GB2608143A - Device with stigmatic lens - Google Patents

Abstract

A device for imaging a biological sample 80 includes an imaging system with a sensor 32 and a stigmatic lens 19. The stigmatic lens includes a first surface 31a and a second surface 31b, which at least partially corrects spherical aberration of the first surface. The stigmatic lens is a singlet lens. A casing receives a biological sample at an imaging location inside the casing and a driver moves the biological sample at the imaging location to bring different areas of the biological sample into a field of view of the imaging system. The imaging system images each area of the biological sample in the imaging system’s field of view. An average or minimum similarity between the optical path lengths (SOPL) of the stigmatic lens may be 95%, 97%, 99% or above. A distance from a centre of the first surface to an object focal plane of the stigmatic lens may be <10mm or <5mm. The casing may receive the biological sample at an imaging location inside the casing, so the biological sample is positioned in an object focal plane of the stigmatic lens. The first surface and the second surface may be predefined by given equations.

Description

DEVICE WITH STIGMATIC LENS FIELD OF THE INVENTION

[0001] The present invention relates to a device for maging a biological sample, and a method of imaging a biological sample with the device.

BACKGROUND OF THE INVENTION

[0002] Conventional systems and methods for biological imaging usually require a microscopic setup operated by humans traversing slides in translational movements, or a very expensive technique such as spectroscopy, flow-cytometry, electrical impedance, or chemical assays. Such technologies are unaffordable for applications of high population impact. Such systems and methods also do not scale and generalise well as they require manual analysis and are based on expensive optics and often provide inaccurate or incompatible results.

SUMMARY OF THE INVENTION

[0003] A first aspect of the invention provides a device for imaging a biological sample, the device comprising: an imaging system with a sensor and a stigmatic lens, the stigmatic lens comprising a first surface, and a second surface which at least partially corrects spherical aberration of the first surface, wherein the stigmatic lens is a singlet lens; a casing configured to receive a biological sample at an imaging location inside the casing; and a driver configured to move the biological sample at the imaging location to bring different areas of the biological sample into a field of view of the imaging system, wherein the imaging system is configured to image each area of the biological sample in the field of view of the imaging system.

[0004] A further aspect of the invention provides a method of imaging a biological sample with a portable device according to the first aspect, the method comprising: inserting a biological sample into the device; moving the biological sample between a series of positions or orientations, each position or orientation bringing a different area of the biological sample into a field of view of the imaging system; and for each position or orientation, operating the sensor to image the area of the biological sample in the field of view of the imaging system.

[0005] The following comments apply to both aspect of the invention.

[0006] Optionally an average or minimum similarity between optical path lengths (SOPL) of the stigmatic lens is 95% or above, 97% or above or 99% or above.

[0007] Optionally a distance from a centre of the first surface to an object focal plane of the stigmatic lens is less than lOmm or less than 5mm.

[0008] Optionally the casing is configured to receive the biological sample at an imaging location inside the casing so that the biological sample is positioned in an object focal plane of the stigmatic lens.

[0009] Optionally the first surface and the second surface are given by the equations 1-5 below, to a tolerance of +/-0.1mm [0010] Optionally the device further comprises a lighting system arranged to illuminate the biological sample at the imaging location.

[0011] Optionally the imaging system is configured to image the biological sample from a front side of the biological sample, and the lighting system is arranged to illuminate the biological sample from a back side of the biological sample.

[0012] Optionally the device has a maximum dimension which is less than 50cm or less than 40cm or less than 30cm [0013] Optionally the device has a weight less than lkg, or less than 700g or less than 500g.

[0014] Optionally the device further comprises a focus drive system configured to move the biological sample at the imaging location in or out of a focal plane of the stigmatic lens [0015] Optionally the device further comprises a processor configured to analyse image or video data from the sensor to automatically classify sample features.

[0016] Optionally the device further comprises: a cartridge with a platform which is configured to enable a sample carrier with a biological sample to be loaded onto the platform; wherein the casing is configured to enable the cartridge to be inserted into the casing after the sample carrier has been loaded onto the platform.

[0017] Optionally the driver is a lateral cartridge drive system configured to move the cartridge within the casing so that the cartridge and the sample carrier move together between a series of lateral positions within the casing, each position bringing a different area of the sample carrier into the field of view of the imaging system. Alternatively the driver may be a drive system which rotates or otherwise the sample carrier on the platform, the cartridge remaining stationary.

[0018] Optionally the casing comprises a slot, and the casing is configured to enable the cartridge to be inserted into the casing via the slot.

[0019] Optionally the device further comprises a battery for powering the imaging system [0020] Optionally the imaging system generates image or video data, and the method further comprises analysing the image or video data to automatically classify features of the biological sample.

[0021] Optionally the imaging system comprises a camera configured to acquire an image of the biological sample.

