System for loading and / or manipulating samples in a sample transfer device

Abstract

The present invention relates to a system (100) for loading samples into a sample transfer device (180) at low temperatures and / or manipulating samples in the sample transfer device (180). The system (100) includes a sample transfer device (180) and a drying oven (110), the sample transfer device (180) being configured to receive a sample through a receiving opening (182) and being configured to transfer the sample to a processing unit or an analysis unit, the drying oven (110) having an interface opening (112) and being configured to be coupled to the sample transfer device (180) such that the interface opening (112) of the drying oven (110) is located opposite to the receiving opening (182) of the sample transfer device (180).

Description

Technical Field

[0001] This invention relates to a system for loading samples into a sample transfer device at cryogenic temperatures and / or for manipulating samples within a sample transfer device. The system includes a sample transfer device configured to receive a sample through a receiving opening and to transfer the sample to a processing unit or analytical unit. More specifically, the sample transfer device of the system according to this invention is used in the field of cryogenic microscopy to transfer a sample to be examined, for example, to a cryogenic electron microscope (cryo-EM) or a cryogenic optical microscope (cryo-LM), or, in another example, to load and / or manipulate a sample or sample carrier or sample holder within the sample transfer device, and then transfer the sample or sample carrier or sample holder to another processing unit, such as a FIB (Focused Ion Beam) device, for further sample processing, or to an analytical unit, such as a cryogenic microscope, for sample examination. Background Technology

[0002] US 10,144,010 B2 discloses a manipulation container for cryogenic microscopy, which substantially corresponds to the sample transfer device of the type described above. Cryogenic microscopy particularly includes cryogenic optical microscopy and cryogenic electron microscopy.

[0003] Cryofixation is a common sample preparation method in cryo-electron microscopy. In this process, an aqueous sample is frozen (cryofixed) very rapidly to a temperature below -150°C, i.e., it is cooled very quickly to avoid the formation of ice crystals. Cryofixation has proven particularly suitable for structural biology research. The object to be studied, such as cells, enzymes, viruses, or lipid layers, is thus embedded in a thin, vitrified layer of ice. The greatest advantage of cryofixation is that biological structures can be obtained in their natural state. For example, biological processes can be stopped at any point in time by cryofixation and studied in this vitrified state, such as in cryo-electron microscopy, or in optical microscopy with corresponding sample cooling; cryo-optical microscopy is mainly used to locate relevant regions in the sample, which can be recorded and then observed in more detail under cryo-electron microscopy.

[0004] The frozen sample is usually placed on a known electron microscope sample carrier, such as a grid or pin stub mount for scanning electron microscopy. The frozen sample must be transferred (under the aforementioned low temperature conditions and after water removal) to the corresponding sample carrier holder, which can then be transferred in a suitable holder into the aforementioned microscope.

[0005] To date, a rather temporary solution has been used, in which liquid nitrogen is stored in, for example, a polystyrene foam container, within which the necessary manipulation steps of transferring the grid to the sample carrier holder are performed. The cryogenic nitrogen gas formed by the liquid nitrogen ensures the necessary low temperature on the one hand, and creates an anhydrous atmosphere in the polystyrene foam container on the other, thereby preventing water contamination of the sample and thus preventing ice crystal contamination.

[0006] To avoid compromising the quality of frozen samples, it is crucial to transfer them in a cooled and contamination-free (especially anhydrous) manner between the processing unit used (e.g., cryogenic fixation device, FIB (“Focused Ion Beam”) device, cryofracture device, or coating device) and the analytical device (in this case, primarily a cryogenic optical microscope and / or cryogenic electron microscope). For this purpose, in routine laboratory practice, rather ad-hoc solutions have historically been employed, or loading and transfer systems have been specially fabricated in-house.

[0007] The sample to be examined must first be placed on a sample carrier / grid, which is then typically placed on a sample holder / cassette. The sample holder / cassette is then transferred to a sample transfer device, also known as a cryogenic-CLEM shuttle (“cryo-optical-electron-microscopy shuttle”). The sample transfer device can be connected to a cryogenic stage, for example, of a cryogenic microscope, and the sample is transferred to the cryogenic microscope by transferring the sample holder / cassette to the cryogenic stage. It should be noted that other embodiments of this process are possible, and other applications are conceivable, such as where the sample or sample carrier is loaded directly into the sample transfer device without a sample holder / cassette.

[0008] In the above-described scenario, the frozen sample is processed in a cold environment, such as in cold gaseous N2 at a level above liquid N2 (LN2), which is, for example, filled within a cavity inside the sample transfer device. During this process, ice crystals form in the transition zone between the cold gas and the surrounding atmosphere containing humid air. When this transition zone is intensely mixed due to movement of the user's hand or tools, even more and larger ice crystals may form during the handling of the frozen sample. The resulting ice crystals or ice flakes may fall onto the frozen sample and potentially contaminate it to the point that it is unusable for subsequent process steps.

