device (not depicted) can be in intimate thermal contact with the specimen holder H, thereby maintaining the specimen holder H (and the specimen S thereon) at, for example, cryogenic temperatures.

[0064] The electron beam B interacts with the specimen S in such a way as to cause it to emit various types of "stimulated" radiation, including (for example) secondary electrons, backscattered electrons, X-rays, and light radiation (cathodoluminescence). If desired, one or more of these radiation types can be detected using an analysis device 22, which can be, for example, a combined scintillator / photomultiplier tube or an EDX or EDS (energy dispersive X-ray spectroscopy) module. In such cases, images can be constructed using essentially the same principles as in an SEM. However, alternatively or additionally, electrons that traverse (pass) the specimen S, emerge / emit from the specimen S, and continue to propagate along axis B' (substantially, but generally with some degree of deflection / scattering) can be examined. This transmitted electron flux enters an imaging system (projection lens) 24, which typically includes a wide variety of electrostatic / magnetic lenses, deflectors, correctors (such as stigmators), and the like. In normal (non-scanning) TEM mode, this imaging system 24 can focus the transmitted electron beam onto a phosphor screen 26, which can be retracted / retracted (schematically indicated by arrow 26') out of the way of axis B' as desired. An image (or diffractogram) of (a portion of) the specimen S is formed on the screen 26 by the imaging system 24, which can be viewed through a viewing port 28 located in a suitable part of the wall of the housing 2. The retraction mechanism for the screen 26 can be, for example, mechanical and / or electrical in nature and is not shown here.

[0065] Instead of observing an image on the screen 26, one can take advantage of the fact that the depth of focus of the electron beam leaving the imaging system 24 is generally very large (e.g., on the order of one meter). As a result, various other types of analytical devices can be used downstream of the screen 26, such as: -TEM camera 30. At the position of camera 30, the electron beam can form a still image (or diffractogram) which can be processed by controller / processor 20 and displayed on a display device 14, such as a flat panel display. When not needed, camera 30 can be retracted / withdrawn (as shown diagrammatically by arrow 30') to move the camera off axis B'. - STEM camera 32. The output from camera 32 can be recorded as a function of the (X, Y) scanning position of beam B on specimen S, and an image can be constructed that is a "map" of the output from camera 32 as a function of X, Y. Camera 32 can also be an electron microscope pixel array detector (EMPAD), but camera 32 can comprise a single pixel, e.g., 20 mm in diameter, as opposed to the pixel matrix typically present in camera 30. Furthermore, camera 32 can generally be a 10 mm pixel array, e.g., a 10 mm pixel array. 2 images / sec) than a much higher acquisition rate (e.g., 10 6 points / sec). Again, when not needed, camera 32 can be retracted / retracted (as indicated diagrammatically by arrow 32') so as to be off axis B' (however, such retraction would not be necessary in the case of, for example, a donut-shaped annular dark field camera 32, in which a central hole allows the passage of the light beam when the camera is not in use). As an alternative to imaging using the camera 30 or 32, a spectroscopic device 34 can also be activated, which can be, for example, an EELS module.

[0066] It should be noted that the order / position of components 30, 32, and 34 is not strict and many possible variations are possible. For example, spectroscopic device 34 could be integrated with imaging system 24.

[0067] In the illustrated embodiment, the microscope M further comprises a retractable X-ray Computed Tomography (CT) module, generally designated by the reference numeral 40. Computed tomography (also called tomographic imaging) uses an electron source and (diametrically opposed) detectors to interrogate a specimen along different lines of sight to obtain insightful views of the specimen from different perspectives.

[0068] It should be noted that a controller (computer processor) 20 is connected to the various illustrated components via control lines (bus) 20'. This controller 20 may provide various functions such as synchronizing actions, providing set points, processing signals, performing calculations, and displaying messages / information on a display device (not shown). Of course, the (schematically depicted) controller 20 may be located (partly) inside or outside the housing 2 and may have a unitary or composite structure, as desired. The controller, as shown in this embodiment, comprises a data processing unit P configured to carry out the methods defined herein.