[0022] Optionally the imaging system comprises a smartphone [0023] Optionally the device is a portable device and/or a handheld device BRIEF DESCRIPTION OF THE DRAWINGS [0024] Embodiments of the invention will now be described with reference to the accompanying drawings, in which: [0025] Fig. 1 is an isometric view of a device for imaging a biological sample; [0026] Fig. 2 is an isometric view of a cartridge of the device of Fig. 1; [0027] Fig. 3 is an end view of the cartridge of Fig. 2; [0028] Fig. 4 is an exploded view showing various parts of the device of Fig. 1; [0029] Fig. 5 shows a slide with a biological sample loaded onto the cartridge of Fig. 2; [0030] Fig. 6 shows the slide being loaded onto the cartridge from above the platform; [0031] Fig. 7 is a plan view of the top part of the casing; [0032] Fig. 8 is an isometric view of the top part of the casing; [0033] Fig. 9 is a cross-sectional view showing the device of Fig. 1 imaging a biological sample; [0034] Fig. 10 s an isometric view of a drive system; [0035] Fig. 11 is an isometric view of the frame and drive members of the focus drive system; [0036] Fig. 12 is an isometric view from below showing the cartridge in an extended position; [0037] Fig. 13 is an isometric view from below showing the cartridge in a retracted position; [0038] Fig. 14 is a plan view showing the cartridge in a first extended position; [0039] Fig. 15 is a plan view, partly in section and with hidden parts shown, with the cartridge in the first extended position of Fig. 14; [0040] Fig. 16A is a plan view, partly in section, with the cartridge in the first extended position of Fig 14; [0041] Fig 16B is a plan view, partly in section, with the cartridge in a first intermediate position; [0042] Fig. 16C is a plan view, partly in section, with the cartridge in a first retracted position; [0043] Fig. 16D is a plan view, partly in section, with the cartridge in a second retracted position; [0044] Fig. 16E is a plan view, partly in section, with the cartridge in a second intermediate position; [0045] Fig. 16F is a plan view, partly in section, with the cartridge in a second retracted position; [0046] Fig. 17A is a side view showing the slide in a lowered position resting on the platform of the cartridge; [0047] Fig. 17B is a side view showing the slide in a raised position; [0048] Fig. 18A is an end view showing the slide in a lowered position resting on the platform of the cartridge, [0049] Fig. 18B is an end view showing the slide in a raised position; [0050] Fig. 19 shows a first embodiment of the stigmatic lens; and [0051] Fig. 20 shows a second embodiment of the stigmatic lens. DETAILED DESCRIPTION OF EMBODIMENT(S) [0052] Figure 1 shows a device 10 for imaging a biological sample. Certain elements of the device are shown in Figure 4, including a sample carrier fin this case a slide 16) for carrying the biological sample; a cartridge 22 carrying the slide 16; a camera 18; and a casing comprising a top part 12a and bottom part 12b.

[0053] The camera 18 may be a smartphone, for example. The camera 18 is configured to capture video and images. Typically, the camera 18 has a weight of approximately 200gm.

[0054] The top part 12a of the casing has a slot 15 at one end, shown in Figure 8, and the camera 18 is fitted into the top part 12a of the casing via the slot 15. The top part 12a of the casing (carrying the camera 18) is then fitted into the lower part 12b. The two parts of the casing have respective slots 14a, 14b which line up when the casing is in its fully assembled state shown in Figure 1. The top and bottom parts of the casing are then secured together by a fastener 8 with a cap 9 shown in Figure 4 [0055] The casing 12a, 12b is configured to enable the cartridge 22 to be inserted into a chamber 33 in the casing via the aligned slots 14a, 14b after the slide 16 has been loaded onto the cartridge 22.

[0056] The slot 14a provides an opening into the chamber 33. As shown in Figure 16A and 16F, the chamber 33 has side walls 30a, 30b, a rear wall 30c, and a shelf 5 shown in Figure 8 with openings 6, 7 shown in Figure 7.

[0057] The side walls 30a, 30b have V-shaped projecting rails 29a, 29b which are received in V-shaped grooves 29c in the side of the cartridge, to guide the cartridge into the casing at the correct height. The rails 29a, 29b are shown most clearly in Figure 9 and the grooves 29c are shown most clearly in Figure 3. Each rail 29a, 29b runs from the slot 14a and terminates a short distance into the chamber 33 as shown most clearly in Figures 16A and 16E. The side walls 30a, 30b, and their respective rails 29a, 29b, extend at an oblique angle to each other so the width of the chamber 33 widens towards the rear wall 30c.

[0058] The cartridge 22 shown in Figures 2 and 3 has a platform 21 which carries the slide 16. Seven barrier segments 23 are provided at a periphery of the platform. The barrier segments 23 are separated by openings.

[0059] As shown in Figure 3, each barrier segment 23 comprises a planar inner side wall 24 and a top wall 25. The side wall 24 extends away from the platform 21 to a convex shoulder 26, and the inner side wall 24 meets the top wall 25 at the shoulder 26.

[0060] In this example, all of the barrier segments 23 are the same height, so that their shoulders 26 and top walls 25 all lie in a plane 27 which is parallel with the platform 21. In other examples, some of the barrier segments 23 may have different heights.

[0061] The shoulders 26 defines a periphery of an opening 28 above the platform 21, and the cartridge 22 is configured to enable the slide 16 to be loaded onto the platform via the opening 28 and unloaded from the platform via the opening 28.

