A sample movement system

Abstract

A microscope stage comprises a lid, a base and a sample movement system. The sample movement system comprises a sample holder, a driver moveable in a first direction, and a support configured to restrict movement of the sample holder relative to the microscope stage in the first direction. The sample holder is coupled to the driver by first and second guide structures. The first guide structure is configured to translate movement of the driver in the first direction into movement of the sample holder in a second direction. The driver is moveable to cause the sample holder to move into sealing contact with the lid. The lid comprises a passage between first and second sides of the lid. The passage narrows from and comprises a ledge between the first and second sides. A tapered portion extends from the ledge to the to one of the sides of the lid.

Description

[0001] A Sample Movement and Access System

[0002] Technical Field of the Invention

[0003] The present invention relates to sample movement and access systems, preferably for microscope stages. In particular the invention relates to imaging systems, like motorised microscope stages, incorporating sample movement systems, and lids for providing access to a sample. Most particularly the invention relates to imaging systems, microscope stages, sample access systems, and sample movement systems for crystallography sample handling. to the Invention

[0004] Microscopes and imaging systems (optical or otherwise) are ubiquitous in many technical disciplines and research applications to facilitate visualisation of sample features and structure that is otherwise invisible to the naked eye or regular camera systems. One such application in which the microscope is vital is the crystal harvesting process required during macromolecular crystallography or protein crystallography experiments.

[0005] The harvesting process is vital in order to select and transfer protein crystals from the liquid into sample mounts, as well as perform pre-treatment steps required for a given experiment. However, this is often a challenging task as the crystals themselves are small, on the order of 10s of microns, fragile, and also come in all different shapes and sizes. Consequently, even to locate a crystal requires high resolution microscopy in the X-Y plane, parallel to focal plane of the microscope, but also perpendicular to the focal plane in the Z- direction. Quick temporal control of the microscope focus / sample position is also important as the protein crystal can move relatively quickly due to micro fluid currents. Additionally, longer processing time due to slow movement increases the risk that the sample deteriorates, for example through evaporation.

[0006] Furthermore, to image using a regular bright-field microscope, any system or apparatus to control the sample position needs to be thin in the Z-direction as space is extremely limited. This presents additional challenges in creating a system / stage to adequately control the sample.

[0007] To attempt to address the above problems, existing solutions have been proposed such as the microscope stage and sample handling system disclosed in Wright, Nathan David, et al. “The low-cost, semi-automated shifter microscope stage transforms speed and robustness of manual protein crystal harvesting.” bioRxiv (2019): 2019-12 (Wright). The microscope stage disclosed in Wright is optimised for crystal harvesting and handling through use of an acrylic lid comprising an access aperture. A microplate comprising a grid of sample wells is fitted to the stage and is moveable beneath the lid in the X-Y plane to select a certain well for processing, movement of the microplate in the Z-direction is controlled by springs and linear electromagnetic actuators acting in the Z-direction. The springs push the microplate up against the lid to allow one well to be accessible through the access aperture and the other wells to remain protected against the underside of the lid. To change wells, the microplate is lowered using the actuators to overcome the force of the springs, the microplate is then clear of the lid and can be moved to select another well for processing.

[0008] While the Wright stage does help the crystal harvesting process, there is a need to improve the crystal handling process and there remain challenges in improving sample control and visualisation during the harvesting process and facilitating more advanced handling procedures while ensuring they can be performed on a regular microscope without significant alteration.

[0009] It is therefore an object of the present invention to at least partially overcome the above issues.

[0010] Summary of the Invention

[0011] In a broad sense, the invention concerns a sample movement system, for example as described below in relation to the first aspect. The invention also concerns a lid, for example as described below in relation to the second aspect. The lid may be for the sample movement system. The lid may be for a sample access system. Each of the lid, sample movement system and sample access system may be for an imaging system. The invention also concerns imaging systems. The imaging system may be any system for imaging a sample or for holding a sample for imaging. The imaging system may be, or comprise, an imaging stage. The imaging stage may be configured to hold the sample movement system for imaging. The imaging system may be a microscope. The imaging stage may be a microscope stage. The imaging stage may be a table or bench. The imaging system may comprise any one or more of the sample movement system, lid and sample access system. The imaging stage may comprise any one or more of the sample movement system, lid and sample access system. The sample movement systems, lids, sample access systems, imaging stages and systems of the invention can therefore be used in a variety of imaging settings whether the sample is visualised by eye, through an eyepiece, a camera, a microscope or other non-optical means.

[0012] While the invention may be applied generally to a wide range of samples, some examples of specific preferred samples relevant to the aspects of the invention are set out below. The aspects of the invention may be for handling of samples suspended or immersed in a liquid. The samples may be for imaging, such as imaging using a microscope. The samples may be biological samples. The biological samples may be microbes, bacteria, fungi or other biological matter. The samples may be for use in crystallography experiments, such as x-ray crystallography. The samples may be proteins, for example protein crystals. As described below, aspects of the invention reduce handling time and exposure of the sample to free air which helps to reduce damage to the samples that may occur due to evaporation of the liquid.

[0013] The sample movement system may comprise a sample holder. The sample holder may be configured to attach to a sample. The sample movement system may comprise a driver. The driver may be moveable in a first direction. The sample movement system may comprise a support. The support may be configured to restrict movement of the sample holder in the first direction. The sample holder may be coupled to the driver. The sample holder may be coupled to the driver by first and second guide structures. The second guide structure may comprise a guide surface. At least part of the first guide structure may be configured to contact the guide surface. At least part of the first guide structure may be configured to contact the guide surface to translate movement of the driver in the first direction into movement of the sample holder in a second direction different to the first direction.

[0014] Accordingly, in an aspect of the invention there is provided a sample movement system, the system comprising a sample holder configured to attach to a sample, a driver moveable in a first direction, and a support configured to restrict movement of the sample holder in the first direction, wherein the sample holder is coupled to the driver by first and second guide structures, wherein the second guide structure comprises a guide surface and at least part of the first guide structure is configured to contact the guide surface to translate movement of the driver in the first direction into movement of the sample holder in a second direction different to the first direction.

[0015] The sample holder may be configured to attach to a sample to be imaged. The driver may be moveable relative to the imaging stage in the first direction. The support may be configured to restrict movement of the sample holder relative to the imaging stage in the first direction.

[0016] Accordingly, in a first aspect of the invention there is provided a sample movement system for an imaging stage, the system comprising a sample holder configured to attach to a sample to be imaged, a driver moveable relative to the imaging stage in a first direction, and a support configured to restrict movement of the sample holder relative to the imaging stage in the first direction, wherein the sample holder is coupled to the driver by first and second guide structures, wherein the second guide structure comprises a guide surface and at least part of the first guide structure is configured to contact the guide surface to translate movement of the driver in the first direction into movement of the sample holder in a second direction different to the first direction.

[0017] Advantageously, the sample movement system is arranged to cause movement of the sample holder in the second direction when the driver is moved in the first direction. This is particularly helpful in situations with limited space in the second direction as the components for causing movement of the sample holder can be separated from it in a different direction.

[0018] As the sample holder is restricted in the first direction, contact of the first guide structure and guide surface can result in movement of the sample holder in the second direction. Advantageously, the guide surface facilitates a high level of control of the movement of the sample holder as the surface can be varied to select the amount of movement of the sample holder that corresponds to a given movement of the driver. This allows both fine control and accuracy of movement but also high speed of movement if required. The invention therefore has advantages over Wright whose electronic actuators do not allow any such fine control of movement in the Z direction. In addition, the Wright solution is susceptible to overheating as the actuators must remain energised to hold the sample down against the springs. In contrast, the driver can be more easily held in the first direction to hold the sample holder in any position in the second direction without an energised component, this is in part due to the contact between the first and second guide structures which provides static friction to help hold the sample holder in one position. This provides for enhanced sealing between the sample and a lid as described below, leading to lower risk of sample deterioration due to evaporation.

[0019] Preferably, the sample movement system may be for a microscope or microscope stage. The sample holder may therefore be configured to attach to a sample to be imaged using a microscope.

[0020] The guide surface is preferably at an angle with respect to the first direction and second direction. Thus, the guide surface is preferably neither perpendicular nor parallel to the first and second directions. Thus, the guide surface effectively translates movement of the driver in the first direction to the sample holder in the second direction.

[0021] The first direction may be perpendicular to the second direction. Thus, the driver then moves in a direction which is orthogonal to the second direction, this helps to save space in the second direction and allows the overall system to be more compact.

[0022] The guide surface may be arranged at: at least 15 degrees; at least 30 degrees; at least 45 degrees; or at least 60 degrees to the first and / or second directions. The guide surface may be arranged at: no more than 75 degrees; no more than 60 degrees; no more than 45 degrees; or no more than 30 degrees, to the first and / or second directions. The guide surface is preferably arranged at 45 degrees to the first and / or second directions. Thus, the guide surface is not arranged at too much of an extreme angle to the first or second directions.

[0023] The guide surface may extend substantially in a plane containing the first and second directions. This helps to minimise the size of the system. The guide surface may extend over at least 10 mm, or at least 15 mm, or at least 20 mm in the second direction. The guide surface may extend over no more than 100 mm, no more than 50 mm or no more than 30 mm in the second direction. The guide surface may extend over at least 10 mm, or at least 15 mm, or at least 20 mm in the first direction. The guide surface may extend over no more than 100 mm, no more than 50 mm or no more than 30 mm in the first direction. The guide surface may be at an angle substantially mid-way between the first and second directions. This helps to ensure a 1:1 relationship between movement of the driver and movement of the sample holder.

[0024] The guide surface may be substantially straight. This helps to ensure that the relative of movement of sample holder in the second direction is always constant over the range of motion of the driver in the first direction. In addition, it helps ensure the first guide structure can smoothly move along the guide surface without getting stuck.

[0025] The support may be substantially planar. The support may comprise a support aperture configured to allow light to pass through the support to the sample. Where the system comprises two or more sample holders, a support aperture may be provided for each sample holder. The driver may rest on the support. The driver may be slidable on the support. Thus, the support facilitates more effective performance of the movement system.

