Microscope stage and method for inspecting sample

Abstract

In a first aspect, there is provided a microscope stage comprising: a receiving surface configured to receive at least a first sample stage having a plurality of sample zones; an imaging region; and a surface moving device for moving the receiving surface in at least two directions, where the surface moving device has a range of movement in the at least two directions such that any one of the plurality of sample regions is alignable with the imaging region. The microscope stage further includes at least one liquid dispensing head configured to dispense a fluid onto the sample stage; and a head moving device configured to move the at least one liquid dispensing head in at least two directions, where the head moving device has a range of movement in the at least two directions such that the at least one liquid dispensing head can be aligned with any one of the plurality of sample zones. In other aspects, corresponding microscopes and methods are provided.

Description

Technical Field

[0001] The invention relates to a microscope stage having a liquid handling head, a corresponding microscope, and a method for examining a sample. Background Art

[0002] Experiments in the life sciences often involve the microscopic study of samples that have been manipulated or treated with various reagents in order to study and understand biological processes. These experiments often require manually bringing the sample into contact with the reagents, such as by pipetting liquids such as reagents onto the sample. This is a time-consuming task, especially in high-throughput experiments, such as when using multi-well plates. Each necessary human-computer interaction reduces the walk-away time of the experiment, thereby reducing the experimental efficiency. Many experiments also require the rapid and continuous addition of multiple reagents to the sample, and the actual reaction to be observed may take minutes, hours, or even days.

[0003] Manually pipetting samples is not only tedious and time-consuming, but also increases the risk of sample contamination. Therefore, people hope to automate the pipetting process as much as possible. Summary of the Invention

[0004] It is therefore an object of the present invention to provide a microscope stage and a method for examining a sample which allow automated pipetting.

[0005] The above objects are achieved by the subject-matter of the independent claims. Advantageous embodiments are defined in the dependent claims and in the following description.

[0006] In a first aspect, a microscope stage is provided. The microscope stage includes: a receiving surface and an imaging area, wherein the receiving surface is configured to receive at least a first sample carrier having a plurality of sample areas. The microscope stage also includes: a surface moving device configured to move the receiving surface along at least two directions, wherein the surface moving device has a moving range along the at least two directions, so that any sample area of ​​the plurality of sample areas can be aligned with the imaging area. The microscope stage also includes: at least one liquid dispensing head configured to dispense fluid onto the sample carrier; and a head moving device configured to move the at least one liquid dispensing head along at least two directions, wherein the head moving device has a moving range along the at least two directions, so that the at least one liquid dispensing head can be aligned with any sample area of ​​the plurality of sample areas.

[0007] The microscope stage is able to dispense liquid to each sample area via the liquid dispensing head, regardless of the specific position of the receiving surface within its range of motion. In particular, liquid can be dispensed to each sample area regardless of which sample area is aligned with the imaging area. This allows for flexible use of the microscope stage. For example, when dispensing fluid onto the sample stage, the fluid can be dispensed according to a specific amount or volume. Preferably, the volume can be in the range of 1 μl to 100 ml, more preferably in the range of 10 μl to 10 ml.

[0008] Furthermore, no human interaction is required, and the process of dispensing liquid onto the sample stage is easily automated. Therefore, the device can be easily integrated into workflow design, particularly through software such as Experiment Designer. The possibility of automation and the reduced human interaction required also reduce the risk of contamination due to human error. Overall, the microscope stage has a long hands-free time, leading to more efficient experimental design.

[0009] Preferably, each sample area of ​​the sample carrier is capable of receiving a biological sample. An example of a biological sample is a cell culture or tissue section. The sample carrier may be a microplate having multiple cavities, each of which is a sample area. In this case, the sample area may be referred to as a sample volume. Preferably, the receiving surface has tongues or grooves to receive corresponding grooves or tongues on the sample carrier. This allows the sample carrier to be securely positioned on the receiving surface, particularly when the receiving surface is moved.

[0010] In a preferred embodiment, the receiving surface can be configured to additionally receive a second sample carrier. In particular, the second sample carrier can have a different sample area layout than the first sample carrier. Furthermore, the sample area of ​​the second sample carrier may have a different geometry than the sample area of ​​the first sample carrier. This allows for flexible use of the microscope stage.

[0011] Preferably, at least the sample area of ​​the sample carrier is transparent to facilitate imaging through the sample carrier.

[0012] Preferably, the imaging zone is used to image one of the sample areas. The imaging zone can be aligned with the optical system of the microscope so that one of the sample areas is imaged when the sample area is aligned with or within the imaging zone. The receiving surface can have at least one opening or cutout such that when any sample area is aligned with the imaging zone, the sample area can be imaged through the opening.

[0013] When the receiving surface is moved by the surface movement device, the sample carrier disposed on the receiving surface is also moved. Preferably, at least two directions of the surface movement device are perpendicular to each other. In particular, at least two directions lie within the plane of the receiving surface. For example, the at least two directions are the x-direction and the y-direction. In a specific embodiment, the surface movement device may include a separate motor that moves the receiving surface in one of the at least two directions.

[0014] In particular, any sample area can be aligned with the imaging area when the imaging area and the sample area are aligned with an axis that is perpendicular to the plane of the receiving surface.