[0062] The cartridge 22 is free of obstructions above the platform 21, so that the slide 16 can be loaded onto the platform from above the platform as shown in Figure 6 The barrier segments 23 collectively provide a barrier which is configured to engage with an edge of the slide 16 in order to inhibit sliding between the platform 21 and the slide 16, after the slide has been loaded as shown in Figure 5 [0063] The slide 16 can be loaded onto the platform 21 from above the platform in a variety of ways. For example, the cartridge 22 may be fully removed from the casing 12a, 12b, and the slide 16 dropped down vertically onto the platform as shown in Figure 6. Alternatively, as the slide 16 is loaded onto the platform 21, a first end of the cartridge 22 may be inside the casing and a second end of the cartridge may protrude from the casing, as shown in Figure 1. In this case, rather than being dropped down onto the platform 21 with the slide 16 remaining parallel with the platform 21, the first end of the slide 16 is loaded onto the platform 21 at an angle, and then the second end of the slide 16 is lowered down onto the platform 21 as the first end of the slide 16 is fed into the casing. The slots 14a, 14b must be sufficiently high to enable this loading method to be used without clashing with the casing.

[0064] In the loading methods described above, the slide 16 is loaded onto the platform 21 by lowering the slide 16 into contact with the platform 21. Equivalently the slide 16 may be loaded onto the platform 21 by raising the platform 21 into contact with the slide 16, although this would be a more cumbersome method. Also, the platform 21 may not be horizontal as the slide 16 is loaded onto the platform 21, although this is preferred [0065] The open structure of the cartridge 22 above the platform 21 provides a number of advantages. Firstly, it makes the cartridge 22 mechanically robust and less fragile than a cartridge designed to enable the sample carrier to be loaded onto the platform by sliding it through a slot of the cartridge. Secondly, it enables the slide 16 to be loaded easily arid quickly onto the platform 21.

[0066] The cartridge 22 is inserted into the interior of the casing by inserting it through the aligned slots 14a, 14b. When fully inserted, the second end of the cartridge 22 may protrude from the casing, or the full length of the cartridge may be received in the casing [0067] The device 10 has a height, length and width which are labelled H, L and W respectively in Figure 1. The device 10 is sufficiently small and light to make it portable. By way of example the height H may be 10cm, the length may be L 20cm and the width W may be 15cm, giving a volume of approximately 1500 cm3. The weight of the device 10 (including the cartridge 22, the slide 16 and the camera 18) may be approximately 400gm.

[0068] The camera 18 is part of an imaging system 18, 18a, 19, shown in detail in Figure 9. The camera 18 has an optical system with a lens or aperture 18a, and a sensor 32. A stigmatic lens 19 in a lens mount 19a is fitted in the casing, with the stigmatic lens 19 aligned with the lens or aperture 18a of the camera as shown in Figure 9. The stigmatic lens 19 has a focal plane and a field of view.

[0069] The camera 18 (or other imaging system) is fitted to the casing -in this example it is fitted to the top part 12a of the casing. The camera 18 in this example is at least partially inside the casing, although it is not completely enclosed by the casing so its touch screen, ports and operating buttons are exposed. In other examples, the camera 18 (or other imaging system) may be fitted to the exterior of the casing so that no part of it is inside the casing.

[0070] When the cartridge 22 is fully inserted, the slide 16 is positioned at an imaging location with the stigmatic lens 19 positioned above the slide 16 as shown in Figure 9. A small area of the slide 16 is in the field of view of the imaging system below the stigmatic lens 19.

[0071] A lighting system shown in Figure 9 is arranged to illuminate the slide 16 (and the biological sample carried by the slide) at the imaging location. The camera 18 is configured to image the biological sample from a front side of the wafer (i.e. from the top of the view of Figure 9). The lighting system comprises a light source 41 which generates a beam of light 42 which is reflected by a pair of mirrors 46, 48 so that the transparent slide 16 is illuminated from its underside (i.e. from the bottom of the view of Figure 9). The beam of light 42 passes through the hole 6 in the shelf 5 on its way up. The light source 41 may be part of the camera 18, or it may be separate from the camera 18.

[0072] A drive system 50 shown in Figure 10 is housed in the lower part 12b of the casing. The drive system 50 comprises a lateral cartridge drive system 60, 61, and a focus drive system 7075 [0073] The drive system 50 comprises a chassis 51 with a hole 52 shown in Figure 12 through which the beam of light 42 passes on its way up to the slide 16.

[0074] The lateral cartridge drive system comprises a pinion gear 60 shown in Figure 10 driven by a motor 61. As shown in Figures 12 and 13, the cartridge has a rack on its underside. The rack extends along a two-dimensional rack path -i.e. a rack path which does not consist only of a single straight line. In this case the two-dimensional rack path has a U-shape with a first straight segment 62, a second straight segment 63 parallel with the first straight segment 62, and a curved transition segment 64 joining the straight segments.

[0075] Figures 1, 12, 14, 15 and 16A show the cartridge 22 in a first extended position with the first end of the cartridge inside the casing and the second end of the cartridge protruding from the casing. In this first extended position, the pinion gear 60 is coupled to the rack at one end of the first straight segment 62 as shown in Figure 15. Rotation of the pinion gear 60 by the motor 61 drives the cartridge 22 to a first intermediate position shown in Figure 16B, then to a first fully retracted position shown in Figure 13 and Figure 16C.

