Cell collection device with alternating wound retrieval thread

Abstract

A swallowable device 200 for collecting cells comprising: a swallowable capsule 201; and a retrieval thread 210 tethered to the swallowable capsule at a distal end 210d of the thread, with a distal en

Description

Oesophageal cancer is one of the most common types of cancer globally, causing an estimated 500,000 deaths globally each year. Like other forms of cancer, treatment of oesophageal cancer is most effective when the cancer is identified early. However, the symptoms of oesophageal cancer can be difficult to identify. One possible warning sign for oesophageal cancer is a condition called Barrett's oesophagus. This is a condition in which ceils in the cells in a patient's oesophagus begin to abnormally grow or change. Barrett's oesophagus is closely correlated with oesophageal cancer, although only a small number of Barrett's oesophagus cases develop into oesophageal cancer. By identifying cases of Barrett's oesophagus, patients at risk of developing oesophageal cancer can be identified, and those patients can then be monitored or treated pre-emptively. There are several methods for identifying Barrett's oesophagus. Endoscopy can be used to inspect the interior of the oesophagus for Barrett's oesophagus, but this is expensive, time-consuming, and invasive. In recent years, an alternative method for-identifying Barrett's oesophagus has been developed, known as the Cytosponge-TTF3 test. This test uses a device called a cytosponge to collect cell samples from the oesophagus of a patient. The cell samples are then processed using the so-called TTF3 laboratory test to identify Barret's oesophagus from biomarkers in the samples. The cytosponge device consists of a swallowable capsule containing a small soft sponge tethered to a retrieval cord. Prior to use, the capsule and cord are removed from a blister pack. The capsule is administered either by a trained healthcare professional or handed to the patient to be swallowed, optionally along with a bundled length of cord. The swallowed capsule travels down the oesophagus while the bundled cord unfurls. The capsule may travel all the way down to the stomach or be held at an intermediary point somewhere in the oesophagus. Next there is a pause (typically several minutes) while the capsule dissolves to release the sponge which then expands. The expanded sponge is then withdrawn by pulling up on the cord. As the sponge is withdrawn it brushes against the walls of the oesophagus, thereby collecting cell samples. After the sponge is recovered from the patient, it is sent to a laboratory where the TFF3 test is undertaken. The Cytosponge-TTF3 test is quicker and simpler to administer than endoscopy and requires less complex equipment and training to perform. This has allowed a greater number of patients to be tested for Barrett's oesophagus more quickly and cheaply. However, there are several problems associated with the cytosponge devices known in the art. Delivery and swallowing the cytosponge device is sometimes difficult and is known to be distressing for some patients. As well as an innate aversion to swallowing foreign objects, humans have a gag reflex (also known as the pharyngeal reflex) which can be triggered when an unusual object is swallowed or touches certain regions in the mouth. The gag reflex may cause the patient to involuntarily try and expel the capsule as it is positioned at the back of the mouth or travels down the throat. Accordingly, there is a need for capsule sponge devices which can be administered to a patient more comfortably and efficiently. Summary of the invention According to a first example, there is provided a swallowable device for collecting cells comprising: a swallowable capsule; and a retrieval thread tethered to the swallowable capsule at a distal end of the thread, with a proximal end of the thread configured for tethering to an applicator device, and a portion of the thread configured in a bundled state for bundling together with the swallowable capsule, wherein in the bundled state, the portion contains a plurality of turns around one or more winding axes, and the direction of winding around the one or more winding axes alternates between each successive turn. The winding axes may be virtual axes in the sense that they may not be defined by the axis of a physical surface around which the thread is wound. In a simple coil, a thread is continually turned in the same direction, such that it winds back on itself to form a helix. A tightly-packaged randomly bundled length of thread will also almost certainly end up 'with long extents of thread bound up in helixes. The pitch of the helix causes the thread to twist, introducing torsion Into the thread. The inventors have found that when a swallowable device for collecting cells including a coil or random bundle of thread is released into the mouth or throat, the release of this torsion can cause the thread to become tangled. This can prevent the capsule from travelling smoothly down the oesophagus to the stomach. In addition, the stored torsion in a conventionally coiled bundle of the thread can cause the bundle to expand in all directions when released. When the bundle is released in the back of a patient's mouth, it may become entangled in the patient’s teeth or wrap around the swallowable capsule, preventing the device for collecting cells from deploying correctly and / or causing discomfort for the patient. The tangies can also introduce difficulties when retrieving the swallowed capsule, as the retrieval thread may be not consistently tensioned along its length. Alternating the direction of winding between successive turns of the bundled first portion of the retrieval thread prevents torsion from building up in the thread, reducing the risk that the thread becomes entangled when it is released. The torsion introduced into the thread by a turn in a first direction (e.g. a clockwise turn), is counteracted by a successive or preceding turn in the opposite direction (e.g. a anticlockwise turn). As a result, the overall torsion in the thread is minimised. This enables the device for collecting cells to be deployed more efficiently and comfortably. The capsule travels smoothly down the patient's throat, avoiding jerks caused by the thread tangling and untangling. The smoother unbundling of the bundled portion ensures that the capsule is deployed to the correct distance in the oesophagus or stomach, wherein it can collect samples. In use, the distal end of the thread is swallowed with the capsule, while the proximal end of the device for collecting cells can be retained by an operator (either the patient themselves, or another person such as a doctor or nurse). In other words, the proximal end of the thread is proximal to the operator in use, and the distal end Is distal from the operator in use. The proximal end of the thread may be configured for tethering to an applicator device by comprising a length of the thread which is not included in the bundled portion, which may be tied or otherwise secured to the applicator device in use. Preferably, the number of turns wound in a first direction is within 1 turn of the number of turns wound in an opposite second direction. If the number of turns in each direction is equal, then the torsion introduced