TILT DEVICE FOR MICROSCOPY

Description

[0001] The invention relates to a tilting device for microscopy and a microscope comprising the tilting device, as well as an associated method and use.

[0002] There are differently designed sample carriers for living cells in which the cells can be cultivated and examined under a microscope at the same time. There are also sample carriers in which cells can be cultivated under flow, or the medium in which the cells are cultivated can be easily exchanged. To achieve such flow in a sample carrier, sample carriers typically have a channel system formed therein, which comprises at least one inlet and one outlet and is otherwise closed. Sample carriers with channel systems are known, for example, from EP 1 458 483 A2, EP 1 397 483 A1 and EP 4 030 216 A1. Such sample carriers are generally designed for microscopic examinations, so that cells cultivated in the channel system can be examined under a microscope.

[0003] To exchange the medium, in particular a liquid, in the channel system, a pump system or external reservoirs can be used, to which the sample carrier is connected, for example, via hoses. One such pump system is disclosed, for example, in EP 1 944 084 A1. In the case of external reservoirs, liquid exchange can be achieved using exclusively passive components via different fill levels of the reservoirs and the principle of communicating tubes. However, both options require an additional device in addition to the sample carrier itself to create a flow within the channel system for exchanging the medium. Alternatively, the sample carrier itself can be tilted to generate flow within the channel system using gravity. A disadvantage of this solution becomes apparent when tilting and microscopy occur simultaneously.Tilting changes the distance between a microscope objective and the sample holder, or between the objective and the area to be examined within the sample holder, so that the objective must be refocused accordingly.

[0004] A tilting device for microscopy is known from the document DE 608 804 C, in which the objective lens can be attached to the microscope in two mutually pivoted positions using a mirror system.

[0005] In view of the aforementioned disadvantages, it is an object of the present invention to provide a tilting device for microscopy, a microscope, and an associated method and use that enable microscopy to be improved for a sample carrier in which a flow is to be generated or present. This object is achieved by the tilting device according to claim 1, the microscope according to claim 9, the method according to claim 12, and the use according to claim 14. Further developments can be found in the respective subclaims.

[0006] According to the invention, a tilting device for microscopy is provided, comprising a sample carrier holder and an optical component having an optical axis, wherein the optical axis is aligned with a base side of the sample carrier holder, wherein the sample carrier holder and the optical component are each tiltably mounted, and wherein the alignment of the optical axis with respect to the base side of the sample carrier holder is maintained when the sample carrier holder and the optical component are tilted.

[0007] If the sample holder and the optical component are tilted, the tilting device according to the present invention maintains the alignment of the optical axis of the optical component with respect to the sample holder during tilting. This eliminates the need to adjust the optical component to the tilt of the sample holder, enabling improved microscopy on a sample holder in a tilted sample holder.

[0008] A tilt is performed around a defined point or axis. The tilt can be clockwise or counterclockwise.

[0009] A sample carrier holder is a device designed to hold a sample carrier. The sample carrier holder has a base facing the optical component. The sample carrier holder can, in particular, have a base with a recess through which microscopy can be performed, and no further element is arranged between the sample carrier and the optical component. Alternatively, the sample carrier holder can also be merely a lateral frame into which a sample carrier is mounted, for example, by clamping, and which partially or completely surrounds the sample carrier.

[0010] The invention also provides a tilting device for a microscope, comprising a sample carrier holder and an optical component having an optical axis, wherein the optical axis is aligned with a base side of the sample carrier holder, wherein the sample carrier holder and the optical component are each tiltably mounted, and wherein the alignment of the optical axis with respect to the base side of the sample carrier holder is maintained when the sample carrier holder and the optical component are tilted.

[0011] The base side of the sample carrier holder may be parallel to a bottom side of a sample carrier held in the sample carrier.

[0012] This ensures that the alignment of the sample carrier is also parallel to the base of the sample carrier holder, which serves as the reference point in the tilting device. This eliminates the need for optical correction during microscopy to account for a potential angular offset of the sample carrier, the actual object of microscopy, relative to the base of the sample carrier holder. An additional source of potential imaging errors is thus avoided.

[0013] The optical axis of an optical component is a line of symmetry through the optical component, for example, a rotational symmetry axis of the optical component. In the case of mirrors or lenses, the optical axis runs through the respective center of curvature and is orthogonal to the remaining axes of symmetry of these optical components. At the same time, in ray optics, the optical axis defines an optical path along which light propagates through an optical system.

[0014] The optical component can be arranged below the sample carrier holder.

[0015] This makes the tilting device particularly suitable for use in conjunction with an inverted microscope.

[0016] The alignment between the optical axis and the base of the sample carrier holder can in particular be vertical.

[0017] This special arrangement enables improved imaging during microscopy using the tilting device. Coma, which is caused by light rays incident at an angle to the optical axis as a combination of astigmatism and spherical aberrations, is suppressed by a perpendicular alignment between the optical axis and the base of the sample holder.

[0018] The optical component can be a lens and / or a mirror.

[0019] Most microscopes, especially transmitted-light microscopes such as inverted microscopes, are designed with a converging lens, or objective, directed at the specimen under microscope observation. With inverted microscopes, examinations are performed on a specimen slide by pointing the objective toward its base. The tilting device can therefore be integrated into an existing microscope, providing the additional advantages described above.

[0020] Instead of a single mirror or lens, the optical component can also consist of several parts, such as a doublet lens (such as an achromat) or a triplet lens. A combination of mirrors and lenses is also possible.

[0021] The use of a multi-component optical component allows for greater flexibility of the tilting device, for example to obtain more mechanical degrees of freedom or to perform optical corrections as with an achromatic lens.

[0022] In particular, the optical component can comprise both an objective lens and a mirror. In one particular configuration, an objective lens is directed at the base of the sample holder and arranged between the sample holder and a mirror. The mirror redirects light passing through the objective lens to a specific target point. When the sample holder is tilted, the objective lens and the mirror tilt around a common axis of rotation, so that the relative alignment of the mirror, the objective lens, and the sample holder remains constant. The optical axis corresponds to the optical path that starts from the sample holder and runs through the objective lens and is redirected by the mirror through reflection.If the tilting device is tilted around an axis that is perpendicular to the optical axis between the sample holder and the objective, and coaxial to the optical axis between the mirror and the target point, the target point does not change due to the tilt. In this case, the mirror deflects the light, specifically at a right angle. Despite the tilt, the optical path between the mirror and the target point remains unchanged.

[0023] The arrangement of mirror and objective can also be reversed, although in this case only the mirror can be considered as the optical component. In this configuration, the mirror is arranged along the optical path between the sample holder and the objective, so that it deflects light coming from the sample holder so that it falls onto the objective. In this case, the objective is fixedly mounted and the mirror and sample holder are tiltably mounted and perform a tilting movement. If the tilting device is tilted about an axis that is perpendicular to the optical axis between the sample holder and mirror, and coaxial to the optical axis between the mirror and objective, and if the light is deflected by the mirror at a right angle, then the point of incidence and the angle of incidence of the light on the objective do not change due to the tilt.Despite the tilt, the optical path between the mirror and the lens remains unchanged.

[0024] An advantage of this latter configuration is that the objective lens is fixed and does not move when the tilting mechanism is tilted. This allows for a simpler design and, in particular, easier integration into an existing microscope that already includes an objective lens. Furthermore, aberrations caused by temporal variation in the objective lens position can be reduced, which can result in improved image quality.