[0015] Distributing a fluid (especially a liquid) using a liquid dispensing head may include using the liquid dispensing head to aspirate the fluid. The distribution and / or aspiration of a fluid may also be referred to as the removal of a fluid. In particular, the fluid may be distributed and / or aspirated in a controlled manner at a specific position on the sample carrier. Preferably, the liquid dispensing head may be fluidically connected to or include a liquid dispensing device, in particular the liquid dispensing device being at least a pump and a fluid connection.

[0016] Preferably, at least two directions of the head movement device are perpendicular to each other. In particular, the at least two directions are parallel to the plane of the receiving surface. For example, the at least two directions are an x-direction and a y-direction. The x-direction and y-direction of the head movement device may be the same as the x-direction and y-direction of the surface movement device. In a specific embodiment, the head movement device may include a separate motor that moves the liquid dispensing head in one of the at least two directions.

[0017] In particular, when the liquid dispensing head is aligned with an axis perpendicular to the plane of the receiving surface, any sample area is aligned with the liquid dispensing head. When the liquid dispensing head is aligned with a specific sample area, the fluid is dispensed specifically onto that sample area.

[0018] In particular, the microscope stage is capable of aligning the liquid dispensing head with any sample area regardless of the specific position of the surface motion device or the sample carrier. Thus, the liquid dispensing head can access any sample area simultaneously or sequentially regardless of the position of the surface motion device or the sample carrier.

[0019] Preferably, the range of movement of the liquid dispensing head, in particular the head movement device, is at least as large as or larger than the range of movement of the receiving surface, in particular the surface movement device. In particular, this allows any sample area to be moved to the imaging area and the sample in this sample area to be imaged while the fluid is being dispensed to any other sample area.

[0020] Preferably, the surface movement device is configured to move the receiving surface along a third direction. This allows for flexible positioning of the receiving surface. The third direction may be referred to as the z-direction. In particular, the third direction is perpendicular to at least two directions of the surface movement device.

[0021] Preferably, the head movement device is configured to move the liquid dispensing head along a third direction. This allows for flexible positioning of the liquid dispensing head. For example, this allows the liquid dispensing head to be moved toward the sample carrier. The third direction may be referred to as the z-direction. In particular, the third direction is perpendicular to at least two directions of the head movement device.

[0022] Preferably, the liquid dispensing head includes at least one seal for sealing at least the sample area to which the liquid dispensing head is directed. This allows for safe and robust dispensing of fluid only to the sample area to which the liquid dispensing head is directed. In particular, the seal can seal the sample carrier. This may result in a cavity between the liquid dispensing head and the corresponding sample area. In a specific embodiment, the seal engages only when the pipetting head is moved in the z-direction toward the sample carrier.

[0023] Preferably, the seal can adapt to different sample area geometries. This allows for flexible use of the microscope stage. In particular, the seal can be actively adaptable. For example, the seal can be inflated to adapt to a specific geometry. In another example, the seal can be passively adaptable. For example, the seal can be a soft seal that can be pressed against the sample area to adjust its fit. Examples of sample areas with different geometries include circular or square well plates.

[0024] Preferably, the seal is configured to pressurize the sample area. This allows for flexible use of the microscope stage. For example, when dispensing a staining reagent onto the sample area, pressurizing the sample area can accelerate the staining reaction. In particular, the seal can be configured to pressurize the cavity of the microplate. Similarly, the liquid dispensing head can be configured to pressurize the sample area, in particular in a manner that dispenses fluid onto the sealed sample area. The pressure of the sealed sample area can be in the range of 1.5 bar to 5 bar.

[0025] Preferably, the liquid dispensing head includes at least one nozzle assembly. This enables precise fluid dispensing onto any sample area. In particular, the nozzle assembly is configured to dispense the fluid onto the sample area to which the liquid dispensing head is directed. The nozzle assembly may include at least one nozzle for dispensing the fluid onto the sample area. Preferably, the nozzle assembly is positioned on the liquid dispensing head so as to face the receiving surface or sample carrier.

[0026] Preferably, the nozzle assembly includes at least an outlet nozzle and an inlet nozzle. This enables flexible use of the microscope stage. In particular, the inlet nozzle and the outlet nozzle can distribute or draw fluid onto the sample area, respectively. For example, a staining reagent can be added to a sample in the sample area through the inlet nozzle and then cultured for a period of time. Subsequently, the staining reagent can be discharged through the outlet nozzle. The inlet nozzle and the outlet nozzle can be connected to a reservoir and a pump fluid to supply or remove fluid. The flow through the outlet nozzle and the inlet nozzle can be controlled independently, for example, by a valve. In a preferred embodiment, the outlet nozzle has a greater length from the nozzle assembly to the sample stage than the inlet nozzle. This enables efficient removal of fluids, especially liquids, from the sample area. In particular, this is the case when the sample area is a cavity. In this case, the outlet nozzle will be arranged at a position closer to the bottom of the cavity than the inlet nozzle.

[0027] Preferably, the liquid dispensing head comprises a plurality of nozzle assemblies, wherein each nozzle assembly is arranged on the liquid dispensing head and, in particular, is used to dispense the fluid onto one of the plurality of sample areas when the liquid dispensing head is aligned with the sample area. This enables high-throughput use of the microscope stage. Therefore, the liquid dispensing head can be aligned with more than one sample area at any time, in particular when there are multiple nozzle assemblies. In this case, each individual nozzle assembly can be aligned with one of the sample areas. However, it is not required that each nozzle assembly be aligned with each sample area. The flow through each nozzle assembly can be independently controlled, for example, by a valve.