[0069] Those skilled in the art will understand that the interior of the enclosure 2 need not be maintained at a strict vacuum. For example, in so-called "environmental TEM / STEM," a background atmosphere of a given gas is intentionally introduced / maintained within the enclosure 2. Those skilled in the art will also understand that in practice it may be advantageous to confine the volume of the enclosure 2, possibly so that the enclosure 2 essentially encloses the axis B', and employ an electron beam that passes through and expands to take the form of a small diameter tube (e.g., about 1 cm in diameter) to accommodate structures such as the source 4, the specimen holder H, the screen 26, the camera 30, the camera 32, the spectrometer 34, etc.

[0070] Referring now to Figure 2, another embodiment of a charged particle device is shown. Figure 2 (not to scale) is a highly schematic illustration of a charged particle microscope M. More specifically, it shows one embodiment of a non-transmission microscope M, which in this case is an SEM (although in the context of the present invention, the non-transmission microscope M could also usefully be, for example, an ion-based microscope). In the figure, parts corresponding to items in Figure 1 are indicated using the same reference numerals and will not be considered separately here. The following parts (among others) have been added to Figure 1: -2a: vacuum port, which can be opened to introduce / remove items (components, specimens) into / from the interior of the vacuum chamber 2, or in addition, for example, auxiliary devices / modules can be attached thereto. The microscope M can be equipped with several such ports 2a if desired. - 10a, 10b: Schematically depicted lenses / optical elements in the illuminator 6. -12: A voltage source that allows the specimen holder H or at least the specimen S to be biased (floated) to a potential relative to ground, if desired. -14: Display such as FPD or CRT. 22a, 22b: a segmented electron detector 22a comprising a number of independent detection segments (e.g. quadrants) arranged around a central aperture 22b (allowing the passage of the beam B). Such a detector can be used, for example, to investigate the (angular dependence of) the flux of output (secondary or backscattered) electrons emerging from the specimen S.

[0071] Here too, there is a controller 20. The controller is connected to a display 14, which in turn may be connectable to a data processing device P configured to carry out the methods defined herein. In the embodiment shown, the data processing device P is a separate structure that does not form part of the controller or even part of the microscope P. The data processing device P may be local or cloud-based and is in principle not limited in location.

[0072] Charged particle instruments, in particular electron microscopes (EM), as shown in Figures 1 and 2, offer several methods for studying biological samples: electron crystallography and single particle analysis are dedicated to the study of proteins and macromolecular complexes, while (cryo)electron tomography of vitreous sections and cryo-EM (CEMOVIS) target organelles and molecular structures.

[0073] As indicated in the introduction, these biological samples can be preserved by flash freezing using vitrification techniques and then studied using cryo-EM techniques such as cryo-TEM. Cryosectioning of the samples using cryo-FIB techniques can also be part of the sample study.

[0074] The samples used in these studies must first be prepared and then stored. To this end, an aqueous sample of biological material (usually a purified protein complex) is taken, applied to a support structure (grid), reduced in size to a very thin layer, and then frozen quickly enough to prevent water crystallization. The sample is then prepared and stored for further handling.

[0075] As indicated at the beginning, one method for storing and handling samples involves a so-called AutoLoader. One embodiment of this prior art will now be described with reference to Figure 3. Figure 3 shows the workflow for using an AutoLoader AL and associated NanoCab N cartridge to collect samples S for transfer to a charged particle microscope M, such as a cryo-TEM. The AutoLoader AL is part of the microscope M. The NanoCab is loaded with multiple samples S, which are then transferred to the AutoLoader AL, which loads the samples into the TEM.