by each turn is counteracted by a reverse torsion introduced by a corresponding counter-turn, such that the net torsion in the thread is zero. However, for reasons of practicality in some examples it may be more convenient to have an additional turn in one direction. For example, the length of the portion of bundled thread may lend itself to an unequal number of turns in each direction, such as 10 clockwise turns and 11 anticlockwise turns. Optionally, each turn winds through an angle of less than 180 degrees, such that the portion comprises a concertina configuration, otherwise known as a zig-zag configuration. In a concertina configuration, in the bundled state the thread does not cross over itself, but rather forms an undulating path. Each turn is wound around a different winding axis in space. The thread in a concertina bundle may be bundled in a flat plane, such that the normal to the plane is parallel to the winding axes. Optionally, each turn winds through an angle of between 180 and 360 degrees, such that the portion comprises a figure-eight configuration. Since each turn is greater than 180 degrees, the thread crosses over itself in the bundled state, forming the figureeight. The turns in one direction are wound around a first winding axis, and the turns in the opposite direction are wound around a second winding axis which is offset in space from the first axis. The thread may be successively wound from one winding axis back to the other, so as to form a stacked figure-eight configuration. Figure-eight bundling provides a number of advantages over other bundling configurations. The process of creating figure-eight patterns involves relatively simple alternating looping of the thread, which can be automated for mass production to a greater extent. This can lead to lower production costs and more consistent bundling results. The figure-eight pattern can also distribute the stress and tension along the length of the thread more evenly. This reduces the risk of introducing twists due to stretching or bending. The loops in a figure-eight pattern provide natural pivot points, making a bundle easier to bend and route in tight spaces without putting excessive strain on the thread. Figure-eight bundling may also inherently provide a level of strain relief because of the looped design. This can help prevent thread damage due to movement or friction as the thread is wound or unwound. Figure-eight bundling also provides advantages compared to concertina bundling. Figure-eight bundling may be easier and more cost-effective to manufacture compared to concertina bundling, due to the simpler looping method required. Figure-eight bundling tends to be less prone to tangling compared to concertina bundling. The structured loops prevent thread from getting entangled with each other, reducing the likelihood of knots and snags as the thread is wound or unwound. Figure-eight bundling can be more space-efficient than concertina bundling, as the loops allow for compact bundling while maintaining flexibility, which can be advantageous in applications with limited space as in the case of the applicator. In other examples, the thread may be wound in a braided pattern which is effectively an extended figure-eight. This involves winding the thread in a first turn around a first winding axis through an angle of between 180 and 360 degrees, then around a second winding axis of less than 180 degrees, then around a third winding axis through a turn of between 180 and 360 degrees, with the direction of winding around alternating between each successive turn (e.g. turns around the first and third winding axis being clockwise, and turns around the second winding axis being anticlockwise). This braiding pattern can be extended for additional winding axes, with the first and last winding axes being wound with turns through between 180 and 360 degrees and the intervening axes being wound with turns of less than 180 degrees. In both the concertina and figure-eight configurations, each turn is followed by a turn in the opposite direction around a different winding axis. This ensures that there is no net buildup of torsion in the thread. It will be appreciated that the thread may be wound in any other suitable pattern in which the thread comprises a series of turns around one or more virtual winding axes with the direction of winding around said axes alternating between successive turns. Preferably, the one or more winding axes are a plurality of winding axes which are oriented parallel or substantially parallel to each other. That is, all the winding axes extend in the same direction. This may simplify manufacture of the bundled portion. In a further example, there comprises a swallowabie device for collecting cells comprising: a swallowabie capsule; and a retrieval thread tethered to the swallowable capsule at a distal end of the thread, with a distal end of the thread configured for tethering to an applicator device, and a portion of the thread configured in a bundled state for bundling together with the swallowabie capsule, wherein the portion is wound in the bundled state in an over-under configuration. In a conventional helical coil the thread is continually wound over itself, such that in a cable wound from a proximal end to a distal end, the proximal end of the thread in each loop (that is, the end of the loop closer along the thread to the proximal end of the thread) of the coil passes adjacent the distal end of the thread in the loop (that is, the end of the loop closer along the thread to the distal end of the thread), and vice-versa for a thread wound from a distal end to a proximal end). This is simply an alternative way of defining the pitch of the helix which the coil forms. In an over-under configuration (sometimes referred to as a countercoiling or flip-coiling configuration), the thread is wound in alternating over-loops and under-loops around a winding axis, such that the proximal end of the thread in an over-loop passes adjacent the distal end of the thread in the loop, and in under-loops the proximal end of the thread is wound under the distal end of the thread in the loop. The over-under configuration also minimises torsion in the portion of the retrieval thread. The thread twists in a first direction around its length in an over-loop, inducing torsion in a first direction, but this is counteracted by the successive under-loop, which twists the thread in the opposite direction and provides a counter-torsion. The over-under configuration thus constitutes an alternative example of the invention which provides the same technical effect in order to solve the same problem identified by the inventors. In a further example, there is provided a swallowabie device for collecting cells comprising: a swallowable capsule; and a retrieval thread tethered to the swallowabie capsule at a distal end of the thread, with a distal end of the thread configured for tethering to an applicator device, and a portion of the thread configured in a bundled state for bundling together with the swallowable capsule, wherein the portion is wound in the bundled state such that there is no net twist around the thread from a distal end of the portion to a proximal end of the portion. In a further example, there comprises a swallowable device for collecting cells comprising: a