[0026] The driver may comprise a drive rail extending in the first direction. The drive rail may extend along an edge of the sample holder. The drive rail may extend completely along an edge of the sample holder. The first or second guide structure may be provided in or on the drive rail. The first and second guide structures may couple the driver and sample holder together in at least two independent points, for example two independent points along the drive rail. There may be two or more drive rails. The two or more drive rails may be connected by one or more support bars. Preferably, two drive rails are provided joined at either end by a respective support bar. The driver may surround a sample holder in directions perpendicular to the second direction. The drive rails and support bars may together surround the sample holder. Thus, the drive rail facilitates more stable movement of the sample holder as it allows the driver and sample holder to couple together at multiple positions.

[0027] At least two sides of the sample holder may be independently coupled to the driver via the first and second guide structures. Opposite sides of the sample holder may be independently coupled to the driver via the first and second guide structures. First and second guide structures may be provided on at least two sides of the sample holder. First and second guide structures may be provided on opposite sides of the sample holder. Thus, the sample holder is better supported and movement is smoother as the guide structures act on multiple sides of the sample holder simultaneously. The sample holder may be independently coupled to the driver towards at least two ends of the sample holder. The sample holder may be rectangular when viewed along the second direction. The sample holder may be independently coupled to the driver towards at least two corners of the sample holder. Preferably, the sample holder may be independently coupled to the driver towards at least four corners, or every corner, of the sample holder. The driver may extend along two sides of the sample holder. A drive rail may be provided on either side of the sample holder. Each drive rail may be coupled to the sample holder in at least two places. Thus, the sample holder is best supported by the driver and guide structures to ensure accurate and stable movement in the second direction.

[0028] Where the first and second guide structures couple the driver to the sample holder at more than one location, a set of first and second guide structures may be provided at each location. Each set of first and second guide structures may be substantially identical. Thus, by providing multiple set of guide structures the movement of the sample is more stable and efficiently controlled.

[0029] The second guide structure may be provided by a drive slot. The guide surface may be provided by the drive slot. The first guide structure may comprise a drive pin receivable in the drive slot. The drive pin may extend in a direction different to the first and second directions. Preferably, the drive pin extends perpendicular to the first and second directions. Thus, the first and second guide structures may have a simple yet robust structure.

[0030] The second guide structure may be provided in, or on, the driver. The guide surface may be provided in, or on, the driver. The drive slot may be provided in the driver. The first guide structure may be provided in, or on, the sample holder. The drive pin may be provided on the sample holder. Thus, preferably, the driver comprises the second guide structure, this can be more suitable as the shape of the sample holder can be more limited as it needs to efficiently attach to the sample and so accommodation of a guide surface is more difficult.

[0031] The drive slot may have a width in a direction perpendicular to the guide surface. The drive slot having a minimum width of at least a diameter of the drive pin. The drive slot may have a maximum width of: at least 1.5 times; at least twice; or at least 3 times, the diameter of the drive pin. The drive slot may have a maximum width of: no more than 3 times; no more than twice; or no more than 1.5 times, the diameter of the drive pin. The drive slot may have a maximum width of at least twice the diameter of the drive pin. The diameter of the drive pin may of course be the width of the drive pin measured parallel to the width of the drive slot where the pin does not have a circular cross section. This Makes the system easier to construct and ensures the pin may move freely in the slot during use without unnecessary friction. In some embodiments, the drive slot width may be substantially the same as the drive pin diameter. Thus a guide path is provided.

[0032] The first / second guide structures may be arranged to permit movement of the driver in the first direction without causing movement of the sample holder in the second direction. The first guide structure may be detachable from the guide surface. The guide surface may provide an upper edge of the drive slot. The drive slot may provide a guide path. The drive slot may be generally triangular. An upper portion of the drive slot may be triangular. The guide surface may be provided by one side of the triangular drive slot. Preferably, the drive slot is a right-angled triangle. The guide surface may be provided by the hypotenuse. The position of the driver in the first direction may thus select a permitted movement range of the sample holder in the second direction. This helps facilitate using multiple samples of different heights because if the highest sample contacts the lid, the driver effectively detaches from its corresponding drive structure (moves into the middle of the slot), this allows the driver to continue moving and raising other shorter samples without the sample holder of the highest sample moving up further and jamming / damaging the sample / lid / system. Then in reverse, the first guide structure of the highest sample moves through the middle of the slot until the driver moves enough to select the sample holder height equivalent to the height of the sample, the first guide structure then contacts the guide surface and the sample is moved down. Furthermore, it enables easier construction as the area to insert the drive pin into the drive slot during construction is maximised without reducing the structural strength of the driver or making it unnecessarily larger.

[0033] The system may comprise a biasing device configured to urge the first and second guide structures into contact. The biasing device may act between the support and the sample holder. The biasing device may be configured to urge the sample holder away from the support, for example in the second direction. Where the system comprises a lid, the biasing device may be configured to urge the sample holder towards, and preferably into contact with, the lid. Where the system comprises a lid, the biasing device may be configured to urge the sample holder into sealing contact with the lid. The biasing device may be a spring, or any other suitable bias device such as an air cushion, hydraulic device, or other resiliently deformable material. A biasing device may be provided at a location corresponding to at least one place the sample holder and driver are coupled together. Preferably a biasing device is provided at a location corresponding to at least half of the places the sample holder and driver are coupled together, and most preferably, at every place the sample holder and driver are coupled together. This helps to ensure more stable operation of the sample holder as contact between the guide surface and first guide structure is maintained at all times.

[0034] Where the system comprises two or more sample holders, each sample holder may be independently biased. Thus, the system can accommodate samples / microplates with different heights as each sample holder is independently biased. For example, this makes it possible to mount plates of different height into the sample holder and then securely seal and move them without altering how the sample movement system is controlled as the independent biasing will passively / automatically ensure the plates are level.

[0035] The support may restrict movement of the sample holder in directions perpendicular to the second direction. The support may restrict movement of the sample holder relative to the support, preferably in the first direction or directions perpendicular to the second direction. The support may restrict movement of the sample holder in the first direction via an aperture and a retaining pin receivable in the aperture. The retaining pin may extend in the second direction. One of the aperture or retaining pin may be provided on the support, the other may be provided on the sample holder. Preferably, the retaining pin is provided on the support. The aperture may be provided on the sample holder. The retaining pin / aperture may be provided at any suitable position, for example centrally across a length of the sample holder. Thus, movement of the sample holder in the first direction is effectively restricted using an aperture and pin arrangement.

[0036] The driver may be mounted to the support. The driver may be mounted to the support via a moveable mounting that facilitates movement of the driver with respect to the support in the first direction. The driver may be mounted to the support at a point towards a middle of the sample holder in the first direction. The support may be configured to restrict movement of the driver in the second direction. The support may be arranged to engage an outside of the driver. The sample holder may be positioned on an inside of the driver. Thus, the support helps to control the driver’ s position and movement to ensure stable and reliable operation of the movement system, as well as ensuring it does not affect the coupling of the driver and sample holder.

[0037] The moveable mounting may comprise a mounting slot extending in the first direction. The moveable mounting may comprise a mounting arm receivable in the mounting slot. The mounting slot may be provided in the driver, for example in a drive rail. The mounting arm may extend in the second direction. The mounting arm may extend in an opposite side of the driver to the sample holder. The mounting arm may extend in the first direction. The mounting arm may extend in the first direction: at least 15%; or at least 25%, the length of the mounting slot in the first direction. The mounting arm may have a length in the first direction that is shorter than the length of the mounting slot, preferably by a distance corresponding to at least the maximum range of motion of the driver. Thus, the mounting arm extends in the first direction, this helps to ensure the driver is adequately supported and does not rotate during operation.

[0038] The second direction is preferably a vertical direction. The second direction is preferably parallel to a Z-direction, or Z-axis, of the imaging system or microscope. The Z- axis or Z-direction may be a vertical direction. The second direction may be perpendicular to a focal plane of the imaging system or microscope. The first direction may be a horizontal direction. The first direction may be parallel to the focal plane of the imaging system or microscope. The first direction may be parallel to an X-direction (X-axis) or Y-direction (Y-axis) of the imaging system or microscope. Thus, the movement system facilitates accurate and efficient control of movement in the Z-direction which is difficult due to the limited space available to fit the system onto a normal microscope.

[0039] The sample movement system may have a size in the second direction of: no more than 60 mm; no more than 50 mm; no more than 40 mm; no more than 30 mm; or, no more than 25 mm. Preferably, the sample movement system has a size in the second direction of no more than 30 mm, for example no more than 22 mm. This ensures it can fit into a regular microscope without unduly limiting the usability of the microscope.

[0040] The system may comprise a prime mover configured to cause the driver to move in the first direction. The prime mover may comprise a motor, for example an electric motor. The prime mover may comprise a stepper motor. The driver may be attached to the motor via a drive axle. The drive axle may be threaded. The drive axle may extend in the first direction. The drive axle may be connected to the driver via a drive aperture, for example a drive aperture in a support bar. The system may comprise a position sensor configured to identify the position of the sample holder and / or driver, this may be integrated into the prime mover. Thus, the system can more efficiently and quickly control movement of the driver using a motor and threaded drive axle. In addition, the system can effectively hold the driver / sample holder in one position as the motor can prevent rotation of the drive axle without needing to be energised. Of course, other means of moving the driver could be used, such as linear motors, hydraulic, pneumatic or piezoelectric actuators / motors. However, these may not be preferred if they need to be energised to maintain a certain position.

[0041] The system may comprise two or more sample holders, for example three or more, or four or more sample holders. Each sample holder may be coupled to the driver via the first and second guide structures. Preferably, at least one set of first and second guide structures is provided for each sample holder. The two or more sample holders may be provided in series. A drive rail may extend along the two or more sample holders. The two or more sample holders may be coupled to one another. Thus, the sample movement system can incorporate multiple sample holders efficiently.