[0025] The sample carrier holder and the optical component of the tilting device can each be connected to a joint and can each be tiltably mounted around the respective joint.

[0026] This means that the optical component and the sample carrier are mounted individually for tilting, yet the alignment remains the same even when tilted. For this purpose, both components can be tilted independently of each other and mounted around their own tilt axis. The tilt axis of the optical component and the tilt axis of the sample carrier holder are coaxial. This allows for greater flexibility and numerous implementation options and possibilities for integrating such a tilting device into a microscope.

[0027] A joint represents a mechanically established and reliable way to realize tilting and rotation of certain elements.

[0028] The sample carrier holder and the optical component can be connected to the same joint and can be tiltably mounted around this joint.

[0029] Such a configuration represents a simple and reliable arrangement for tilting the optical component and the sample holder, maintaining the described perpendicular alignment between the optical axis and the base of the sample holder during tilting. In particular, this prevents unwanted relative movement between the optical component and the sample holder during tilting, as both components are tilted together.

[0030] Typical examples of joints include ball joints and swivel joints or hinge joints. While a swivel joint only allows rotation around a single axis, a ball joint allows rotation around multiple axes arranged in a single plane. A ball joint therefore offers greater flexibility with regard to the tilt axis. At the same time, a swivel joint allows rotation around a well-defined axis, thus offering better precision and stability. For the special configurations for the sample carrier and the optical component described above, a swivel joint is ideal because it allows rotation only around a well-defined axis.

[0031] The sample carrier holder and the optical component can be rigidly connected to each other.

[0032] A rigid connection between the sample holder and the optical component provides a simple way to maintain the vertical alignment of the optical axis of the optical component relative to the base of the sample holder when the two components are tilted. Furthermore, a rigid connection is characterized by its high robustness, ensuring that the relative alignment of the components remains particularly stable. This is advantageous in the context of the precision required in microscopy because it prevents relative movement between the optical component and the sample holder, which could lead to imaging errors that may vary over time.

[0033] The tilting device can be designed such that the sample carrier holder and the optical component are tilted about a tilting axis that is aligned perpendicular to the optical axis.

[0034] In other words, the tilt axis can be located in a plane perpendicular to the optical axis and the tilt is performed around this axis.

[0035] The restriction that the tilt axis is aligned perpendicular to the optical axis nevertheless allows for a high degree of flexibility with regard to tilting. For example, a coordinate system can be defined around the tilting device in which the optical axis is aligned along the Z-axis. In this case, tilting occurs around a tilting axis perpendicular to the Z-axis, for example, around the X-axis, the Y-axis, or any superposition of these two axes. In the latter case, the tilting device has the highest possible number of degrees of freedom for tilting, because rotation around the Z-axis does not correspond to tilting.

[0036] The tilting device can be designed such that the sample carrier holder and the optical component of the tilting device can be tilted with respect to a horizontal position of the sample carrier holder by a tilting angle between 0 degrees and 1 degree, in particular between 0 degrees and 20 degrees.

[0037] In particular, the tilting device can be designed such that the sample carrier holder and the optical component of the tilting device can execute a pendulum-circular motion. This is understood to be a time-dependent tilting motion in which a vector parallel to the optical axis describes a circular elliptical path. This motion is generated by a time-dependent superposition of a tilt about the X-axis and a tilt about the Y-axis.

[0038] Depending on the range of achievable tilt angles, the tilting device allows for different applications. Precise tilting can be achieved within a narrow range between 0 degrees and 1 degree, for studies requiring only small but precise tilt angles. As described above, the tilting device can be used to transport liquids in a sample carrier. The flow rate can be set particularly low and precisely in this way, allowing cells to be examined under well-defined conditions. A wider range of tilt angles, for example, between 0 degrees and 20 degrees, increases the versatility of possible investigations. At the same time, a liquid, such as cell media, can be exchanged quickly. A pendulum-like circular motion can generate a circular flow in a sample carrier.

[0039] The tilting device may further comprise a movement device, wherein the movement device is designed such that it can move the optical component in a plane parallel to the base side of the sample carrier holder, or wherein the movement device is designed such that it can move the sample carrier holder in a plane perpendicular to the optical axis.

[0040] In this case, the movement device can move the sample carrier holder while the optical component remains fixed. Alternatively, the movement device can move the optical component while the sample carrier holder remains fixed.

[0041] The movement device can further be designed such that it can move the optical component perpendicular to the base side of the sample carrier holder, or parallel to the optical axis of the optical component, or that it can move the sample carrier holder parallel to the optical axis of the optical component.

[0042] In this case, too, the movement device can move the sample carrier holder while the optical component remains fixed. Alternatively, the movement device can move the optical component while the sample carrier holder remains fixed.

[0043] This embodiment does not apply to a tilting device in which the optical component and the sample carrier holder are rigidly connected to each other.

[0044] By enabling relative movement between the optical component and the sample holder in a plane parallel to the base of the sample holder, the distance between the optical component and the sample holder, or the perpendicular alignment between the optical axis and the base of the sample holder, remains unchanged. At the same time, it is possible to examine a sample holder inserted into the sample holder from different locations, particularly during a tilting movement. Adjusting the optical component, particularly refocusing an objective, is not necessary in this case.

[0045] Furthermore, relative movement between the sample holder and the optical component parallel to the optical axis also allows the focus of the optical component to be located at different depths within a sample holder. Thus, in addition to the horizontal relative movement between the sample holder and the optical component described above, a complete three-dimensional examination of a sample holder is now possible. The advantages of the tilting device described above apply in the same way.

[0046] The movement device can be manually controlled, for example. For this purpose, the sample carrier holder or the optical component can be equipped with a translation platform (English term: "translation stage"). Manual movement of the connected component can be achieved using a corresponding adjusting screw on the translation platform. The movement device can further comprise a locking screw or a similar element with which the movement device can be fixed after adjustment, thus preventing further relative movement between the optical component and the sample carrier holder.

[0047] Conventional translation platforms typically allow adjustment precision in the range of a few tens of micrometers, which is sufficient for most microscopy applications.

[0048] At the same time, the movement device can also be motorized, for example in the form of a motorized translation platform (" motorized translation stage"). Apart from that, the same considerations apply as for a manual embodiment. It goes without saying that a motorized movement device requires an associated control system. This is described below.

[0049] A motorized motion device offers several advantages. Firstly, the resolution and precision of the adjustment are typically higher than in a manual version. Furthermore, the motorized motion device can be automated and controlled externally, for example, via an external control device such as a computer. This enables not only precise control of the relative position between the optical component and the sample carrier, but also time-controlled and automated motion control.

[0050] The tilting device further comprises a tilting device with a motor, wherein the motor is connected to the optical component and / or the sample carrier holder, and wherein the motor is configured to tilt the sample carrier holder and the optical component.

[0051] This tilting device allows the tilt angle to be adjusted automatically, particularly using an external control device such as a computer. This generally allows for greater precision than manual adjustment. Furthermore, microscopic observation can take place simultaneously with tilting and does not need to be interrupted. In particular, the design of the tilting device, and in particular the shape of the motor, can depend on the tilt angle to be achieved. For very small tilt angles in the range of around 1 degree or less, a motor in the form of a piezoelectric actuator is suitable. These enable the angle to be adjusted with very high precision and reproducibility. The electrical voltage required for the piezoelectric actuator can be provided by the external control device described.