[0009] The standard solution is to create a stable flow of cryogenic gas (e.g., gaseous N2) around the sample region surrounding the frozen sample. However, this solution has the drawback of requiring the evaporation of a large amount of liquid cryogenic gas to maintain a sufficient flow. Furthermore, this flow can induce turbulence at edges or obstacles, and the eddies from this turbulence can potentially transport ice crystals into the sample region.

[0010] To mitigate the effects of this turbulent flow, it is common practice to cover any openings in the sample area with a cap, at least when no manipulation is being performed. Typically, a sliding mechanism is provided so that the cap can be opened to release only the minimum necessary area for manipulation. On the one hand, this restricts free manipulation; on the other hand, the risk of introducing ice crystals through residual openings remains. Summary of the Invention

[0011] The purpose of this invention is to provide a system for loading samples into a sample transfer device at low temperatures and / or for manipulating samples placed in a sample transfer device, the use of which minimizes the risk of contamination or devitrification of samples loaded into and / or manipulated in a sample transfer device of the aforementioned type.

[0012] This invention provides a system according to claim 1 for loading a sample into a sample transfer device at low temperature and / or for manipulating a sample in the sample transfer device. In this context, the term "manipulate" includes unloading a sample from the sample transfer device. In the context of this application, "sample" means including the sample itself, a sample carrier carrying the sample, and / or a sample holder carrying the sample carrier and / or the sample. The system includes a sample transfer device configured to receive a sample through a receiving opening and configured to transfer the sample to a processing unit or analysis unit. In other words, the sample and / or sample carrier and / or sample holder are received inside or in a chamber of the sample transfer device through the receiving opening. The system also includes a drying chamber having an interface opening and configured to be connected to the sample transfer device such that the interface opening of the drying chamber and the receiving opening of the sample transfer device face each other, allowing the sample to be transferred from the drying chamber to the sample transfer device. In other words, the drying chamber is configured to be coupled to the sample transfer device through the interface opening. When the drying oven is connected to the sample transfer device, the interface opening of the drying oven is typically located above or opposite the receiving opening of the sample transfer device. The sample / sample carrier / sample holder can be transferred from the drying oven to the sample transfer device and vice versa through the receiving opening. Preferably, the interface opening provides an entrance to the interior of the outer shell portion of the drying oven, which forms a volumetric space suitable for user operations as described in more detail below.

[0013] Using the system conceived according to the present invention, the sample transfer device and the drying oven can be coupled or connected to each other, and the resulting connection preferably constitutes a closed or sealed connection that provides minimal leakage gas flow. Since a slight overpressure, particularly overpressure of cryogenic gases, is preferred inside the system when the sample transfer device is coupled to the drying oven, the connection does not necessarily need to be sealed.

[0014] Furthermore, it is preferable if the drying oven and the sample transfer device can be connected to each other by mechanical and / or magnetic connection. For this purpose, the contact surfaces of the drying oven and the sample transfer device can be made of or include a magnetic material providing such magnetic connection, and / or can be formed of or include mechanical elements that interact with each other to provide mechanical connection.

[0015] It is important to note that the system conceived in this invention provides an alternative to systems that handle sample transfer devices inside a glove box. While such systems are highly effective in preventing contamination, manipulating small samples or sample carriers (such as TEM grids) within such a glove box is cumbersome. Furthermore, both transferring samples into and out of the glove box require suitable locking systems. In contrast, the system conceived in this invention uses a drying oven with an interface to the sample transfer device, and a sample transfer device with an interface to the drying oven, allowing both the drying oven and the sample transfer device to be connected to each other. Since samples can be frozen and / or even vitrified inside the drying oven, or samples in their frozen or vitrified state can be transferred to and processed within the drying oven, a sample locking system is unnecessary. Furthermore, since the sample transfer system is not located inside the drying oven, a corresponding locking system for the sample transfer device is not required.

[0016] In an embodiment, the drying chamber includes an interface opening cover for opening and closing the interface opening of the drying chamber. The interface opening cover is used for purposes such as enabling the drying chamber to be closed, for example, for creating a suitable atmosphere inside the drying chamber, and preferably includes an inert gas such as gaseous nitrogen as its main component, for example from a gas cylinder or a vaporized cryogenic gas (such as vaporized LN2 (liquid nitrogen)).