[0028] Preferably, the liquid dispensing head is replaceable, in particular independently replaceable. Thus, the liquid dispensing head can be removed from the microscope stage and replaced with another one. This allows for flexible use of the microscope stage. For example, different liquid dispensing heads can be used for different sample carriers, in particular those with different geometries.

[0029] Preferably, the liquid dispensing head includes at least one fluid line for coupling the liquid dispensing head, in particular the nozzle assembly, to the liquid reservoir. This allows for efficient fluid supply to the liquid dispensing head, in particular the nozzle assembly. In a specific embodiment, the liquid dispensing head can be further coupled to a pump for pumping fluid between the liquid reservoir and the liquid dispensing head, in particular the sample area.

[0030] Preferably, the microscope stage may also include a waste area. The liquid dispensing head, particularly the nozzle assembly, may be aligned with the waste area. When the liquid dispensing head is aligned with the waste area, fluid may be flushed through the liquid dispensing head, particularly the nozzle. This allows the liquid dispensing head or nozzle to be cleaned without contaminating the sample area.

[0031] In another aspect, a replaceable fluidic link for a laboratory analytical device is provided. The replaceable fluidic link includes a first connector, a second connector, and at least one fluid line between the first connector and the second connector. The first connector and the second connector can be reversibly connected to respective fluid ports or fluid manifolds.

[0032] In particular, when the first or second connector is moved toward the respective fluid port in the direction of flow through the connector, the first and second connectors are respectively configured to form a fluid-tight seat in the respective fluid port by engaging with a releasable locking mechanism. For example, the first and second connectors are reversibly connected to the respective fluid ports by pressing the first and second connectors onto the respective fluid ports via a releasable snap connector or fastener, rather than tightening the first and second connectors onto the respective fluid ports via a threaded joint.

[0033] Preferably, the first and second connectors may respectively include O-rings to achieve fluid sealing with the respective fluid ports.

[0034] Therefore, the first and second connectors can be quickly connected to their respective fluid ports. After the first and second connectors are connected to their respective fluid ports, fluid can flow through the fluid ports connected to the first and second connectors, the first and second connectors, and the fluid line between the first and second connectors.

[0035] Interchangeable fluid connectors allow for quick replacement of fluid lines in laboratory analytical devices. For example, if a fluid line becomes contaminated or if a different analytical protocol is required, requiring different reagents to flow through the fluid line, interchangeable fluid connectors make it easy to change the flow path that comes into contact with the fluid or reagent.

[0036] Preferably, the replaceable fluid connection, in particular its flow path, is temperature-resistant and / or chemically inert. For example, at least the flow path can be made of a fluoropolymer, in particular a perfluoropolymer.

[0037] Preferably, the replaceable fluid connector includes at least two fluid lines between a first connector and a second connector, wherein each of the first connector and the second connector includes a corresponding plug connector for each fluid line. This allows for rapid replacement of multiple fluid lines in a laboratory analysis device. The first connector receives a first end of each of the at least two fluid lines, and the second connector receives a second end of each of the at least two fluid lines.

[0038] The fluid ports include corresponding port receivers for the plug connectors. Thus, each fluid line connects to a dedicated port receiver via one of the plug connectors. This allows for efficient replacement of several independent fluid lines between two fluid ports or manifolds in a single operation.

[0039] Preferably, the first and second connectors each include an orientation indicator corresponding to a corresponding orientation indicator on the fluid port. This allows the first and second connectors to be securely connected to their respective fluid ports, particularly in the correct orientation, when the replaceable fluid connection comprises multiple fluid lines. The orientation indicator may be a visual marker for aligning the connector and fluid port when connected. Alternatively or additionally, the orientation indicator may be a tongue and corresponding groove on the connector and fluid port, respectively.

[0040] Preferably, at least one fluid line of the microscope stage includes the aforementioned replaceable fluid connector. In particular, the liquid dispensing head may include at least one fluid port configured to receive a first or second connector of the replaceable fluid connector, for example, to connect the liquid dispensing head to a fluid reservoir. The replaceable fluid connector allows for rapid replacement of fluid lines between the liquid dispensing head and another pipetting element, such as a fluid reservoir or pump.

[0041] In yet another aspect, a microscope is provided, comprising the aforementioned microscope stage. In particular, the microscope may further comprise an optical system aligned with an imaging region of the microscope stage, and the microscope may be configured to image a sample disposed in a sample region aligned with the imaging region. In a specific embodiment, the microscope may be an inverted microscope.

[0042] In another aspect, a method for examining a sample using the aforementioned microscope is provided. The method includes the step of dispensing at least one reagent onto one of the sample areas of a sample carrier using a liquid dispensing head. In particular, this step may include moving the liquid dispensing head using a head movement device so that it is aligned with one of the sample areas. The method also includes moving a receiving surface using a surface movement device so that one of the sample areas is aligned with an imaging area of ​​the microscope stage. The method also includes the step of imaging one of the sample areas, in particular, imaging the sample area using the optical system of the microscope.