[0076] As shown in FIG. 3 , the top row, from left to right, is the preparation of a NanoCab N. Multiple specimens S (i.e., biological samples provided on a grid) are provided in a grid box G. The grid box G with the specimens S is placed in a loading station 101. The loading station 101 is filled with liquid nitrogen 103 to keep the specimens S and grid box G at a desired low temperature. A cassette C is also provided in the liquid nitrogen 103. The specimens S are manually transferred from the grid box G to the cassette C. Once the cassette is full, the Nanocab device N is connected to the loading station 101, and the cassette is provided inside the Nanocab N. The Nanocab N device now contains the cassette C with the desired specimens S, and the Nanocab N device is filled with liquid nitrogen to keep the specimens S at a desired low temperature. When or after the cassette C is introduced into the Nanocab device N, the liquid nitrogen is removed from the loading station so that the loading station 101 can return to room temperature.

[0077] The bottom part of Figure 3 shows that a Nanocab N with a cassette C containing multiple samples S is connected to an Autoloader AL module, which is connected to or part of a microscope.

[0078] The Autoloader AL module includes a cassette arm 113 and a sample arm 111. The interior of the Autoloader AL housing is maintained at a desired low temperature and is configured to store cryogenic samples. The Autoloader AL module includes two valve elements 115, 117. The first valve element 115 can provide connection to a connected Nanocab N. The second valve element 117 can provide connection to a microscope M.

[0079] The procedure for loading a sample from the Nanocab N into the microscope M is as follows: The Nanocab N is connected to the Autoloader AL as shown in the bottom part of Figure 3. The valve 115 is opened and the cassette arm 113 reaches downward to grip the cassette C with the sample S, after which it starts its upward movement to move the desired sample S in front of the sample arm 111. The valve 115 can be closed again.

[0080] The sample arm 111 can then collect the sample S, after which the cassette arm 113 moves the cassette C with the remaining samples further up and out of the way of the sample arm 111.

[0081] Valve 117 can then be opened and sample arm 111 moves the sample towards sample holder H of microscope M. Once sample S has been transferred to microscope M, sample arm 111 can return and valve 117 can be closed again. The sample can then be observed or manipulated.

[0082] As shown, this known Autoloader AL system provides excellent results, particularly in terms of sample transfer quality and screening throughput. However, there is a desire to improve this system, particularly with regard to sample loading, complexity, ease of installation and maintenance, and associated costs.

[0083] To this end, the present invention provides a system for handling and storing cryogenic charged particle samples, such as cryo-EM samples. Generally, the system includes a storage apparatus, a charged particle apparatus, and a transfer device configured to transfer the cryogenic sample from the storage apparatus to the charged particle apparatus.

[0084] FIG. 4 shows one embodiment of the storage device L. The top row of FIG. 4 shows how the sample S is loaded into the storage device L. For this purpose, the sample is provided in a grid box G. The grid box is placed in the housing 201 of the storage device L, which is partially filled with liquid nitrogen 203. A cassette C is also provided in the liquid nitrogen 203. The sample is then manually transferred from the grid box G to the cassette C (step 1). Once the sample S has been transferred, the cassette C remains in the housing of the storage device L (step 2). The cassette C can be moved to a separate storage position in the storage device (not shown), for example using a cassette arm 211 (see the bottom of FIG. 4).

[0085] As shown in Figure 4, cassettes C with samples S are stored inside a housing 201 of a storage device L. In this sense, the housing 201 with liquid nitrogen 203 provides a cryogenic storage chamber for safe storage of samples inside the storage device.

[0086] When a required sample is required, the following procedure can be followed: First, a transfer device T as defined herein is provided, said transfer device T being connected to a storage unit S.

[0087] The transfer device T comprises an elongated housing 303 filled with gaseous nitrogen 303, in which the sample S to be transferred can be temporarily stored at an appropriate temperature. The transfer device T comprises a transfer arm 311 with a gripper 331. The gripper 331 may be used to collect the sample S. The gripper with the sample S can then be moved inside the housing 303 of the transfer device T.