[0076] As the cartridge 22 is driven along a first drive path segment as shown in Figures 16A-16C, it translates along a substantially straight path, roughly parallel with the side wall 30a of the chamber 33. During this phase of the drive path, all of the rail 29a is received in the groove 29c in the left-hand edge of the slide, and only part of the rail 29b is received in the groove 29c in the right-hand edge of the slide.

[0077] As the pinion gear 60 continues to rotate, it engages with the curved segment 64 of the rack path and drives the first end of the cartridge sideways. This causes the cartridge to pivot from the orientation of Figure 16C to the orientation of Figure 16D. As the pinion gear 60 continues to rotate further, it engages with the second straight segment 63 of the rack path and drives the cartridge 22 back to a second intermediate position shown in Figure 16E, then to a second extended position shown in Figure 16F.

[0078] As the cartridge 22 is driven along a second drive path segment as shown in Figures 16D-16F, it follows a substantially straight path, roughly parallel with the side wall 30b of the chamber 33 During this phase of the drive path, all or most of the rail 29b is received in the groove 29c in the right-hand edge of the slide, and only part of the rail 29a is received in the groove 29c in the left-hand edge of the slide.

[0079] Thus the lateral cartridge drive system 60-64 is configured to move the cartridge 22 along a two-dimensional drive path (i.e. a drive path which does not consist only of a translation in a single straight line) as described above and shown in Figures 16A-16F, with only a single motor 61.

[0080] The centre of the field of view traces a corresponding two-dimensional path (i.e a path which does not consist only of a translation in a single straight line) over the slide as shown in Figure 15 The two-dimensional path of the centre of the field of view has a first substantially straight segment 90 (corresponding with the first straight segment 62 of the rack path), a second substantially straight segment 91 (corresponding with the second straight segment 63 of the rack path) and a transition segment 92 (corresponding with the curved segment 64 of the rack path).

[0081] Other two-dimensional shapes are possible for the rack path, and the related path of the centre of the field of view. For instance either path may have a V-shape, a zig-zag shape, a sinuous shape (such as a sine wave) or any other shape which drives the cartridge in a two-dimensional back-and-forth motion [0082] The slide 16 is non-circular, with an elongate shape (i.e. a length which is greater than its width) and a rectangular periphery. This makes the slide 16 unsuitable for being driven by a pure rotation. Thus preferably the two-dimensional path of the centre of the field of view does not consist only of a circle or a portion of a circle.

[0083] A largely translational motion is preferred because of the elongate, non-circular, shape of the slide 16.

[0084] In other embodiments, an alternative lateral cartridge drive system may be used to move the cartridge by a pure rotation (i.e. a rotation about its centre with no translation) In this case the two-dimensional path of the centre of the field of view may be circular, [0085] The lateral cartridge drive system 60-64 is configured to move the cartridge 22 in the chamber 33 within the casing 12a, 12b as described above, so that the cartridge 22 and the slide 16 move together between a series of lateral positions within the casing. Each lateral position brings a different area of the slide 16 into the field of view of the imaging system 18, 18a, 19, 32.

[0086] Returning to Figure 10, the other part of the drive system 50 is a focus drive system 7075 configured to lift the slide 16 off the platform 21 into the focal plane of the imaging system 18, 18a, 19, 32.

[0087] The focus drive system comprises a frame 70 which carries three drive members 71, 72, 73. The frame has a first shaft 74 coupled to a first axial drive motor 74a, and a second shaft 75 coupled to a second axial drive motor 75a. The axial drive motors 74a, 75a are configured to move the frame 70 up and down.

[0088] Each drive member 71-73 has a respective contact surface which is configured to contact an underside of the slide 16 in the casing. The contact surfaces lie in the same horizontal plane.

As shown in Figure 11, each contact surface has a respective centre 71a, 72a, 73a, and the centres of the contact surfaces are non-collinear.

[0089] The centres 71a, 72a, 73a of the contact surfaces are also well spaced apart to provide a stable support for the slide 16 as it lifts off the platform.

[0090] The use of three drive members 71-73 provides a more stable support for the slide than only a single drive member. Also, a focus drive system with only a single drive member would require the drive member to be located precisely at the centre of the slide. The use of three drive members 71-73 enables the drive members to be offset from the centre of the slide by some distance.

[0091] In this example there are only three drive members 71-73, but in other embodiments the focus drive system may have more than three drive members.

[0092] As shown in Figure 2, the cartridge has a hole 29a in the platform 21. Two of the drive members 72, 73 are configured to move into contact with the underside of the slide 16 through this hole 29a.

[0093] The cartridge also has a recess 29b in a side of the platform 21. The other drive member 71 is configured to move into contact with the underside of the slide 16 through this recess 29b.

[0094] The device 10 is designed to use gravity to keep the slide 16 on the platform 21 before being engaged by the drive members 71-73. This requires the device 10 to be positioned parallel or at less than a 90 degree angle with respect to the floor. Another implementation uses one or more springs to hold the slide 16 in place. In such a case, the spring holds the slide in its place and is flexible enough for the focus drive system to move the slide.

[0095] The focus drive system 70-75 solves the problem of how to bring the sample into focus, without having to move the cartridge 22. Therefore a relatively large motor 61 can be used to move the cartridge 22 laterally, and relatively small axial drive motors 74a, 75a can be used to drive the sample axially and into focus.