[0017] In an embodiment, the sample transfer device includes a receiving opening cover for opening and closing the receiving opening of the sample transfer device. On one hand, the receiving opening cover is used to allow the interior of the sample transfer device to be opened for loading a sample into the device and / or for manipulating the sample within it. On the other hand, the receiving opening cover is used to close the receiving opening, for example, before connecting the sample transfer device to a processing unit or analytical unit for sample transfer. Furthermore, the receiving opening cover can be closed before loading the sample / sample carrier into the sample transfer device to create a suitable atmosphere inside the device, such as, for example, a cold cryogenic gas atmosphere (e.g., vaporized LN2). Typically, the interior of the sample transfer device is filled with LN2 to a level below the sample holder, such that the sample / sample carrier / sample holder is in close proximity to the liquid nitrogen bath. Additionally, the sample holder may have or be connected to "tentacles" extending into the liquid nitrogen bath to enhance cooling.

[0018] In this context, it is preferable that a drying oven, including an interface opening cover in its closed state, can be connected to a sample transfer device, including a receiving opening cover in its closed state. Thus, a closed sample transfer device can be connected to a closed drying oven, each of which is specifically provided with a suitable atmosphere. After connecting the two units, the interface opening cover can be opened to open the interface opening, and then the receiving opening cover can be opened, particularly through the interface opening of the drying oven, to open the receiving opening of the sample transfer device. In this state, the sample can be transferred from the drying oven to the sample transfer device.

[0019] In this embodiment, with the drying chamber connected to the sample transfer device, it is particularly preferred that the distance between the closed interface opening cover and the closed receiving opening cover be as small as possible, preferably in the range of 0 to 10 mm or 0 mm to 5 mm. Using these preferred distances, the space creating a dead volume between the closed interface opening and the closed receiving opening can be kept as small as possible. This dead volume typically includes air with a certain humidity, which will be forced into the drying chamber when the interface opening cover is opened and / or into the interior of the sample transfer device when the receiving opening cover is opened.

[0020] In an embodiment, the drying chamber includes an inlet for introducing an inert gas into the interior of the drying chamber. For example, gaseous nitrogen, such as from a gas cylinder, can be introduced, or liquid nitrogen can be vaporized outside the drying chamber and introduced into the drying chamber through the inlet. Alternatively or additionally, an inert gas (such as LN2) in its liquid state, such as in a Dewar container, can be arranged inside the drying chamber such that the vaporized inert gas can fill the volume of the drying chamber.

[0021] In an embodiment, the drying chamber includes an outlet for discharging gas from the interior of the drying chamber. In this context, the term "outlet" includes any gas leakage, such as at the interface where the drying chamber is connected to the sample transfer device or at other unsealed inlet openings into the drying chamber.

[0022] In this embodiment, the drying chamber includes a sample supply container opening configured to connect with a sample supply container. This sample supply container may contain tissue sections from a cryo-microtome or sample carriers from a grid plunger. The sample supply container is connected to the drying chamber such that the sample / sample carrier can be transferred from the sample supply container to a sample transfer device through the sample supply container opening of the drying chamber. This transfer takes place inside the drying chamber, preventing contamination, particularly freezing of water, or even devitrification. In the next step, the sample / sample carrier is typically mounted onto a sample holder / cassette.

[0023] In this embodiment, it is preferable that the drying oven includes a sample supply container opening cover for opening and closing the sample supply container opening of the drying oven. This cover allows the sample supply container opening to be opened only after a suitable dry and cool atmosphere has been created inside the drying oven.

[0024] As described above, it is preferable if the drying oven includes an inert gas opening configured to connect to an inert gas storage container. This storage container can be a Dewar container connected to the drying oven via the inert gas opening, allowing vaporized inert gas to fill the interior of the drying oven. Similarly, additionally or alternatively, an inert gas such as gaseous nitrogen can be taken from, for example, a gas cylinder. Likewise, it is preferable if the inert gas opening can be opened and closed by a corresponding inert gas opening cap.

[0025] In a preferred embodiment, the sample transfer device itself includes an inert gas reservoir for cryogenic conditions. As described above, the internal chamber of the sample transfer device can be filled with liquid nitrogen as an example of a cryogenic gas, which evaporates to fill the interior of the sample transfer device with a dry, cold, and inert atmosphere. Alternatively, this source of cryogenic gas can be used alone to fill a drying chamber; when the sample supply container is connected to the drying chamber, another source of cryogenic gas can be provided through the sample supply container. However, it is preferred to use an additional source of cryogenic gas to establish the cryogenic atmosphere over a shorter period of time.

[0026] In this embodiment, the drying chamber includes a humidity sensor and / or measuring device for detecting the humidity inside the drying chamber. The humidity sensor can be used to detect a sufficiently low humidity level inside the drying chamber, preferably a relative humidity of less than 10% or even less than 5%, allowing the use of the drying chamber, i.e., connecting the drying chamber to a sample transfer device, and taking further steps of loading and / or manipulating the sample / sample carrier.