[0088] 4, the storage device L comprises a valve member 215. The transfer device T also comprises a valve member 315 or transfer port 315. The storage device comprises a first docking member 221 configured to mate with a second docking member 321 of the transfer device T (shown schematically). The storage device may comprise a slot 221 into which the housing portion 321 of the transfer device may slide to provide a connected state of the transfer device T and the storage device. In this way, translational docking is provided. Other docking mechanisms or ways of connecting the transfer device T to the storage device L are also contemplated. It is advantageous if the docking member 321 of the transfer device T functions as a male connector 321 and the docking member 221 of the storage device L functions as a female connector 221.

[0089] As defined herein and explained in more detail below, the system comprises at least one suction disk mechanism 340 for securing the connection between the transfer device T and the storage apparatus L. Here, the suction disk mechanism 340 comprises a first sealing ring 341 and a second sealing ring 342 which together with the transfer device T and the storage apparatus L define an annular ring-shaped suction disk volume 345. It should be noted that the second sealing ring 342 surrounds the transfer port 315 (valve 315) such that the transfer port 315 is not part of the suction disk volume 345.

[0090] The transfer device T may be connected (or docked) to the storage device L. When the transfer device T contacts the storage device and the suction disk volume 345 is established and closed, the pressure inside the suction disk volume 345 may be reduced. In this way, the reduced pressure ensures a suction force between the transfer device T and the device L, so that the connection is temporarily fixed and movement between the transfer device T and the device L is substantially prevented. The suction disk mechanism thus ensures that the connection is easy, safe and secure, without the need for, for example, complex latching mechanisms.

[0091] Once the transfer device T is connected (or docked) to the storage apparatus L, the transfer of the sample S can take place. The valve 315 of the transfer device T is opened, and the valve of the storage apparatus 215 is also opened. The cassette arm 211 positions the desired sample S along the transfer arm 311 of the transfer device T. The transfer arm 311 moves within the housing 201 of the storage apparatus L and removes the sample S from the cassette C using the gripper 331. The transfer device T is thus configured to acquire the sample S from said cassette C. The gripper 331 with the sample S is then moved inside the housing 303 of the transfer device T. All valves 215, 315 are then closed. The transfer device T can then be disconnected from the storage apparatus L and moved to the charged particle device.

[0092] 4 shows that the step of positioning the desired sample S using the cassette arm 211 is performed mechanically, and specifically automatically, without the need for handling by a human operator. A human operator can select the desired sample through a user interface, but the movement, positioning, collection, and transfer are performed automatically. This limits the potential for error.

[0093] FIG. 5 shows the transfer device T in a cut state, with the sample S securely seated in the gripper 331 of the transfer arm 311. The sample is contained within the housing 303, which is filled with gaseous nitrogen to keep the sample at the desired low temperature. The heat capacity of the gaseous cold nitrogen within the housing 303 is such that the transfer device maintains the sample at the desired temperature range for several minutes, e.g., 15 minutes. Additional cooling means may be provided on or within the transfer device T to provide active cooling of the sample S within the housing 331. The transfer device T is transportable by a human operator. The dimensions of the transfer device T are selected so that an average human operator can carry the transfer device from a first location to a second location, e.g., from the storage device L to the charged particle microscope M. The device has a length on the order of centimeters, decimeters, or even meters. In practical embodiments, the device T has a length between 40 cm and 80 cm, although other dimensions are also contemplated. The weight of the device T may be on the order of one to several kilograms.

[0094] 6 shows a transport device T connected to a microscope M. The microscope M is provided with a first docking member 421 that can mate with a second docking member 321 of the transport device T. As previously indicated, the docking member 321 of the transport device T may be formed by an external housing part of the transport device T. The microscope M may be provided with a slot 421 that can receive the transport device T, or at least its second docking member 321.