[0052] However, a piezo-driven actuator is unsuitable for larger angles because the required stroke cannot be achieved. A suitably designed electric motor or a rotary motor, for example, would be a suitable alternative.

[0053] The tilting device is further configured to generate a continuous tilting movement, in particular a rocking movement of the tilting device. A rocking movement is a continuous tilting movement in which the direction of the tilting movement changes at well-defined time intervals. To achieve this, the tilting device must allow a time-dependent angular velocity, which, in particular, also allows for a change in the sign of the angular velocity.

[0054] Certain cell types require continuous flow. Tilting the tilting device, and thus also the sample carrier, provides a way to create this continuous flow without additional components. By changing the direction of the tilting movement, the liquid in the sample carrier can be kept constantly moving without the need for additional liquid refills.

[0055] In addition to the motor-driven tilt mechanism, it is also possible to allow for additional manual adjustment. For this purpose, the tilt mechanism can, for example, include a locking screw that can be loosened and retightened manually. This has the advantage, for example, that a large adjustment of the tilt angle can be made manually, while the more precise adjustment is motorized. This means that the motor only needs to be able to provide a narrower range of tilt angles.

[0056] The tilting device may further comprise an inclination sensor and a control device, wherein the inclination sensor is designed such that it can detect and output a value of a tilt angle of the tilting device, and wherein the control device is designed such that it receives the value output by the inclination sensor and, based on the received value and a predetermined target value, transmits a control signal to the tilting device so that the tilting device sets the tilt angle to the predetermined value.

[0057] This design, with a tilt sensor and a control device, allows for automated adjustment of the tilt angle, offering the same advantages as automating the motion device. Furthermore, these additional features also enable a feedback mechanism that can stabilize the tilt angle at a specific value. This allows for examinations to be conducted over long periods of time and under particularly stable and / or well-defined conditions.

[0058] Various embodiments are conceivable for the implementation of an inclination sensor. In a simple form, an angle scale or a similar visual marking can be visibly attached to the tilting device, from which the tilt angle can be read. In addition, an inclination sensor can be attached to the tilting device, which can detect the value of the tilt angle using, for example, three perpendicular acceleration sensors or by means of a capacitive liquid sensor or a magnetoresistive sensor and output it electronically. This output angle can then be displayed by the external control device or otherwise output and / or used. In particular, the value of the tilt angle can be transmitted to the control device. This transmission can take place, for example, via radio, Bluetooth, WLAN, RFID, LAN, or other known transmission mechanisms.

[0059] The control device can receive the tilt angle value output by the tilt sensor. The control device can include a processor to determine or calculate the control signal based on the received value and a predetermined target value for the tilt angle. This control signal can then be transmitted from the control device to the tilt device, with the same options available for this transmission as between the tilt sensor and the control device.

[0060] The tilting device can receive the control signal and, based on this, control the motor so that the tilt angle is adjusted to the specified target value.

[0061] The control device can also be the described external control device, which includes the tilt device as well as the control device. The external control device can include one or more processors to determine the control signals for the associated devices.

[0062] The tilting device may further comprise a compensating optic, for example a movable mirror.

[0063] The compensation optics can be designed such that they compensate for the movement due to the tilting of the tilting device in such a way that the point of incidence and / or angle of incidence of light passing through the sample carrier holder and the optical component remain unchanged even during tilting.

[0064] The movable mirror may be a mirror mounted on a conventional motorized mirror holder (" motorized mirror mount") and is movable via a corresponding electrical signal. The electrical signal can be provided, for example, by the external control device.

[0065] The additional compensating optics simplify, among other things, the integration of the tilting device into an existing, conventional microscope. For example, a microscope typically comprises an objective lens, at least one or more deflecting mirrors and an eyepiece with which a virtual image is projected onto a sensor or the human eye. The tilting device described can now be integrated into such a microscope, for example, by replacing the objective lens and a stage with the tilting device described. The tilting device can therefore be an exchange module with which a conventional microscope can be converted. Tilting changes the optical path of light in the microscope. In order to avoid affecting imaging in general, the point of incidence and the angle of incidence of light passing through the objective lens must remain unchanged as a result of the tilting.This can be achieved using the compensation optics described.

[0066] Furthermore, the present invention includes a microscope comprising a previously described tilting device, a stand and an imaging system with an imaging lens, in particular an eyepiece.

[0067] The use of a tilting device described in a microscope also results in the advantages mentioned in connection with the tilting device.

[0068] Inverted microscopes are typically preferred for cultivating and observing cells in specially designed sample carriers. This is because the cells are usually arranged at the bottom of the sample carrier. In an inverted microscope, the objective lens is directed from below onto the object to be examined, allowing the objective lens to be brought particularly close to the cells. This enables higher optical resolution. However, the tilting device described here can also be used in a microscope in which the objective lens is directed from above onto the sample carrier, because the basic design of the two types of microscopes mentioned only differs in the arrangement of the imaging components, not the components themselves.

[0069] The imaging system comprises, in particular, an eyepiece that produces a viewable image. Furthermore, the imaging system may include other optical elements, such as one or more mirrors or a prism for redirecting the light. The eyepiece itself may be constructed from one or more lenses. It is possible to view the image produced by the eyepiece with the human eye.

[0070] The invention further provides a microscope comprising a sample carrier holder, and an optical component with an optical axis, a stand and an imaging system with an imaging lens, in particular an eyepiece, wherein the optical axis is aligned with a base side of the sample carrier holder, wherein the sample carrier holder and the optical component are tiltably mounted, wherein the alignment of the optical axis with respect to the base side of the sample carrier holder is maintained when the sample carrier holder and the optical component are tilted, and wherein the imaging lens is arranged between the optical component and the imaging component.

[0071] The imaging system of the microscope may further comprise one or more mirrors, in particular movable mirrors, wherein the mirrors are mechanically coupled or individually electronically controllable. The imaging system may comprise an imaging component, in particular a camera with an imaging sensor.

[0072] An imaging component in the form of a camera allows for automated and, if necessary, continuous acquisition of image data with the microscope. This image data can be directly evaluated, for example, by a dedicated processor.

[0073] The mirrors primarily serve to transmit an image from the lens to the imaging component. Thus, the mirrors can be designed to redirect the light from the lens to the imaging component; they are therefore known as deflection mirrors. The mechanical coupling of the mirrors or their electronic controllability serves the purpose of adjusting the optical path of the light, which changes as a result of tilting the tilting device, in such a way that the point of incidence and angle of incidence on the imaging component remain unchanged.

[0074] The mechanical coupling can be formed between two or more mirrors, so that these coupled mirrors perform a correlated movement. For example, the two or more mirrors can be directly connected to each other via a mechanical element.

[0075] At least one of the mirrors can also be mounted on a motorized mirror mount that can adjust the mirror's alignment. The motor can be connected to and controlled by a dedicated device. This can, for example, be the external control device described above, which can also control the tilt device and the steering device. Individual control of the microscope's mirrors allows optimal control of the optical path through the microscope and thus precise adjustment of the mirror's alignment, ensuring that the image is not affected by tilting.

[0076] Furthermore, the microscope can comprise a display device, in particular a monitor. This allows the image generated by the imaging component to be displayed.