[0096] A method of imaging a biological sample with the device 10 will now be described [0097] First the slide 16 is loaded with a biological sample 80 shown in Figure 6. The biological sample 80 may be carried on an upper surface of the slide 16, the slide 16 may comprise a cover slip which covers the biological sample 80, or the slide may have a chamber into which the biological sample 80 is loaded.

[0098] The biological sample 80 can be obtained from any biological source, animal or human. Typically, the biological sample 80 is obtained from a living organism.

[0099] The biological sample 80 may be, for example: sputum/oral fluid, amniotic fluid, blood, a blood fraction, fine needle biopsy samples (e.g. surgical biopsy, fine needle biopsy, etc.), urine, semen, stool, vaginal fluid, peritoneal fluid, pleural fluid, tissue explant, organ culture, cell culture, and any other tissue or cell preparation, or fraction or derivative thereof or isolated therefrom.

[0100] A staining substance may be used to dye the sample 80 and the different molecular elements. In some implementations, the dye is a dry dye. In some implementations, the dry dye includes methylene blue and/or eosin, cresyl violet or some other staining product, including those related to fluorescence assays.

[0101] The application of the dye or other reagent(s) can be delivered in a various ways. In one example, a small quantity of dye (e.g., about 5 uL of the dye) is deposited in or on the slide 16. In another example, about 2 uL of the stain or other reagent is taken up by a tube or vial in a previous preparation step. In another example, the stain or other reagent is smeared across the slide by a traditional smearing mechanism.

[0102] In some implementations, an external test tube is configured with anticoagulant to prepare a stained biological sample as an intermediate step before loading the biological sample onto the slide 16 [0103] Next, the slide 16 is loaded onto the platform 21, using one of the methods described above. Then the cartridge 22 is inserted into the casing, either manually or by rotating the pinion gear 60.

[0104] When the slide 16 is at a desired position, the focus drive system is operated to move the contact surfaces of the drive members 71-73 into contact with an underside of the slide 16 and then lift the slide 16 off the platform 21 to move the biological sample 80 into the focal plane of the imaging system This focusing process is shown in Figures 17A-18B.

[0105] Figures 17A and 18A show the slide 16 in a lowered position, resting on the platform 21. Figures 17B and 18B show the slide 16 in a raised position, having been lifted off the platform 21 into the focal plane of the imaging system.

[0106] Figures 17B and 18B indicate the plane 27 at the level of the shoulder 26 and top wall 25 of the barrier. As shown in Figures 17B and 18B, the cartridge is configured to enable the focus drive system to lift the slide 16 higher than the barrier -i.e. higher than the shoulder 26 of the barrier and higher than the top 25 of the barrier. This enables a large range of axial motion if the focal plane is above the plane 27 at the top of the barrier.

[0107] Once the biological sample 80 is in the focal plane, the camera 18 is operated to image the biological sample 80. The device 10 may be operated to acquire only a single image, but more typically it is operated to generate a series of images or videos, each image or video capturing a different part of the biological sample 80 [0108] Thus the lateral cartridge drive system is operated to move the cartridge 22 and the slide 16 together between a series of lateral positions within the casing, each lateral position bringing a different area of the biological sample 80 into the field of view of the imaging system. For each lateral position of the slide 16, the camera 18 is operated to image the area of the biological sample 80 in the field of view of the imaging system. The areas imaged by the camera 18 may be overlapping or non-overlapping.

[0109] The lateral cartridge drive system is configured to move the cartridge relative to the drive members 71-73 of the focus drive system, such that for each lateral position a different area of the underside of the slide is contacted by the contact surfaces of the drive members 71-73.

[0110] Typically for each lateral position of the slide 16, the following sequence of steps is performed in order: (a) the focus drive system is operated to lift the slide 16 off the platform to move the biological sample 80 into the focal plane of the imaging system, (b) the imaging system is operated to image the area of the biological sample 80 in the field of view of the imaging system; and (c) the focus drive system is operated to lower the slide 16 back onto the platform. After the slide 16 has landed back on the platform, the cartridge 22 is driven to the next lateral position and steps (a)-(c) repeated [0111] Optionally the contact surfaces of the drive members 71-73 remain in contact with the underside of the slide 16 as the cartridge 22 is moved by the lateral cartridge drive system. In this case each contact surface is configured to make a sliding contact with the underside of the slide, and the sliding contact is configured to enable the underside of the slide 16 to slide across the contact surface as the cartridge 22 is moved by the lateral cartridge drive system.

[0112] Alternatively the contact surfaces of the drive members 71-73 may disengage from the underside of the slide 16 at the end of step (c) above, and re-engage with a different area of the underside of the slide 16 at the beginning of the next step (a) above. In this case no sliding interface is required.

[0113] Once sufficient images have been taken, the cartridge is fully or partially withdrawn from the casing 12a, 12b through the slots 14a, 14b, and the slide 16 is unloaded from the platform 21 by a reversal of one of the loading methods described above.

[0114] The camera 18 may take a series of still images, with the slide 16 held stationary as each image is taken. Alternatively, a video may be taken as the slide 16 moves continuously.

[0115] The image or video data acquired by the camera 18 may be stored and/or post processed by the device 10 and/or transmitted from the device 10 for remote storage or post processing.