[0095] As defined herein and explained in more detail below, the system comprises at least one suction disk mechanism 340 for securing the connection between the transfer device T and the storage apparatus L. Here, the suction disk mechanism 340 comprises a first sealing ring 341 and a second sealing ring 342 which together with the transfer device T and the storage apparatus L define an annular ring-shaped suction disk volume 345. It should be noted that the second sealing ring 342 surrounds the transfer port 315 (valve 315) such that the transfer port 315 is not part of the suction disk volume 345.

[0096] In this embodiment, the suction disk mechanism (and in particular the sealing ring) is provided primarily on the transfer device, so that in principle a single suction disk mechanism is sufficient to establish a secure connection with all desired devices. However, it will be clear that the suction disk mechanism can also be provided on the device so that the transfer device is free from any suction disk mechanism, and in particular free from any sealing ring. However, a preferred embodiment uses at least one sealing ring on the transfer device. Further details of this suction disk mechanism are given with reference to FIG. 8.

[0097] The transfer device T can be connected (or docked) to the chart particle apparatus CPA. Once the transfer device T is in contact with the CPA and the suction disk volume 345 is established and closed, the pressure in the suction disk volume 345 can be reduced. In this way, the reduced pressure ensures a suction force between the transfer device T and the CPA, so that the connection is temporarily fixed and movement between the transfer device T and the CPA is substantially prevented. The suction disk mechanism thus ensures that the connection is easy, safe and secure, without the need for, for example, complex latching mechanisms.

[0098] The microscope M has a valve member 415. Once the transport device T is connected and secured to the microscope M, or generally to the charged particle instrument CPA, the valves 315, 415 can be opened and the transfer arm 311 can move inside the microscope to transfer the sample S to the holder H of the microscope M. This completes the transfer of the sample from storage to the charged particle instrument, such as the electron microscope M.

[0099] The transfer device T can be detached from the microscope M, and while the microscope is examining the first sample S, transfer of the second sample S2 can occur.

[0100] Figures 7a-7f show a schematic representation of a sample handling and storage system 500 as defined herein.

[0101] Figure 7a shows that the system 500 comprises a storage device L for storing a plurality of samples S, S2. The storage device L may comprise a user input device 114, for example in the form of a conventional personal computer having a screen.

[0102] The system further comprises a charged particle instrument (CPA) M, such as a SEM, TEM, STEM and / or FIB. The CPA M is positioned at a distance from the storage device L. This means that in one embodiment, the CPA M is positioned at a distance of at least 50 cm from the storage device L. For example, the CPA may be positioned at a distance of one to several meters from the storage device. In practice, the distance between the storage device L and the charged particle instrument M is so large that direct transfer from the storage device L to the instrument M is not possible, but an intermediate transfer step is required. An advantage of such a system is that the system is relatively flexible, since the storage device L and the charged particle instrument can be positioned at any desired location, even in different rooms with different environmental conditions.

[0103] To ensure that a safe and reliable sample transfer between the charged particle apparatus CPA and the storage device L is possible, the system 500 comprises a transfer device T. The transfer device T can be handled by a human operator 600. The human operator 600 can carry the transfer device T to and from the storage device and to and from the charged particle apparatus CPA M.

[0104] Referring now to FIG. 7b, a transfer device T is shown releasably connectable to the storage device L. As previously shown with respect to FIG. 4, the transfer device is configured to acquire a sample S from the plurality of samples S, S2 when connected to the storage device L. In the illustrated embodiment, the sample is a cryogenic sample. Transfer occurs by connecting the transfer device T to the storage device L, for example, by inserting the transfer device T into a slot or recess present in the storage device. The connection is then secured by a suction disk mechanism (not shown), which has already been described with reference to FIGS. 4 and 6 and will also be described with reference to FIG. 8. After connection and securing, sample transfer can occur as described in FIG. 4. As shown in FIGS. 7b and 7c, a sample is moved from the storage device L to the transfer device T at a docking position of the transfer device T relative to the storage device L. Sample transfer from the storage device L to the transfer device T occurs automatically, in one embodiment, without the need for sample handling by a human operator.