[0077] The imaging lens can be mounted so as to be movable along its optical axis or can have a variable focal length, whereby a movement of the imaging lens along its optical axis and / or the focal length can be individually controlled.

[0078] Depending on the position of the rotation axis when the tilting device is tilted, the length of the optical path can also change, which may not be compensated for by the mirrors described above. As a result, the imaging component is no longer in the focal plane of the imaging lens, resulting in a blurred image. By changing the focal length or the position of the imaging lens, its focal plane (image plane) can be adjusted so that it always lies on the imaging component, producing a sharp image.

[0079] The imaging lens can be mounted movably, particularly in a rail, so that only movement along the optical axis of the imaging lens is possible. This, together with the compensating optics and / or the microscope mirrors, provides sufficient degrees of freedom to compensate for any change in the optical path resulting from tilting, so that the image remains unchanged. Movement of the imaging lens perpendicular to its optical axis is not absolutely necessary for this.

[0080] The movement can be performed either manually or controlled by the external control device. The same considerations apply as described for adjusting the tilt angle of the tilting device using the tilting device.

[0081] In addition to or instead of the movable mount, the imaging lens may also have a variable focal length, such as a varifocal lens (" varifocal lens A varifocal lens comprises a plurality of individual lenses that can be moved relative to one another, changing the overall focal length of the system. This lens also solves the technical problem of compensating for a change in focus caused by tilting the tilting device. Here, too, the focal length can be adjusted manually or via the external control device.

[0082] The variable position and variable focal length of the imaging lens can also be combined or used together. Furthermore, the imaging lens, in particular an eyepiece, can be designed with multiple lenses. In this case, one, several, or all of the lenses can be arranged movably and / or have a variable focal length. Each of the positions and focal lengths of the lenses can be controlled and adjusted manually and / or by the external control device.

[0083] The mechanisms for adjusting the imaging lens described above allow for considerable flexibility in the microscope. In a special embodiment, the optical component can be an objective corrected to infinity. The working distance of the objective is approximately its focal length, so that the light rays after the objective are essentially parallel. Therefore, a deviation in the path length between the objective and the imaging component due to tilting does not necessarily lead to a different focus of the imaging lens. A sharp image is therefore still generated on the imaging component, and adjustment of the imaging lens is not necessary.

[0084] The microscope can be enclosed by an incubation system that regulates temperature, gas concentration, and / or humidity at least at one location of the optical component and the sample carrier holder. Such an incubation system is known, for example, from EP 2 148 921 A2.

[0085] An incubation system can precisely adjust and control cell cultivation conditions. This means that both observation and cell cultivation can be carried out in a single device.

[0086] The incubation system can be designed in such a way that it forms a space, particularly a closed one, around the microscope. No structural changes are required to the microscope itself to integrate it into the incubation device.

[0087] The present invention further comprises a method. The method comprises the following steps: Providing a previously described tilting device for microscopy or a previously described microscope; holding a sample carrier in the sample carrier holder; and tilting the sample carrier holder, wherein the sample carrier comprises a first reservoir, a second reservoir and a channel, wherein the first reservoir is connected to the second reservoir via the channel, wherein by tilting the sample carrier holder a liquid is transported from the first reservoir to the second reservoir and wherein in particular by transporting the liquid a flow is created, and wherein cells are cultivated under this flow.

[0088] Complete implementation of this method makes it possible to transport a liquid within a sample carrier without the presence of an external device, such as a pumping device, but simply by tilting the sample carrier. This liquid transport creates a flow under which cells are cultivated in this sample carrier. Such a flow is necessary, for example, to supply the cells with nutrients or to exchange used liquid. Furthermore, the method also offers the possibility of continuously microscopy the sample carrier even during tilting, because the working distance and alignment between the sample carrier and the optical component do not change, and the optical component therefore does not need to be adjusted to the changed focus during microscopy. This allows for efficient microscopy.

[0089] A sample carrier is a platform for examining cells. The sample carrier can, in particular, have a flat underside, which is particularly advantageous for microscopic examinations through this underside, especially in the case of inverted microscopy. Furthermore, the sample carrier is preferably made of a transparent material, for example, from plastics such as COC (cycloolefin copolymer), COP (cycloolefin polymer), PC (polycarbonate), PS (polystyrene), PE (polyethylene), PMMA (polymethylmethacrylate), or a transparent thermoplastic or an elastomer, or a mixture thereof.

[0090] By using the materials and processes mentioned, the sample carriers can be produced cost-effectively, in large quantities, and with consistent quality. This is due to the fact that injection molding with plastics is an established and reliable process and is particularly applicable to the aforementioned plastics. The use of a transparent plastic is particularly advantageous for conducting optical examinations in the sample carrier, for example, via microscopy.

[0091] The described method can further be carried out with a tilting device comprising an inclination device, wherein the sample carrier further comprises a liquid sensor, and wherein the liquid sensor detects and outputs a value of one or more of a liquid level, a flow velocity or a flow direction within the sample carrier held in the sample carrier holder, and wherein the control device receives the value output by the sensor and, based on the received value, transmits a control signal to the inclination device such that the inclination device adjusts a tilt angle of the tilting device such that one or more of the liquid level, the flow velocity or the flow direction within the sample carrier are adapted to a predefined target value.

[0092] Cell cultivation in a sample carrier should preferably take place under well-defined environmental conditions, including, in particular, the aforementioned parameters of fluid level, flow rate, and flow direction. These parameters can be precisely and reliably controlled and adjusted by the control device in conjunction with the fluid sensor, thus providing optimal and stable conditions for cell cultivation in the sample carrier. The control of these parameters can be automated, so that the entire cultivation process can run automatically without continuous supervision by a human operator.

[0093] In addition, the present invention includes a use of a previously described tilting device for microscopy or a previously described microscope for transporting a liquid within a sample carrier, wherein the sample carrier is held in the sample carrier holder, wherein the sample carrier comprises a first reservoir, a second reservoir and a channel, wherein the first reservoir is connected to the second reservoir via the channel, wherein by tilting the sample carrier holder a liquid is transported from the first reservoir into the second reservoir and wherein in particular by the transport of the liquid a flow is created, and wherein cells are cultivated under this flow.

[0094] This offers the same advantages as the method described above. This particularly applies to the cultivation of cells under flow in a sample carrier and the possibility of continuous microscopy while tilting the tilting device, because the focus of the optical component does not need to be corrected.

[0095] Further features and advantages are explained below using the example figures. They show: Figures 1A and 1B show a schematic cross-section in front view of a tilting device according to a first and a second embodiment; Figure 2A shows a schematic cross-section in front view of a tilting device according to a further embodiment; Figure 2B shows a schematic cross-section in side view of a tilting device according to a further embodiment; Figure 3A shows a schematic tilting device comprising a movement device as a plan view; Figure 3B shows a schematic tilting device comprising a movement device in cross section; Figure 4 shows a schematic cross-section in side view of a tilting device according to a further embodiment; Figure 5A a schematic microscope according to a first embodiment in cross section; Figure 5B a detailed view of the microscope in Figure 5A; Figure 5C shows a schematic cross-section of a microscope according to a further embodiment; Figure 5D shows a schematic microscope according to a further embodiment in cross-section; Figure 6A shows a flowchart for a method for microscopy; and Figures 6B to 6D show a method for microscopy.

