Sample preparation device, microscopy device and method for preparing a sample for microscopy

Abstract

To relate to sample preparation devices (1, 2 and 3) for preparing one or more samples (300) to be examined in a microscope (410).SOLUTION: In preparing, one or more liquids being supplied to one or more sample receptacles (202) for said one or more samples (300) is / are included, and a sample preparation device (100) has: a base (102); and a storage structure (104) that is adapted to store one or more sample receptacles (202), and the sample preparation device (100) further has a pipetting guide (106) that is fixed in a relatively movable way to the storage structure (104) or can be fixed thereto. The pipetting guide (106) has one or more pipette guiding structures (108) that is / are relatively positionable to one or more sample receptacles (202).SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] The present invention relates to a sample preparation device for preparing one or more samples to be examined in a microscope, wherein a pipetting guide is fixed or fixable so as to be movable relative to a receiving structure for one or more sample receptacles, said pipetting guide having one or more pipette guide structures positionable relative to said one or more sample receptacles; the invention also relates to a corresponding microscopy apparatus and a method of preparing a sample for microscopy. [Background technology]

[0002] The present invention relates to the supply of liquids by pipetting into sample containers to be observed under a microscope, which may be required, for example, for adding bacterial strains, chemical or immunological reagents, growth factors, culture, treatment or embedding agents, nutrient solutions, or buffers and washing solutions. The correspondingly treated samples may include biological or non-biological samples or non-biological materials of (micro)biological origin that can be prepared or pre-treated in any conceivable way, for example by culturing, sectioning, embedding, smearing, etc., and the term "sample" as used in the present invention may relate to any such material that can be examined or prepared for examination, with the purpose of observation under a microscope.

[0003] The present invention is particularly relevant to cases where one or more samples are contained in one or more sample containers and processed by supplying liquid to the same containers by a pipette, while the containers are contained in and selectively fixed to a receiving structure on a microscope stage of a microscope, as will be further explained below.

[0004] The microscope used in the context of the present invention may in particular be an optical microscope in an inverted or reverse configuration, i.e., in which a sample, positionable using a microscope stage, is illuminated by light from above and observed by microscope optics arranged below the sample. Such a configuration generally improves sample accessibility compared to conventional, non-inverted microscopes. However, the present invention is not limited to use with the inverted microscopes described, but can be used with regular, i.e., non-inverted, microscopes as well.

[0005] When pipetting liquids into sample containers (e.g., individual containers in multiwell plates and Petri dishes) on a microscope stage, or more generally, into sample containers on a microscope device's receiving structure for such containers, handheld and hand-guided pipettes are typically manually positioned so that they are positioned at a predetermined angle to the edge of the sample container, and the liquid is injected at a fixed distance and in contact with the container wall, if possible, without contacting the sample in the sample container. One problem with this approach is that the pipette is not reliably guided during pipetting, which can result in user error, such as the sample touching the pipette tip or the pipette tip not touching the container wall, resulting in an inaccurate injection. Visual control of the pipetting process is difficult, particularly with known multichannel pipettes.

[0006] It should be noted that "pipetting" as referred to herein refers to liquid transfer processes performed by handheld and hand-guided pipettes with standard-sized, interchangeable tips; such pipettes and their interchangeable tips are configured for withdrawing, dispensing, and decanting small volumes of liquid, typically between 0.1 and 5000 microliters. Because the pipettes used in accordance with the present invention are handheld and hand-guided, they are not themselves fixed to a structure coupled to a microscope. The present invention does not relate to devices used in in vitro fertilization techniques, etc., in which (micro)pipettes are fixed to and manipulated by a micromanipulator. Summary of the Invention [Problem to be solved by the invention]

[0007] The object of the present invention is to solve the above-mentioned problems, i.e. to improve the process of pipetting liquid into sample containers used to support samples to be examined by microscope, particularly in terms of ease of handling, reliability, reproducibility and sample protection. [Means for solving the problem]

[0008] Against this background, the present invention provides a sample preparation device for preparing one or more samples to be examined in a microscope, a microscopy device, and a method for preparing a sample for microscopy, having the characterizing features of the independent claims, in which a pipetting guide is fixed or fixable so as to be movable relative to a receiving structure for one or more sample receptacles, said pipetting guide having one or more pipette guide structures positionable relative to said one or more sample receptacles. Preferred embodiments of the invention are the subject of the dependent claims and the following description.