[0043] In particular, first, a sample is provided within one of the sample areas. Thus, for example, when at least one reagent is dispensed onto one of the sample areas, the sample comes into contact with the reagent. Furthermore, when imaging one of the sample areas, it is preferred that the sample disposed within one of the sample areas be imaged. For example, the at least one reagent dispensed into one of the sample areas is a staining reagent.

[0044] The method enables efficient analysis of multiple samples, wherein each sample is arranged in one of the sample zones of a sample carrier arranged on a receiving surface. In particular, the dispensing of reagents, including subsequent removal and imaging of the samples, can be automated to enable high-throughput analysis of multiple samples.

[0045] Preferably, the method steps are performed for at least one further sample area, in particular another sample arranged in the at least one further sample area. The steps may include: moving the liquid dispensing head so that it is subsequently aligned with each sample area of ​​the at least one further sample area; and moving the receiving surface so that each sample area is subsequently aligned with the imaging area. In particular, "subsequently" may refer to a temporal sequential process, i.e., imaging of the sample areas is performed one by one.

[0046] Preferably, the steps of moving the receiving surface to align one of the sample areas with the imaging area and / or imaging one of the sample areas are performed simultaneously with the step of dispensing at least one reagent onto another sample. This allows for efficient inspection of the sample. In particular, the reagent can be dispensed onto a sample area other than the imaged sample area. Thus, the imaging and dispensing steps can be performed simultaneously for different sample areas.

[0047] Preferably, the movement of the receiving surface and the movement of the liquid dispensing head are synchronized. This allows the reagent to be accurately dispensed onto one of the sample areas even when the receiving surface, and therefore the sample carrier, is moved. In particular, the directions and speeds of these two movements may be the same.

[0048] Preferably, at least one reagent is dispensed while the liquid dispensing head is moved. This enables efficient examination of biological samples.

[0049] Preferably, during the imaging step, the receiving surface is moved so as to move one of the sample areas within the imaging area. In particular, this enables a subsequent imaging or scanning of a portion of the sample in one of the sample areas.

[0050] Preferably, during the step of dispensing the at least one reagent, a second reagent is dispensed onto one of the sample areas of the sample carrier via a liquid dispensing head. In particular, the second reagent is delivered to the liquid dispensing head via the same fluid line as the at least one reagent. Specifically, the second reagent and the at least one reagent are subsequently delivered to the liquid dispensing head. This step can be referred to as fluid accumulation.

[0051] Preferably, the microscope is configured to perform the above method.

[0052] The microscope, the replaceable fluid connection and the method have the same advantages as the microscope stage. Furthermore, the microscope, the replaceable fluid connection and the method can also be supplemented with the features of the microscope stage herein, in particular the features of the dependent claims of the microscope stage. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] The specific embodiments will be described below with reference to the accompanying drawings, in which:

[0054] Figure 1 is a schematic perspective view of a microscope stage;

[0055] Figure 2 is a schematic top view of the microscope stage;

[0056] Figure 3 is a schematic side view of the microscope stage;

[0057] Figure 4 is a schematic side view of the liquid dispensing head of the microscope stage in two positions;

[0058] Figure 5 is a schematic top view of a microscope stage according to another embodiment;

[0059] Figure 6 is a schematic top view of a microscope stage according to yet another embodiment;

[0060] Figure 7 is based on Figure 6 A schematic side view of the microscope stage is shown;

[0061] Figure 8 is based on Figure 6 Schematic side views of a microscope stage with a liquid dispensing head shown in two positions;

[0062] Figure 9 is a schematic diagram of a connector and a fluid line of a replaceable fluid connection;

[0063] Figure 10 is a schematic diagram of a manifold having fluid ports;

[0064] Figure 11 is a schematic diagram of an alternative connector for a replaceable fluid connection;

[0065] Figure 12 is a schematic diagram of an alternative manifold having fluid ports;

[0066] Figure 13 It is based on replaceable fluid connections Figure 6 Schematic diagram of the microscope stage shown;

[0067] Figure 14 It is based on replaceable fluid connections Figure 2 Schematic diagram of the microscope stage shown;

[0068] Figure 15 It is based on replaceable fluid connections Figure 6 Schematic diagram of the microscope stage shown;

[0069] Figure 16 is a schematic flow chart of a method for examining a sample. DETAILED DESCRIPTION

[0070] Figure 1 1 is a schematic perspective view of a microscope stage 100. The microscope stage 100 comprises a receiving surface 102. Arranged on the receiving surface is a sample carrier 104. The sample carrier 104 may comprise a plurality of sample areas for receiving samples.

[0071] The microscope stage 100 further comprises a liquid dispensing head 106 configured to dispense a fluid onto the sample carrier 104. The liquid dispensing head 106 allows a fluid, in particular a liquid, to be dispensed onto the sample carrier 104, in particular onto a sample area. Fluid dispensing can include aspirating the fluid using the liquid dispensing head 106. Thus, a fluid can be added to any sample area of ​​the sample carrier 104 and / or removed therefrom. In particular, a fluid can be dispensed to a specific location on the sample carrier 104 in a specific amount or volume. Dispensing and / or aspirating a fluid can also be referred to as pipetting a fluid.