[0096] In the following and in the figures, the same reference numerals are used for the same or corresponding elements in the various embodiments, unless otherwise specified.

[0097] Figure 1Ashows a cross-section of a tilting device 10 according to the invention for microscopy according to a first embodiment. The tilting device 10 comprises a sample carrier holder 20 and an optical component 30. The optical component 30 is shown only schematically in this example. The optical component 30 can be, for example, an objective lens, wherein the objective lens can be a converging lens or a lens system comprising a plurality of lenses. The optical component is connected to the sample carrier holder 20 via a holder 31. In this example, this connection is particularly rigid, so that no relative movement between the optical component 30 and the sample carrier holder 20 is possible.

[0098] The sample carrier holder 20 also includes an insertion rail 21 into which a sample carrier can be inserted and, if necessary, secured. This insertion rail 21 can be formed circumferentially on the upper side of the sample carrier holder 20. It is also possible for the insertion rail 21 to be formed only in certain sections on the upper side of the sample carrier holder, for example, so that the corners of the sample carrier rest against the insertion rail 21. In this example, the base side of the sample carrier holder 20 can be identified as its upper side, to which the insertion rail 21 is also attached and onto which a sample carrier can be inserted.

[0099] The sample carrier holder 20 is connected to a joint 40 via a holding device 41 and is simultaneously mounted so that it can be tilted about this joint 40. The joint 40 can be, for example, a ball joint or a swivel joint (hinge joint). In the case of a swivel joint, the tilt axis runs into the drawing plane and through the center of the joint 40. For a ball joint, the tilt axis is located in a horizontal plane that runs through the center of the joint 40.

[0100] Last shows Figure 1Athe optical axis OA of the optical component 30. The optical axis OA is aligned perpendicular to the above-described base side of the sample carrier holder 20 and runs through the geometric center and in particular through the center of curvature of the optical component 30. Furthermore, in the example shown, the optical axis OA is aligned perpendicular to the previously described tilt axis; the alignment is always maintained in the tilting device 10.

[0101] The described tilting device from Figure 1A is in Figure 1Bshown in the tilted state, wherein the tilting was performed about the joint 40 and about a tilting axis extending into the plane of the drawing and through the center of the joint 40. Since the optical component 30 and the sample carrier holder 20 are rigidly connected to one another, they were tilted in the same way, so that, in particular, even after the tilting, the optical axis OA of the optical component is aligned perpendicular to the base side of the sample carrier holder 20.

[0102] The tilting device 10 was rotated by the angle α relative to the horizontal alignment of the tilting device, as shown in Figure 1A , and tilted around the described tilt axis. The horizontal alignment can be considered the starting position of the tilting device 10.

[0103] Another embodiment of a tilting device 10 is shown in Figure 2AThis figure shows a cross-section of the tilting device 10 in front view. The tilting device 10 comprises, as already shown in the embodiment according to Figure 1A known, a sample carrier holder 20 with an insertion rail 21 and an optical component 30. In this case, the optical component 30 consists of an objective lens and a mirror, the objective lens being shown only schematically for the reasons mentioned above. The mirror is mounted in a mirror holder 32. In a simple form, the mirror holder 32 is a plate with a recess, with the mirror being mounted in this recess. However, the mirror holder 32 is not limited to this example.

[0104] The mirror mount 32 is rotated relative to the base of the sample holder 20, with the rotation axis of the mirror and the mirror mount 32 parallel to the base of the sample holder 20 and in the plane of the drawing. In particular, the rotation angle is 45 degrees, so that light passing through the objective lens along the optical axis is deflected at a right angle and exits perpendicularly from the plane of the drawing.

[0105] The tilting device 10 is designed in such a way that a tilting axis 33 is arranged on the mirror holder 32 (not in this figure, but in Figure 2B shown) and runs centrally through the mirror. The tilting device 10 is thus rotatably mounted about this tilting axis 33. The tilting axis 33 points perpendicularly out of the plane of the drawing and is also perpendicular to the optical axis OA. The tilting device 10 can be tilted clockwise or counterclockwise, as shown by the arrows.

[0106] In this embodiment of the tilting device 10, it is possible to perform a tilt without changing the optical path of the light after the optical component 30. This is because the center of rotation of the tilting device 10 is located at the location of the mirror, whereby the point of incidence and angle of incidence of light on the mirror remain constant regardless of a tilting of the tilting device 10.

[0107] A tilting device 10 according to a further embodiment is shown in cross section and in a side view in Figure 2B Here, a mirror alone forms the optical component 30. The mirror is mounted in a mirror holder 32 and the surface of the mirror is rotated relative to the base of the sample carrier holder 20, in particular by 45 degrees. The mirror holder 32 further comprises a tilt axis 33, which, as with respect to Figure 2Adescribed, perpendicular to the optical axis and centrally aligned through the mirror. Furthermore, the tilt axis 33 lies in the plane of the drawing in this side view. In particular, the arrangement of the tilt axis 33 in the two examples is according to Figures 2A and 2B identical. Tilting of the tilting device 10 is achieved by rotation about the tilting axis 33, for example, about a corresponding joint 35, with the direction of rotation being indicated by the arrows.

[0108] The objective lens 34 is not part of the tilting device 10 and is, in particular, fixedly mounted so that it does not move regardless of the tilting device 10. This arrangement has the advantage that the objective lens, which is of great importance for generating an image, does not need to be moved. This suppresses aberrations induced by relative movement between the mirror and the objective lens. The objective lens 34 can, in particular, be a component of a microscope, especially if the tilting device 10 is integrated into an existing microscope.

[0109] Figure 3Ashows a tilting device 10 comprising a movement device 50 in a top view, wherein the movement device 50 is designed such that it moves the optical component 30 relative to the fixed sample carrier holder 20. In this specific case, the movement device 50 is a translation platform in which the optical component 30 is movable in a plane parallel to the base of the sample carrier holder. The translation platform can be a conventional manual model comprising an adjusting screw 51, a return spring 52, and a readable scale 53 for each of the two axes. By rotating the adjusting screw 51, the optical component 30 can be moved along the associated axis.Because there are two axes arranged perpendicular to each other, each with an adjusting screw 51, which form a two-dimensional translation platform, the optical component 30 can be moved horizontally in a plane and relative to the sample carrier holder 20.

[0110] By means of a comparable form of the movement device, the sample carrier holder 20 can also be movably mounted and moved by the movement device 50, while the optical component 30 is fixed.

[0111] As in the previously described embodiments, the tilting device further comprises an insertion rail 21 on the top side of the sample carrier holder 20, wherein the insertion rail 21 is designed for a rectangular sample carrier and fixes the sample carrier at the four corners, and a holder 31 for the optical component 30.

[0112] In Figure 3BA further embodiment of the movement device 50 is shown, with which it is possible to move the optical component 30 additionally parallel to its optical axis OA. For the embodiment in Figure 3A Analog components are not explained again here, but only the differences are highlighted.

[0113] The section of the tilting device 10 shown comprises a base plate 55, which is fixedly arranged with respect to the sample carrier holder 20. Motors 54 or comparable drive devices are arranged symmetrically between the base plate 55 and the holder 31 of the optical component, which perform a vertical movement along the optical axis OA of the optical component 30. In order for the optical component 30 to be moved along the optical axis OA, the two motors 54 must be driven synchronously. For example, this can be a piezoelectric actuator or an electric motor. In particular, the movement device shown here can be used with the embodiment from Figure 3A be combined so that the movement device enables a relative movement between the sample carrier holder 20 and the optical component 30 along all three spatial directions.