[0009] The present invention provides a sample preparation device for preparing one or more samples to be examined in a microscope. As described above, the microscope used in connection with the sample preparation device of the present invention is an optical microscope, such as a wide-field microscope, equipped with optics for visual and / or camera-based observation. The microscope may have illumination and detection modalities commonly known in the art, such as fluorescent, infrared, and / or white light sources and optional corresponding detection modalities. The microscope may also be a scanning microscope, such as a confocal microscope, or may have any other configuration for illumination and / or detection, such as a light sheet microscope adapted to provide a horizontal or oblique light sheet.

[0010] The sample preparation performed according to the present invention includes pipetting one or more liquids into one or more sample receptacles for one or more samples. For further details, please refer to the explanations already given above. It should be noted again that, according to the present invention, the above-mentioned pipetting operations are performed by handheld pipettes of the above-mentioned type, i.e., pipettes that are adapted for free use, separate from micropipettes used in micromanipulators, and equipped with exchangeable (plastic) pipette tips, e.g., standardized for defined volumes or volume ranges. In pipettes used according to the present invention, the volumes that can be delivered by the pipettes can be fixed or adjustable. The pipettes can be single-channel or multi-channel pipettes. Single-channel pipettes are used with a single pipette tip and are adapted to deliver a single volume at a time, whereas multi-channel pipettes are adapted to be used with multiple pipette tips arranged at standardized intervals that match corresponding multi-well plates, particularly those with 6, 12, 24, 48, 96, or 384 wells, as known in the art. Multichannel pipettes can be used to pipette multiple liquid volumes in parallel.

[0011] As also mentioned above, according to the present invention, the above-described pipetting operations are performed by hand-held and hand-guided pipettes that are freely movable and positionable except by the means provided by the present invention and described below. That is, the hand-held and hand-guided pipettes can be freely moved and positioned by hand except for being supported by the structure described below. Thus, the present invention does not relate to pipettes that are fixedly or removably attached to a positioning system, such as a micromanipulator, adapted to position the pipette itself relative to a sample or sample container.

[0012] A sample preparation device according to the present invention comprises a base and a receiving structure adapted to receive one or more of the above-described sample receptacles. The base may be, in particular, a motorized or manually movable microscope stage adapted for horizontal and optionally vertical movement of the sample relative to the microscope optics, or may be attached thereto or fixedly or movably positioned relative thereto. The receiving structure may be a structure such as a recess, a well, a group of wells, a frame, a fence, a mechanical stop or a collection of mechanical stops that limit movement in at least one direction, and the receiving structure may also be adapted to at least temporarily and / or releasably secure one or more sample containers against unintentional removal or displacement due to forces exerted during pipetting of liquids according to the present invention.

[0013] According to the present invention, the sample preparation device further includes a pipetting guide that is movably fixed or fixable relative to the receiving structure. As used herein, the phrase "movably fixed or fixable relative to the receiving structure" refers to movably fixed to the base described above, or to a structure to which the base is movably or fixedly connected, or to a structure to which the base is movably or fixedly connected. For example, the pipetting guide may also be movably fixed or fixable to a housing that surrounds a sample zone in which one or more sample containers can be positioned. Such a housing may be particularly adapted to have a defined atmosphere and / or to be at a defined temperature. The pipetting guide may also be movably fixed or fixable to a microscope stand that supports a stage, or to a structure in which the receiving structure is formed or to which the receiving structure is attached, substantially as described above. In summary, the pipetting guide, according to the present invention, may be movably fixed or fixable to at least one of the base, an element connected to the base, a housing at least partially surrounding the base, and a structure at least partially supporting the base.

[0014] The pipetting guide according to the invention comprises one or more pipette guide structures that can be positioned relative to the one or more sample receptacles, in particular by moving the pipetting guide that is movably fixed or fixable relative to the receiving structure as described above. As will be explained further below, such positioning may include, for example, rotating the pipetting guide relative to the base, thereby moving it to the operating position. In particular, the correspondingly moved pipetting guide can be locked in position when the one or more pipette guide structures are positioned relative to the one or more sample receptacles to prevent unintentional movement thereof, in particular by clicking or snapping it into position by a suitable structure and / or by providing another locking structure such as a locking pin or bar.

[0015] In other words, in a sample preparation device according to a preferred embodiment of the present invention, the pipetting guide is configurable such that the pipetting guide structure is pivotable to one or more locked operating positions relative to one or more of the sample receptacles. Hence, a sample preparation device configured according to the present invention is configurable such that one or more of the pipetting guide structures are positionable by moving the pipetting guide and / or receiving structure relative to the base, for example by swiveling, inverting or rotating about one or more axes, in particular about an axis perpendicular to the sample surface, which may be an axis perpendicular to a plane defined by the opening of a sample container.