[0042] The support may be configured to restrict movement of the two or more sample holders relative to the imaging stage in the first direction. Movement of the driver in the first direction may be translated into simultaneous movement of the two or more sample holders in the second direction. Thus, all the sample holders can move simultaneously using the same driver. This ensures that the sample is always raised and accessible for experimentation / processing, it also ensures all the sample holders are securely sealed against the lid which helps prevent sample deterioration.

[0043] The sample holder may be configured to attach to any suitable sample, for example a microplate. The microplate may comprise a plurality of sample wells, preferably arranged in a grid, for example an 8x12 grid. The microplate may have a length x width of about 127.8 mm x 85.5 mm. The sample holder may comprise a central aperture surrounded by a support flange. The support flange may extend about 10 mm perpendicular to the second direction. The microplate may be mountable on the support flange. Thus, a microplate or other microscopy sample may be easily mounted to the sample movement system.

[0044] Aspects of the invention also provide a lid comprising a passage for access to a sample through the lid. The passage thereby provides an access aperture in the lid. The lid may comprise a first side. The lid may comprise a second side. The passage may comprise an entrance. The entrance may be provided on the first side of the lid. The passage may comprise an exit. The exit may be provided on the second side of the lid. The passage may narrow from the entrance to the exit. The passage may comprise a ledge. The ledge may be provided between the entrance and exit. The passage may comprise a tapered portion. The tapered portion may extend from the ledge. The tapered portion may extend to the exit.

[0045] Thus, in a second aspect of the invention, there is provided a lid comprising a passage for access to a sample through the lid, wherein the lid comprises first and second sides, and the passage comprises an entrance and an exit on the first and second sides of the lid respectively, wherein the passage narrows from the entrance to the exit and comprises a ledge provided along the passage between the entrance and exit, and a tapered portion extending from the ledge to the exit.

[0046] Advantageously, the ledge is offset from the first side of the lid. Thus, the narrowing passage with ledge and tapered portion facilitates a reduction in size of the exit while maintaining good access through the passage because the passage is more open on the entrance side. This improves sample handling processes through the lid and allows better access to the bottom of sample wells through the lid. In addition, the passage ensures that the portion of the lid around the exit remains mechanically strong due to the two stages of a ledge then a tapered portion which facilitates a wider entrance without significant sacrifices in lid thickness. This works synergistically with the sample holders comprising multiple sample wells to facilitate access to one well, while securely sealing the surrounding wells to the underside of the lid around the exit. In particular, this enables better sample processing and longevity when used in combination with the sample movement system of the first aspect. The lid is thereby optimally suited for handling of samples for imaging with a microscope and crystallography experiments.

[0047] The lid may be for a sample access system. The lid may be for a sample movement system. The sample access system and / or sample movement system may be for an imaging system or imaging stage as described herein. Preferably, the lid may be for a sample movement system of the first aspect. This can help ensure that good access is provided to the sample and strong sealing action is achieved via the combined features of the lid and movement system.

[0048] The passage may be continuously narrowing from the entrance to the exit. The passage may not widen at any point when travelling from the entrance to the exit. Thus, this ensures good access and makes the lid easier to manufacture.

[0049] An axis of the passage, P axis, may be defined as extending substantially through the passage from the entrance to the exit. The P axis may be perpendicular to a plane of the exit. The plane of the exit may be parallel to the second side of the lid around the exit. The P axis may be perpendicular to a plane of the entrance. The plane of the entrance may be parallel to the first side of the lid around the entrance. Thus, the passage provides axis directly through the lid which makes sample handling easier.

[0050] The P axis may extend through a centre of the exit. The P axis may extend through a centre of the entrance. The passage may be linear. That is, the passage may extend in a straight line between the entrance and exit. Thus, there are no significant curves or bends in the passage that need to be navigated which makes access easier and reduces manufacturing complexity.

[0051] The exit may be sized / shaped to correspond to the size and / or shape of a container which contains the sample. The exit may be at least as large as the container. The container size may be defined by a container width. The exit may provide an opening defined by an exit width. The exit width may be the minimum distance across the exit from one side to the other, and preferably through the centre of the exit. The exit width may be at least 1.5 times, at least 2 times, or at least 3 times larger than the container. The exit width may be no more than 4 times, no more than 3 times, or no more than 2 times larger than the container. Preferably, the exit width is about 2 times larger than the container. The exit width may be at least 4 mm, at least 6 mm or at least 8 mm. The exit width may be no more than 12 mm, no more than 10 mm or no more than 8 mm. The exit may be any suitable shape, preferably, the exit is substantially circular. Where the exit is circular, the exit width may define a diameter of the exit. Thus, the exit is suitably sized to allow access to samples provided in microplates. The lid may have a thickness measured between the first and second sides. The lid thickness may be about 6 mm. The lid may have a minimum thickness around an edge of the exit. The minimum thickness of the lid may be no more than 50%, no more than 25% or no more than 10% the thickness of the lid between its first and second sides. The minimum thickness of the lid is preferably about 10% the thickness of the lid between its first and second sides. The minimum thickness of the lid may be no more than 2 mm, no more than 1 mm, or no more than 0.5 mm. The minimum thickness of the lid may be at least 0.1 mm, at least 0.25 mm, or at least 0.5 mm. The minimum thickness of the lid is preferably about 0.5 mm. This ensures the sample can be easily accessed through the passage as the area of the lid around the exit is very thin.

[0052] The entrance may be shaped to correspond to the shape of exit. The entrance may provide an opening defined by an entrance width. The entrance width may be the minimum distance across the entrance from one side to the other, and preferably through the centre of the entrance. The entrance width may be at least 4 times, at least 6 times, at least 8 times or at least 10 times larger than the exit width. The entrance width may be no more than 20 times, no more than 15 times or no more than 10 times larger than the exit width. The entrance width is preferably 10 times larger than the exit, for example 80 mm. The entrance may be any suitable shape, preferably, the entrance is substantially circular. Where the entrance is circular, the entrance width may define a diameter of the entrance. Thus, the entrance is suitably sized to allow easy access via the passage.

[0053] The entrance may be overlapping with the exit. The entrance may be aligned with respect to the exit. The entrance may be centred over the exit. Thus, this ensures the passage provides easy access therethrough.

[0054] The lid may be substantially planar. The first side may be substantially flat. The second side may be substantially flat. This assists in simple manufacture and also making the lid more easy to use, as it can more efficiently seal against multiple sample containers where they are provided at the same height and also provides easier access through the entrance of the passage.

[0055] The tapered portion may span at least a third of the thickness of the lid. The tapered portion may span at least half the thickness of the lid. The tapered portion may span no more than three quarters the thickness of the lid. The tapered portion may span no more than half the thickness of the lid. Preferably, the tapered portion spans about half the thickness of the lid, or about 3 mm. This ensures the lid remains sufficiently rigid and strong immediately around the tapered portion, such as in register with the ledge, for sealing against sample containers as described below.

[0056] The tapered portion may be annular. The tapered portion may extend around the exit a given arc length. The tapered portion may surround at least half the exit. Preferably, the tapered portion surrounds the whole exit. This facilitates better access at any angle through the passage.

[0057] The tapered portion may define an exit field of view from the exit towards the entrance. The exit field of view may cover a solid angle defined by exit lines drawn from the centre of the exit through the passage and out of the entrance. The exit lines may be lines which maximises an angle between the exit line and P axis without contacting the tapered portion. The exit lines may be at an angle of at least 45 degrees, at least 50 degrees or at least 60 degrees with respect to the P axis. The exit lines may be at an angle of no more than 80 degrees, no more than 70 degrees or no more than 60 degrees with respect to the P axis. The exit lines may be at an angle of about 60 degrees with respect to the P axis. The exit lines may define a solid angle (or exit field of view) of at least 2 sr, or at least 2.5 sr, or at least 3 sr. The exit field of view may be centred on the P axis. Thus, the tapered portion provides a sufficiently wide field of view from the exit to allow easy access thereto.

[0058] The tapered portion may be angled with respect to the P axis. The tapered portion may be at an angle of at least 45 degrees, at least 50 degrees or at least 60 degrees with respect to the P axis. The tapered portion may be at an angle of at least 45 degrees, at least 50 degrees or at least 60 degrees with respect to the P axis. The tapered portion may be at substantially the same angle as the exit lines. The tapered portion may be frustoconical. The tapered portion may have substantially flat walls. Thus, the tapered portion provides a convenient shape to allow access to the exit and is easy to manufacture. Of course, in other variants, the tapered portion may have curved, undulating and / or stepped walls. The tapered portion may still nonetheless have a substantially tapered shape and provide the advantages of the invention as set out above.

[0059] The tapered portion may extend over at least 5%, at least 10% or at least 15% of the distance from the exit to the entrance in directions perpendicular to the P axis. The tapered portion may extend over no more than 30%, no more than 20% or no more than 15% of the distance from the exit to the entrance in directions perpendicular to the P axis. The tapered portion may extend over about 15% of the distance from the exit to the entrance in directions perpendicular to the P axis.

[0060] The ledge may be annular. The ledge may extend around the tapered portion a given arc length. The ledge may extend around the tapered portion the same arc length that the tapered portion extends around the exit. The ledge may surround at least half the tapered portion. Preferably, the ledge surrounds the whole tapered portion. This facilitates better access at any angle through the passage.

[0061] The ledge may form a ledge aperture in the passage where it meets the tapered portion. The ledge may define a ledge field of view from the ledge aperture towards the entrance. The ledge field of view may cover a solid angle defined by ledge lines extending from a centre of ledge aperture to and out of the entrance. The ledge lines may not otherwise contact the ledge / passage. The ledge lines may be lines which maximises an angle between the ledge line and P axis without contacting the ledge and / or passage and / or entrance. The ledge lines may be at an angle of at least 60 degrees, at least 70 degrees or at least 80 degrees with respect to the P axis. The ledge lines may be at an angle of about 85 degrees with respect to the P axis. The ledge lines may define a solid angle of at least 4 sr, or at least 5 sr, or at least 5.5 sr. Thus, the ledge provides a very wide field of view from the ledge to the exit to allow excellent access to the tapered portion and then on into the sample.