[0114] A tilting device 10 according to a further embodiment is shown in Figure 4 This initially includes some components of the first embodiment according to Figure 1A , so only the differences are explained below.

[0115] The tilting device 10 shown comprises, on the one hand, a movement device 50 designed to move the optical component 30 in the vertical direction, or along the optical axis OA. It should be noted that, due to its design, the optical component 30 must tilt in the same way as the sample carrier holder 20, in particular around the same axis (or a coaxial axis), but the two components are not rigidly connected to one another because relative movement can occur between the components. The movement device comprises a mount 31 for the optical component 30 and a motor, for example, an electric motor or a piezoelectric actuator, which can move the movement device 50.

[0116] The movement device 50 is controlled by an electronic controller 58, which regulates the movement of the motor. The electronic controller 58 comprises a signal input 55, a processor 56, and a signal output 57. For example, a target coordinate for the optical component 30 can be entered into the signal input. The input can be made in associated control software or on an integrated keyboard or a similar device. This input is then used by the processor 56 to generate a control signal. This control signal is output by the electronic controller 58 via the signal output 57 and transmitted to the movement device 50. The movement device 50 then moves the optical component 30 by means of the motor so that it assumes the specified target coordinate.

[0117] The tilt angle of the tilting device 10 can be controlled via a tilting device 60. This tilting device 60 can, for example, be a rotary motor, in particular an electrically controllable one. The rotary motor simultaneously includes the joint 40 around which the tilting is performed.

[0118] Furthermore, the tilting device 10 has an inclination sensor 61, which detects the tilt angle of the tilting device 10 relative to a horizontal starting position. Capacitive or magnetoresistive liquid inclination sensors are suitable, for example. The inclination sensor 61 outputs a specific value for the tilt angle or another measured value that depends on the tilt angle and transmits it to the control device 70.

[0119] Similar to the electrical controller 58, the control device 70 comprises a signal input 71, a processor 72, and a signal output 73. The value output by the tilt sensor 61 is input to the signal input 71. A specific target value for the tilt angle to which the tilting device 10 is to be set can also be entered via the signal input 71. The processor 72 uses this value and the specified target value to generate a control signal, which is output via the signal output 73 and transmitted to the tilting device 60. In the example shown, the control signal is transmitted directly to the rotary motor, a component of the tilting device 60. The rotary motor receives the control signal and tilts the tilting device 10 so that the tilt angle is adjusted to the specified target value.

[0120] The tilt angle can be controlled, in particular, as a feedback loop. For this purpose, the tilt angle is continuously regulated by the tilt sensor 61 continuously outputting a measured value, and the control device 70 continuously generates a control signal and transmits it to the tilt device 60 to maintain the tilting device 10 at a specific tilt angle. This allows the tilt angle to be maintained particularly stable over long periods of time.

[0121] The electronic controller 58 and the control device 70 can be comprised of a control device 80, which can perform the entire described control of the tilting device. The control device 80 can have a plurality of signal inputs, processors, and signal outputs connected to the respective devices of the tilting device 10.

[0122] Figure 5AIllustrates the schematic structure of a microscope 100 according to the invention, in the case shown an inverted transmitted-light microscope, in cross-section. The microscope 100 comprises a tilting device 10 described above and an imaging system 105. A stand 101, typical for such a microscope, serves as a holder and stabilizing element.

[0123] The microscope 100 can, in principle, be equipped with the tilting devices explained in this description, so that in this figure it is shown only in the relevant components, namely the sample carrier holder 20 with an insertion rail 21, the optical component 30, and a tilting device 60. The optical component 30 can, in particular, be an objective lens, but is shown only schematically here.

[0124] The microscope 100 can have a modular design; in particular, the tilting device 10 can be a replaceable part that can be subsequently integrated into the microscope 100. Different embodiments of the tilting device 10 can be compatible with the microscope 100.

[0125] The imaging system 105 comprises a plurality of mirrors 110 and an imaging lens 120, which in the present example is in the form of an eyepiece. The imaging lens is mounted in a rail 121 such that the imaging lens 120 is movably mounted along its optical axis. Just as with the optical component 30 of the tilting device 10, the optical axis of the imaging lens 120 also runs through the center of curvature and is orthogonal to the remaining axes of symmetry. The imaging system 105 further comprises an imaging component 130. The imaging component can be, for example, a camera with an LCD chip or another imaging sensor, which can be mounted on the microscope 100 to electronically generate and output an image.

[0126] The mirrors 110 serve to direct the light from the optical component 30 through the imaging lens 120 to the imaging component 130 and are therefore referred to as deflecting mirrors. In the example shown, three mirrors 110 are used for this purpose; however, a microscope 100 according to the invention is not limited to this number and configuration. Additionally, further optical elements for beam guidance, such as a prism, can be present along the optical path.

[0127] Also in Figure 5AShown is the optical path of light propagating through the microscope 100. Starting from a light source above the microscope (for example, a condenser, not shown), the light first passes through a sample carrier, possibly mounted in the sample carrier holder 20, and then through the optical component 30. Tilting the tilting device 10 changes the refraction of light in the optical component 30 and, consequently, also the optical path through the microscope 100. Therefore, the point of incidence and the angle of incidence on the imaging lens 120 and the imaging component 130 change. This change can be compensated for by the mirrors 110 of the imaging system 105. For this purpose, the mirrors 110 are movably mounted and can be rotated such that said point of incidence and angle of incidence remain unchanged.The adjustment of the mirrors 110 can be carried out manually or, as explained below, by a control device provided for this purpose.

[0128] If the length of the optical path changes significantly, an image imaged by the imaging lens 120 may no longer be in focus. In this case, the imaging lens 120 is mounted in a rail 121 so that it can move along its optical axis, allowing the distance between the imaging lens and the imaging component 130 to be adjusted and a sharp image to be obtained. Alternatively, the lens can be set to infinity, so that changing the length of the optical path between the lens and the imaging lens 120 does not result in a shift of the image plane.

[0129] In Figure 5BA detailed view of the microscope 100 from Figure 5A is shown, in which the imaging system 105 is explained in more detail. Two of the included mirrors 110 each comprise a motor 111, with which the mirrors 110 can be rotated in order to compensate for a described change in the point of incidence and the angle of incidence on the imaging lens 120 and the imaging component 130. These can be mirrors that are mounted in a conventional, piezo-driven mirror holder (" motorized mirror mount "), as is common in connection with such optical applications.

[0130] Furthermore, the imaging lens 120 is mounted in a motorized rail 121, with which the imaging lens 120 can be electronically moved along its optical axis. The motors 111 and the rail 121 are controlled via an electronic control device 140 comprising a signal input 141, a processor 142, and a signal output 143. The signal input can be provided, for example, by the imaging component 130, which detects that an impact point and / or an impact angle on the component is / are no longer correct and / or that the image is no longer in focus. The signal can then be, for example, an error signal reflecting the deviation of the impact angle and / or the impact point. This signal is received by the signal input 141 and transmitted to the processor 142, which calculates a necessary correction of the mirror positions and / or the position of the imaging lens 120.This correction signal is output from signal output 143 and transmitted to motors 111 and / or rail 121, where the corresponding correction of the optical path and / or the focal point of imaging lens 120 is performed. The control device 140 can, in particular, be equipped with a feedback mechanism so that the described correction can take place continuously. Furthermore, the control device 140 can be part of the external control device 80, i.e., integrated therein.