[0016] In other words, according to the invention, multi-channel and single-channel pipettes can be guided towards the wall of a sample vessel, for which the invention provides a pipetting guide that includes, in particular, a pipette guide structure in the form of a swing-type pipetting aid that can be swiveled above the sample and locked in place.

[0017] In a preferred embodiment of the sample preparation device of the present invention, the pipetting guide may have a flat region with a first surface and a second surface extending parallel to the first surface, and one or more of the pipette guide structures may have one or more V-shaped material indentations on one or more peripheral edges of the flat region. In particular, two parallel lateral areas extending longitudinally along the sides of the flat region may be provided, each of which has a pipette guide structure. In particular, one of the lateral areas may have a pipette guide structure in the form of a single V-shaped indentation, while the other lateral area may have a sawtooth structure consisting of several V-shaped indentations for guiding multichannel pipettes. As described below, the pipetting guide may be inverted so that the correspondingly positioned V-shaped indentations can be positioned on the opposite side, particularly to selectively improve handling for left-handed and right-handed operators.

[0018] In a particularly advantageous embodiment of the sample preparation device according to the present invention, the side surfaces of one or more of the V-shaped material recesses may be inclined relative to the first and second surfaces of the flat area to define a working angle for a pipette guided by one or more of the pipette guide structures. In particular, each recess may be angled symmetrically, allowing the pipetting guide to achieve the same working angle from both the top and bottom. This feature is particularly used to adapt the pipetting guide to both left-handed and right-handed users, as described above, and to switch between multi-channel and single-channel pipetting. This arrangement also facilitates, in particular, the release of droplets at the pipette tip. Furthermore, the angled contact surface allows for a uniquely targeted guide of the pipette tip toward the wall of the sample container above the actual sample, thereby avoiding sample damage by the pipette tip. However, in another embodiment, the side surfaces are not beveled.

[0019] Thus, as already mentioned above, the pipetting guide can be fixed to the base and / or an element connected thereto in a first orientation in which the first surface faces one or more of the sample receptacles, and / or in a second orientation in which the second surface faces one or more of the sample receptacles, to provide the left-handed and right-handed operating positions and / or the single-channel and multi-channel operation.

[0020] In the sample preparation device according to the present invention, the accommodation structure may advantageously be adapted to accommodate a plurality of sample receptacles in a geometric arrangement relative to one another, and the pipetting guide has a plurality of pipette guide structures, the positions of at least some of the plurality of pipette guide structures being correlated to the geometric arrangement of the plurality of sample receptacles relative to one another.

[0021] In this embodiment, the receiving structure may be adapted to receive sample receptacles, such as known sample caps, for example, with sizes ranging from 100 microliters to 2 milliliters, in the form of individual, i.e., non-interconnected, receptacles, particularly by having a corresponding plurality of receiving wells. That is, the receiving structure may have a plurality of wells adapted to receive individual containers, each forming one of the sample receptacles. However, the sample preparation device may also be configured such that the receiving structure is adapted to support and receive a multiwell plate having a plurality of sample receptacles and defining the geometric arrangement. The positions of at least some of the plurality of pipette guide structures may be correlated to the geometric arrangement by being arranged in a spaced relationship with the geometric arrangement, particularly with a spaced relationship with a plurality of pipette tips of a multichannel pipette.

[0022] In another embodiment, the sample preparation device can also be configured such that the receiving structure is adapted to receive a single-sample receptacle, and the one or more pipette guide structures can correspond to one or more positions at the bottom of the single-sample receptacle. The single-sample receptacle can be provided in the form of a Petri dish or a rectangular culture vessel typically used for cell culture, or a customer-specific vessel that can be adapted for the present invention.

[0023] In particular, in the sample preparation device according to the invention, the receiving structure may be movable relative to said base and said pipetting guide via an actuator, which in this configuration of the sample preparation device may in particular be an electric actuator operable on the basis of a signal responsive to a user input.

[0024] In such an embodiment, the sample vessel or the arrangement of the sample vessels may be predefined by the user, for example in the operating software. Since pipetting is possibly performed with both hands, the sample or sample vessel can be moved to the next loading position relative to the pipetting guide, for example by voice command or foot switch. Depending on the sample vessel or the arrangement of the sample vessels, the starting position for loading can also be approached automatically.