[0062] The ledge aperture may provide an opening along the passage where the ledge meets the tapered portion. The ledge aperture may provide an opening defined by a ledge aperture width. The ledge aperture is preferably provided about halfway through the passage from the entrance to the exit. The ledge aperture width may be the minimum distance across the ledge aperture from one side to the other, and preferably through the centre of the ledge aperture. The ledge aperture width may be at least 1.5 times, or at least 2 times larger than the exit width. The ledge aperture width may be about twice the exit width, for example 19 mm. The ledge aperture may be any suitable shape, preferably, the ledge aperture is substantially circular. Where the ledge aperture is circular, the ledge aperture width may define a diameter of the ledge aperture. The ledge aperture may be centred with respect to the exit. Thus, the ledge and tapered portion are suitably sized to allow easy access via the passage.

[0063] A tubular portion may extend between the entrance and the ledge, preferably completely between the entrance and the ledge. The tubular portion may only extend in directions parallel to the P axis. The tubular portion may extend over at least 10%, at least 20% or at least a third of the lid thickness. The tubular portion may extend over no more than 50%, no more than 40% or no more than a third of the lid thickness. The tubular portion may extend over about a third of the lid thickness. The tubular portion may be cylindrical.

[0064] The ledge may extend in a direction perpendicular to the P axis between the entrance and the tapered portion. Preferably, in directions perpendicular to the P axis, the ledge extends completely between the entrance and tapered portion. The ledge may extend at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the distance from the exit to the entrance in directions perpendicular to the P axis. The ledge may extend no more than 95% or no more than 90% of the distance from the exit to the entrance in directions perpendicular to the P axis. Preferably, the ledge extends about 90% of the distance from the exit to the entrance in directions perpendicular to the P axis. The ledge may extend further than the tapered portion in directions perpendicular to the P axis. Thus, the ledge provides the majority of the narrowing of the passage. This helps ensure the passage narrows in a way which maintains its strength.

[0065] The ledge may extend in a direction parallel to the P axis. The ledge may have a ledge thickness defined as the distance the ledge extends parallel to the P axis. The ledge thickness may be at least 10% , or at least 15% the lid thickness. The ledge thickness may be no more than 25%, or no more than 20% the lid thickness. Preferably the ledge thickness is about one sixth the lid thickness. Thus, the ledge extends across and optionally along the passage. This helps to provide enhanced access and control rigidity of the lid in the ledge region.

[0066] The ledge may comprise a stepped profile. The ledge may comprise at least two steps. The ledge may be (otherwise) substantially planar. The ledge may comprise first and second ledges offset from one another along the passage. The second ledge may be provided between the entrance / tubular portion and the first ledge. The tapered portion may extend from the first ledge to the exit. Thus, by providing first and second ledges the passage can be further tailored to provide better control of lid rigidity and sample access.

[0067] The first ledge may be provided at a point at least 40%, or at least 50% of the way from the entrance to the exit along the passage. The first ledge may be provided at a point no more than 60%, or no more than 50% of the way from the exit to the entrance along the passage. Preferably, the first ledge is provided about halfway along the passage. The second ledge may be provided at a point at least 20%, or at least a third of the way from the entrance to the exit along the passage. The second ledge may be provided at a point at least 50%, or at least two thirds of the way from the exit to the entrance along the passage. Preferably, the second ledge is provided about a third of the way along the passage from the entrance to the exit. Thus, the effective thickness of the lid in regions covered by the second ledge is about two thirds the lid thickness.

[0068] The first ledge may be annular. The second ledge may be annular. The first ledge may extend around the tapered portion. The second ledge may extend around the first ledge. The first ledge may extend a majority of the way from the tapered portion to the entrance in directions perpendicular to the P axis, preferably at least 60%, or at least two thirds of the way. The first ledge may extend about two thirds of the way from the tapered portion to the entrance in directions perpendicular to the P axis. The second ledge may extend a minority of the way from the entrance to the tapered portion in directions perpendicular to the P axis, preferably no more than 40%, or no more than a third of the way. The second ledge may extend about a third of the way from the tapered portion to the entrance in directions perpendicular to the P axis. The first and second ledge together may extend completely between the tapered portion and entrance in directions perpendicular to the P axis. Thus, the first ledge provides a region of enhanced access to the exit, while the second ledge ensures lid rigidity is maintained further from the exit.

[0069] The first ledge may be substantially planar. The first ledge may be substantially parallel to the first and / or second sides of the lid. The second ledge may be substantially planar. The second ledge may be substantially parallel to the first and / or second sides of the lid. A chamfered portion may be provided between the first and second ledges. The chamfered portion may extend from the first ledge to the second ledge. The chamfered portion may be provided at an angle of at least 30 degrees, at least 40 degrees or at least 45 degrees to the P axis. The chamfered portion may be provided at an angle of no more than 60 degrees, no more than 50 degrees or no more than 45 degrees to the P axis. The chamfered portion may be angled at about 45 degrees to the P axis. Thus, planar ledges and the chamfered portion each provide enhanced access and ease of use, as well as simpler manufacture of the lid / passage.

[0070] The lid may extend away from the entrance by a distance that is at least the entrance width. On at least two sides of the entrance, the lid may extend away from the entrance by a distance of at least the entrance width. On at least three sides of the entrance, the lid may extend away from the entrance by a distance of at least the entrance width. The lid may be substantially flat on its second side in register with the entrance. This ensures the lid adequately covers larger samples or sample arrays and that it can effectively seal against samples not being accessed via the passage.

[0071] The lid may be constructed from a transparent or translucent material. The lid may be constructed from glass. The lid may be constructed from a hard plastics material, such as an acrylic material. Thus, the lid is simple to construct and allows light to pass through which enables visualisation of samples under the lid.

[0072] In a third aspect of the invention, there is provided a sample access system comprising a lid according to the second aspect and a sample holder.

[0073] The sample holder may comprise a plurality of containers. Each of the plurality of containers may be configured to hold a sample. The passage may be configured to provide access to one or more of the containers, for example a first container of the plurality of containers. The passage may be configured to provide access to only the first container at one time. The lid may be configured to obscure a second container while providing access to the first container. The lid may be configured to obscure all of the containers not being the first container while providing access to the first container. Thus, the lid assists in ensuring a sample may be access but that samples in other containers are also protected / obscured by the lid.

[0074] The lid may be configured to seal against one or more of the plurality of containers. The lid may be configured to seal against the second container. The lid may be configured to seal against one or more containers that are not the first container. The lid may be configured to seal against one or more, or preferably all, containers that are completely covered by the lid. Containers at least partially in register with the exit may not be completely covered by the lid. The second side of the lid may be shaped to seal against one or more containers. Preferably, the lid seals against one or more containers while access is provided to the first container. Thus, the lid ensures other containers are sealed which reduces risk of sample contamination and deterioration, for example through evaporation.

[0075] The plurality of containers may be arranged side by side. The plurality of containers may be at substantially the same height. The plurality of containers may be arranged in an array. Preferably at least 50 containers are arranged in the array, for example 384 containers may be provided. For example for a 96 well microplate where each well comprises 4 containers. The array may be a rectangular array. The array may have a regular periodic grid spacing. A grid spacing may be defined as the distance between the centres of two adjacent containers. The grid spacing may include both the width of the container (or other node in an array) and the separation of containers (or nodes). The grid spacing may alternate between a first spacing and a second spacing. The first spacing may be smaller than the second spacing, for example about 10% to 20% smaller. The first spacing may be about 3.5 mm to about 3.8 mm. The second spacing may be about 4.2 to about 4.5 mm. The exit may be sized such that it spans no more than three adjacent containers. This helps ensure efficient packing of containers while also maintaining sample quality and avoiding sample deterioration.

[0076] The plurality of containers may be arranged in a series of sub arrays. Each sub array may comprise a 2x2 grid of adjacent containers. Each sub array may comprise a rectangular array of containers, or a substantially square array of containers. The containers in a sub array may have substantially constant grid spacing. The containers in the sub array may have a spacing equal to the first spacing. Preferably, the sample holder may comprise 48 sub arrays, or 96 sub arrays. The sample holder may comprise a multi-well microplate. Each sub array may correspond to a well of a microplate.

[0077] The series of sub arrays may be arranged in a grid to form the array of the plurality of containers. The sub array grid may be a regular grid. The sub array grid may have a constant grid spacing. The sub array grid spacing may be equal to the first spacing added to the second spacing. The exit width may be no more than the sub array grid spacing. The sub array grid spacing may be about 8 mm. The sub array grid may be rectangular.

[0078] Each container may have a size defined by a container width. The exit may be sized so that no more than three, or preferably no more than two, containers may fit completely within the exit. The exit may be sized so that only one container may fit completely within the exit. This ensures that good access is provided to one container while the remainder are at least partially sealed / obscured by the lid.

[0079] Each container may be sized with a storage volume depending on its size and depth. Typically, each container may have a storage volume of no more than 1 ml, no more than 0.1 ml, no more than 10 pl, no more than 1 pl, or no more than 0.1 pl. Thus, the containers are a suitable size for crystal growth, processing and analysis.

[0080] In a broad aspect, the invention concerns an imaging stage for holding a sample. The imaging stage may be a microscope stage. The imaging stage may have any one or more features of the microscope stage as outlined below. Generally, wherever a microscope is referred to herein, the invention may equally apply to other imaging systems or mounts whether a microscope or not. In one example, there is provided an imaging stage comprising the sample movement system of the first aspect. The imaging stage preferably may comprise a base configured to hold the sample movement system such that the sample may be imaged. The imaging stage preferably may comprise a lid provided over the sample movement system. The imaging stage may comprise the sample access system of the third aspect. The imaging stage may comprise the lid of the second aspect. Thus, the different aspects of the invention can be selectively used to form an imaging stage with improved sample handling and access performance.