swallowable capsule at least partially filled with a weighting material; and a retrieval thread tethered to the swallowable capsule at a distal end of the thread, with a distal end of the thread configured for tethering to an applicator device, and a portion of the thread configured in a bundled state for bundling together with the swallowable capsule. By itself, the swallowable capsule and its contents may have a low density, meaning that its weight is low compared to any resistance forces as it is swallowed (e.g. friction forces as the capsule moves past the walls of the oesophagus or other particies / fluid in the oesophagus). These resistance forces can therefore significantly affect the trajectory of the capsule as it is swallowed, increasing the time it spends in the oesophagus or even causing it to become stuck, causing discomfort to the patient in either case. Including a weighting material within the capsule increases its weight without significantly increasing its volume, ensuring that the capsule drops down the throat without slowing down or deviating from its trajectory under resistive forces. The increased weight of the capsule compared to the retrieval thread also increases the tension in the retrieval thread as the capsule is swallowed and retrieved. This reduces the likelihood of the bundle expanding in a lateral direction and / or becoming entangled around itself or another object. Preferably, the weighting material comprises polythene glycol. Polythene glycol is which non-toxic, inert and soluble in water, meaning that it can be harmlessly released into the body when the capsule opens. Preferably, the capsule houses an abrasive material for collecting cells, preferably a sponge material. The swallowable capsule may be configured to dissolve or open after a period of time within the patient's body or when the capsule reaches a specific part of the oesophagus or stomach, releasing the abrasive material. The abrasive material is then used to scrape cell samples off the internal lining of the body. A sponge material can also absorb liquid samples from the body, such as mucus or stomach acid. Preferably, the distal end of the retrieval thread is tethered to the contents of the capsule, such as an abrasive material as described above, such that when the solid capsule dissolves or opens, the contents are is retained at the distal end of the retrieval thread, whereupon they can be withdrawn up the oesophagus. Preferably, the bundled state the portion is located along the thread proximal or adjacent to the distal end of the thread. This ensures that the bundled portion can be easily swallowed with the capsule, preferably in a single swallowing action. Preferably, the portion of the retrieval thread has a length of at least 450mm. This allows the capsule to drop all the way down the patient's throat, while the proximal end of the thread is retained outside the patient's mouth. In a further example, there is provided a packaging apparatus for administering a swallowable device for collecting cells to a patient, comprising the swallowable device for collecting cells as described herein, and an applicator device tethered to a proximal end of the retrieval thread and configured to releasably stow the device for collecting cells and portion of the retrieval thread for direct administration to the patient. Optionally, the applicator device comprises a mechanical release mechanism for administering the device for collecting cells, facilitating smooth deployment of the device for collecting cells without twisting or deforming the bundied retrieval thread. In a further example, there is provided a method of administering a swallowable device for collecting cells as described herein, comprising the steps of: depositing the bundle and capsule in a patient's mouth; causing the patient to swallow the capsule and bundle, while the distal end of the retrieval thread is retained; collecting a cell sample from an interna! region of the patient using the swallowable capsule, and retrieving the swallowable capsule by withdrawing the distal end of the retrieval thread from the patient's mouth. According to a further example, there is provided a method for manufacturing a swallowable device for collecting cells, comprising the steps of: tethering a swallowable cell capsule to a distal end of a retrieval thread; and bundling a portion of the retrieval thread by winding a plurality of turns around a winding axis, alternating the direction of winding around the winding axis for each successive turn. These steps may be performed in a different order to that in which they are set out. For example, the thread may be bundled before the distal end of the thread is attached to the swallowable capsule. To attach the device for collecting cells to an applicator device, the method may further comprise the steps of: stowing the capsule and portion of the retrieval thread within the applicator device; and tethering a proximal end of the retrieval thread to the applicator device. These steps may also be performed in a different order. For example, the proximal end of the retrieval thread may be tethered to the applicator device before the device for collecting cells is stowed. Preferably, the portion is bundled using a winding apparatus. A winding apparatus simplifies manufacture / assembly of the device for collecting cells, as it enables an operator to wind the thread into a desired configuration more quickly and with greater repeatability. Optionally, the winding apparatus comprises a pair of winding posts protruding in parallel from a surface of the winding apparatus such that the posts define the winding axis, and the portion is bundled by winding a figure-eight pattern around the winding posts. Winding a figure-eight pattern may comprise alternately winding the retrieval thread in a first direction around the first winding post, and then winding the retrieval thread in an opposite direction around the second winding post. For example, the thread may be wound clockwise around the first winding post, and anticlockwise around the second winding post. The winding apparatus may comprise a cutout or indentation on the surface of the winding apparatus between the winding posts. This allows the operator to grasp the thread from opposing sides (either with their fingers, or with a tool), in order to retrieve the bundled thread from the winding apparatus. The separation distance between posts may be between 1cm and 3cm in width, with the cutout being equal in width or narrower. This provides sufficient room for a user's finger to be positioned between the posts, allowing the user to pinch the thread with their fingers and then remove it from the winding apparatus. Optionally, the winding apparatus may instead comprise: a pair of opposing trapping regions, the width of each trapping region providing an interference fit with the retrieval thread, and a gap separating the trapping regions, and the portion is bundled by winding the retrieval thread in a concertina pattern across the gap and through the trapping regions. Winding the concertina pattern may comprise, alternately, for each trapping region: pulling the retrieval thread through the trapping region from a gap-facing inner side of the trapping region to an outer side of the trapping region, such that the thread is held in