[0072] In order to reach several locations or sample areas on the sample carrier 104 using the liquid dispensing head 106, the microscope stage 100 may include a head movement device. The head movement device may include spindle drives 108, 110, and 112 for moving the liquid dispensing head 106 in specific directions. Specifically, the spindle drive 108 can move the liquid dispensing head 106 in the x-direction; the spindle drive 110 can move the liquid dispensing head 106 in the y-direction; and the spindle drive 112 can move the liquid dispensing head 106 in the z-direction. The spindle drives 108 and 110, and their corresponding x- and y-directions, enable the liquid dispensing head 106 to move in a direction parallel to the plane of the receiving surface 102 or the sample carrier 104. The spindle drive 112, and its corresponding z-direction, enables the liquid dispensing head 106 to move in a direction closer to or farther from the receiving surface 102 or the sample carrier 104. Thus, the head moving device can move the liquid dispensing head 106 relative to the sample carrier 104 disposed on the receiving surface 102 and align the liquid dispensing head 106 with a specific location (e.g., a sample area) on the sample carrier 104. The head moving device, in particular the spindle drives 108 and 110, can be suspended from a frame 113 of the microscope stage. In particular, the frame 113 schematically illustrates the range of movement of the head moving device in the x-direction and the y-direction.

[0073] In another alternative embodiment, the head movement apparatus may include only the spindle drives 108, 110, and the liquid dispensing head 106 may be movable only in the x-direction and the y-direction.

[0074] Microscope stage 100 may be comprised of a microscope, such as an inverted microscope. Figure 1 Components of such a microscope are illustrated, specifically, an optical system 114 and an illumination system 116. When the sample carrier 104 is arranged on the receiving surface 102, the optical system 114 can be configured to image the sample area of ​​the sample carrier 104, in particular the sample in the sample area. Similarly, the illumination system 116 can be configured to illuminate the sample area being imaged via the optical system 114.

[0075] The microscope stage 100 further comprises a surface movement device 118 configured to move the receiving surface 102. By moving the receiving surface 102, the sample carrier 104 arranged on the receiving surface 102 is also moved.

[0076] Surface movement device 118 enables sample carrier 104, in particular a specific sample area on sample carrier 104, to be aligned with optical system 114. Specifically, surface movement device 118 may include a drive that moves receiving surface 102 in the x-direction and the y-direction.

[0077] In another alternative embodiment, the surface moving device 118 may further include a driver configured to move the receiving surface 102 in the z-direction.

[0078] The surface movement device 118 has a certain range of movement in the x- and y-directions, allowing any sample area on the sample carrier 104 to be aligned with the optical system 114. Furthermore, the head movement device, particularly the spindle drives 108 and 110, has a certain range of movement in the x- and y-directions, allowing the liquid dispensing head 106 to be aligned with any sample area, regardless of the specific x- and y-direction positions of the sample carrier 104. Thus, the liquid dispensing head 106 can be moved so as to be aligned with any sample area on the sample carrier 104 at any time. Thus, the microscope stage 100 enables the dispensing of fluid to any sample area on the sample carrier 104 via the liquid dispensing head 106.

[0079] Figure 2is a schematic top view of the microscope stage 100. The sample carrier 104 and other sample carriers 200 are arranged on the receiving surface 102. The sample carrier 104 includes 20 sample areas 202. For example, the sample carrier 104 can be a microplate, and the sample areas 202 are round-bottomed wells. In contrast, the sample carrier 200 can be a microplate with 8 sample areas 204. For example, the sample carrier 200 can be a microplate, and the corresponding sample areas 204 are square-bottomed wells. Therefore, the receiving surface 102 can receive several sample carriers 104, 200 with different configurations.

[0080] By moving the receiving surface 102, any of the sample areas 202, 204 can be aligned with the imaging area 206 of the microscope stage 100. For example, a specific sample area 202, 204 aligned with the imaging area 206 can be imaged by the optical system 114. Specifically, the focal plane of the optical system 114 can be arranged so that the sample in the sample area 202, 204 aligned with the imaging area 206 can be imaged by the optical system 114. To this end, the corresponding imaging plane of the optical system 114 can be arranged on the detector surface so as to image the sample arranged on the focal plane.

[0081] The receiving surface 102 may have an opening so that the optical system 114 can image one of the sample regions 202 , 204 aligned with the imaging region 206 .

[0082] For example, the liquid dispensing head 106 can be connected to a liquid dispensing device via a fluid line 208. In particular, the liquid dispensing head 106 can be connected to a liquid reservoir, a pump, and / or a manifold. The fluid can be supplied to the liquid dispensing head 106 via the fluid line 208, and then dispensed by the liquid dispensing head 106.

[0083] Figure 3 1 is a schematic side view of microscope stage 100. Liquid dispensing head 106 is shown in a position away from sample carrier 104. Liquid dispensing head 106 can be moved toward sample carrier 104 by spindle drive 112 to dispense fluid specifically onto one of sample areas 202.

[0084] exist Figure 3 In the illustrated view, a sample 300, such as a biological cell, is disposed in each sample region 202. A portion of the sample region 202 is filled with a fluid 302 dispensed by the liquid dispensing head 106.

[0085] The liquid dispensing head 106 may include a nozzle assembly 304 disposed toward the sample carrier 104. For example, the nozzle assembly may include an inlet nozzle 306 and an outlet nozzle 308. In particular, the liquid dispensing head 106 may dispense a fluid 302 onto the sample area 202 through the inlet nozzle 306. Similarly, the fluid 302 may be aspirated from the sample area 202 through the outlet nozzle 308.