[0027] In a further embodiment, the drying chamber includes at least one at least partially closable user opening, providing a user access to the interior of the drying chamber. Through such a user opening, a user can enter the interior of the drying chamber to load and / or manipulate samples using appropriate user tools, such as a pair of tweezers. To protect the low-temperature atmosphere inside the drying chamber, such a user opening should be at least partially closable, for example, through a foil cover and / or through a corresponding user opening door. The foil cover may have one or more slits, preferably two slits perpendicular to each other, allowing the user's hand to move through the foil cover.

[0028] In another preferred embodiment, the user opening of the drying chamber, alternatively or additionally, includes a glove mount for installing gloves that extend into the interior of the drying chamber upon installation. Such gloves, mounted on the glove mount, allow the user to work inside the drying chamber without affecting the low-temperature atmosphere within the chamber.

[0029] In a further embodiment, the drying chamber includes an electromechanical or mechanical mechanism for disengaging and engaging the drying chamber with the sample transfer device. Such a engagement mechanism allows the respective contact surfaces of the drying chamber and the sample transfer device to be joined together, making connection between the two units possible where the interface opening of the drying chamber and the receiving opening of the sample transfer device face each other. The connection between the two units can be achieved simply with their respective contact surfaces above each other. This connection can be reinforced by corresponding contours in the contact surfaces that interlock with each other. However, it is not mandatory; other mechanical and / or magnetic connection means can be used to achieve a more robust and reliable connection between the two units. In embodiments providing an engagement mechanism, engagement of the two units is facilitated. Generally, such an engagement mechanism can consist of or include electromechanically controlled engagement of the two units such that they are connected to each other, or a positive-drive (e.g., track-guided or threaded) mechanical mechanism or a combination of these mechanisms for engaging the two units.

[0030] In a preferred embodiment, the coupling mechanism includes an eccentric mechanism such that a full rotation of the corresponding cam member causes the two units to be disengaged and coupled. More specifically, it is preferred if the eccentric mechanism includes an eccentric wheel on the bottom side of the drying chamber. In this embodiment, the drying chamber is mounted on a bracket, support, or frame to support it on the ground. The eccentric wheel is mounted at the bottom of the bracket / support / frame such that a full rotation of the eccentric wheel raises the drying chamber and lowers it again. The sample transfer device can be placed on the same ground below the drying chamber at a location that allows the two units to be coupled. The coupling of the two units is achieved by lowering the frame of the drying chamber by the rotation of the eccentric wheel, while further rotation of the eccentric wheel causes the drying chamber to be raised, thereby causing the two units to be disengaged.

[0031] In another embodiment, the drying chamber includes a magnified window on the top side of the drying chamber, such that a user looking through the window into the interior of the drying chamber perceives a magnified image of any object behind the magnified window.

[0032] The present invention also relates to a drying oven configured for use within a system according to the present invention. The drying oven itself has been described in detail above; to avoid unnecessary repetition, please refer to the previous description. It should be noted that disclosure of a system including the drying oven also implies disclosure of the drying oven itself, or, if necessary, disclosure of a drying oven configured for use with a system according to the present invention. In particular, only some features of the drying oven are mentioned; the drying oven preferably includes at least one of the following features:

[0033] An interface opening configured to connect to a sample transfer device; the interface opening provides an inlet to the interior of a housing portion of the drying oven, which forms a volumetric space for user operation; an interface opening cover for opening and closing the interface opening of the drying oven; an inlet for introducing inert gas into the interior of the drying oven; an outlet for discharging gas from the interior of the drying oven; a sample supply container opening configured to connect to a sample supply container; a sample supply container opening cover for opening and closing the sample supply container opening; an inert gas opening configured to connect to an inert gas storage container; and a humidity sensor. A measuring device for detecting humidity inside a drying oven; at least one at least partially closable user opening providing access to the interior of the drying oven; a foil cover at least partially covering the user opening; the user opening including a glove mount for installing gloves, which extend into the interior of the drying oven when installed; an electromechanical or mechanical coupling mechanism for disengaging and coupling the drying oven to a sample transfer device; the coupling mechanism including an eccentric mechanism; the eccentric mechanism including an eccentric wheel at the base or bottom side of a bracket / frame of the drying oven; and a magnifying window on the top side of the drying oven.

[0034] It should also be noted that the above features of the embodiments of the present invention can be combined in whole or in part to achieve other embodiments that still fall within the scope of the present invention as defined in the appended claims.

[0035] As used herein, the term “and / or” includes any and all combinations of one or more associated listed items and may be abbreviated to “ / ”.