place by the interference fit with the trapping region; pulling the retrieval thread back through the trapping region from the outer side of the trapping region to the inner side, such that the thread is held in place by the interference fit with the trapping region; and extending the thread across the gap to the gap-facing inner surface of the other trapping region. The gap may have a with of between 1 and 3cm in width, allowing a user to insert their fingers into the gap, and then pinch their fingers around the bundled thread to retrieve the bundle from the winding apparatus. Preferably, the winding apparatus comprises a capsule retainer for locating the swallowable capsule during winding. The capsule retainer may actively retain the capsule in place, for example by means of a clasp comprising a resilient member, which grips the capsule or the distal end of the retrieval thread. Alternatively, the capsule retainer may be a pocket or indentation which conforms around the shape of the capsule or the distal end of the retrieval thread, so as to assist a user in locating the capsule in place. For example, a user may place the capsule in the pocket, and then hold it in place using a finger while they wind and bundle the retrieval thread. According to a further example, there comprises a method for manufacturing a packaging apparatus for administering a swallowable device for collecting cells, comprising the steps of: tethering a swallowable cell capsule to a distal end of a retrieval thread; bundling a portion of the retrieval thread by winding a plurality of loops around a winding axis in an over-under pattern; stowing the capsule and portion of the retrieval thread within an applicator device; and tethering a proximal end of the retrieval thread to the applicator device. Preferably, the portion is bundled using a winding apparatus, the winding apparatus comprising: a winding surface defining the winding axis and tapering from a wide end to a narrow end; and a capsule retainer proximal the narrow end of the winding surface, and the portion is bundled by winding the retrieval thread in an over-under pattern around the winding surface. The winding surface is tapered, such that in use the end of the winding surface closer to the location of the capsule is narrower. This enables the wound bundle to be removed from the winding apparatus by displacing it along the winding axis towards the narrow end of the winding surface, i.e. towards the capsule. Hence, the capsule and wound bundle can be removed from the winding apparatus by pinching the capsule and wound bundle together, and then pulling both off the narrow end of the winding surface. The cell capsule, thread, winding pattern and / or applicator device used in the methods described above may comprise any of the optional features of such components described herein with reference to other examples of the invention. According to further examples, there are provided various winding apparatuses as described herein. The applicator device may be elongate and / or may have a handle at one end and a means for stowing the device for collecting cells and portion of the retrieval thread at an opposite end. This may enable the operator to position the device for collecting cells at the back of the patient's tongue using the handle, providing good control of the distal end of the applicator without the operator needing to insert their fingers into the patient's mouth. Providing a mechanical release mechanism for administering the device for collecting cells advantageously allows the operator to release a device for collecting cells stowed at distal end of the applicator device by means of a control located at a proximal end of the applicator device. Thus, the operator can correctly position the distal end of the applicator device within the patient's mouth, and then release the device for collecting cells, without having to remove the applicator device or insert their fingers into the patient's mouth. Although the apparatus has been described in relation to cell collection for the TTF3 test, it will be understood that that it is also suitable for other applications. For example, the apparatus can also be used to collect cell samples or other material from the oesophagus for other kinds of test, such as those used for cytological, histological, or molecular analysis. Providing a sufficiently long retrieval thread ensures that the capsule will travel all the way into the stomach before the sponge is released. The apparatus can then be used to collect samples of the stomach lining or contents (e.g. a sample of stomach acid), before being retrieved by withdrawal up the oesophagus. In still other embodiments, appropriately adapted embodiments of the invention may be used to release probes into body cavities other than the mouth. For example, a device for collecting cells may be inserted though a nostril, in order to release a probe which can then collect samples from inside the nasal cavity or pharynx. In another example, a device for collecting cells may be inserted though a patient's anus, releasing a probe which can collect samples from the patient's rectum and / or sphincter. The design of the device for collecting cells may be adapted for different orifices. For example, the capsule of a device for collecting cells for insertion into the nostril may be physically smaller than one for insertion into the mouth, and the retrieval thread may be shorter in total length and made of a finer thread. A device for collecting cells may also be adapted for use on animal subjects. This may involve using a tougher swallowable capsule, for example, which can resist being bitten by an animal's teeth. Brief description of the drawings Figure 1 shows a section of a thread, coiled in the conventional manner as a helix. Figure 2 shows a device for collecting cells comprising a portion of retrieval thread bundled in a figure-eight configuration. Figure 3 shows a device for collecting cells comprising a portion of retrieval thread bundled in a concertina configuration. Figure 3a shows the bundled portion expanded to show its geometry, while Figure 3b shows the bundle as it would be packaged. Figure 4 shows a device for collecting ceils comprising a portion of retrieval thread bundled in a concertina configuration. Figure 4a shows the bundled portion expanded to show its geometry, while Figure 4b shows the bundle as it would be packaged. Figure 5 is a flow chart illustrating a method for manufacturing a device for collecting cells for incorporation into a packaging apparatus. Figures 6a and 6b show isometric views of a winding apparatus for use in manufacturing a device for coilecting ceils with an figure-eight configuration bundle. Figures 7a and 7b show isometric views of a winding apparatus for use in manufacturing a device for collecting ceils with a concertina configuration bundle. Figures 8a and 8b show isometric views of a winding apparatus for use in manufacturing a device for collecting ceils with an over-under configuration bundle. Figure 6a, 7a, and 8a additionally show the position of the capsule and retrieval thread on the respective winding apparatus, in use. Figures 9a and 9b respectively show plan and side, views of an example of a packaging apparatus for releasing a device for collecting cells; Detailed description