[0105] Once the sample is in the transfer device T, a human operator can retrieve the transfer device T from the storage apparatus L. The transfer device T with the desired sample S can then be moved to a further location, such as a microscope. The human operator 600 can walk to the further location where the transfer device T is carried by the human operator 600.

[0106] 7e, a transfer device T with a sample S is shown connected to a microscope M (or charged particle device in general). A transfer mechanism of the transfer device T then transfers the sample S from the transfer device T to a sample holder H of the microscope M.

[0107] The sample can then be viewed and / or inspected under microscope M as described with respect to FIGS.

[0108] As shown in FIGS. 4-7, the transfer device T includes a transfer mechanism 311, 331 configured to retrieve the sample S (a cryogenic sample in the illustrated embodiment, although other samples can be used as well) from the storage device L when connected to the storage device L, and to deliver the sample to the CPA when connected to the CPA. In this manner, a single mechanism can be used to transfer samples between two external devices. The device should be configured to cooperate with the transfer mechanism, but need not have such a mechanism. Furthermore, the device may include additional means, including a mechanical arm 211, valves 215, 415, etc., to optimize sample transfer and to interface with the transfer mechanism 311, 331 of the transfer device.

[0109] In one embodiment, the transfer mechanism includes a movable arm 311. The movable arm can be configured for translational movement. The outer end of the movable arm 311 can include a gripper 331 configured to grasp and release samples, particularly samples including samples mounted on a specimen grid. The specimen grid can also be connected to other grid elements, which serve to facilitate sample handling. The grid elements can include, for example, a C-clip ring (i.e., AutotGrid, Thermo Fisher Scientific™) to which the specimen grid can be attached, and a C-clip for securing the specimen grid within the C-clip ring. Of course, other grids are also contemplated.

[0110] 7a-7f, the storage device L comprises an operator input device 114 in the form of a computer and a control unit 220 connected to the operator input device 114 and configured to perform at least some functions of the storage device L or the system 500, for example when the transfer device T is connected to the storage device L. The operator input device is configured in one embodiment to allow a human operator 600 to select a sample S, S2 to be transferred from the storage device to the charged particle microscope M. The control unit 220 is configured to control the storage device L and the transfer device T in the connected state to transfer the selected sample S from the storage device L to the transfer device T.

[0111] The storage device L, including the operator input device 114, can form a first workstation, allowing a human operator to quickly and reliably transfer prepared samples to the storage device L. For example, the top of the housing 201 of the storage device L can match the disk mechanism of the workstation. The top of the housing 201 and / or the disk mechanism of the workstation can include a lid that can be opened and closed by a human operator so that a grid box G (see FIG. 4 , step 1) that receives the sample S can be inserted into the storage device L and the sample grid S can be transferred to the container C. The lid can also be used to replenish the liquid nitrogen level 203 within the housing 201. The operator input device and / or a controller can be connected to the housing 201 so that information related to the housing 201 can be provided to the human operator. For example, the storage device can include multiple sensor elements, such as temperature sensors, liquid level sensors, etc., for monitoring the status of the storage device. The operator input device 114 can provide feedback to the user regarding one or more of these conditions.

[0112] It is further contemplated that the operator input device 114 may be used for feature labeling and tracking. In one embodiment, the operator input device 114 may be wirelessly connected to the charged particle instrument such that information about the sample S may be transferred to the charged particle instrument. The information may include sample input information, for example, information entered into the operator input device 114 by a human operator when loading the sample S into the cassette C.

[0113] Referring now to Figure 8, an embodiment of the suction disc mechanism defined herein will be described in more detail.