[0036] Although some aspects have been described in the context of the apparatus or device, it is clear that these aspects also represent a description of the method of operating such an apparatus or device.

[0037] Further embodiments and advantages of the present invention are described below with reference to the accompanying drawings. Attached Figure Description

[0038] Figure 1 An embodiment of a system conceived according to the present invention is illustrated schematically.

[0039] Figure 2 Schematic illustration of passing through Figure 1 A top view of the system's drying oven in a horizontal cross-section.

[0040] Figure 3 and Figure 4 The connection state is shown in a transparent side view. Figure 3 ) and deconnection state ( Figure 4 The system under ).

[0041] Figure 5 An embodiment of a drying oven according to the present invention is illustrated schematically.

[0042] List of reference numerals

[0043] 100 System

[0044] 110 Drying Oven

[0045] 112 Interface Opening

[0046] 116 Outer shell

[0047] 152 Measuring device

[0048] 160 users spoke

[0049] 162 Foil Cover

[0050] 164 User Opening Door

[0051] 170 Eccentric Mechanism

[0052] 172 Eccentric Wheel

[0053] 174 Brackets, Frames

[0054] 176 Base

[0055] 180 Sample Transfer Device

[0056] 184 Adapter Rod

[0057] 185 baffle

[0058] 186 Receiving section for sample holder

[0059] 188 connecting pipe

[0060] 190 Zoom in window

[0061] 214 Interface opening cover

[0062] 220 Inlet for inert gases

[0063] 230 Sample supply container opening

[0064] 232 Sample supply container

[0065] 234 Sample supply container opening cap

[0066] 240 Inert gas opening

[0067] 242 Inert Gas Opening Cap

[0068] 250 Humidity Sensor

[0069] 282 Receiving opening

[0070] 284 Receiving opening cover

[0071] 344 Inert gas storage container Detailed Implementation

[0072] The accompanying drawings are fully described, and the same reference numerals refer to the same or at least structurally equivalent elements.

[0073] Figure 1 An embodiment of the system conceived according to the present invention is illustrated schematically in perspective view, with the drying oven shown transparently. The system is labeled 100, the sample transfer device is labeled 180, and the drying oven is labeled 110.

[0074] Figure 1 The sample transfer device 180 includes a transfer rod 184, the transfer rod 184 having a receiving portion 186 at its other end for a sample holder / cassette, such as Figure 1 As shown. In operation, the transfer rod 184 is telescopic, such that the receiving portion 186 is located inside the sample transfer device 180 to receive the sample holder (see also) normally arranged in the receiving opening 282 of the sample transfer device 180. Figure 2 Typically, a sample holder is positioned in the loading position, and the sample or sample carrier is placed on or inside the sample holder. In the next step, the transfer rod 184 moves axially such that, when the baffle 185 is in its open position, the receiving portion 186 of the transfer rod can receive the sample holder, which has moved through and to the outside of the connecting tube 188. The sample on the sample holder is then transferred to the transfer position, where the sample holder itself can be transferred to, for example, the cryogenic stage of a cryogenic microscope. Figure 1 The state of the sample transfer device 180 shown is for illustrative purposes only, in order to better understand the design and function of the sample transfer device 180.

[0075] The outer shell portion 116, including the volumetric space of the drying oven 110 (see also...) Figure 5 It can be made of transparent or translucent materials, and Figure 1The embodiment includes a magnifying window 190 that allows the operator to observe the drying chamber and monitor its interior. When the magnifying window 190 is aligned with the interface opening 112, any component in the line of sight can be viewed in magnified form. The humidity of the atmosphere in the volume space of the housing portion 116 can be monitored by connecting to a humidity sensor 250 (see [reference]). Figure 2 The measuring device 152 is used for measurement. For example... Figure 1 As shown, the drying oven 110 also has an interface opening 112, the frame of which is configured to allow it to be placed on top of the sample transfer device 180. When the interface opening 112 engages with the top side of the sample transfer device 180, the connection between the two units 180 and 110 is achieved. In the connected state, the receiving opening 282 of the sample transfer device 180 (see...) Figure 2 The interface opening 112 facing the drying oven 110 allows the sample and / or sample carrier and / or sample holder to be transferred from the drying oven to the sample transfer device. The connection between the two units 180 and 110 as described above does not need to be a (sealed) connection, but needs to be a sufficiently tight connection to avoid excessive gas leakage.

[0076] like Figure 1 As shown, the drying chamber 110 also includes two at least partially closable user openings 160, providing user access to the interior of the drying chamber 110. The user openings 160 are partially closed by a foil cover 162, which covers the user openings 160 and has two perpendicular slits, allowing a user's hand to enter the drying chamber 110 by pushing open the flexible slit foil cover 162. Additionally, the user openings 160 can be closed by corresponding user opening doors 164.