Turning to Figure 1, a section of a coiled thread 110 is shown. The thread 110 is coiled around a winding axis W, with a winding direction D which is clockwise when looking along the direction of the winding axis W. The coiling of the thread 110 induces a twist T around the axis 110a of the thread 110 itself. Since the thread 110 is resilient, the twist T of the thread induces a torsion force which acts to oppose the twist T and return the thread to an uncoiled state. For every turn of the coil, the thread 110 twists further and the opposing torsion force increases. For the purposes of illustration, the thread is shown as having a polygonal cross-section rather than circular. The twist T of the cable can be seen from the angle a made between the winding axis W and the side 110b of the polygonal cross-section. As the thread 110 coiis around the winding axis W, the angle a increases in the anticlockwise direction around the thread axis 110a, due to the twist T, from al to o2 to a3. Turning to Figure 2, an example of a device for coilecting cells 200 is shown, comprising a capsule 201 tethered to the distal end 210d of a retrieval thread 210. The proximal end 210p of the retrieval thread 210 is configured for attaching to an applicator device (not shown). A portion 211 of the retrieval thread 210 is bundled in a configuration with a plurality of turns in alternating directions around respective winding axes. In the example shown in Figure 2, this is a figure-eight configuration. In the figure-eight configuration, the bundle consists of turns 203 of between 180 and 360 degrees wound alternately around a first winding axis 202a and a second winding axis 202b. The winding axes 202 are perpendicular to the page and substantially parallel to each other, and are defined as pointing out of the page. The turns 203a around the first winding axis 202a are anticlockwise, and the turns 203b around the second winding axis 202b are clockwise. A plurality of turns 203 are wound around each of the winding axes 202, with each turn 203 preceded and succeeded by a turn 203 in the alternate direction. As a result, the net torsion in the retrieval thread 210 is minimised at any point aiong its length. When the device for collecting ceils is released, the bundled portion 211 is thus more likely to unwind smoothly along its whole length, without becoming tangled in itself. The capsule 201 (contents not shown) comprises a sponge in a packaged state within a releasable housing or casing. In preferred embodiments, in its closed state the capsule 201 has a length in the range from 23 to 24mm, smaller than the standard size 00 capsule which is known to be easily swallowable for most patients. The capsule may have an internal volume of at least 1ml, providing space for the sponge. The capsule casing may be translucent or opaque, so that the patient is not distressed by seeing the sponge contained within as they prepare to ingest the capsule 201. The capsule wall may be formed of Hydroxypropyl Methylcellulose (HPMC), or other nontoxic material. Once swallowed and ingested into the stomach, the capsule wall dissolves or splits open to release the sponge. The capsule wall may be formed as a single part, or alternatively the capsule wall may be formed from multiple components to allow it to split open. As well as the sponge, the capsule 201 may contain a weighting material such as polythene glycol, to increase the overall density of the capsule and provide it with sufficient weight to drop cleanly down the patient's oesophagus. The retrieval thread 210 may be formed from polyester surgical suture thread, or other non-toxic material. The thread 210 may be formed of a single thread, or of multiple threads braided together. The retrieval thread 210 may have a total length ranging from 10cm to 40cm. The capsule 201 may comprise a small opening, through which the retrieval thread 210 can pass to connect to the sponge. In some examples, during assembly the sponge may be tethered to the retrieval thread 210, and then the capsule formed around the sponge and thread 210, such that the capsule forms around the thread 210 with no opening. Turning to Figures 3a and 3b, another example of a device for collecting ceils 300 is shown, comprising a capsule 301 tethered to the distal end 310d of a portion of retrieval thread 310. The proximal end 310p of the retrieval thread 310 is configured for attaching to an applicator device (not shown). A portion 311 of the retrieval thread 310 is bundled in an alternative configuration with a plurality of turns in alternating directions around respective winding axes. In the example shown in Figure 2, this is in a zig-zag or concertina configuration. In the concertina configuration, the bundle consists of turns 303 of approximately 180 degrees wound alternately around a first set of winding axes 302a and a second set of winding axes 302b. The winding axes 302 are perpendicular to the page and substantially parallel to each other, and are defined as pointing out of the page. The turns 303a around the first set of winding axes 302a are anticlockwise, and the turns 303b around the second set of winding axes 302b are clockwise. Note that the winding axes 303 may be virtual, in the sense that the thread 310 is not necessarily wound around a physical surface to achieve the concertina configuration and / or may be held in the configuration without physical axes extending through the turns. Due to the length of thread 310 in the example shown, there are three clockwise turns 303a and four anticlockwise turns 303b, It will be appreciated that other examples may comprise any number of turns, but the number of turns in one direction is preferably close to the number of turns in the opposite direction in order to minimise the net torsion. More preferably the number of turns in the first direction is equal to, or within one of the number of turns in the opposite direction A plurality of turns 303 are wound around each of the winding axes 302, with each turn 303 is preceded and succeeded by a turn 303 in the alternate direction. As a result, the net torsion in the retrieval thread 310 is minimised. The winding axes 302 in each set of winding axes 302a, 302b are parallel and aligned along a straight line, such that the bundled portion 311 is flat and forms a regular pattern. This further minimises twisting in the bundled portion 311. Figure 3a shows the concertina configuration expanded in order to more clearly demonstrate the positions of the winding axes 302a, 302b, In use, the bundled portion is preferably arranged in a more compact arrangement wherein the alternating turns contact each other along their length, as shown in Figure 3b. Turning to Figure 4, another example of a device for collecting cells 400 is shown, comprising a capsule 401 tethered to the distal end 410d of a portion of retrieval thread 410. The proximal end 410p of the retrieval thread 410 is configured for attaching to an applicator device (not shown). A portion 411 of the retrieval thread 410 is bundled in an over-under configuration. As can be seen in Figure 4b, in an over-under configuration the bundle 411 comprises alternating over-loops 403a and under-loops 403b. In an over-loop 403a, the proximal end of the thread in the loop passes over the distal end of the thread in the loop, in the