[0086] The liquid dispensing head 106 may further include a seal 310. The seal may seal the liquid dispensing head 106 against the sample carrier 104, particularly when the liquid dispensing head 106 is in a position facing the sample carrier 104.

[0087] Figure 4 The liquid dispensing head 106 is at a position away from the sample carrier 104 (eg Figure 4 ) and in a position facing the sample carrier 104 (as shown in the left part of Figure 4 Schematic side view of the embodiment of the present invention (shown on the right side).

[0088] When in a position away from the sample carrier 104, the liquid dispensing head 106 can be moved in the x-direction and / or the y-direction and aligned with a specific sample area 202. The liquid dispensing head 106 can then be moved in the z-direction to a position toward the sample carrier 104. When in the position toward the sample carrier 104, the seal 310 engages the sample carrier 104 to seal the sample area 202. In particular, when in the position toward the sample carrier 104, the liquid dispensing head 106 can dispense or aspirate fluid.

[0089] The seal between seal 310 and sample area 202 can further enable pressurization of sample area 202, for example, by introducing fluid into the sealed sample area 202 via nozzle assembly 304 of liquid dispensing head 106. Pressurization can increase the reaction rate between the fluid dispensed into sample area 202 and sample 300, thereby improving the efficiency of all methods performed using microscope stage 100.

[0090] Figures 5 to 8 is a schematic diagram of an alternative embodiment of a microscope stage.

[0091] Figure 5 FIG2 is a schematic top view of a microscope stage 500 with an elongated liquid dispensing head 502. Liquid dispensing head 502 includes eight nozzle assemblies 504. Each nozzle assembly 504 can be aligned with a different sample area 202 at any time. By providing multiple nozzle assemblies 504, liquid dispensing head 502 can dispense fluid to or draw fluid from more than one sample area 202 at any time. For example, each nozzle assembly 504 can be connected to a reservoir or pump via a fluid line 208.

[0092] Figure 6 is a schematic top view of a microscope stage 600 with a liquid dispensing head 602. Figure 7 FIG2 is a schematic side view of a microscope stage 600 with a liquid dispensing head 602. The liquid dispensing head 602 includes 40 nozzle assemblies 604. Each nozzle assembly 604 can be aligned with a different sample area 202 at any time. By providing multiple nozzle assemblies 604, the liquid dispensing head 602 can dispense fluid to or draw fluid from more than one sample area 202 at any time. For example, each nozzle assembly 604 can be connected to a reservoir or pump via a fluid line 208.

[0093] Figure 8 The liquid dispensing head 602 is at a position away from the sample carrier 104 (eg Figure 8 ) and in a position facing the sample carrier 104 (as shown in the upper part of Figure 8 Schematic side view of the bottom part of the figure).

[0094] The liquid dispensing head 602 can be moved in the z-direction, in particular, by the two spindle drives 112, to a position facing the sample carrier 104. When in the position facing the sample carrier 104, the plurality of nozzle assemblies 604 are each aligned with a specific sample area in the sample area 202. In particular, when in the position facing the sample carrier 104, the liquid dispensing head 602 can dispense or aspirate fluid.

[0095] Figures 9 to 12 is a schematic diagram of replaceable fluid connections. Figure 9 Schematic diagram of a connector 900 with replaceable fluid connectors and a fluid line 902. The connector 900 includes a plug connector 904 for forming a fluid-tight connection with a corresponding fluid port. The plug connector 904 may include an O-ring 906 for forming a fluid-tight seal.

[0096] The connector 900 may further include a releasable locking mechanism 908 configured to engage with a corresponding mechanism on the fluid port.

[0097] The replaceable fluid connection comprises two connectors 900 connected by a fluid line 902 .

[0098] Figure 10 is a schematic diagram of a manifold 1000 having a fluid port 1002 configured to receive a connector 900 (eg, Figure 10 ). The fluid port 1002 is configured to form a fluid seal with the plug connector 904 of the connector 900. In particular, the fluid port 1002 engages with the O-ring 906 of the connector 900 to form a fluid seal.

[0099] Manifold 1000 further includes a releasable locking mechanism 1004 for engaging with locking mechanism 908 of connector 900. Figure 10 , connector 900 is engaged with fluid port 1002. In particular, when connector 900 is moved toward fluid port 1002 in the direction of flow through connector 900, connector 900 forms a fluid-tight seat in fluid port 1002 by engaging releasable locking mechanism 908 with releasable locking mechanism 1004.

[0100] Figure 11 1 is a schematic diagram of a connector 1100 for replaceable fluid connections having three fluid lines 902. The connector 1100 includes one plug connector 904 for each fluid line 902. Thus, several fluid lines 902 can be connected together simultaneously or in the same operation via the connector 1100.

[0101] Figure 12 1 is a schematic diagram of a manifold 1200 for receiving a connector 1100. The manifold 1200 includes three fluid ports 1002, each configured to receive one of the plug connectors 904 of the connector 1100. The releasable locking mechanisms 908, 1004 can additionally serve as orientation indicators, allowing the connector 1100 to be connected to the manifold 1200 in only one orientation. Thus, the releasable locking mechanisms 908, 1004 allow each plug connector 904 to be connected to only one of the fluid ports 1002 of the manifold 1200.