[0081] In a fourth aspect of the invention, there is provided an imaging stage comprising the sample movement system of the first aspect above, lid of the second aspect above, or sample access system of the third aspect above, or any of these as described in general / broad terms herein. Of course, mentions of the sample movement system may also apply to the sample access system. Preferably, the imaging stage may be a microscope stage.

[0082] The imaging stage may comprise a base. The base may be configured to hold the sample movement system such that the sample may be imaged. The base may be attachable to a microscope or other imaging system. The base may be free-standing. The base may be configured to stand on a table or floor. The base may be configured to fit over a microscope or other imaging system, for example over an illuminator of the microscope. The base may comprise a base aperture configured to allow light to pass through the base towards the sample. The base aperture may have a diameter of about 100 mm. The base may comprise a plurality of legs. The legs may support the base. The leg height may be adjustable. The legs may comprise feet. Thus, the stage is conveniently supported by the base.

[0083] The imaging stage may comprise a translator. The sample movement system may be mounted to the base via the translator. The translator may be configured to move the sample movement system relative to the base. The translator may be configured to move the sample movement system relative to the base in a direction different to the second direction, and preferably perpendicular to the second direction. The translator may be configured to move the sample movement system in an X-Y plane such as the microscope X-Y plane. Thus, the sample may be efficiently moved in directions perpendicular to the second direction by the translator to view different parts of the sample with the microscope. In addition, as the sample movement system is mounted on the translator, it can move the sample while X-Y movement happens simultaneously. This can reduce sample movement times and reduce risk of damage to the sample and smearing on the lid.

[0084] The translator may comprise one or more rails, preferably two rails. The one or more rails may extend in a direction of movement facilitated by the translator. The sample movement system may be mounted to the one or more rails. The translator may comprise a prime mover configured to move the sample movement system along the one or more rails. The prime mover may comprise a motor. The motor may be connected to a threaded translation axle extending parallel to the one or more rails. The motor may be directly connected to the translation axle. Of course, indirect attachment of the motor to the axle can also be facilitated if necessary. The drive unit may be attached to the sample movement system. Thus, the motor can turn the threaded translation axle and move the sample movement system along the rails via the drive unit.

[0085] The imaging stage may comprise two translators mounted to one another, preferably arranged at orthogonal angles. The imaging stage may comprise an X-translator configured to move the sample movement system in the X-direction. The imaging stage may comprise an Y-translator configured to move the sample movement system in the Y-direction. The sample movement system may be mounted to one of the X-translator or Y-translator. The other of the Y- or X-translator may be mounted to the base. The X- or Y- translator supporting the sample movement system may be mounted to the base via the other of the Y- or X- translator. The X- and Y- translators may be mounted to one another via a support plate. The support plate may comprise a support plate aperture to allow light to pass through the support plate to the sample. Thus, the sample movement system is efficiently mounted to the base and the imaging stage can move the sample in three dimensions.

[0086] The imaging stage may comprise a lid, for example the lid of the second aspect above. The lid may be attached to the base. The lid may be mounted directly to the base. The lid may be fixed relative to the microscope or other imaging system. The lid may be provided over the sample movement system. The imaging stage may comprise a sample movement system configured to move the sample holder into sealing contact with the lid. The driver may be moveable to cause the sample holder to move into sealing contact with the lid. The lid may comprise an access aperture, for example provided by the passage of the second aspect. A field of view of the imaging system (e.g. microscope) may be within the access aperture. The access aperture may allow a part of the sample to be accessed. The access aperture may correspond to the size of a sample well. Thus, the lid and access aperture protect the sample during processing while allowing a single sample well to be easily accessed. Of course, multiple access apertures can be provided if needed.

[0087] According to a fifth aspect of the present invention, there is provided an imaging system comprising the sample movement system of the first aspect and / or the lid of the second aspect and / or the sample access system of the third aspect and / or the imaging stage of the fourth aspect.

[0088] The imaging system is preferably a microscope. In such embodiments, the microscope preferably comprises an imaging stage of the fourth aspect, wherein the imaging stage is a microscope stage.

[0089] The sample movement system, lid, sample access system, imaging stage and imaging system of the first to fifth aspects may of course include any one or more features of one another, whether optional or otherwise. The microscope may be an optical microscope. Of course, the microscope could also be another type of microscope. The microscope may be a bright- field microscope. The microscope may comprise an illuminator. The microscope may comprise an objective lens. The objective lens may be provided on a rotating turret. The microscope may comprise an arm. The arm may be configured to mount the objective lens above the illuminator. The microscope may comprise an eyepiece. The microscope may comprise a camera. The microscope may comprise a focus wheel.

[0090] The microscope stage may be configured to hold the sample in a focal plane of the microscope. The microscope stage may be configured to hold the sample above the illuminator. The microscope stage may be configured to hold the sample in the field of view of the objective lens.

[0091] According to a sixth aspect of the present invention, there is provided a method of adjusting the position of a sample on an imaging stage, wherein the sample is mounted in a sample holder, wherein the sample holder is coupled to a driver via first and second guide structures, the second guide structure comprising a guide surface, the method comprising: restricting movement of the sample holder in a first direction relative to the imaging stage; and moving the driver in the first direction to cause the first guide structure to contact the guide surface and translate movement of the driver in the first direction into movement of the sample holder in a second direction different to the first direction.

[0092] The method of the sixth aspect may be a method of using a sample movement system of the first aspect or as described in broad terms / generally herein, or a method of using an imaging stage of the fourth aspect, or an imaging system of the fifth aspect.

[0093] According to a seventh aspect of the present invention, there is provided a method of providing access to a sample, the method comprising providing a lid according to the second aspect, and covering the sample with the lid such that the sample may be accessed through the passage.

[0094] The method may comprise providing a sample in a first container of a plurality of containers. The method may comprise aligning the first container with the passage. The method may comprise sealing one or more of the containers not being the first container against the second side of the lid. The methods of the sixth and seventh aspects may include any one or more features of the first to fifth aspects optional or otherwise, as well as the features of one another.

[0095] The aspects described above may also be used in conjunction with a sample manipulation tool. This can allow more controlled and efficient sample manipulation and handling. The sample manipulation tool may be robotic, for example it may be a robotic arm. The sample manipulation tool may be automated, semi- automated or manually controlled. Suitable tools include robotic arms or other sample handling equipment. In some examples, the sample manipulation tool may comprise a tweezer, pipette, suction tube, syringe, or a stirrer, etc. The sample manipulation tool may be configured to process or otherwise manipulate the sample. In one example, the invention provides a system comprising the sample movement system of the first aspect and a sample manipulation tool arranged to manipulate the sample. In another example, the invention provides a system comprising the sample access system of the third aspect and a sample manipulation tool arranged to manipulate the sample through the passageway of the lid. This can beneficially improve access to the sample as it becomes more convenient and better controlled while minimising sample damage due to effects like evaporation. The features of the sample manipulation tool may of course apply or be combined with any aspect and any of the optional features of the aspects described above.

[0096] Detailed Description of the Invention

[0097] In order that the invention may be more clearly understood one or more embodiments thereof will now be described, by way of example only, with reference to the accompanying drawings, of which:

[0098] Figure 1 is a side plan view of a microscope and microscope stage;

[0099] Figure 2 is a top plan view of the microscope stage of Figure 1 ;

[0100] Figures 3A-C are top plan views of the sample movement system of the microscope stage of Figure 1 during movement;

[0101] Figures 4A-C are sectional views along line A-A of Figure 2 of the sample movement system of the microscope stage of Figure 1 during movement; Figure 5A-C are sectional views along line B-B of Figure 2 of the sample movement system of the microscope stage of Figure 1 during movement;

[0102] Figure 6 a perspective view of the passage of the lid of the microscope stage of Figure 1;

[0103] Figure 7 a perspective cross-sectional view of the lid of the microscope stage of Figure 1 along line C-C of Figure 6;

[0104] Figure 8 a side cross-sectional view of the lid of the microscope stage of Figure 1 along line C-C of Figure 6;

[0105] Figure 9 a side cross-sectional view of the detail section D shown in Figure 8; and

[0106] Figure 10 a plan view of a plurality of containers held in the sample holder of the microscope stage of Figure 1.

[0107] Referring to Figures 1 to 5C, a microscope 1 and a microscope stage 100 are shown. In this embodiment, both the microscope 1 and microscope stage 100 are free-standing and configured to be placed on suitable surface, such as an optical table or laboratory bench (not shown). The microscope 1 is a standard bright field microscope and comprises an illuminator 2 to illuminate a sample 10, an objective lens 3 held above the sample 10 by an arm 4, and an eyepiece 5 to view the sample through the objective lens 3. The position of the lens 3 and eyepiece 5 can be adjusted using a focus wheel 6 positioned on the arm. In this embodiment, the objective lens 3 is provided on a rotating turret 7 which allows different lenses to be selected. In this embodiment, the sample 10 comprises a protein crystal for x-ray crystallography experiments immersed in a liquid. Of course, in other embodiments, many other types of sample may be used.

[0108] Of course, in other embodiments, the microscope may be of a different type or comprise other features, for example, a camera may be arranged to record images or video of the sample through the objective lens or provide a live video feed to a computer. In addition, the microscope or stage may comprise various other modifications, such as custom optics and illumination specific to a certain application. Equally, the invention may apply to imaging stages and systems generally whether microscopes or not. The features of the invention thereby may apply more generally to sample access and handling systems irrespective of how the sample is imaged or viewed. For example, the invention may also be used in circumstances where non-optical imaging is used.

[0109] In this embodiment, the microscope stage 100 is configured to hold the sample 10 in a position so that it can be imaged using the microscope 1. The stage 100 comprises a base 101 supported by four legs 102. The base 101 is rectangular with a leg 102 provided at each corner of the base 101. In this embodiment, the legs 102 simply comprise poles that extend through holes in the base 101. The legs 102 can be fixed at different positions in the holes which allows the height of the base 101 to be adjusted to fit different microscopes. The legs 102 also comprise feet 103 which provide additional stability to the microscope stage 100 and prevent it from slipping.