[0077] like Figure 1 As can be further seen, the drying oven 110 includes a bracket or frame 174 that holds the interface opening 112 of the drying oven 110 at a height corresponding to the height of the top side of the sample transfer device 180, such that it can be accessed from... Figure 1 As seen, the bracket or frame 174 includes a base 176 supported by the ground and comprising two eccentric wheels 172, thereby forming an eccentric mechanism 170, which will later be combined with... Figure 3 or Figure 4 Describe it. In Figure 1 In the state shown, the eccentric mechanism 170 connects the drying chamber 110 to the sample transfer device 180 by lowering the interface opening 112 of the drying chamber 110 to the top side of the sample transfer device.

[0078] Figure 2 A perspective view is schematically shown from above through the system 100 to the top side of the sample transfer device 180 and to the elements arranged in the bottom plate area of ​​the volume space of the drying oven 110.

[0079] Now, let's describe from left to right. Figure 2 The components are shown. On the left is a sample supply container opening 230, and a sample supply container 232 can be magnetically connected to, for example, the sample supply container opening 230. From... Figure 2 As can be seen, the sample supply container 232 includes a perforated plate, typically located above the bath of liquid cryogenic gas, and the perforated plate includes a small sample transfer container loaded with a grid or sapphire plate. The sample supply container opening 232 can be opened and closed via the sample supply container opening cover 234. Figure 2 The next component shown is an interface opening cover 214 for opening and closing the interface opening 112. The interface opening of the drying oven 110 allows access to the sample transfer device 180 arranged below the interface opening 112. Figure 2 The next element shown is an inert gas opening cover 242, which is shown in its closed state, covering the inert gas opening 240. This inert gas opening 240 is for the purpose of allowing cold inert gas to flow inside the drying chamber 110. The inert gas opening 240 can be connected to an inert gas storage container 344 (see [reference]). Figure 3 Alternatively, 240 may specify another sample supply container opening that can be connected to the sample supply container, the sample supply container opening 240 being closable by a sample supply container opening cover 242.

[0080] Reference numeral 220 designates another inlet, quick connector, or valve for introducing inert gas into the interior of the drying chamber. For example, gaseous nitrogen from a cylinder can be introduced via quick connector 220 to efficiently generate a sufficiently low humidity dry atmosphere in a short period of time.

[0081] Depending on the specific application, it may be sufficient to use only the sample supply container 232 and / or the sample transfer device 180 as a source of cold inert gas flowing into the drying chamber 110. However, in order to achieve an atmosphere with even lower humidity inside the drying chamber 110 over shorter time intervals, it is useful to use another source of inert gas, such as a nitrogen cylinder or an inert gas storage container 344.

[0082] In operation, the drying oven 110 is positioned relative to the sample transfer device 180 via its frame or bracket 174, such that the interface opening 112 is positioned above the receiving opening 282 of the sample transfer device 180. If the receiving opening 282 is closed by the receiving opening cover 284, the interface opening 112 is positioned above the receiving opening cover 284, as... Figure 2 As shown below. Figure 3 and Figure 4 The eccentric mechanism 170, described in more detail, has its interface opening 112 lowered onto the top surface of the sample transfer device 180 (see also...). Figure 1 This is to achieve a basic closed system for the two units 180 and 110. Next, inert gas is introduced into the drying chamber 110, preferably by opening the inert gas inlet 220. The incoming inert gas displaces the air inside the drying chamber 110, and the humidity of the low-temperature atmosphere is measured by a measuring device 152 connected to a humidity sensor 250. Since system 100 is not sealed, humid air can be displaced by any existing air leaks. A relative humidity of less than 5% is achievable and desirable. It should be noted that the inert gas can be automatically introduced into the drying chamber 110 by a control unit (which may be part of the measuring device 152) and a valve, the amount of inert gas flowing in being controlled by the humidity sensor 250 or simply by adjusting the amount of gas released from the gas cylinder.

[0083] Preferably, the dead volume between the closed interface opening cover and the (transparent) receiving opening cover 284 is kept as small as possible to minimize the amount of humid air within that dead volume. First, the interface opening cover 214 is opened to allow air from the dead volume to flow into the drying chamber 110. Then, if present, the receiving opening cover 284 of the sample transfer device 180 is removed. Typically, the interior of the sample transfer device 180 is also under a cryogenic atmosphere. However, it is also conceivable to use a sample transfer device 180 without the receiving opening cover 284, whereby the cryogenic atmosphere inside the sample transfer device 180 is provided by cryogenic gas from the drying chamber 110.