sense that at the crossing point of the over-loop 404a the proximal end of the thread in the loop is above the distal end of the thread in the loop relative to the plane of the page. In an under-loop 403b, the proximal end of the thread in the loop passes under the distal end of the thread in the loop, in the sense that at the crossing point 404b of the under-loop the proximal end of the thread in the loop is below the distal end of the thread in the loop relative to the plane of the page. Each over-loop 403a twists the thread in one direction about the axis of the thread, inducing torsion. However, each successive under-loop 403b twists the thread in the other direction around the axis of the thread, counteracting the torsion. For the purpose of clarity, only a single over-loop and single under-ioop is shown in Figure 4a, but in other examples the bundle 411 may comprise a plurality of over-loops 403a and a plurality of under-loops 403b, alternating successively. In use, as shown in Figure 4b, the bundle 411 may appear like a conventionally wound coil. The over-loops 403a and under-loops 403b may be wound around a common winding axis 402, using known winding techniques for winding over-under configurations, such as those used for winding electrical cables. However, carefully unwinding the bundle 411 permits the over-under configuration of Figure 4a to be seen. An example of a method 500 for manufacturing a device for collecting cells will now be described with reference to Figure 5. In step 501, a swallowable cell capsule is tethered to a distal end of a retrieval thread. In step 502, a portion of the retrieval thread is bundled. In some examples, the portion of the retrieval thread is bundled 502 by winding a plurality of turns around one or more winding axes, alternating the direction of winding around the winding axes for each successive turn. This may produce either a concertina or figure-eight bundle configuration as described above, depending on whether the angle of the turn is more (figure-eight) or less (concertina) than 180 degrees. In other examples, the thread is bundled 502 in an over-under configuration as described above. A winding apparatus may be used to facilitate the bundling step. In step 503, the bundle is arranged with the capsule (for example proximal or adjacent to the capsule) as a device for collecting cells, ready for connection to and / or insertion into an applicator device. The bundle may be found to be of approximately the same length of the capsule to facilitate holding or packing the bundle along with the capsule. To form a packaging apparatus, in step 504 the proximal end of the retrieval thread is tethered to an applicator device. In step 505, the device for collecting cells including the capsule and bundled portion are stowed within the applicator device, ready for deployment. It will be appreciated that steps 503 to 505 are optional. For example, in some embodiments, only steps 501 to 503 may be performed in order to provide a cell collection device separate from an applicator device. Figures 6a to 8b show examples of winding apparatus 600, 700, 800 for use winding a bundled portion of a retrieval thread as described above in step 502 of the method 500. Figures 6a and 6b show a winding apparatus 600 for winding the portion in a figureeight pattern. The winding apparatus 600 comprises a pair of winding posts 606, around which the retrieval thread 610 is wound in a figure-eight pattern. In other words, the central axis of each winding post 606 defines a winding axis as the thread is being wound. In some examples, the thread is wound in a clockwise direction around the first winding post 606a, and in an anticlockwise direction around the second winding post 606b. The winding posts 606 are tapered, so as to enable the thread 610 to be easily pulled off the posts 606 once wound into a bundle. It will be appreciated that after the thread 610 is wound, it may be removed from the winding apparatus 600, after which point the alternating turns will be defined around virtual winding axes. A capsule retainer 605 is used to locate the capsule 601 and keep it in place while the thread is wound. The capsule retainer 605 comprises an indentation which is substantially the same shape as the capsule 601, into which the capsule can be fitted. A hole 605a at the back of the capsule retainer 605 allows a user to push the capsule out of the indentation when the thread 610 has been wound into a bundle. The winding apparatus 600 comprises a cutout 607 to enable a user to pinch the bundled thread 610 from the top and bottom, in order to remove it from the winding apparatus while retaining the figure-eight configuration. The cutout 607 is larger than a finger's width (e.g. 1cm to 3cm), to provide space for a user's finger. Figure 7 shows a winding apparatus 700 for winding the retrieval thread in a concertina pattern. The winding apparatus 700 comprises a pair of opposing trapping regions 706a, 706b. The trapping regions 706 are opposing in the sense that they face each other, separated by a gap 706. The trapping regions 706 each comprise a slot which is sized so as to provide an interference fit with the retrieval thread. That is, the sides of the slot in the trapping regions 706 pinch the thread 710 tightly enough to prevent the thread 710 from sliding out or along the slot, or otherwise being inadvertently dislodged, but not so tightly as to prevent the thread from being pulled through the slot during winding, or during retrieval of the wound bundle from the winding apparatus 700. In the example shown, the trapping regions 706 are both arranged along an arm 708, which is curved back on itseif so that the trapping regions 706 are opposing one another. In other examples, the trapping regions 706 may be arranged on separate arms. A capsule retainer 705 shaped to the profile of the capsule 701 is used to locate the capsule 701 in place during bundling. The slots have a common open end 709 towards the capsule retainer 705. Winding the concertina pattern may comprise: first, pulling the retrieval thread 710 through the first trapping region 706a from the gap-facing inner side of the trapping region 706a (i.e. the inside of the arm 708) to the outer side of the trapping region (i.e. the outside of the arm 708), such that the thread 710 is held in place by the interference fit with the trapping region 706a; pulling the retrieval thread 710 back through the trapping region 706a from the outer side of the trapping region 706a to the inner side, such that the thread 710 is held in place by the interference fit with the trapping region 706a; and extending the thread 710 across the gap 707 to the gapfacing inner surface of the second trapping region 706b. This process is then repeated, alternating the first 706a and second 706b trapping regions, until the concertina pattern is wound for some or the whole of the length of the slots in the trapping regions 706. Using their fingers, the user then pinches the bundled portion of the thread stretching between the trapping portions 706, and pulls the bundled portion out of the common open end 709 of the slots, such that the concertina configuration is maintained. Figure 8 shows a winding apparatus 800 for winding a bundle in an over-under pattern. The winding apparatus 800 comprises a capsule