[0116] In the post processing, the image or video data may be analysed to automatically classify sample features. If the post processing is performed by the device 10, then the device 10 comprises a processor configured to analyse the image or video data to automatically classify sample features.

[0117] An implementation moves the slide 16 up and down in order to avoid a feedback system to bring the biological sample 80 into focus. A video is taken by the camera 18 as the slide 16 moves up and down with a continuous sinusoidal movement. For certain frames of the video the sample will be in focus, and these frames can be selected a posteriori as part of image post-processing. This implementation reduces the need for communication between a controller (not shown, however, may be part of the camera 18) and the focus drive system resulting in a significant reduction and device size minimisation from sampling area movement and reduction of the complexity of the device 1, and sampling method and mechanism.

[0118] The device 10 is battery powered, with one or more batteries for powering the camera 18, the drive system 50 and the lighting system 41. Optionally the camera 18 is a smartphone with a battery 17 shown schematically in Figure 9. The drive system 50 and the lighting system 41 may all be powered by the battery 17.

[0119] The device 10 may comprise a communication mechanism (either wired e.g. USB, or unwired, e.g. Bluetooth) for communicating data (such as video or image data) from the device 10 to another device, such as a server.

[0120] The camera 18 has a sensor 32 which takes a series of images as the slide 16 moves, each image capturing a respective image area In order to maximise the amount of useful image data acquired from the biological sample 80, it is desirable to maximise the area of the sample 80 which can be imaged, and this can be achieved in a number of ways.

[0121] One solution to this problem is to provide a two-dimensional scan across the full area of the slide 16. However this approach suffers from a number of problems: first, the increased time taken to complete the two-dimensional scan, and second the bulk and weight introduced by the necessary drive system.

[0122] Another solution to the problem is to increase the field of view of the camera 18, which enables each image to capture a larger image area.

[0123] Spherical aberration of the optical system can mean that peripheral regions of the field of view are not clear, so image data from these peripheral regions is not useful and has to be discarded. Thus the effective area of the field of view may be less than the total area of the field of view. So another solution to the problem is to increase the effective area of the field of view, by reducing the spherical aberration of the imaging system. A common method of reducing spherical aberration is to introduce a stack of lenses (stacked along the optical axis) which collectively provide a lens system with low spherical aberration. A problem with this solution is that the stack of lenses occupies a lot of space, which is not available in the compact and portable design of the device 10 (the height dimension H being of the order of 10cm). Another problem is that the lenses in such a stack can clash with each other and crack.

[0124] The device 10 solves the problem with the stigmatic lens 19. The stigmatic lens 19 reduces (or completely removes) spherical aberration which increases the effective area of the field of view. The stigmatic lens 19 is a singlet lens, rather than a stack of lenses, which solves the problems mentioned above associated with a stack of lenses.

[0125] Optionally the camera 18 has a further lens 18a; or the stigmatic lens 19 may be the only lens of the imaging system. In this case, lens or aperture 18a may be an aperture 18a, or the stigmatic lens 19 may be fitted into the camera 18 as a substitute for the further lens I 8a.

[0126] Figure 19 is a schematic view showing an embodiment of the stigmatic lens 19 The stigmatic lens 19 has a first surface 31a which faces the biological sample 80 on the slide 16, and a second surface 31b which faces the sensor 32 of the camera 18. The first surface 31a is an anterior or input surface, and the second surface 31a is a posterior or output surface [0127] The biological sample 80 is positioned at an object plane of the stigmatic lens 19, and the sensor 32 is positioned at an image plane of the stigmatic lens 19, so that light from a point on the biological sample 80 is focused by the stigmatic lens 19 to a point on the sensor 32.

[0128] The stigmatic lens 19 may be a collimating plane-aspheric lens, which is characterized by having a central image without spherical aberration. The stigmatic lens 19 may be obtained from carrying out an analytical method which maintains the optical path length as constant.

[0129] The first surface 31a may be any shape, and the second surface 3 lb may be designed on the basis of the shape of the first surface 31a, such that the second surface 31b corrects spherical aberration of the first surface and the overall spherical aberration of the stigmatic lens is zero, or small.

[0130] In the case of Figure 19, the first surface 31a facing the sample 80 is spherical, but in an alternative embodiment the first surface 31a facing the sample 80 may be planar.

[0131] Figure 20 shows an alternative design for the stigmatic lens 19, in this case with more complex surfaces 3 la, 3 lb [0132] The point P in Figure 20 is a point on the first surface, where P=(za(ra), ra). The point Q is a point on the second surface, where Q-(zb(r"), rb(ra)) Arrow Z in Figure 20 indicates the direction of the optical axis, the horizontal coordinate [0133] The definition of a stigmatic lens is a lens such that all ray paths passing through the lens have the same optical path length (OPL). The OPL is the product of the geometric length of the path followed by light (the ray) through a given system, and the refractive index of the medium through which it propagates.

[0134] For both Figure 19 and Figure 20, the second surface 31b may be designed according to equations 1-5 below. Equations 1-5 are such that all rays that pass through the lens have the same optical path length. Thus, the lens 19 designed with equations 1-5 is a stigmatic lens.