[0110] The microscope stage 100 further comprises a lid 104 mounted to the base and provided over the sample 10. The lid 104 is configured to protect the sample 10 and the rest of the components of the base 101 during use. The lid 104 comprises an access aperture 200. The access aperture 200 is provided at a position corresponding to the microscope 1 field of view through the objective lens 3. Thus, the access aperture 200 ensures the image of the sample 10 is not obscured by the lid 104. In addition, the access aperture 200 is sized to allow access to the sample 10 as described further below in relation to Figures 6-10. In this embodiment, the microscope stage 100 is configured to support a microplate 20 comprising an 8x12 grid of sample wells including a first sample well 22, and a plurality of other sample wells 23. The microplate 20 is therefore a 96 well microplate as is common in the art, and each well may hold, for example, about 0.2 ml of liquid containing the sample 10. In this embodiment, the sample 10 is provided in a first sample well 22 and the access aperture 200 is sized to allow access to one sample well, e.g. the first sample well 22. Thus, the other sample wells 23 are protected by the lid 104.

[0111] In this embodiment, the sample 10 is mounted to the base 101 via an X-translator 110, Y-translator 120 and sample movement system 130 (SMS) as described below.

[0112] In this embodiment, the base 101 is supported over the illuminator 2 of the microscope 1 by the legs 102 such that the sample 10 and access aperture 200 are positioned in the microscope 1 field of view. The base 101 is a rigid planar sheet of material, for example a sheet of metal such as aluminium. The base 101 comprises a base aperture 101a in a position corresponding to the illuminator 2, this allows light to pass through the base 101 towards the sample 10. As the base 101 itself is not moveable relative to the microscope 1, the base aperture 101a can be sized just large enough to let enough light through, for example it may have a diameter of 100 mm, and thereby minimise unwanted light and reflections from reaching the sample 10.

[0113] In this embodiment, the sample 10 is moveable in three dimensions via the X- translator 110, Y-translator 120 and SMS 130. The X-translator 110 and Y-translator 120 facilitate movement of the sample 10 in X- and Y- directions respectively, that is directions parallel to the focal plane of the microscope 1, or in the X-Y plane.

[0114] In this embodiment, the X-translator 110 comprises a pair of rails 111 fixed to the base 101 and extending in parallel along the base 101 in the X-direction. A support plate 106 is mounted to the rails 111 via four rail grippers 112, two grippers 112 are provided on each rail 111 at either end of the support plate 106 along the rail 111. The rail grippers 112 are shaped to enclose the rail 111 such that they cannot be lifted off the rail but can move along the rail 111 in the X-direction, as described below. The rail grippers 112 thereby enable stable mounting of the support plate 106 to the base 101 in a way which allows it to move in the X-direction.

[0115] The X-translator 110 further comprises a translation axle 113 mounted to the base 101 by brackets 115 provided at either end of the axle 113. The translation axle 113 is a threaded axle extending parallel to the rails 111. In this embodiment, the X-translator 110 comprises a prime mover in the form of a translation motor 114 that is fixed to the base 101 and directly connected to the translation axle 113. A drive unit 116 is provided on the support plate 106 and the translation axle 113 extends through an aperture (not shown) in the drive unit 116 which engages the thread of the translation axle 113. In this embodiment, the translation motor 114 is arranged to turn the threaded translation axle 113, this generates a force in the X-direction between the support plate 106 and base 101 causing movement of the support plate 106 along the rails 111.

[0116] In this embodiment, the support plate 106 comprises a support plate aperture 106a. This is provided in the support plate 106 to allow light to pass through the support plate 106 towards the sample 10. The support plate aperture 106a is large enough to let sufficient light through irrespective of the position of the sample 10 as translated on the X-translator 110 and Y-translator 120. Thus, as the support plate aperture 106a must align with both the base aperture 101a and sample 10, the support plate aperture 106a is fairly large and covers all regions accessible by the sample 10 via the X- and Y- translators 110, 120.

[0117] In this embodiment, the Y-translator 120 is constructed in the same way as the X- translator 110 so like numerals are used for corresponding features and only the differences are described. The main differences are that: the rails 121 and translation axle 123 extend in the Y-direction; and the Y-translator 120 rails 121 are provided on the support plate 106 and a support 131 of the SMS 130 is mounted to the rails 121 of the Y-translator.

[0118] In this embodiment, as shown in Figures 4A-5C, the rails 121 have a recess 121a provided along their length on either side. The rail grippers 122 have a corresponding protrusion 122a extending along their length that is received in the recess 121a. Thus, the grippers 122 can move along the rails 121 but can’t be removed / lifted off due to the recess 121a and protrusion 122a. The rails 111 and rail grippers 112 of the X-translator also have similar recesses and protrusions (not shown).

[0119] In this embodiment, referring to Figures 3A-5C in particular, the SMS 130 is mounted to the Y-translator 120 as described above. The SMS 130 facilitates movement of the sample 10 in the Z-direction, that is in a direction perpendicular to the X- and Y- directions, and perpendicular to the focal plane of the microscope 1.

[0120] In this embodiment, the SMS 130 comprises a support 131 that is planar and facilitates the attachment of two microplates 20 to the SMS 130. The microplates 20 are arranged in series along the X-direction, and the support 131 extends under both of them. At positions corresponding to the sample wells 22, 23 of each microplate 20, the support 131 comprises a support aperture 131a. Each support aperture 131a is configured to allow light to pass through the support 131 to a respective microplate 20 when it is being imaged.

[0121] In this embodiment, the SMS 130 comprises a sample holder 132 corresponding to each microplate 20. Each sample holder 132 is annular with an internal shape that corresponds to the outer perimeter of the sample it holds, so in this embodiment, the sample holder 132 is rectangular to match the microplate 20. Each 96 well microplate being of standard dimensions of about 127.8 mm x 85.5 mm. Each sample holder 132 comprises a support flange 133 that extends inwards and allows a microplate to be placed in the sample holder 132 resting on the flange 133, for example, the flange may extend in about 10 mm, e.g. 12 mm. Thus, the sample can be easily fitted to the SMS 130 via a sample holder 132, in addition, the flange 133 ensures that sufficient light can pass through the sample holder 132 to allow the sample 10 to be imaged.

[0122] Each sample holder 132 is mounted to the support 131 by a biasing device in the form of four springs 134 each arranged near a respective comer of the sample holder 132. In this embodiment, the spring 134 are configured to urge the sample holder 132 upwards away from the support 131, but in other embodiments they could pull the sample holder 132 down.

[0123] In this embodiment, the support 131 is configured to restrict movement of the sample holder 132 with respect to the rest of the support 131 and the rest of the microscope stage 100 in the X- and Y-directions. The support 131 comprises a retaining pin 135 provided on either side midway along the long sides (length) of each sample holder 132. Each sample holder 132 comprises apertures 136 configured to receive a corresponding retaining pin 135. The retaining pins 135 extend in the Z-direction and thus when received in the apertures 136 restrict movement of the sample holder 132 in the X- and Y- directions but not in the Z- direction.

[0124] In this embodiment, the SMS 130 comprises a driver in the form of two drive rails 137 extending in the X-direction and provided either side of the sample holders 132. In this embodiment, the drive rails 137 are about 340 mm long, but in other embodiments, their length may be different depending on the size and number of sample holders moved by the SMS 130. The drive rails 137 are connected at either end by support bars 138, the drive rails 137 and support bars 138 thereby form a rectangular ring around the sample holders 132. Of course, in other embodiments, the drive rails and support bars may be arranged differently, for example a support bar may be provided between adjacent sample holders. The support bars 138 thus provide structural support for the drive rails 137 and also mechanically couple them together.

[0125] In this embodiment, the two drive rails 137 rest on the support 131 and are slidable along the support in the X-direction as described below. The drive rails 137 are also mounted to the support 131 via a moveable mounting in the form of a mounting slot 139 provided in the drive rails 137 and extending in the X-direction and mounting arms 140. The support 131 comprises the mounting arms 140, which extend from the support 131 and are received in a corresponding mounting slot 139. A mounting slot 139 and corresponding mounting arm 140 are provided on either side of each sample holder 132. So in this embodiment, there are four mounting slots 139 and four mounting arms 140. In this embodiment, each mounting slot 139 extends about 80 mm along a drive rail 137, and each mounting arm 140 is about 25% the length of the corresponding mounting slot 139.

[0126] In this embodiment, the mounting arm 140 are provided on an outside of the drive rails 137 with the sample holders 132 between the rails 137. This helps to ensure the rails 137 can more closely fit against the sample holders 132 and also that the mounting arms 140 can better prevent movement of the drive rails in the Y- and Z- directions.

[0127] In this embodiment, the drive rails 137 are coupled to the sample holders 132 via first and second guide structures. The first guide structure is provided by a drive pin 141 extending out from the side of each sample holder 132 in the Y-direction. The second guide structure is provided by a drive slot 142 in each drive rail 137 and which receives a corresponding drive pin 141. A corresponding pin 141 and slot 142 thereby form a set. In this embodiment, there are four sets of drive pins and slots 141, 142 for each sample holder 132, with a set being provided towards each corner of the sample holder 132.

[0128] In this embodiment, each drive slot 142 is triangular with a right-angled triangle shape. The slot 142 has two edges (approx. 20 mm in length) parallel to the X- and Z- directions respectively connected by a hypotenuse 143. The slot 142 is arranged with the hypotenuse 143 defining the upper edge of the slot 142, a flat bottom edge parallel to the X- direction and the other side connecting vertically. The slot 142 spans the entire height of the drive rail 137 in the Z-direction (about 20 mm) with the hypotenuse 143 arranged at a 45 degree angle to the X- and Z- directions.

[0129] Each drive slot 142 has a width defined perpendicular to the hypotenuse 143. The width is approximately double the diameter of the pin 141 at its widest point corresponding to the middle of the hypotenuse 143, this allows the pin 141 to be easily received in the slot 142 during manufacture.