[0114] FIG. 8a shows an overview of the transfer device T. The transfer device T comprises an elongated housing 303. On one side of the elongated housing 303, a support handle 305 is provided, which allows a user to easily transport and manipulate the transfer device T. On the opposite side of the elongated housing, the transfer device T comprises a connection surface 306. The connection surface 306 is provided with a suction disk mechanism 340. The suction disk mechanism 340 is configured to secure a connection between the transfer device T and a desired device, such as a storage device L or a CPA M. In the illustrated embodiment, the suction disk mechanism 340 comprises a first sealing ring 341 and a second sealing ring 342. The first sealing ring 341 is provided along the outer edge of the connection surface 306. The second sealing ring 342 is provided near the center of the connection surface 306. The connection surface 306 also comprises a transfer port 315 or transfer valve 315. The transfer port 315 is surrounded by the second sealing ring 342. 8a, the suction disk volume 345 is ring- or donut-shaped, with the transfer valve 315 being provided in the "hole" of the ring / donut. In this way, the transfer port 315 does not form part of the suction disk volume 345, but is surrounded by it. In an alternative embodiment (not shown), it is conceivable that the transfer port 315 is not surrounded by the suction disk volume 340, but rather the suction disk volume is located at a distance from the transfer port 315. However, by surrounding the transfer port 315 with the suction disk volume, a safe and secure connection between the transfer device T and the desired apparatus L, M is established, further reducing the risk of contamination of the sample during transfer.

[0115] The suction disk mechanism 340 can be operated to establish a connection between the transfer device T and the desired device L, M. For this purpose, the connection surface 306 is brought into contact with the desired device and excess air is removed from the suction disk volume 345. The transfer device T is equipped with an exhaust port 346 that can be used to remove excess air.

[0116] As can be seen in Fig. 8a, the transfer device T comprises electrical contact elements 355. These electrical contact elements 355 are configured for connection to further electrical contact elements 355 provided on the desired devices L, M. The electrical connection provided by the electrical contact elements 355 allows information to be exchanged between the connected device and the desired device, but also allows operations of the parts of the transfer device, which operations are initiated, for example, by the desired device. The information may relate to sample type, temperature, sample storage conditions, but may also include, for example, information about a successful connection.

[0117] The transfer device T further comprises an interface opening 359 that, in some embodiments, can be used to operate a transfer mechanism located inside the transfer device. In one embodiment, the interface opening 359 allows compressed air to pass from the desired apparatus L, M to the transfer device (or vice versa) to operate the transfer mechanism 311, 331.

[0118] Once the transfer device T is connected (or docked) to the desired apparatus L, M and the suction disc mechanism 340 is operated, it becomes possible to transfer the sample S from the transfer device T to the desired apparatus L, M (or vice versa). As can be seen in more detail in Figure 8b, the transfer device comprises a latch mechanism 351 for opening the valve 315. The latch mechanism 351 basically consists of a sliding door mechanism. The latch mechanism 351 comprises a recess in the sliding door that can be operated by a hook element 461 that is part of the desired apparatus L, M. In this way, unintentional and unwanted opening of the valve is prevented and can only be done in a truly connected state of the transfer device.

[0119] 8d shows an embodiment of a docking member 421 for a desired device, which in the illustrated embodiment is for a microscope but can also be implemented for a storage device L, wherein the desired device L, M is configured to be connectable to a transfer device T according to the embodiment shown in FIGS. 8a-8c. Here, the first docking member 421 can mate with the second docking member 321 of the transport device T as shown in FIGS. 8a-8c. The docking member 421 comprises a slot or recess having a bottom wall 406 and a side wall 407. An electrical contact element 455 is provided which can be connected to an electrical contact element 355 of the transfer device T. When the transfer device T is connected to the docking member 421, the sealing rings 341, 342, the connecting surfaces of the desired device L, M and the bottom wall 406 define a suction disk volume 345. Excess air may be removed from this suction disk volume 345 by the exhaust port 346 of the transfer device and / or the exhaust port 446 of the desired device L, M to ensure a secure connection between the transfer device T and the desired device L, M. Transfer may then be initiated by opening the respective valves 315, 415, and the hook 461 may be used to open the latch mechanism 351 of the transfer device T.