retainer 805 configured to provide an interference fit with the retrieval thread 810. The distal end of the thread 810, proximal the capsule 801, is inserted into the capsule retainer 805, thereby inhibiting movement of the capsule 801. The winding surface 806 of the winding apparatus defines a winding axis 803. The winding surface 806 tapers from a wide end 806b to a narrow end 806, with the capsule retainer 805 proximal the narrow end 806a. The retrieval thread 810 is wound in an over-under pattern around the winding surface 806. To remove the bundled portion 811 of the retrieval thread 810 from the winding apparatus 800, the user slides the bundled portion 811 of thread 810 towards the narrow end 806a of the winding surface 806, i.e. towards the capsule retainer 805. The tapering of the winding surface 806 facilitates easy removal of the wound bundle 811. Turning to Figure 9, an exemplary packaging apparatus 900 comprises a device 900b for collecting cells as described above and an applicator device 900a for administering the device 900b. The applicator device 900a comprises an elongate main body 901 and slider 902. The main body 901 has a handle 901a at a proximal end enabling the user to precisely position the applicator device 900a in the mouth. The slider 902 is configured to slide relative to the main body 901 of the applicator device 900a. In preferred embodiments, the applicator device 901 is substantially larger than a size 000 capsule, the largest size of capsule which can be readily swallowed. This ensures that the applicator device 900a itself is not inadvertently swallowed or lost in the patient's mouth. All parts of the apparatus 900 are configured to lack sharp edges which could cause discomfort or injury to the patient. The capsule 908 and retrieval thread 910 together form the swallowable device for collecting ceils 900b. The capsule is shown in dotted lines as it and the bundled portion 911 of retrieval thread 910 are not visible in plan and side view before deployment. The retrieval thread 910 connects the capsule 908 to the applicator device 900a, allowing the applicator device to be used to pull the sponge back out of the patient. A proximal end of the thread 910 is tethered to the applicator device, such that the thread 910 is securely attached to the applicator device 900a but without impeding the deployment of the thread 910 as the slack extends. The swallowable capsule 908 is packaged with a bundled portion 911 of the retrieval thread 910 in a chamber 905 at a distal end of the main body 901 of the applicator device 900a. In the example shown, the bundled state of the portion 911 is a figureeight configuration, but in other examples the bundled state could be a concertina or over-under configuration, as previously described. In use, the bundled portion 911 of thread 910 is released with the capsule 908 at the back of the patient's tongue towards the opening to the oesophagus, well dear of the patient's teeth or the applicator device 900a itself. This reduces the risk of the thread becoming entangled prior to or during ingestion. The bundled portion 911 is positioned to the side of the capsule 908 within the chamber 905, reducing the risk of the thread becoming entangled with the capsule 908 as it is released. The length of thread 910 bundled in the portion 911 may be at least 450mm, providing sufficient length for the sponge to travel down the entire length of the oesophagus into the stomach. The walls of the chamber 905 may be formed by an upper chamber wall 904a on the main body, and a lower chamber wall 904b on the slider 902. While the slider 902 is fully extended (i.e., translated towards the distal end of the device 900a), the capsule 910 and bundled portion 911 of thread 910 are stowed and retained within the chamber 905. To reiease the capsule 908 and portion 911 of thread 910, the slider is retracted to open the chamber 905 (i.e., translated towards the proximal end of the device 900a). The upper chamber wall 904a on the main body 901 holds the capsule in place as the lower chamber wall 904b is retracted with the slider 902. The slider 902 may comprise a thumb grip 903a at the proximal end of the slider 902, which is configured to slide along a groove 903b in handle 901a of the main body 901. By pulling back the thumb grip 903a with their thumb (or with any other finger, according to the operator's preferred grip of the handle 901a), the operator can slide the thumb grip 903a from the forwards stowed position to the backwards released positions, thereby retracting the slider 902. A method of administration will now be described in detail. First, the apparatus 900 is partially inserted into a patient's mouth, with the distal end of the applicator device 900a including the chamber 905 positioned behind the patient's teeth, and the proximal end of the applicator device 900a is positioned outside of the patient's mouth in front of the patient's front teeth. The apparatus 900 is positioned so that the handle 901a of the main body 900a protrudes from the patient's mouth such that the operator can grasp the handle 901a without needing to place their hands or fingers inside the patient's mouth. Once the apparatus 900 is in position, the operator (typically a clinician such as a nurse) slides the thumb grip 903a backwards along the groove 903b, thereby retracting the slider 902. This causes the lower chamber wail 904b to retract, opening the chamber 905. The capsule 908 and portion 911 of thread 910 is released to drop onto the back of the patient's tongue. The slider mechanism allows the bundled portion 911 to be released without twisting or distorting the bundled thread, and thereby introducing torsion into the thread 910 which could induce tangling. The patient can then swallow the capsule 908 along with at least part of the bundled portion 911. Once the capsule 908 is swallowed, it travels down the oesophagus on the end of the length of thread 910. The capsule 908 may travel all the way down to the patient's stomach. The operator retains the capsule 908 by means of the thread 910 attached to the applicator device 900a. The operator or patient holds the applicator device 900a steady, for example by holding the applicator device 900a against the patient's cheek. After a period has elapsed (typically several minutes) the capsule wall dissolves or otherwise opens to release the sponge. The sponge is then pulled up the oesophagus by pulling back the applicator device 900a so as to withdraw the thread 910 from the patient. As the sponge is pulled up the oesophagus, it collects cell samples from the 5 walls of the oesophagus, as is understood in the art. The operator continues to withdraw the sponge out of the oesophagus, through and out of the mouth of the patient. The TTF3 test can then be carried out on the cells collected by sponge in the conventional manner. Prior to being sent for testing, the sponge may be detached from the rest of the apparatus 900, for example by severing or un-tethering the 10 retrieval thread 910. While certain embodiments have been described above, these embodiments have been presented by way of example, and it will be appreciated that various omissions, substitutions, changes or additions may be made without departing from the scope of 15 the invention as defined by the following claims.