[0130] In this embodiment the SMS 130 comprises a prime mover in the form of a stepper motor 144 which is arranged to move the drive rails 137 in the X-direction. In this embodiment, the stepper motor 144 is an off-the-shelf component with rpm of 100-600, and holding torque of 1.5-4 Ncm. The stepper motor 144 is directly connected to a threaded drive axle 145 extending in the X-direction. The drive axle 145 is received in an aperture (not shown) in one of the support bars 138. The stepper motor 144 can thereby turn the drive axle 145 to cause the support bars 138 and drive rails 137 to be moved in the X- direction.

[0131] The X-translator 110, Y-translator 120 and SMS 130 all further comprise a respective linear position sensors (not shown) and integrated into their respective stepper motors as is common in the art.

[0132] As described above, the support 131 restricts movement of the sample holder in the X- and Y- directions through the retaining pins 135 and apertures 136. The support also restricts movement of the drive rails 137 in the Y- and Z- directions with the mounting slots 139 and arms 140. Thus, the only way the sample holder and rails can move with respect to the support is in the Z-direction and X-direction respectively.

[0133] In addition, the drive rails 137 are coupled to the sample holder 132 such that movement of the drive rails 137 in the X-direction (e.g. a first direction) causes movement of the sample holder in the Z-direction (e.g. a second direction) through the drive pins 141 and slots 142. The springs 134 urge the sample holders 132 upwards and thus the drive pins 141 are urged into contact with the hypotenuse 143 of the drive slots 142. When the drive rails 137 are moved in the X-direction, the drive slots 142 move relative to the sample holders 132 causing the pins 141 to slide along the hypotenuse 143. As the hypotenuse 143 is angled and the pins 141 are urged against it, the pins 141 and sample holder 132 move in the Z-direction as the rails 137 slide in the X-direction. Thus, the hypotenuse provides a guide surface that translates movement of the drive rails 137 in the X-direction into movement of the sample holders in the Z-direction.

[0134] In use, a sample 10 is provided in a first well 23 of a microplate 20. Other samples may also be provided in the other wells 22 of the microplate. The microplate 20 is then loaded into the sample holder 132. The stepper motor 144 is then controlled to move the drive rails 137 such that the sample holder 132 is moved down so that the lid 104 can be fitted or closed over the sample holder 132 without touching the microplate 20. The lid 104 is then fitted / closed over the sample holder 132. Next, the X-translator 110 and Y-translator 120 are controlled to move the first well 23 into a position such that it is directly beneath the access aperture 200. The SMS 130 is then controlled to raise the sample holder 132 such that the microplate 20 contacts the underside of the lid 104 with the first well 23 exposed by the access aperture 200 and the remaining wells 22 sealed against the lid 104. The user can then image the sample 10 in the first well 23 and perform any necessary processing / experimental steps.

[0135] Once the sample processing is complete, the microscope stage 100 can be controlled to lower the sample holder 132, move it in the X-Y plane to select one of the other wells 22, and raise the sample holder 132 so that one of the other wells 22 may be imaged / processed. This process can then be repeated until all samples have been handled / processed.

[0136] As the sample holder 132 can be held at different points in the Z-direction, the SMS 130 can also be controlled to allow more advanced imaging such as Z-stacks where successive images are taken at different positions in the Z-direction. It also allows the speed of movement in the Z-direction to be varied. This is helpful to prevent sample spillage and damage as the speed can be reduced as the microplate 20 comes into contact with the lid 104.

[0137] The system is also advantageous as the SMS 130 can achieve high speed changes in position, for example under 300 ms for lifting / lowering the sample holders 132 by about 10 mm. Furthermore, the motor 144 may be at rest whenever the sample holder 132 is not moving, this overcomes overheating issues of the Wright solution which requires the actuators to be energised to hold the samples down.

[0138] The SMS 130 can also hold microplates 20 of different heights. The springs 134 ensure that microplates 20 will be sealed against the lid 104 at the same time irrespective of their height, this reduces evaporation loses from other wells 22 during sample handling.

[0139] Furthermore the drive slots 142 are shaped so that the position of the drive rail 137 effectively selects a permitted range of motion of the drive pins 141 in the Z-direction, from the bottom of the slot 142 to the part of the hypotenuse 143 selected by the drive rail position. This allows a variety of height samples to be fitted and used in the same SMS 130. If one sample is taller than the other, it contacts the lid 104 first when being moved up. However, the drive rails 137 can continue lifting the shorter sample as the pins 141 corresponding to the taller sample simply detach from the hypotenuse 143 and move across the middle of the slot 142. Then when lowering the samples, the pins 141 of the taller sample move back across the middle of the slot 142 until the hypotenuse 143 contacts the pins 141 and lowers the sample.

[0140] To construct the microscope stage 100, the various components may be formed from any suitable rigid material, for example aluminium or stainless steel. The different components can be machined into the required shapes or formed using other known processes. The motors 114, 124, 144 and position sensors 151, 152, 153 are off the shelf components that are widely available. Once the components are sourced / made, they can be simply bolted / screwed together to form the microscope stage 100 as described herein.

[0141] Referring to Figures 6-10 the lid 104 in this embodiment comprises an access aperture 200, or passage 200, with unique features to provide enhanced access to the sample 10 while also ensuring the lid 104 remains rigid and that other samples held in neighbouring parts of the microplate 20 can be effectively sealed against the lid 104.

[0142] In this embodiment, the lid 104 comprises a first side 104a and an opposite second side 104b, the first side 104a being a top side of the lid 104 in use and facing away from the sample. The first and second sides 104a, 104b being substantially flat and defining a generally planar lid. The lid 104 therefore has a thickness between the first and second sides 104a, 104b, which in this embodiment is about 6 mm. This assists in ensuring the lid 104 is easy to manufacture and can effectively seal samples against the second side 104b.

[0143] The passage 200 comprises an entrance 201 provided in the first side 104a of the lid 104. The entrance 201 is circular, with a diameter, or entrance width, of about 80 mm. From the entrance 201, the passage 200 extends through the lid 104 in a direction substantially perpendicular to the first and second sides 104a, 104b to an exit 202 provided on the second side 104b. The exit 202 is also circular and is centred with respect to the entrance 201. The exit 202 has a diameter, or exit width, of about 8 mm and thus the passage narrows from the entrance 201 to the exit 202 as described below.

[0144] A P axis can be defined through the centre of the entrance 201 and exit 202, see Figure 8. In this embodiment, as the entrance 201 and exit 202 are centred with respect to each other, the P axis passes through the passage 200 perpendicular to the lid 104. Starting from the entrance 202 and working towards the exit 202, the passage 200 continuously narrows, that is, it does not widen in directions from the entrance 201 towards the exit 202. This provides better access to the sample through the passage 200 while also allowing the rigidity of the lid 104 around the exit 202 to be controlled by the degree of narrowing of the passage 200, as described below.

[0145] The passage 200 comprises a ledge in the form of a first ledge 203 and a second ledge 204 connected by a chamfered region 205. The ledge therefore has a stepped profile with two steps provided by the first and second ledges 203, 204. The second ledge 204 is provide about one third of the distance from the entrance to the exit along the P axis. The second ledge 204 is annular and surrounds the first ledge 203 which is also annular. The first ledge 203 is provided about half the way from the entrance to the exit along the P axis. The chamfered region 205 is therefore also annular in order to connect the first and second ledges 203, 204. In this embodiment, the chamfered region 205 has a chamfer arranged at an angle of about 45 degrees with respect to the P axis. Of course in other embodiments, the chamfer could have a different angle or not be present, or the passage could comprise a different number of ledges, e.g. 1, 3, 4 or more.

[0146] In this embodiment, extending from the first ledge 203 to the exit 202 is a tapered portion 206. The tapered portion 206 is annular and frustoconical in shape and extends over the remaining thickness of the lid 104, which in this embodiment is about half the lid 104. This enables the thickness of the lid 104 immediately around the exit 202 to be minimised down to, in this embodiment, about 0.5 mm. This helps provide better access to samples through the passage 200.

[0147] The tapered portion 206 is angled with respect to the P axis by about 60 degrees and thus extends over about 15% of the distance from the exit towards the entrance in a direction perpendicular to the P axis. The first ledge 203 then extends from the tapered portion 206 to the chamfered region 205 and covers about 60% of the total distance from the exit to the entrance in a direction perpendicular to the P axis. The second ledge 204 then spans the total remaining distance perpendicular to the P axis from the chamfered region 205 to the entrance 202. Thus, in this embodiment, both the first and second ledges 203, 204 are flat and parallel to the first and second sides 104a, 104b. However, in other embodiments they may not be flat and may be angled or curved. In addition, the tapered portion may not have a straight or smooth taper and may be curved or stepped to provide an overall tapered shape.

[0148] In this embodiment, between the entrance 202 and second ledge 204 there is provided a tubular portion 208. In this embodiment, the tubular portion 208 is cylindrical and extends parallel to the P axis, but of course in other embodiments it might have different shapes and may extend in other directions.

[0149] Exit lines EL can be defined from the centre of the exit 202 towards and out of the entrance 201 which maximise their angle with respect to the P axis without contacting the tapered portion 206 or first ledge 203, and example of one exit line is drawn on Figure 8. The exit lines EL then together define an exit field of view (EFOV) which indicates the variety of different direct approach angles that can be used to access the sample through the exit 202. In this embodiment, the exit lines EL are angled at about 60 degrees to the P axis and therefore the EFOV covers at least 3 sr and is centered on the P axis.

[0150] Where the tapered portion 206 and first ledge 203 meet, a ledge aperture 207 is defined by the inner edge of the first ledge 203. In this embodiment, the ledge aperture 207 is circular with a diameter, or ledge aperture width, of about 19 mm Similarly with the exit lines EL, ledge lines LL can be defined extending from the centre of the ledge aperture 207 towards and out of the entrance which maximise their angle with respect to the P axis without contacting the ledges or passage. An example of a ledge line LL is drawn on Figure 8. The ledge lines LL together define a ledge field of view (LFOV) which indicates the variety of different direct approach angles that can be used to access the tapered portion through the entrance 202. In this embodiment, the ledge lines LL are angled at about 85 degrees to the P axis and the LFOV covers at least 5.5 sr and is centered on the P axis. Thus, the passage provides excellent access to the sample via its narrowing shape that helps provide wide angles of approach.