1" 4 (ra)(ra + (-ta +za(ra))4 (ra)) ez fra) (ru +(-ta+zu (ru))za(r1j))2 n2 (r5+(ta-za (ra))2)(1+(zc, (ta))2) (ra))2 -sgn(tc)rtjrZ + (ta -za (ra))2 (1+ (4(ra) 4(r11) (r0 ru+7a(t al)zia(ra))2 2. Pr fra) = +(-ta+za ra) n2 (Tiz+ (ta -za (ra))2)(i+(zra (ra))2) -sgn(ta)n.jrZ + (ta-(ra))2 (1+ (4 (ra))2) (-1 +n)t -ta+ z" (r") + sgn(t + (z "(r3 -t n-Qz(ra) 4. z, (r) = Za (ra) (ra)Qz (ra) 5. r(r) = Ta + 79(ra)eir(ra) [0135] In equations 1-5 the first surface 31a of the lens is defined by a function za(ra), where ra is an independent variable.

[0136] ta is a distance from an origin at the centre of the first surface 31a to an object focal plane of the stigmatic lens 19 [0137] n is a refractive index of the lens.

[0138] Qz(f-a) and er(ra) are cosine directions of a ray traveling inside the lens from the first surface to the second surface, in horizontal and vertical directions, respectively.

[0139] sgn(ta) is the sign of ta [0140]19(ra) is a distance that each ray need to travels from the first surface to the second surface.

[0141] z b(ra) and rb(ra) are components of the second surface, in horizontal and vertical directions, respectively.

[0142] za(ra), zb (Tlt) and rb(ra) are functions of ra, where ra is the independent variable.

[0143] the units of za(ra), zb(r") and rb (ret) are in mm, so for a given value ra there is a respective value of za(ra), zb (ra) and rb(ra).

[0144] Preferably the stigmatic lens 19 is perfectly stigmatic, such that all rays that pass through the stigmatic lens 19 have the same optical path length In this case, the second surface 31b completely corrects spherical aberration of the first surface 31a [0145] However it will be appreciated that the stigmatic lens 19 may not be perfectly stigmatic, for various reasons. One reason may be errors due to manufacturing tolerances. Another reason is that the stigmatic lens 19 may not be designed according to equations 1-5 above, but instead designed according to different equations, or by empirical testing. If the stigmatic lens 19 is not perfectly stigmatic, then the second surface 31b only partially corrects spherical aberration of the first surface 31a.

[0146] To test if the stigmatic lens 19 is sufficiently stigmatic for the device 10, the OPL between rays passing through the stigmatic lens 19 can be tested. The similarity between optical path lengths (SOPL) measures the similarity between two OPLs of different rays.

[0147] The way to compute the SOPL is with the following expression. SOPL = 100%* (1-[-t + n t + tam/7-j + (ta -za 0-0)2 -n.j(rb(ra) -ra(ra))2 + (zb(ra) -za(ra))2 + zb(ra)]) [0148] Where t is a thickness of the lens at a centre of the lens, as indicated in Figures 20 and 21 [0149] From the last expression, if two rays have the same OPL, then they have an SOPL of 100%. If the rays have different OPLs, then the measurement given by the SOPL will be below 100%. One of the rays is an axial-ray, incident at the centre of the lens.

[0150] For a perfectly stigmatic lens, the SOPL will be 100% for any pair of rays.

[0151] If the stigmatic lens 19 is not perfectly stigmatic, then the pair of rays will not have the same OPL, and this difference between the OPLs decreases the quality of the image generated by the imaging system. However, if an average or minimum SOPL of the stigmatic lens 19 is sufficiently high, then a high-quality image will still be generated.

[0152] One way to test the stigmatic lens 19 is to measure the coordinates (zei(r,,),rei) and (zb(ra) , rb(ra)) for several pairs of rays, compute the SOPL for each pair of rays using the expression above, and then compute the average SOPL of the stigmatic lens 19. This average SOPL should be 95% or above, more preferably 97% or above, or most preferably 99% or above in order to consider the stigmatic lens 19 sufficiently stigmatic. Alternatively the OPLs can be measured directly by Fizeau interferometers with spherical mirrors.

[0153] Another way to test the stigmatic lens 19 is to measure the coordinates (za (fa), ra) and (zb(ra) , rb(ra)) for several pairs of rays, compute the SOPL for each pair of rays using the expression above, and then identify the minimum SOPL of the stigmatic lens 19. This minimum SOPL should be 95% or above, more preferably 97% or above, or most preferably 99% or above in order to consider the stigmatic lens 19 sufficiently stigmatic. Alternatively the OPLs can be measured directly by Fizeau interferometers with spherical mirrors.

[0154] Preferably the values of physical model za(ra), zb(ra) and rb(ra) should not varuy outside a tolerance of +0 Olmm with respect of the mathematical expressions of za(ra), zb(ria) and rb(ra). So for example ifr = 0 z,(0) = 12mm, then in the physical model zb(0) should be in the range of 11.9mm to 12.1mm [0155] By way of example, the distance ta for the stigmatic lens 19 may be 3mm; and the central thickness t of the stigmatic lens 19 may be 0.4 millimetres.

[0156] ti, is a distance from a centre of the second surface 3 lb to an image focal plane of the stigmatic lens. Being a collimating lens, th may tend to infinity.