[0025] A microscopy apparatus constructed in accordance with the present invention comprises a microscope and a sample preparation device according to any one of the above-described embodiments. Reference is therefore made to the above description. A microscopy apparatus constructed in accordance with the present invention is advantageous for the reasons described above.

[0026] The same applies to a method of preparing one or more samples for microscopy configured according to the present invention, in which one or more liquids are supplied by a pipette to one or more sample receptacles having one or more of the above-mentioned samples, in which the method uses a sample preparation device according to any one of the above-mentioned embodiments and / or the microscopy device described immediately above, and in which the pipetting guide is used to position the pipette during the supply of one or more liquids by the pipette to one or more of the above-mentioned sample receptacles.

[0027] Some or all of the steps may be performed by (or using) a hardware apparatus, such as, for example, a processor, microprocessor, programmable computer, or electronic circuitry. In some embodiments, any one or more of the critical steps may be performed by such an apparatus.

[0028] Depending on certain implementation requirements, embodiments of the present invention may be implemented in hardware or software. This implementation may be performed by a non-transitory storage medium, such as a digital storage medium, for example, a floppy disk, a DVD, a Blu-ray, a CD, a ROM, a PROM, an EPROM, an EEPROM, or a FLASH memory, on which electronically readable control signals are stored, which cooperate (or can cooperate) with a programmable computer system to implement the respective methods. Therefore, the digital storage medium may be computer-readable.

[0029] Some embodiments of the present invention include a data carrier having electronically readable control signals that can cooperate with a programmable computer system to perform any of the methods described herein.

[0030] In general, embodiments of the present invention may be implemented as a computer program product comprising program code, which may be stored on a machine-readable carrier, that operates to perform any of the methods when the computer program product is run on a computer.

[0031] Further embodiments comprise the computer program for performing any of the methods described herein, stored on a machine readable carrier.

[0032] In other words, an embodiment of the present invention is, therefore, a computer program having a program code for performing any of the methods described herein when the computer program runs on a computer.

[0033] Therefore, another embodiment of the invention is a recording medium (or data carrier or computer readable medium) containing a computer program stored thereon for performing any of the methods described herein when executed by a processor. The data carrier, digital recording medium or recording medium is typically tangible and / or non-transitory. Another embodiment of the invention is an apparatus as described herein, comprising a processor and a recording medium.

[0034] A further embodiment of the present invention is, therefore, a data stream or a sequence of signals representing the computer program for performing any of the methods described herein, the data stream or sequence of signals being adapted to be transmitted via a data communication connection, such as for example the Internet.

[0035] Another embodiment comprises a processing means, for example a computer, or a programmable logic device configured to or adapted to perform any of the methods described herein.

[0036] Another embodiment comprises a computer having installed thereon the computer program for performing any of the methods described herein.

[0037] Another embodiment of the present invention includes an apparatus or system configured to transfer (e.g., electronically or optically) a computer program for implementing any of the methods described herein to a receiver. The receiver may be, for example, a computer, a mobile device, a storage device, etc. The apparatus or system may include, for example, a file server for transferring the computer program to the receiver.

[0038] In some embodiments, a programmable logic device (e.g., a field programmable gate array) may be used to perform some or all of the functionality of the methods described herein. In some embodiments, a field programmable gate array may cooperate with a microprocessor to perform any of the methods described herein. In general, the methods are advantageously performed by any hardware apparatus.

[0039] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0040] While some aspects have been described in the context of an apparatus, it will be apparent that these aspects also represent a description of a corresponding method, where a block or apparatus corresponds to a step or feature of a step, and similarly, aspects described in the context of a step also represent a description of a corresponding block or item or feature of a corresponding apparatus.

[0041] In the following, several aspects of the present invention will be described with reference to the accompanying drawings illustrating preferred embodiments of the invention. It should be noted that the aspects of the present invention described above and below individually or in a specific combination can equally be used in other combinations or alone, insofar as this is encompassed by the claims. [Brief explanation of the drawings]