[0131] Figure 5C shows a microscope 100 according to the invention according to a further embodiment. This differs from the embodiment of Figure 5A by the design of the tilting device 10, the optical component 30 and the imaging system 105. These differences will be discussed in more detail below.

[0132] First, a tilting device 10, as shown in Figure 2Bshown. The tilting device 10 comprises a mirror as the optical component 30. The mirror is connected, in particular rigidly, to the sample carrier holder 20 by means of a corresponding device. The tilting axis 33 of the mirror, and thus also of the entire tilting device 10, is aligned such that it runs parallel to the base of the sample carrier holder 20 and through the geometric center of the mirror. The tilting device 10 is then tilted about said tilting axis 33.

[0133] As already described above, the embodiment of the tilting device 10 allows the optical path of the light to remain unchanged after reflection from the mirror, despite tilting. Therefore, it is possible to combine the tilting device with an objective 34 integrated in the microscope 100. In particular, it does not need to be readjusted in the event of tilting, which allows for particularly efficient microscopy. The objective 34 can generally be mounted so that it can be moved, for example, to adjust its position along the optical path so that a sharp image is generated at the beginning of a microscopic examination.

[0134] The imaging system comprises two deflection mirrors 110, an imaging lens 120 movably mounted in a rail, and an imaging component 130. In particular, with regard to the imaging lens 120 and the imaging component 130, the same considerations apply as in the previous embodiment of the Figure 5A.

[0135] A microscope 100 according to the invention according to a further embodiment is described with reference to Figure 5D explained. Therein, the microscope 100 also comprises a described tilting device 10, which need not be explained in more detail at this point, and a stand 101. Furthermore, the microscope 100 comprises an imaging system 105 with an imaging lens 120 and an imaging component 130, in particular a camera with a CCD chip or similar device.

[0136] The sample carrier holder 20 is connected to the stand 101 via a mount 102 and is mounted so that it can rotate or tilt relative to the stand 101. The rotation or tilt occurs about an axis that is aligned coaxially with the mount 102.

[0137] The optical component 30, the imaging lens 120, and the imaging component 130 are connected to one another by a tube 125, which is particularly closed around its circumference. The connection is such that the three components cannot move relative to one another. The tube 125 not only serves as a stable mount but also prevents light, such as stray light, from entering the imaging component 130 from the side. This ensures high imaging quality.

[0138] The tube 125 is connected to the sample carrier holder 20, so that when tilted, the entire system consisting of the tilting device 10 and the imaging system 105 performs a joint tilting movement, and the optical path through the system does not change as a result of tilting. Therefore, corrections to the optical path, for example, using deflecting mirrors, are not necessary.

[0139] Alternatively, the objective lens 30 can be mounted movably along the vertical axis to change the distance between the objective lens 30 and the sample carrier holder 20. In particular, the objective lens 30 can be set to infinity, so that the imaging lens 120 does not need to be adjusted to a changed position of the objective lens 30.

[0140] The above statements apply to the implementation of tilting. For example, the tilting can be motorized, whereby, for example, the mount 102 can be rotated by a suitably designed motor. The same considerations also apply to the possible mobility of the objective lens. This can also be implemented by a suitably designed motor. It is also possible for the tilting device included in the microscope 100 to comprise a movement device with the aforementioned properties.

[0141] The imaging component 130 is connected, in particular electronically, to a display device 150, for example, a monitor, which may be part of the microscope 100, in order to transmit an electronic signal from the imaging component 130 to the display device 150. Thus, the images generated by the imaging component 130 are displayed to a user by the display device 150.

[0142] Figure 6A shows a method for microscopy according to the invention as a flowchart. In the first step S1 of the method, a tilting device 10 described here or a microscope 100 described here is provided. The method can in principle be carried out with all embodiments presented here.

[0143] In the subsequent step S2, a sample carrier 200 is held in the sample carrier holder 20 of the tilting device 10. The sample carrier 200 comprises a first reservoir, a second reservoir, and a channel connecting the first reservoir to the second reservoir. The sample carrier 200 contains a liquid and cells or a cellular structure, wherein the cells can be distributed in a reservoir, a channel, or at multiple locations within the sample carrier.

[0144] Now, in step S3, the sample carrier holder 20 is tilted, with no restrictions regarding the tilt angle and / or tilt axis. In particular, tilts are performed at an angle between 0 degrees and 20 degrees. This tilt generates a flow by gravity as a result of liquid transport from the first reservoir through the channel into the second reservoir.

[0145] Under this flow, the cells are cultured in the sample carrier 200 (step S4).

[0146] The previously described microscopy procedure will be described in more detail with reference to the Figures 6B to 6D illustrated.

[0147] In the first step of the procedure, as in Figure 6Bshown, a previously described tilting device 10 is provided. The tilting device 10 is shown in cross-section as a front view. However, the method can also be carried out in the same way with a described microscope 100 comprising the tilting device 10. According to the invention, the tilting device 10 comprises a sample carrier holder 20 and an optical component 30. Furthermore, the sample carrier holder 20 has an insertion rail 21 and the optical component 30 has a holder 31 that rigidly connects the sample carrier holder 20 and the optical component 30. According to the previously described embodiment, the tilting device 10 further comprises a movement device 50 and an inclination device 60, which simultaneously serves as a joint 40 about which tilting takes place. For a more detailed explanation of the components, reference is made to the associated embodiment in Figure 4 referred to.

[0148] In the following process step (see Figure 6C ) a sample carrier 200 is now inserted into the sample carrier holder 20 and held therein. For this purpose, the sample carrier 200 is inserted into the insertion rail 21, which can be precisely adapted to the size of the sample carrier. In order to further prevent the sample carrier from moving within the insertion rail 21 or in the sample carrier holder 20 in general, further fastening devices can be provided. For this purpose, for example, a locking screw is suitable, which runs laterally through the insertion rail 21 and presses the sample carrier 200 against the insertion rail 21 and thereby fixes it. This can be advantageous because the sample carrier 200 can easily slip in a sample carrier 20 that is not ideally adjusted as a result of tilting, and the microscopic examination is thus significantly impaired.

[0149] The sample carrier itself comprises a first reservoir 201a, a second reservoir 201b, and a channel 202 connecting the first reservoir 201a to the second reservoir 201b. The terms first reservoir 201a and second reservoir 201b can be used interchangeably, as they are structurally identical. A liquid, in particular a cell medium, as well as cells or cell structures ZS are located in the sample carrier 200. These can be introduced into the sample carrier 200 as part of the method or can already be present in the sample carrier 200. The cells themselves can be located at a specific location within the channel 202, as shown, but they can also be arranged in a reservoir 201a, 201b, or distributed over a larger area within the sample carrier 200.

[0150] The sample carrier also includes a liquid sensor 203, which in this example is arranged within the channel 202 and is configured to detect a flow velocity within the channel. The determined value can then be output electronically.

[0151] Then, as in Figure 6D As shown, the tilting device 10, and thus also the sample carrier holder 20 and the optical component 30, are tilted by an angle α. To carry out the tilting, an inclination device 60 is used, as in the previously described embodiment of a tilting device 10.