[0157] The independent variable ra may range from -1.5mm to 1.5mm, i.e. the diameter of the stigmatic lens may be 3mm.

[0158]

Claims (20)

1. CLAINIS1 A device for imaging a biological sample, the device comprising: an imaging system with a sensor and a stigmatic lens, the stigmatic lens comprising a first surface, and a second surface which at least partially corrects spherical aberration of the first surface, wherein the stigmatic lens is a singlet lens; a casing configured to receive a biological sample at an imaging location inside the casing; and a driver configured to move the biological sample at the imaging location to bring different areas of the biological sample into a field of view of the imaging system, wherein the imaging system is configured to image each area of the biological sample in the field of view of the imaging system.
2. 2 A device according to claim 1, wherein an average or minimum similarity between optical path lengths (SOPL) of the stigmatic lens is 95% or above.
3. 3 A device according to claim 1, wherein an average or minimum similarity between optical path lengths (SOPL) of the stigmatic lens is 97% or above.
4. 4 A device according to claim 1, wherein an average or minimum similarity between optical path lengths (SOPL) of the stigmatic lens is 99% or above.
5. A device according to any preceding claim, wherein a distance from a centre of the first surface to an object focal plane of the stigmatic lens is less than lOmm.
6. 6. A device according to any preceding claim, wherein a distance from a centre of the first surface to an object focal plane of the stigmatic lens is less than 5mm.
7. 7 A device according to any preceding claim, wherein the casing is configured to receive the biological sample at an imaging location inside the casing so that the biological sample is positioned in an object focal plane of the stigmatic lens.
8. 8 A device according to any preceding claim, wherein the first surface and the second surface are given by equations 1-5 below, to a tolerance of +/-0.1mm: 1. (2-,,+(-tu+za(r"))4(r"))2 (ra)(ra+ (-ta+za(ra))4(ra)) 4 "2 ("d+(ta-za (ra))2) (1 + (ra))2) ezfra) -± -sgn (ta)njr, + (ta-za(ra))2(1±(4.(ra))2) (ra) 11 (ra-4-ta+7a(ra))4(ra»2 2. Or (ra) = +(-tu+zu 0-0)4(r") n2 (4+ Eta -zo (ra))2)(,+(zra (Ta))2) -sgn(to)njr.4 +(to -za (ra))2(1+ (ra))2) 3' .1.9(r") - (-1+ n)t-ta + z" (ra)+ sgn (ta) +(za(ra)-ta)2 n-e,01,) 4. zb(Ta) = za(ra) + 19(7a)ez(ra) 5. r, (r) = ra + t9(ra)or(ra) where: the first surface of the lens is defined by a function za(ra) where ra is an independent variable; ta is a distance from an origin at the centre of the first surface to an object focal plane of the stigmatic lens; n is a refractive index of the stigmatic lens; z (r,,) and pr(ra) are cosine directions of a ray traveling inside the stigmatic lens from the first surface to the second surface, in horizontal and vertical directions, respectively.sgn(ta) is the sign of ta 19(ra) is a distance that each ray need to travels from the first surface to the second surface; and zb(ra) and rb(ra) are components of the second surface, in horizontal and vertical directions, respectively.
9. 9 A device according to any preceding claim, further comprising a lighting system arranged to illuminate the biological sample at the imaging location.
10. 10. A device according to claim 9, wherein the imaging system is configured to image the biological sample from a front side of the biological sample, and the lighting system is arranged to illuminate the biological sample from a back side of the biological sample.
11. 11 A device according to any preceding claim, wherein the device has a maximum dimension which is less than 50cm or less than 40cm or less than 30cm.
12. 12. A device according to any preceding claim, wherein the device has a weight less than 1kg, or less than 700g or less than 500g.
13. 13. A device according to any preceding claim, further comprising a focus drive system configured to move the biological sample at the imaging location in or out of a focal plane of the stigmatic lens.
14. 14. A device according to any preceding claim, further comprising a processor configured to analyse image or video data from the sensor to automatically classify sample features.
15. 15. A device according to any preceding claim, further comprising: a cartridge with a platform which is configured to enable a sample carrier with a biological sample to be loaded onto the platform; wherein the casing is configured to enable the cartridge to be inserted into the casing after the sample carrier has been loaded onto the platform.
16. 16. A device according to claim 15, wherein the driver is a lateral cartridge drive system configured to move the cartridge within the casing so that the cartridge and the sample carrier move together between a series of lateral positions within the casing, each position bringing a different area of the sample carrier into the field of view of the imaging system.
17. 17. A device according to claim or 16, wherein the casing comprises a slot, and the casing is configured to enable the cartridge to be inserted into the casing via the slot.
18. 18. A device according to any preceding claim, further comprising a battery for powering the imaging system.
19. 19. A method of imaging a biological sample with a portable device according to any preceding claim, the method comprising: inserting a biological sample into the device; moving the biological sample between a series of positions or orientations, each position or orientation bringing a different area of the biological sample into a field of view of the imaging system; and for each position or orientation, operating the sensor to image the area of the biological sample in the field of view of the imaging system.
20. 20. A method according claim 19, wherein the imaging system generates image or video data, and the method further comprises analysing the image or video data to automatically classify features of the biological sample.