[0042] [Figure 1A] 1 shows a sample preparation device in a first configuration according to a first embodiment of the present invention; FIG. [Figure 1B] 1B illustrates a sample preparation device according to the first embodiment of the present invention shown in FIG. 1A in a second configuration. [Figure 2A] FIG. 2 shows a sample preparation device in a first configuration according to a second embodiment of the present invention; [Figure 2B]2B shows the sample preparation device according to the second embodiment of the present invention shown in FIG. 2A in a second configuration. [Figure 3] FIG. 10 shows a sample preparation device according to a third embodiment of the present invention. [Figure 4] 1 is a cross-sectional view of a pipetting guide of a sample preparation device according to an embodiment of the present invention. [Figure 5A] FIG. 1 illustrates a sample preparation device in a first configuration for use with a multi-channel pipette, according to one embodiment of the present invention. [Figure 5B] 5B illustrates a sample preparation device in a second configuration according to the embodiment shown in FIG. 5A for use with a multi-channel pipette. [Figure 6A] FIG. 1 illustrates a sample preparation device in a first configuration, according to one embodiment of the present invention, for use with a single channel pipette. [Figure 6B] 6B illustrates a sample preparation device in a second configuration according to the embodiment shown in FIG. 6A for use with a single channel pipette. [Figure 7] 1 illustrates a microscopy apparatus according to an embodiment of the present invention; DETAILED DESCRIPTION OF THE INVENTION

[0043] The same reference numerals in multiple figures are intended to indicate parts of the same or equivalent configuration, design, structure and / or function, which will not be described repeatedly for the sake of brevity.

[0044] 1A and 1B show a sample preparation device in a first and second configuration, respectively, according to a first embodiment of the present invention. The sample preparation device is designated by reference numeral 1 and may be part of a microscope in a microscopy apparatus, which is described in more detail below and in one particular embodiment in FIG. 7. For clarity, not all reference numerals used in FIG. 1A are also used in FIG. 1B.

[0045] The sample preparation device 1 is adapted to prepare one or more samples 300, which, in the case of Figures 1A and 1B, are contained in one or more sample receptacles 202 of a multiwell sample plate 200, only one of which is indicated by reference numeral. The multiwell sample plate 200 is shown here as having 24 wells, A1-D6, although it will be understood that the present invention can be used with multiwell sample plates having different, and particularly greater, numbers of wells, as discussed above.

[0046] The multiwell plate 200, and thus its sample receptacles 202, are received in a receiving structure 104, which is shown only diagrammatically for the sake of generality. As noted above, the receiving structure 104 may include, for example, a recess, a well, a group of wells, a frame, or a mechanical stop or set of mechanical stops that limit movement of the multiwell sample plate 200, and thus the sample receptacles 202, as well as other means for limiting movement as described above. In the illustrated embodiment, the receiving structure 104 is formed in a base 102, which may be, for example, a surface of or part of a microscope stage or other structure of a microscope.

[0047] 1A and 1B, the sample preparation device 1 further includes a pipetting guide 106 that is movably secured relative to the receiving structure 104. As shown, the pipetting guide 106 is movably secured to a support element 126, which is itself coupled to the base 102. In an alternative configuration, as shown in FIG. 7, the support element 126 may be secured or securable to a housing that at least partially surrounds the base 102 and / or to a structure that at least partially supports the base 102.

[0048] In the illustrated embodiment, the pipetting guide 106 has a plurality of pipette guide structures 108 that are positionable relative to one or more sample receptacles 202. As shown, the pipetting guide 106 can be positioned into an operating position by moving the pipetting guide 106 by rotating it about an axis 128 that is perpendicular to the base or its surface, in which the pipette guide structures 108 are locked into position relative to one or more of the sample receptacles 202. This is indicated by the quadrant arrows. FIG. 1A shows a configuration in which the pipetting guide 106 is rotated into the operating position, while FIG. 1B shows a configuration in which the pipetting guide 106 is rotated into a position that is not in the operating position but is usable for loading the receiving structure 104 with one or more sample receptacles 202. Alternatively, such positioning can be achieved by moving the receiving structure 104 relative to the base 102.

[0049] As can be seen particularly in connection with Figure 4, which shows a cross-sectional view of the pipetting guide 106, the pipetting guide 106 has a flat region 110 with a first surface 112 and a second surface 114 extending parallel to the first surface 112, and the pipette guide structures 108 are formed as V-shaped material depressions at the edges 116, 118 of the flat region 110. As can be seen again in Figure 4, where one of the V-shaped material depressions 120 is truncated at its tip (i.e., at the point of maximum depression), the V-shaped material depression 120 is inclined relative to the first surface 112 and the second surface 114 of the flat region 110, thereby defining an action angle for the pipette 500, guided by one or more pipette guide structures 108. In Figure 4, the distal end of the pipette, to which a pipette tip 502 is attached, is shown schematically.

[0050] 1A and 1B, in one embodiment of the present invention, the base 102 is movable relative to the pipetting guide 106 to position other sample containers for pipetting. Such positioning can be achieved by means described in more detail above.