Claims

1. A swallowable device for collecting cells comprising: a swallowable capsule; and5 a retrieval thread tethered to the swallowable capsule at a distal end of thethread, with a proximal end of the thread configured for tethering to an applicator device, and a portion of the thread configured in a bundled state for bundling together with and externally to the swallowable capsule,wherein in the bundled state, the portion contains a plurality of turns around10 one or more winding axes, and the direction of winding around the one or more winding axes alternates between each successive turn.

2. The swallowable device for collecting cells of claim 1, wherein the number of turns wound in a first direction is within 1 turn of the number of turns wound in an15 opposite second direction.

3. The swallowable device for collecting cells of claim 1 or 2, wherein each turn winds through an angle of less than 180 degrees, such that the portion comprises a concertina configuration.

204. The swallowable device for collecting cells of claim 1 or 2, wherein each turn winds through an angle of between 180 and 360 degrees, such that the portion comprises a figure-eight configuration.25 5. The swallowable device for collecting cells of any of claims 1 to 4, wherein theone or more winding axes are a plurality of winding axes which are oriented parallel to each other.

6. A swallowable device for collecting cells comprising:30 a swallowable capsule; anda retrieval thread tethered to the swallowable capsule at a distal end of the thread, with a distal end of the thread configured for tethering to a packaging apparatus, and a portion of the thread configured in a bundled state for bundling together with and externally to the swallowable capsule,35 wherein the portion is wound in the bundled state in an over-underconfiguration.05 09 247. A swallowable device for collecting cells comprising:a swallowable capsule; anda retrieval thread tethered to the swallowable capsule at a distal end of the thread, with a distal end of the thread configured for tethering to an applicator device, 5 and a portion of the thread configured in a bundled state for bundling together with and externally to the swallowable capsule,wherein the portion is wound in the bundled state such that there is no net twist around the thread from a distal end of the portion to a proximal end of the portion.10 8. A device for collecting cells according to any preceding claim, wherein thecapsule houses an abrasive material for collecting cells, preferably a sponge material.

9. A device for collecting cells according to any preceding claim, wherein in the bundled state the portion is located along the thread proximal to the distal end of the 15 thread.

10. A device for collecting cells according to any preceding claim, wherein the portion of the retrieval thread has a length of at least 450mm.20 11. A packaging apparatus for administering a swallowable device for collecting cellsto a patient, comprising the swallowable device for collecting cells of any previous claim, and an applicator device tethered to the proximal end of the retrieval thread and configured to releasably stow the device for collecting cells and portion of the retrieval thread for direct administration to the patient.2512. A method of administering a swallowable device for collecting cells according to any preceding claim, comprising the steps of:depositing the bundle and capsule in a patient's mouth;causing the patient to swallow the capsule and bundle, while the distal end of 30 the retrieval thread is retained;collecting a cell sample from an internal region of the patient using the swallowable capsule, andretrieving the swallowable capsule by withdrawing the distal end of the retrieval thread from the patient's mouth.3513. A method for manufacturing a swallowable device for collecting cells, comprising the steps of:tethering a swallowable cell capsule to a distal end of a retrieval thread; and05 09 24bundling a portion of the retrieval thread externally to the capsule by winding a plurality of turns around one or more winding axes, alternating the direction of winding around the winding axes for each successive turn.5 14. The method of claim 13, wherein the portion is bundled using a windingapparatus.

15. The method of claim 14, wherein the winding apparatus comprises a pair of winding posts protruding in parallel from a surface of the winding apparatus such that 10 the posts each define a winding axis, and the portion is bundled by winding a figureeight pattern around the winding posts.

16. The method of claim 14, wherein the winding apparatus comprises:a pair of opposing trapping regions, the width of each trapping region providing 15 an interference fit with the retrieval thread, anda gap separating the trapping regions,and the portion is bundled by winding the retrieval thread in a concertina patten across the gap and through the trapping regions.20 17. The method of any of claims 14 to 16, wherein the winding apparatus comprisesa capsule retainer for locating the swallowable capsule during winding.

18. A method for manufacturing a packaging apparatus for administering a swallowable device for collecting cells, comprising the steps of:25 tethering a swallowable cell capsule to a distal end of a retrieval thread;bundling a portion of the retrieval thread externally to the capsule by winding a plurality of loops around a winding axis in an over-under pattern;stowing the capsule and portion of the retrieval thread within the applicator device; and30 tethering a proximal end of the retrieval thread to the applicator device.

19. The method of claim 18, the portion is bundled using a winding apparatus, the winding apparatus comprising:a winding surface defining the winding axis and tapering from a wide end to a 35 narrow end;and a capsule retainer proximal the narrow end of the winding surface, and the portion is bundled by winding the retrieval thread in an over-under pattern around the winding surface.

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