[0084] In the next step, the sample supply container is connected to the sample supply container opening 230 of the drying oven. When the inert atmosphere inside the drying oven 110 has the desired low humidity, the sample supply container opening cover 234 is opened. The sample can now be transferred from the sample supply container 232 to, for example, a smaller sample carrier / grid and / or a sample holder / cassette inside the receiving opening 282 of the sample transfer device 180. Furthermore, other types of manipulation, including unloading, can be performed on the sample / sample carrier / sample holder without any risk of contamination or devitrification.

[0085] Figure 3 An embodiment of system 100 is schematically shown in a transparent side view. Similarly, the sample transfer device is depicted as 180, the drying oven 110, and the frame or bracket 174 of the drying oven. From Figure 3 As can be seen, the inert gas storage container 344 is received inside the bracket or frame 174 of the drying oven 110. (As combined...) Figure 2 As discussed, the inert gas storage container 344 can be connected to the inert gas opening 240. Alternatively, according to... Figure 2In the illustrated embodiment, the sample supply container 232 may be included in the lower part of the bracket or frame 174, replacing the inert gas storage container, or other than the inert gas storage container. In this regard, reference is made to... Figure 2 The explanation.

[0086] The bracket or frame 174 includes a bottom or base 176 extending substantially parallel to the ground, on which the sample transfer device 180 is placed. The base 176 of the bracket or frame 174 includes an eccentric mechanism 170, which includes an eccentric wheel 172 on the left side of the base 176 and another eccentric wheel 172 on the right side of the base 176 (also as...). Figure 1 As shown). In such Figure 3 The position of the eccentric wheel 172 is shown, and the frame or bracket 174 is in a lowered position so that the drying oven 110 and the sample transfer device 180 can be connected.

[0087] Figure 4 It shows Figure 3 The only difference in the system 100 is that the eccentric wheel 172 is in another position, in which the base 176 of the bracket or frame 174 is raised, so that the drying oven 110 is in a slightly tilted position and is unconnected to the sample transfer device 180.

[0088] Figure 5 With similar Figure 1 The perspective view schematically illustrates an embodiment of the drying oven 110 according to the present invention, but without the sample transfer device.

[0089] The outer shell portion 116, which includes the volumetric space of the drying oven 110, can be made of a transparent or translucent material. The drying oven 110 has an interface opening 112 (see...). Figure 1 The frame of the interface opening 112 is configured such that it can be placed on top of the sample transfer device 180, as... Figure 1 As shown. Figure 5 As shown, the drying chamber 110 also includes two at least partially closable user openings, providing user access to the interior of the drying chamber 110. These user openings can be closed via corresponding user opening doors 164 (shown in the closed state). For example, in Figure 5 As can be further seen, the drying oven 110 includes a bracket or frame 174 that holds the outer shell portion 116 of the drying oven 110, including the interface opening 112, at a height corresponding to the height of the top side of the sample transfer device 180, such as... Figure 1 As shown. The bracket or frame 174 includes a base 176, which is supported by the ground and includes two eccentric wheels 172, thereby forming the upper connection. Figure 3 or Figure 4The eccentric mechanism 170 has already been described. In... Figure 5 In this state, the eccentric mechanism 170 connects the drying oven 110 to the sample transfer device 180 by lowering the interface opening 112 of the drying oven 110 to the top side of the sample transfer device.

[0090] The measuring device 152 has a display for operating the device and / or for displaying the relative humidity value inside the outer casing 116 of the drying chamber 110. The measuring device 152 measures the relative humidity of the atmosphere inside the outer casing 116 via a humidity sensor 250. A relative humidity of less than 5% is achievable and desirable. It should be noted that inert gas can be automatically introduced into the drying chamber 110 via a control unit and / or the measuring device 152 and valve. The amount of inert gas flowing in can be controlled via the humidity sensor 250 or simply by adjusting the amount of gas released from the gas cylinder.

[0091] Combination Figures 1 to 4 Other features of the drying oven 110 have been discussed, and can be found in Figure 5 These features are implemented individually or in combination in the drying oven 110.

Claims

1. A system (100) for loading a sample into a sample transfer device (180) at cryogenic temperatures and / or for manipulating a sample in the sample transfer device (180), comprising: The sample transfer device (180) is configured to receive a sample through its receiving opening (282) and to transfer the sample to a processing unit or analysis unit. A drying oven (110) having an interface opening (112) and configured to connect to the sample transfer device (180) such that the interface opening (112) of the drying oven (110) and the receiving opening (282) of the sample transfer device (180) face each other to allow a sample to be transferred from the drying oven (110) to the sample transfer device (180). in, The drying chamber (110) includes a bracket (174) for supporting the drying chamber (110) on the ground, and wherein the drying chamber (110) is configured such that, in operation, the drying chamber (110) is placed relative to the sample transfer device (180) via the bracket (174) such that when the sample transfer device (180) is placed on the ground below the drying chamber (110), the interface opening (112) is located above the receiving opening (282) of the sample transfer device (180).