[0051] Figures 2A and 2B show a sample preparation device in a first and second configuration, respectively, according to a second embodiment of the present invention. The sample preparation device is designated by reference numeral 2 and may similarly be part of a microscope in a microscopy apparatus, which is described in more detail below and in one particular embodiment in Figure 7. Again, for clarity, not all reference numerals used in Figure 2A are used in Figure 2B.

[0052] The sample preparation device 2 is shown substantially similar to the sample preparation device 1 according to the first embodiment shown in Figures 1A and 1B. However, in the embodiment shown in Figures 2A and 2B, the pipetting guide 106 can be positioned into an operating position by moving the pipetting guide 106 horizontally relative to the base or its surface, i.e., by rotating it about an axis 128a arranged parallel to the plane of the paper, in which the pipetting guide structure 108 is locked in position relative to one or more of the sample receptacles 202. This is depicted by the arrow around axis 128a. Again, Figure 2A shows a configuration in which the pipetting guide 106 is rotated into the operating position, while Figure 2B shows a configuration in which the pipetting guide 106 is rotated so that it is not in the operating position but is in a position that can be used to load the receiving structure 104 with one or more sample receptacles 202.

[0053] FIG. 3 illustrates a sample preparation device 3 according to a third embodiment of the present invention. Unlike the embodiments illustrated in the preceding figures, the sample preparation device 3 illustrated in FIG. 3 is arranged to accommodate a single sample receptacle 202a, such as a Petri dish in a correspondingly configured receiving structure 104a, or alternatively, a customized container adapted to this design. For further explanation, please refer to the explanations associated with the preceding figures. All features not specifically described as different can be implemented here as well. The axis 128 illustrated in association with the sample preparation device 3 according to FIG. 3 can be arranged similarly to FIGS. 2A and 2B in alternative embodiments.

[0054] 4 shows a cross-sectional view of a pipetting guide 106 like the pipetting guide 106 shown in the previous figures, although reference is made to the above description for further explanation that is also applicable to other configurations of the sample preparation device.

[0055] As shown in Figures 5A, 5B, 6A, and 6B, in the sample preparation device 1 shown in Figures 1A and 1B, or in the sample preparation device 3 shown in Figure 3, which is interchangeable therewith and is again depicted in a simplified form and with a limited number of elements, the pipetting guide 106, in one embodiment, can be fixed in a first orientation (Figures 5A and 6A) in which the first surface shown in Figure 4 faces the sample receptacle 102 (and the second surface 114 faces the viewer, and therefore is indicated by the reference numeral). This pipetting guide 106 can also be fixed in a second orientation (Figures 5B and 6B) in which the second surface 114 faces the sample receptacle 102 (and the first surface 112 faces the viewer, and therefore is indicated by the reference numeral). In this embodiment, operating positions for left-handed and right-handed operation are provided by reversing the pipetting guide 106. This is shown in Figures 5A and 5B for a multi-channel pipette 500 and in Figures 6A and 6B for a single-channel pipette 500. Note that the multi-channel pipette 500 shown in Figures 5A and 5B will generally have more than the four channels shown, corresponding to the number of sample receptacles 202 in the multiwell plate. In all cases, the axis 128 can also be positioned as shown for axis 128A in Figures 2A and 2B.

[0056] 7 shows a microscopy apparatus according to one embodiment of the present invention, generally designated by the reference numeral 400. In the illustrated embodiment, the microscopy apparatus 400 comprises an inverted microscope 410 and a sample preparation device 1, which has already been shown in specific embodiments. For reasons of generality, the sample preparation device 1 is depicted as a transparent block and can take any conceivable configuration, in particular as has already been depicted for sample preparation devices 2 and 3.

[0057] The microscopy apparatus 400 shown in FIG. 7 includes a computer system 450. Alternatively or additionally, the microscope may be part of or connected to a distributed system. The microscopy apparatus 400 may be configured, among other things, to perform the methods described herein. The microscope 410 may be configured to capture images and is connected to the computer system 450. The computer system 450 may be configured to implement at least some of the methods described herein. The computer system 450 may be configured to execute machine learning algorithms. The computer system 450 and the microscope 410 may be separate entities or may be integrated into a common housing. The computer system 450 may be part of a central processing system of the microscope 410 and / or may be part of a subordinate component of the microscope 410, such as a sensor, actor, camera, or lighting unit of the microscope 410.