[0151] The shape of the passage 200 and the ledges also ensures that while the entrance 202 is wide, the lid 104 retains at least half of its thickness over the vast majority of the region around the exit 201. The only points which are under half thickness are those in register with the tapered portion 206, which only constitutes about 15% of the distance from the exit to the entrance. This helps ensure the lid 104 remains rigid enough to securely seal against samples not being accessed, for example as shown in Figure 4C. Referring to Figure 10, the lid 104 and passage 200 are especially useful when using a series of samples provided in an array of containers 220. For example, this could be the wells 22, 23 of a microplate 20 as described above in relation to Figures 1 to 5C, or in some embodiments each container 220 could be formed in alternative ways. In one preferred embodiment, a microplate 20 as described above is modified such that each well comprises a sub array 221 of four sample containers 220. In this embodiment, each sub array 221 is provided in a 2x2 arrangement. Each container 220 is about 3 mm in diameter and is configured to contain a sample of no more than 0.1 ml, for example depending on the container 220 depth, it may contain about 30 pl, or it may contain less, such as 0.1 to 1 pl. Of course, the container size and volume is purely exemplary and can be varied to suit a specific application.

[0152] In this embodiment, each sub array 221 is slightly rectangular with a grid spacing DI (or first spacing), defined as the distance between the centres of adjacent containers, of 3.75 mm and 4.25 mm in the two directions of the array respectively. Of course, this shape is purely exemplary and the sub array could be a square grid. In this embodiment, the sub arrays 221 form an array that is defined by the wells 22 of the microplate 20. The sub arrays 221 thereby have a sub array grid spacing and this defines the distance between the centres of adjacent sub arrays 221. In this embodiment, this is characterised by distance D2 (or second spacing) which defines the distance between adjacent containers 220 of adjacent sub arrays 221. The sub array grid spacing is then DI + D2. In this embodiment, the sub array grid spacing is about 8 mm. D2 is therefore about 4.25 mm where DI is 3.75 mm.

[0153] Referring to Figure 10, the diameter of the exit 202, or exit width, is denoted by R and in this embodiment is about 8 mm, or equal to the sub array grid spacing. This ensures that the passage 200 is able to provide very good access to a first container 223, while ensuring that neighbouring containers 220 are protected by the lid 104 and sample quality is maintained in them. For example, as illustrated, the first container 223 is easily accessible through the passage 200 but all the neighbouring containers are at least partially covered with generally only a minority of their surface area exposed by the exit 202. In addition, the exit 202 is sized such that it can only fit at most two containers completely within it and that, at most, it overlaps with up to seven containers at any one time. In this embodiment, the lid 104 is transparent and formed of a hard plastic, such as an acrylic. The lid 104 and passage 200 may be manufactured through many known and widely available processes. For example, it may be formed by injection moulding of plastics such as acrylic. Alternatively, the lid may be provided as a sheet of material, such as glass, that is then machined to form the passage.

[0154] In this embodiment, the passage 200 is provided separated from the edges of the lid by at least the entrance width. This ensures that the lid 104 can adequately cover other sample containers of the microplate 20.

[0155] Use of the lid 104 is as described above in relation to Figures 1-5C, the passage 200 and ledges 203, 204 provide additional room and access angles to allow larger tools to be introduced through the passage 200 and used to manipulate, process and analyse the sample. It also makes it easier for tools to access the bottom of a sample well or container through the passage. Simultaneously, the second side 104b works synergistically with the SMS 130 to seal the lid against the other sample containers 220 to seal them and protect the samples held therein.

[0156] In other embodiments, the SMS 130 and lid 104 may be used in conjunction with robotic sample manipulation tools (not shown), whether automated, semi-automated or manually controlled. Suitable tools include robotic arms or other sample handling equipment. In some examples, the manipulation tools may include tweezers, pipettes, suction tubes, syringes, stirrers, etc. that can be used to process or otherwise manipulate the sample. Beneficially, each of the SMS 130 and lid 104 may individually be used with such a tool and can improve use as access to the sample is more convenient and better controlled while minimising sample damage due to effects like evaporation.

[0157] The one or more embodiments are described above by way of example only. Many variations are possible without departing from the scope of protection afforded by the appended claims.

Claims

CLAIMS1. A sample movement system for an imaging stage, the system comprising a sample holder configured to attach to a sample to be imaged, a driver moveable relative to the imaging stage in a first direction, and a support configured to restrict movement of the sample holder relative to the imaging stage in the first direction, wherein the sample holder is coupled to the driver by first and second guide structures, wherein the second guide structure comprises a guide surface and at least part of the first guide structure is configured to contact the guide surface to translate movement of the driver in the first direction into movement of the sample holder in a second direction different to the first direction.

2. The sample movement system of claim 1 , wherein the first direction is perpendicular to the second direction.

3. The sample movement system of claim 1 or 2, wherein the driver comprises a drive rail extending in the first direction along an edge of the sample holder, the first or second guide structure being provided in or on the drive rail.

4. The sample movement system of any preceding claim wherein at least two sides of the sample holder are independently coupled to the driver via the first and second guide structures.

5. The sample movement system of any preceding claim, wherein the guide surface is provided by a drive slot and the first guide structure comprises a drive pin receivable in the drive slot.

6. The sample movement system of any preceding claim, further comprising a biasing device configured to urge the first and second guide structures into contact.

7. The sample movement system of any preceding claim, wherein the support restricts movement of the sample holder with the driver in the first direction via an aperture and a retaining pin receivable in the aperture, wherein the retaining pin extends in the second direction.

8. The sample movement system of any preceding claim, wherein the driver is mounted to the support via a moveable mounting that facilitates movement of the driver withrespect to the support in the first direction and restricts movement of the driver in the second direction.

9. The sample movement system of any preceding claim, wherein the second direction is a vertical direction parallel to a Z-axis of the imaging stage.

10. The sample movement system of any preceding claim comprising a prime mover configured to cause the driver to move in the first direction, wherein the prime mover comprises a motor and the driver is attached to the motor via a threaded drive axle, the drive axle extending in the first direction.

11. The sample movement system of any preceding claim comprising two or more sample holders, wherein the two or more sample holders are each coupled to the driver via two or more sets of first and second guide structures and the support is configured to restrict movement of the two or more sample holders relative to the imaging stage in the first direction, wherein movement of the driver in the first direction is translated into simultaneous movement of the two or more sample holders in the second direction.

12. An imaging stage comprising the sample movement system according to any preceding claim, and a base configured to hold the sample movement system such that the sample may be imaged.

13. The imaging stage of claim 12 comprising a lid attached to the base and provided over sample movement system, wherein the driver is moveable to cause the sample holder to move into sealing contact with the lid.

14. The imaging stage of claims 12 or 13 wherein the imaging stage is a microscope stage.

15. A method of adjusting the position of a sample on an imaging stage, wherein the sample is mounted in a sample holder, wherein the sample holder is coupled to a driver via first and second guide structures, the second guide structure comprising a guide surface, the method comprising: restricting movement of the sample holder in a first direction relative to the imaging stage; and moving the driver in the first direction to cause the first guide structure to contact the guide surface and translate movement of the driver in the first direction into movement of the sample holder in a second direction different to the first direction.

16. A lid comprising a passage for access to a sample through the lid, wherein the lid comprises first and second sides, and the passage comprises an entrance and an exit on the first and second sides of the lid respectively, wherein the passage narrows from the entrance to the exit and comprises a ledge provided along the passage between the entrance and exit, and a tapered portion extending from the ledge to the exit.

17. The lid of claim 16 wherein the lid is substantially planar and the first and second sides are substantially flat.

18. The lid of claim 16 or 17 wherein the tapered portion spans at least half the thickness of the lid between the first and second sides.

19. The lid of any of claims 16 to 18 wherein the tapered portion is annular and surrounds the exit.

20. The lid of claim 19 wherein the ledge is annular and surrounds the tapered portion.

21. The lid of any of claims 16 to 20 wherein the entrance is at least five times wider than the exit.

22. The lid of any of claims 16 to 21 wherein the ledge comprises first and second ledges offset from one another along the passage, the second ledge provided between the entrance and the first ledge, and the tapered portion extending from the first ledge to the exit.

23. The lid of claim 22 wherein a chamfered portion is provided between the first and second ledges.

24. The lid of any of claims 16 to 23 wherein the lid is constructed from a transparent or translucent material.

25. The lid of any of claims 16 to 24 wherein the lid is for a sample access system for an imaging system.

26. A sample access system comprising the lid of any of claims 16 to 25 and a sample holder, wherein the sample holder comprises a plurality of containers and the passage is configured to provide access to a first container of the plurality of containers.

27. The sample access system of claim 26 wherein the second side of the lid is shaped to seal against a second container of the plurality of containers while access is provided to the first container.

28. The sample access system of claim 26 or 27 wherein the plurality of containers are arranged in an array and the exit has a width that is no more than the separation distance of adjacent containers.

29. The sample movement system of any of claims 1 to 11 comprising the lid of any of claims 16 to 25 wherein the sample movement system is configured to move the sample holder up to the second side of the lid such that a sample may be accessed through the passage.

30. An imaging system comprising the sample movement system of any of claims 1 to 11 or 29.

31. An imaging system comprising the lid of any of claims 16 to 25 or the sample access system of any of claims 26 to 27.

32. The imaging system of claim 30 or 31 wherein the imaging system is a microscope.

33. A method of providing access to a sample, the method comprising providing the lid of any of claims 16 to 25 and covering the sample with the lid such that the sample may be accessed through the passage.

34. The method of claim 33 further comprising providing a sample in a first container of a plurality of containers, aligning the first container with the passage and then sealing one or more of the containers not being the first container against the second side of the lid.

Images