[0120] The system has been described in more detail above using five exemplary embodiments, and the desired protection is provided by the appended claims.

Claims

1. A sample handling and storage system, - A storage device for storing multiple samples, - A charged particle device (CPA) located away from the aforementioned storage device, - A sample handling and storage system comprising: a storage device and a transfer device detachably connectable to the CPA, wherein the system is configured to transfer a sample from the storage device to the transfer device when the transfer device is connected to the storage device, and to transfer the sample from the transfer device to the CPA when it is connected to the CPA; A sample handling and storage system comprising the transfer device and at least one suction disk mechanism for ensuring the connection between the transfer device and at least one of the storage device and the CPA.

2. The sample handling and storage system according to claim 1, wherein the transfer device comprises an elongated housing, and each of the storage device and the CPA comprises a corresponding recess for receiving the elongated housing.

3. The sample handling and storage system according to claim 2, wherein the side wall of the recess provides a guide surface for the housing of the transfer device, and the bottom wall of the recess provides a contact surface for the housing.

4. The sample handling and storage system according to claim 3, wherein the elongated housing, when connected, has a connecting surface that faces the bottom wall of the recess.

5. The sample handling and storage system according to claim 1, wherein the suction disc mechanism is provided on the transfer device.

6. The sample handling and storage system according to claim 5, wherein the suction disc mechanism is provided on the connection surface of the transfer device.

7. The sample handling and storage system according to claim 5, wherein the transfer device comprises a transfer port provided on the connection surface, and the bottom wall of the recess comprises a transfer opening.

8. The sample handling and storage system according to claim 7, wherein the suction disc mechanism surrounds the transfer port.

9. The sample handling and storage system according to claim 1, wherein the transfer device and at least one of the storage device and the CPA are provided with electrical contact elements, and the electrical contact elements are configured to contact each other when the transfer device is connected to at least one of the storage device and the CPA.

10. The sample handling and storage system according to claim 1, further comprising a transfer mechanism configured to acquire the sample from the storage device when the transfer device is connected to the storage device, and to deliver the sample to the CPA when the transfer device is connected to the CPA.

11. A transfer device for transferring samples for use in a sample handling and storage system according to claim 1, wherein the transfer device is releasably connectable to a storage device for storing a plurality of samples, and when the transfer device is connected to the storage device, samples can be transferred from the storage device to the transfer device, and the transfer device is further releasably connectable to a charged particle apparatus (CPA), and when the transfer device is connected to the CPA, samples can be transferred to the CPA, The transfer device is characterized by comprising at least one suction disk mechanism for ensuring the connection between the transfer device, the sample handling and storage system, and the CPA.

12. The transfer device according to claim 11, wherein the transfer device comprises an elongated housing having at least one connection surface.

13. The transfer device according to claim 12, wherein the suction disk mechanism is provided on the transfer device.

14. The transfer device according to claim 12, wherein the transfer device comprises a transfer port provided on the connection surface.

15. The transfer device according to claim 13, wherein the suction disk mechanism surrounds the transfer port.

16. The sample handling and storage system according to claim 1, wherein one of the at least one suction disc mechanisms comprises a first seal ring and a second seal ring that at least partially define the volume of the suction disc.

17. The sample handling and storage system according to claim 16, wherein the second sealing ring surrounds the transfer port and excludes the transfer port from the volume of the suction disk.

18. The sample handling and storage system according to claim 16, wherein the first seal ring is provided along the outer edge of the connection surface of the transfer device.

19. The sample handling and storage system according to claim 1, further comprising an interface opening operably coupled to a transfer mechanism.

20. The sample handling and storage system according to claim 19, wherein the interface opening allows compressed air to pass from the CPA to the transfer device.

Images