[0058] Computer system 450 may be a local computing device (e.g., a personal computer, laptop, tablet computer, or mobile phone) with one or more processors and one or more storage devices, or may be a distributed computing system (e.g., a cloud computing system with one or more processors and one or more storage devices distributed across various locations, such as local clients and / or one or more remote server farms and / or data centers). Computer system 450 may include any circuit or combination of circuits. In one embodiment, computer system 450 may include one or more processors, which may be of any type. As used herein, processor may contemplate any type of computing circuit, such as, but not limited to, a microprocessor of a microscope or microscope component (e.g., a camera), a microcontroller, a complex instruction set computing (CISC) microprocessor, a reduced instruction set computing (RISC) microprocessor, a very long instruction word (VLIW) microprocessor, a graphics processor, a digital signal processor (DSP), a multi-core processor, a field programmable gate array (FPGA), or any other type of processor or processing circuit. Other types of circuits that may be included in computer system 450 may be custom circuits, application specific integrated circuits (ASICs), etc., such as one or more circuits (e.g., communications circuits) used in wireless devices such as cell phones, tablet computers, laptop computers, two-way radios, and similar electronic systems. Computer system 450 may also include one or more storage devices, which may include one or more memory elements suitable for a particular application, such as main memory in the form of random access memory (RAM), one or more hard drives and / or one or more drives that handle removable media, such as compact discs (CDs), flash memory cards, digital video discs (DVDs), etc.Computer system 450 may also include a display device, one or more speakers and a controller which may include a keyboard and / or mouse, trackball, touch screen, voice recognition device, or any other device that allows a user of the system to input information to and receive information from computer system 450.

[0059] As shown in this particular embodiment, the microscope 410, which may be configured as a more general inverted microscope known per se but lacking some of the components described below, or may also be configured as a non-inverted microscope, comprises a microscope housing 402 that encloses illumination optics 412, the sample preparation device 100, which is in particular part of or connected to a microscope stage 414, and imaging optics 416.

[0060] The built-in sample chamber 418 is disposed within the microscope housing 402 and is formed by a separate housing portion 420 within the microscope housing 402. The housing portion 420 has a hinged door lid 422 that, when open, provides direct access to the microscope stage 414 for placing, exchanging, or manipulating elements such as the aforementioned multiwell plate 200 onto the microscope stage 414, or more precisely, onto the sample preparation device 1. A sliding door could be used instead of the hinged door lid 422 as well.

[0061] The embodiment shown in Figure 7 has a microscope 410 in the form of an inverted transmitted light microscope, as described above, with illumination optics 412 located within housing portion 420, while imaging optics are located in a separate portion of housing 402 below microscope stage 414 and not individually referenced by reference numeral.

[0062] The imaging optics 416 typically include as major components a microscope objective and an image detector, which typically comprises a camera that generates a microscope image that is displayed on a display screen 452 typically external to the microscope housing 402.

[0063] The configuration of the microscope housing part 420 allows (after closing the door lid 422) to form a dedicated sample chamber, which constitutes an incubable, preferably enclosed space, in which biological samples, such as cells, can be maintained under favorable and stress-free environmental conditions during microscopic examination / imaging of the sample. To this end, the housing part 420 has an interface 430 for connecting an external incubation environmental conditioning unit 432, which allows the environmental conditions in the sample chamber 418 to be controlled. [Explanation of symbols]

[0064] 1, 2, 3 Sample preparation device 102 Foundation 104, 104a Containment structure 106 Pipette Operation Guide 108 Pipette guide structure 110 flat area 112 First Surface 114 Second Surface 116, 118 Periphery 120 Material dent 126 Supporting Elements 128, 128a axis 200 multi-well sample plate 202, 202a Sample Receptacle 300 samples 400 Microscope inspection equipment 402 Housing 410 Microscope 412 Illumination optical system 414 Microscope Stage 416 Imaging Optical Systems 418 Sample Chamber 420 Housing 422 Door cover 430 Incubation Interface 432 Environmental Conditioning Unit 450 Computer Systems 452 display screen 500 pipettes 502 Pipette Tips

Claims

1. A sample preparation device (1, 2, 3) for preparing one or more samples (300) to be examined in a microscope (410), comprising: The preparation includes pipetting one or more liquids into one or more sample receptacles (202) for one or more of the samples (300), the sample preparation device (100) having a base (102) and a receiving structure (104) adapted to receive one or more of the sample receptacles (202), the sample preparation device (100) further having a pipetting guide (106) fixed or fixable so as to be movable relative to the receiving structure (104), the pipetting guide (106) having one or more pipette guide structures (108) positionable relative to the one or more sample receptacles (202), the pipetting guide (106) is rotatable to an operating position in which one or more of the pipetting guide structures (108) are locked in position relative to one or more of the sample receptacles (202); Sample preparation device (1, 2, 3).