[0152] As a result of the tilting, the liquid is transported from the first reservoir 201a toward the second reservoir 201b. This liquid transport creates a flow, particularly at the location of the cells, whereby the cells are cultivated under this flow. As described, the tilting device 10 allows precise adjustment and control of the tilt angle and thus the flow. For this purpose, the liquid sensor 203 can be used in particular, which transmits a corresponding measured value to the control device 70. From the measured flow velocity, the processor can determine a target value for the tilt angle and, from this, a control signal, which is then transmitted to the tilting device 60. The tilting device thus adjusts the tilt angle accordingly.This method can also be carried out in the same way with a measured liquid level or a measured flow direction, whereby the liquid sensor 203 must be designed accordingly.

[0153] The described method can be extended beyond the described steps by varying the tilt angle over time. For this purpose, the tilting device 60 must be designed such that it can continuously adjust the tilt angle α. For example, the tilt angle can be changed linearly or periodically, such as sinusoidally, over time. In particular, a change in the sign of the tilt angle occurs, as a change in the tilt direction, so that the flow direction within the sample carrier 200 is reversed.

[0154] This described method allows a continuous flow of cell medium to be generated in the sample carrier 200 without the need for external devices, because the liquid can be continuously kept in motion by periodically reversing the tilting direction. Furthermore, the tilting angle can be continuously controlled and adjusted, for example, using a feedback mechanism of the tilting device 60 in conjunction with a liquid sensor and a tilt sensor 61.

[0155] The described method is not limited to the shown combination of a tilting device 10 and a sample carrier 200. In particular, the method can be carried out with all tilting devices 10 and microscopes 100 presented in this description. Likewise, the combination of features of the sample carrier 200 is not restrictive. Thus, sample carriers are suitable for the method provided they have two reservoirs 201a, 201b connected by a channel 202 and can be used effectively with the tilting device 10 or the microscope 100. The sample carrier 200 can, for example, have microfilter structures or valves in addition to the components mentioned.

Claims

1. Tilting device (10) for microscopy, comprising: a sample carrier mount (20), an optical component (30) with an optical axis (OA), and an inclination unit (60) with a motor (13), where said optical axis (OA) is aligned with respect to a base side of said sample carrier mount (20), where said sample carrier mount (20) and said optical component (30) are mounted to be tiltable, and where the alignment of said optical axis (OA) with respect to said base side of said sample carrier mount (20) is maintained when said sample carrier mount (20) and said optical component (30) are tilted, where said motor (13) is connected to said optical component (30) and / or to said sample carrier mount (20), where said motor (13) is configured such that it tilts said sample carrier mount (20) and said optical component (30), and where the inclination unit (60) is configured such that it generates a continuous tilt motion, in particular a seesaw motion, of the tilting device (10).

2. Tilting device (10) according to claim 1, where said optical component (30) is an objective and / or a mirror.

3. Tilting device (10) according to one of the preceding claims, where said sample carrier mount (20) and said optical component (30) are each connected to a joint (40) and are mounted to be tiltable about said respective joint (40).

4. Tilting device (10) according to one of the preceding claims, where said tilting mechanism (10) is configured such that said sample carrier mount (20) and said optical component (30) are tilted about a tilt axis (33) which is aligned to be perpendicular to said optical axis (OA).

5. Tilting device (10) according to one of the preceding claims, where said sample carrier mount (20) and said optical component (30) can be tilted by a tilt angle between 0 degrees and 1 degree, in particular between 0 degrees and 20 degrees, with respect to a horizontal position of said sample carrier mount (20).

6. Tilting device (10) according to one of the preceding claims, furthermore comprising a motion device (50), where said motion unit (50) is configured such that it can move said optical component (30) in a plane parallel to said base side of said sample carrier mount (20), or where said motion unit (50) is configured such that it can move said optical component (30) perpendicular to said base side of said sample carrier mount (20), or parallel to said optical axis (OA), respectively.

7. Tilting mechanism according to claim 6, where said motion unit (50) is configured such that it can move said sample carrier mount (20) in a plane perpendicular to said optical axis (OA) of said optical component (30), or where said motion device (50) is configured such that it can move said sample carrier mount (20) parallel to said optical axis (OA).

8. Tilting device (10) according to claim 7, furthermore comprising: an inclination sensor (61), and a control unit (70), where said inclination sensor (61) is configured such that it can detect and output a value of a tilt angle of said tilting mechanism (10), and where said control unit (70) is configured to receive the value output by said inclination sensor (61) and, based on the value received and a predetermined target value, to transmit a control signal to said inclination unit (60) so that said inclination unit (60) adjusts the tilt angle of said tilting mechanism (10) to said predetermined target value.

9. Microscope (100) comprising, a tilting device (10) according to one of the claims 1 to 8, a stand (101), and a projection system (105) with a projection lens (120), in particular an eyepiece.

10. Microscope (100) according to claim 9, where said projection system (105) furthermore comprises: one or more mirrors (110), where said mirrors (110) are mechanically coupled or controllable electronically individually, and / or an imaging component (130), for example a camera with an imaging sensor.

11. Microscope (100) according to one of the claims 9 or 10, where said projection lens (120) is mounted to be movable along its optical axis, and / or where a focal length of said projection lens (120) is variable, and where a motion of said projection lens (120) along its optical axis and / or said focal length can be controlled individually.

12. Method for microscopy comprising: providing a tilting device (10) for microscopy according to one of the claims 1 to 9 or a microscope (100) according to one of the claims 9 to 11; mounting a sample carrier (200) in said sample carrier mount (20); and tilting said sample carrier mount (20), where said sample carrier (200) comprises a first reservoir (201a), a second reservoir (201b), and a channel (202), where said first reservoir (201a) is connected to said second reservoir (201b) by way of said channel (200), where a fluid is transported from said first reservoir (201a) into said second reservoir (201b) by tilting said sample carrier mount (20), where a flow is produced in particular by the transport of said fluid, and where cells (ZS) are cultured under this flow.

13. Method according to claim 12, where a tilting device (10) according to claim 8 or 9 is provided, and where said sample carrier (200) furthermore comprises a fluid sensor (203), where said fluid sensor (203) detects and outputs a value of one or more of a fluid level, a flow rate, or a flow direction within said sample carrier (200) mounted in said sample carrier mount (20), and where said control unit (70) receives the value that is output by said fluid sensor (203) and, based on the value received, transmits a control signal to said inclination unit (60), so that said inclination device (60) adjusts the tilt angle of said tilting device (10) so that one or more of the fluid level, the flow rate, or the flow direction within said sample carrier (200) are adjusted to a predefined target value.

14. Use of a tilting device (10) for microscopy according to one of the claims 1 to 8 or a microscope (100) according to one of the claims 9 to 11 for transporting a fluid within a sample carrier (200), where said sample carrier (200) is mounted in said sample carrier mount (20), where said sample carrier (200) comprises a first reservoir (201a), a second reservoir (201b), and a channel (202), where said first reservoir (201a) is connected to said second reservoir (201b) by way of said channel (200), and where a fluid is transported from said first reservoir (201a) into said second reservoir (201b) by tilting said sample carrier mount (20), where a flow is produced in particular by the transport of the fluid, and where cells (ZS) are cultured under this flow.