[0102] Figures 13 to 15 A microscope stage 100, 600 including replaceable fluid connections is shown. Figure 13 is a schematic diagram of a microscope stage 600 having a replaceable fluid connection, which includes two connectors 900 respectively arranged at both ends of a fluid line 902. One of the connectors 900 is connected to a manifold 1000 on a liquid dispensing head 602. The other connector 900 is connected to the manifold 1000 and can be connected to a liquid reservoir, for example.

[0103] The replaceable fluid connection comprising the two connectors 900 and the fluid line 902 is easily replaceable, for example in case the fluid line 902 becomes contaminated.

[0104] Figure 14 1 is a schematic diagram of a microscope stage 100 having replaceable fluidic connectors, which include four connectors 900 and two fluid lines 902. Each fluid line 902 is connected to two connectors 900. One of the connectors 900 is connected to a manifold 1000 on a liquid dispensing head 106. The other connector 900 is connected to the manifold 1000 and can be connected to, for example, a liquid reservoir.

[0105] The replaceable fluid connection comprising the two connectors 900 and the fluid line 902 is easily replaceable, for example in case the fluid line 902 becomes contaminated.

[0106] Figure 15 1 is a schematic diagram of a microscope stage 600 having replaceable fluid connectors, which include a connector 1100 and three fluid lines 902. One end of each fluid line 902 is connected to a liquid dispensing head 602. In particular, each fluid line 902 provides fluid to one of the nozzle assemblies 604. The other end of each fluid line 902 is connected to a connector 1100. Connector 1100 includes three plug connectors 904, one for each fluid line 902. For example, connector 1100 can be connected to a manifold 1200.

[0107] This enables quick replacement of the liquid dispensing head 602 along with the replaceable fluid connection including the connector 1100 and the three fluid lines 902 .

[0108] Figure 16 is a flow chart of a method for examining a sample. The method begins at step S1600. In step S1602, at least one reagent is dispensed onto the sample carrier 104, 200, particularly onto one of the sample areas 202, 204, via the liquid dispensing head 106, 502, 602. To this end, the liquid dispensing head 106, 502, 602 can be moved within its range of motion by the head moving device 108, 110, 112.

[0109] Subsequently, in step S1604 , the receiving surface 102 may be moved by the surface moving device 118 so as to align one of the sample regions 202 , 204 in step S1602 with the imaging region 206 .

[0110] Subsequently, in step S1606 , one of the sample areas 202 , 204 in the imaging area 206 , in particular the sample in the sample areas 202 , 204 , may be imaged. For example, the imaging may be performed by the optical system 114 .

[0111] The method ends at step S1608.

[0112] Preferably, step S1602 is performed for another sample area 202, 204, in particular, while steps S1604 and / or S1606 are performed for one of the sample areas 202, 204. Therefore, microscope stage 100, 500, 600 can perform method steps for at least two sample areas 202, 204 in parallel.

[0113] Furthermore, in step S1602, the liquid dispensing head 106, 502, 602 may dispense several reagents onto the sample carrier 104, 200 or the sample area 202, 204. In addition, the liquid dispensing head 106, 502, 602 may aspirate the reagents to remove them from the sample area 202, 204.

[0114] The reagent can be a staining reagent that can specifically stain at least one structure of the sample in sample areas 202 and 204. One example is hematoxylin-eosin staining, in which the sample is contacted with an aqueous hematoxylin and eosin Y solution. Specifically, this stains the cell nucleus blue and the cytoplasm and extracellular matrix pink, thereby facilitating detection in a subsequent imaging step.

[0115] In a specific example of the method, the liquid dispensing head 106, 502, 602 and the receiving surface 102 can be synchronously moved by the head moving devices 108, 110, 112 and the surface moving device 118, respectively. In particular, the liquid dispensing head 106, 502, and 602 can dispense the reagent during movement. Since the receiving surface 102 and the sample carrier 104, 200 move at the same speed, the reagent will be dispensed onto one of the sample areas 202, 204.

[0116] The same reference symbols are used in all figures to represent the same or similar elements. The term "and / or" used herein includes any one and all combinations of one or more of the related listed items and can be abbreviated as " / ".

[0117] Although some aspects are described in the context of an apparatus, it is apparent that these aspects also represent descriptions of corresponding methods, where a block or device corresponds to a method step or a feature of a method step. Similarly, aspects described in the context of a method step also represent descriptions of corresponding blocks, items, or features of corresponding apparatus.