2. The pipetting guide (106) has a flat area (110) with a first surface (112) and a second surface (114) extending parallel to the first surface (112); the one or more pipette guide structures (108) have one or more v-shaped material recesses (120) on one or more peripheral edges (116, 118) of the flat region (110); 2. A sample preparation device (1, 2, 3) according to claim 1.

3. A sample preparation device (1, 2, 3) for preparing one or more samples (300) to be examined in a microscope (410), comprising: The preparation includes pipetting one or more liquids into one or more sample receptacles (202) for one or more of the samples (300), the sample preparation device (100) having a base (102) and a receiving structure (104) adapted to receive one or more of the sample receptacles (202), the sample preparation device (100) further having a pipetting guide (106) fixed or fixable so as to be movable relative to the receiving structure (104), the pipetting guide (106) having one or more pipette guide structures (108) positionable relative to the one or more sample receptacles (202), The pipetting guide (106) has a flat area (110) with a first surface (112) and a second surface (114) extending parallel to the first surface (112); the one or more pipette guide structures (108) have one or more v-shaped material depressions (120) on one or more peripheral edges (116, 118) of the flat region (110); a side surface (122) of the one or more v-shaped material recesses (120) is inclined relative to the first surface (112) and the second surface (114) of the flat region (110) to define an action angle for a pipette (500) guided by the one or more pipette guiding structures (108); Sample preparation device (1, 2, 3).

4. The one or more pipette guide structures (108) are positionable by moving the pipetting guide (106) and / or the receiving structure (104) relative to the base (102). A sample preparation device (1, 2, 3) according to any one of claims 1 to 3.

5. the pipetting guide (106) is movably fixed or fixable to at least one of the base (102), an element coupled to the base (102), a housing at least partially surrounding the base (102), and a structure at least partially supporting the base (102); A sample preparation device (1, 2, 3) according to any one of claims 1 to 4.

6. the pipetting guide (106) is securable to the base and / or an element coupled to the base in a first orientation in which the first surface (112) faces one or more of the sample receptacles (102) and / or in a second orientation in which the second surface (114) faces one or more of the sample receptacles (102); A sample preparation device (1, 2, 3) according to claim 2 or 3.

7. The receiving structure (104) is adapted to receive a plurality of sample receptacles (202) in a geometric arrangement relative to one another, and the pipetting guide (106) has a plurality of pipette guide structures (108), and positions of at least some of the plurality of pipette guide structures (108) are correlated to the geometric arrangement of the plurality of sample receptacles (202) relative to one another. A sample preparation device (1, 2, 3) according to any one of claims 1 to 6.

8. the receiving structure (104) is adapted to support and receive a multiwell plate (200), the multiwell plate (200) having a plurality of the sample receptacles (202) defining the geometric arrangement; A sample preparation device (1, 2, 3) according to claim 7.

9. The receiving structure (104) has a plurality of wells adapted to receive individual containers each forming one of the plurality of sample receptacles (202); A sample preparation device (1, 2, 3) according to claim 7.

10. The receiving structure (104) is adapted to receive a single sample receptacle (202), and one or more of the pipette guide structures (108) correspond to one or more positions on the bottom of the single sample receptacle (202). A sample preparation device (1, 2, 3) according to any one of claims 1 to 6.

11. The receiving structure (104) is movable relative to the base (102) and the pipetting guide (106) via an actuator (130). A sample preparation device (1, 2, 3) according to any one of claims 1 to 10.

12. the actuator (130) is an electric actuator operable based on a signal responsive to a user input; A sample preparation device (1, 2, 3) according to claim 11.

13. A microscopy device (400) comprising a microscope (410) and a sample preparation device (100) according to any one of claims 1 to 12.

14. 1. A method of preparing one or more samples (300) for microscopy, comprising: The method includes pipetting one or more liquids into one or more sample receptacles (202) containing one or more of the samples (300); The method comprises using a sample preparation device (100) according to any one of claims 1 to 12 and / or a microscopy device according to claim 13, and using the pipetting guide (106) by positioning a pipette (500) with the pipetting guide (106) during the pipetting of one or more liquids into one or more sample receptacles (202). method.

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