2. The system (100) according to claim 1, wherein the drying chamber (110) includes an interface opening cover (214) for opening and closing the interface opening (112) of the drying chamber (110).

3. The system (100) according to claim 2, wherein the sample transfer device (180) includes a receiving opening cover (284) for opening and closing the receiving opening (282) of the sample transfer device (180).

4. The system (100) according to claim 3, wherein the drying chamber (110) including the interface opening cover (214) in its closed state is configured to be connected to the sample transfer device (180) including the receiving opening cover (284) in its closed state.

5. The system (100) according to claim 4, wherein when the drying oven (110) is connected to the sample transfer device (180), the distance between the interface opening cover (214) in its closed state and the receiving opening cover (284) in its closed state is in the range of 0 to 10 mm.

6. The system (100) according to claim 4, wherein when the drying oven (110) is connected to the sample transfer device (180), the distance between the interface opening cover (214) in its closed state and the receiving opening cover (284) in its closed state is in the range of 0 to 5 mm.

7. The system (100) according to any one of claims 1 to 6, wherein the drying oven (110) and the sample transfer device (180) are connectable to each other by mechanical and / or magnetic connection.

8. The system (100) according to any one of claims 1 to 6, wherein when the drying oven (110) and the sample transfer device (180) are connected to each other, the resulting connection constitutes a closed connection.

9. The system (100) according to any one of claims 1 to 6, wherein when the drying oven (110) and the sample transfer device (180) are connected to each other, the resulting connection constitutes a sealed connection.

10. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes an inlet (220) for introducing an inert gas into the interior of the drying chamber (110).

11. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes an outlet for discharging gas from the interior of the drying chamber (110).

12. The system (100) according to any one of claims 1 to 6, wherein the drying oven (110) includes a sample supply container opening (230) configured to connect to a sample supply container (232).

13. The system (100) of claim 12, wherein the drying chamber (110) includes a sample supply container opening cover (234) for opening and closing the sample supply container opening (230) of the drying chamber (110).

14. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes an inert gas opening (240) configured to be connected to an inert gas storage container (344).

15. The system (100) according to any one of claims 1 to 6, wherein the sample transfer device (180) includes an inert gas reservoir at low temperature.

16. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes a humidity sensor (250) and / or a measuring device (152) for detecting the humidity inside the drying chamber (110).

17. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes at least one user opening (160) that is at least partially closable, the user opening (160) providing a user entrance to the interior of the drying chamber (110).

18. The system (100) of claim 17, wherein the drying chamber (110) includes a foil cover (162) that at least partially covers the user opening (160).

19. The system (100) of claim 17, wherein the user opening (160) of the drying chamber (110) includes a glove mount for installing a glove that extends into the interior of the drying chamber (110) when installed.

20. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes an electromechanical coupling mechanism for disconnecting the drying chamber (110) from the sample transfer device (180) and for connecting the drying chamber (110) to the sample transfer device (180).

21. The system (100) according to claim 20, wherein the electromechanical connection mechanism includes an eccentric mechanism.

22. The system (100) according to claim 21, wherein the eccentric mechanism (170) includes an eccentric wheel (172) on the bottom side of the drying chamber (110).

23. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes a mechanical coupling mechanism for disengaging the drying chamber (110) from the sample transfer device (180) and for coupling the drying chamber (110) to the sample transfer device (180).

24. The system (100) of claim 23, wherein the mechanical coupling mechanism includes an eccentric mechanism.

25. The system (100) according to claim 24, wherein the eccentric mechanism (170) includes an eccentric wheel (172) on the bottom side of the drying chamber (110).

26. The system (100) according to any one of claims 1 to 6, wherein the drying chamber (110) includes an enlarged window (190) on the top side of the drying chamber (110).

27. A drying oven (110) configured for use within a system (100) according to any one of claims 1 to 26, the drying oven (110) having an interface opening (112) and configured to connect to the sample transfer device (180) such that the interface opening (112) of the drying oven (110) and the receiving opening (282) of the sample transfer device (180) face each other to allow a sample to be transferred from the drying oven (110) into the sample transfer device (180). in, The drying chamber (110) includes a bracket (174) for supporting the drying chamber (110) on the ground, and wherein the drying chamber (110) is configured such that, in operation, the drying chamber (110) is placed relative to the sample transfer device (180) via the bracket (174) such that when the sample transfer device (180) is placed on the ground below the drying chamber (110), the interface opening (112) is located above the receiving opening (282) of the sample transfer device (180).

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