[0118] Reference numerals

[0119] 100, 500, 600 microscope stages

[0120] 102 receiving surface

[0121] 104, 200 sample carrier

[0122] 106, 502, 602 liquid dispensing heads

[0123] 108, 110, 112 head moving device, spindle drive

[0124] 113 Framework

[0125] 114 Optical System

[0126] 116 Lighting System

[0127] 118 Surface Moving Device

[0128] 202, 204 sample areas

[0129] 206 Imaging Area

[0130] 208, 902 fluid pipelines

[0131] 300 samples

[0132] 302 Fluid

[0133] 304, 504, 604 nozzle assemblies

[0134] 306 inlet nozzle

[0135] 308 outlet nozzle

[0136] 310 seals

[0137] 900, 1100 connectors

[0138] 904 plug connector

[0139] 906 O-ring

[0140] 908, 1004 Releasable locking mechanism

[0141] 1000, 1200 manifold

[0142] 1002 fluid port

Claims

1. A microscope stage (100, 500, 600), comprising: a receiving surface (102) configured to receive at least a first sample carrier (104, 200), the first sample carrier having a plurality of sample areas (202, 204); an imaging area (206); a surface moving device (118) configured to move the receiving surface (102) in at least two directions, wherein the surface moving device (118) has a moving range in the at least two directions so that each of the plurality of sample areas (202, 204) can be aligned with the imaging area (206); at least one liquid dispensing head (106, 502, 602) configured to dispense fluid onto the sample carrier (104, 200); and A head moving device (108, 110, 112) is configured to move the at least one liquid dispensing head (106, 502, 602) in at least two directions, wherein the head moving device (108, 110, 112) has a moving range in the at least two directions so that the at least one liquid dispensing head (106, 502, 602) can be aligned with each of the plurality of sample areas (202, 204).

2. The microscope stage according to claim 1, wherein the surface movement device (118) is configured to move the receiving surface (102) along a third direction.

3. The microscope stage according to any one of the preceding claims, wherein the head moving device (108, 110, 112) is configured to move the liquid dispensing head (106, 502, 602) along a third direction.

4. The microscope stage according to any of the preceding claims, wherein the liquid dispensing head (106, 502, 602) comprises at least one seal configured to seal at least the sample area (106) to which the liquid dispensing head is aimed.

5. The microscope stage of claim 4, wherein the seal (310) is adaptable to different sample area geometries.

6. The microscope stage according to any one of the preceding claims 4 or 5, wherein the seal (310) is configured to enable pressurization of the sample area (202, 204).

7. The microscope stage according to any of the preceding claims, wherein the liquid dispensing head (106, 502, 602) comprises at least one nozzle assembly (304, 504, 604).

8. The microscope stage of claim 7, wherein the nozzle assembly (304, 504, 604) comprises at least an outlet nozzle (308) and an inlet nozzle (306).

9. A microscope stage according to any one of the preceding claims 7 or 8, wherein the liquid dispensing head (106, 502, 602) includes a plurality of the nozzle assemblies (304, 504, 604), wherein each nozzle assembly (304, 504, 604) is arranged on the liquid dispensing head (106, 502, 602) so as to dispense the fluid onto one of the plurality of sample areas (202, 204) when the liquid dispensing head (106, 502, 602) is aligned with the sample area (202, 204).

10. The microscope stage according to any of the preceding claims, wherein the liquid dispensing head (106, 502, 602) is replaceable.

11. The microscope stage according to any of the preceding claims, wherein the liquid dispensing head (106, 502, 602) comprises at least one fluid line (208, 902) for coupling the liquid dispensing head (106, 502, 602) to a liquid reservoir.

12. A replaceable fluid connector for a laboratory analytical device, comprising: A first connector (900, 1100) and a second connector (900, 1100); as well as at least one fluid line (208, 902) between the first connector (900, 1100) and the second connector (900, 1100), The first connector (900, 1100) and the second connector (900, 1100) are reversibly connected to the corresponding fluid port (1002).

13. The replaceable fluid connection according to claim 12, comprising: At least two fluid lines between the first connector (900, 1100) and the second connector (900, 1100), wherein the first connector (900, 1100) and the second connector (900, 1100) respectively include a corresponding plug connector (904) for each of the fluid lines (208, 902).

14. A replaceable fluid connection according to any one of the preceding claims 12 or 13, wherein the first connector (900, 1100) and the second connector (900, 1100) each include an orientation indicator corresponding to a respective orientation indicator on the fluid port (208, 902).

15. The microscope stage according to claim 11, wherein the at least one fluid line (208, 902) comprises an exchangeable fluid connection according to any one of the preceding claims 12 to 14.

16. A microscope comprising a microscope stage according to any one of the preceding claims 1 to 11 or 15.

17. A method for examining a sample by means of the microscope of claim 16, comprising the steps of: dispensing at least one reagent onto one of the sample areas of the sample carrier (104, 200) through the liquid dispensing head (106, 502, 602); Moving the receiving surface (102) by the surface moving device (118) such that one of the sample areas (202, 204) is aligned with the imaging area (206) of the microscope stage; and One of the sample areas (202, 204) is imaged.

18. The method of claim 17, wherein the steps of the method are performed on at least another of the sample regions (202, 204).

19. A method according to any one of the preceding claims 17 to 18, wherein the step of moving the receiving surface (102) so that one of the sample areas (202, 204) is aligned with the imaging area (206) and / or the step of imaging one of the sample areas (202, 204) is performed simultaneously with the step of dispensing at least one reagent onto the other sample (202, 204).

20. The method according to any of the preceding claims 17 to 19, wherein the movement of the receiving surface (102) and the movement of the liquid dispensing head (106, 502, 602) are synchronized.

21. The method according to any of the preceding claims 17 to 20, wherein the at least one reagent is dispensed while the liquid dispensing head (106, 502, 602) is moved.

22. The method according to any of the preceding claims 17 to 21, wherein during the imaging step the receiving surface (102) is moved in order to move one of the sample areas (202, 204) within the imaging area (206).

Images