Device and method for in vivo cytology acquisition

A device, system and method for cytology acquisition which may be performed with a swallowable in vivo device, specifically with a swallowable endoscopy capsule. The swallowable capsule may comprise a rotatable drum, a brush attached onto the drum for brushing against a tissue and acquiring cytology, and a porthole through which the brush may be in contact with the tissue.

FIELD OF THE INVENTION

The present invention relates to cytology acquisition and to cytology acquisition by a swallowable in-vivo device in particular.

BACKGROUND OF THE INVENTION

Examination of cellular tissue acquired through endoscopes, either by brush cytology or biopsy, has become the most common form of acquisition of tissue from the body, specifically from the gastrointestinal (GI) tract, to assess the presence or absence of cancer or diagnose other forms of cancer. As of today, merely imaging the tissue is not enough in order to assess whether or not the tissue is malignant. Cytology and biopsy may assist in providing better diagnosis of the tissue's condition.

Cytology acquisition and biopsy are the most common form of intervention at flexible endoscopy. However, cytology acquisition and biopsy that are performed through endoscopes may be inconvenient to the patient undergoing the endoscopy procedure. Flexible endoscopes, as flexible as they may be, still cause discomfort during insertion into the patient and have the disadvantage of not being able to reach a large portion of the small bowel and some portions of the colon.

There is, therefore, a need for a device that could enable cytology acquisition and biopsy at any location along the GI tract, in a more patient-friendly procedure.

SUMMARY OF THE INVENTION

The present invention provides a device, system and method for cytology acquisition which may be performed with a swallowable in vivo device, specifically with a swallowable endoscopy capsule.

According to some embodiments of the present invention, a swallowable capsule that may perform cytology acquisition or biopsy may be maneuvered to a region of interest. The capsule may typically be maneuvered by magnetic fields; however, other methods of maneuvering may be used.

In some embodiments, the capsule may include at least one controllably openable and closable porthole behind which is located a cytology brush or a porous material. When the porthole is opened, the cytology brush or porous material may contact a surface of the region of interest. The brush cytology or porous material may be moved, for example by being rotated, against the region's surface so that the brush collects cells from that region's surface, or the porous material absorbs body fluids or collects cells, during movement of the brush/porous material.

In some embodiments, the port through which the brush cytology, or porous material, collects cells may be closed, for example, subsequent to cells collection, so that the brush, or porous material, is not contaminated with fluids and particles that flow in-vivo, other than the acquired cells.

According to some embodiments, after the cells acquisition is completed and the porthole is closed so that the cells are not contaminated, the capsule may be released from the force, which is typically magnetic, that holds the capsule near the region of interest. The capsule may then naturally pass through the GI tract and out of the patient. In other embodiments, the capsule may be attached to a delivery device (e.g., wire), which inserts the capsule in-vivo, and, following completion of the procedure of cytology acquisition or biopsy, the capsule may be extracted (e.g., backwards) through the patient's mouth and out of the patient.

The details of one or more embodiments are set forth in the accompanying figures and the description below. Other features, objects and advantages of the described techniques will be apparent from the description and drawings and from the claims.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Embodiments of the present invention provide devices and methods for cytology acquisition. Typically, the in-vivo device is a swallowable autonomous capsule, which may comprise or be equipped with a mechanism for performing cytology or biopsy acquisition. By “autonomous capsule” is generally meant a capsule capable of being moved in the GI system without using threads, strings, wires, cables, etc., but by peristalsis or by wireless maneuvering.

By “capsule” is generally meant a diagnostic or therapeutic device which is small enough to be swallowed, and which may be encased, for example, in a cylindrical container that may contain an electronic circuit and/or optical components and/or surgery tools, and/or a moving mechanism for operating a tool internally (inside the device) or externally. According to the present invention, such a capsule may also be capable of harvesting tissue cells or tissue specimen (e.g., for performing biopsy or cytology) by using a sampling wheel, and holding the cellular/tissue material usually until the capsule has left the body either naturally (through excretion) or by being retrieved, for example, through the mouth by using, for example, a string or a wire. The capsule may be designed such that the cells/tissue sample(s) harvested by the sampling wheel and momentarily stored in the capsule can be extracted easily for analysis (e.g., by a pathologist) after the capsule is retrieved either through the mouth or through the anus. The sampling wheel may include one or more sampling cavities, each sampling cavity may include or contain a brush, for example as shown inFIGS. 7 and 8, or a porous material (e.g., sponge), for example as shown inFIG. 12. Each sampling cavity may have a porthole through which the brush can scrape tissues, or the porous material can absorb a body fluid or scrape tissues.

A sampling wheel may be static in the sense that it does not have to be rotated in order for a sampling cavity (and a cells/tissue sampling means which it may contain, be it, for example, a brush or a porous material) and a porthole window (through which sampling may take place) to be aligned, because each sampling cavity (and thus each sampling means) typically has its own porthole. A static sampling wheel is shown, for example, inFIGS. 7 and 8, in which the sampling means is a brush. A static sampling wheel may be thought of as a sampling wheel that includes on-board portholes. A sampling wheel may be dynamic in the sense that it has to be rotated in order to align a sampling cavity and a porthole, because the sampling cavities of the sampling wheel use one, common, porthole that is stationary, and the sampling cavities can be used only one sampling cavity at a time. A dynamic sampling wheel may be thought of as a sampling wheel that does not include an on-board porthole but rather uses a porthole window in the capsule's shell (A dynamic sampling wheel is shown, for example, inFIGS. 11 and 12.

Although using an autonomous cytology capsule has advantageous, for example such a capsule may take cells/tissue samples from inside the GI system or other parts of the body without patient discomfort, the capsule may be connected to a thread, cable or wire by which it may be pulled out, for example, through the mouth. That is, the capsule may be swallowed with a thread attached thereto, and used, for example, to ‘brush’ the cardio-esophageal junction when it reaches the mucosal junction between the stomach and the esophagus—usually between 35-40 centimeters from the teeth—and then withdrawn to look for evidence of Barratt's tissue or cancer. The capsule may include an image sensor, but knowing the length of the esophagus may render the image sensor unnecessary. A capsule without an image sensor may take random specimens from the small intestine looking for diffuse abnormalities such as celiac disease in the proximal intestine, Crohn's disease in the lower small intestine, colitis in the colon, etc. The sampling wheel of the cytology capsule may be operated (e.g., rotated) in various ways as described herein (e.g., by using external magnet, external electromagnetic field, spring, or motor), though other methods for operating the sampling wheel may be used.

Reference is now made toFIGS. 1 and 2, which illustrate a schematic upper view of a cytology capsule100and a schematic exploded view of cytology capsule100, respectively, in accordance with an embodiment of the present invention. In some embodiments, cytology capsule100may be suitable for acquiring cytology in tubular regions of the GI system. Capsule100may comprise a shell101attached to two ends, or domes,102(one on each side of shell101), each typically shaped as a cone. In some embodiments, capsule100may comprise a drum-like sampling wheel105(or “drum”, for short). Drum105may be rotated around the longitudinal axis of capsule100. Capsule100may comprise one or two spindles103around which drum105may rotate. Drum105may have attached to it a cytology brush107which, when moved against a tissue surface, may acquire cells from the (scraped) tissue. Capsule's shell101may comprise an opening, window or porthole104through which the cytology brush107may contact and scrape the tissue. Typically, the cytology brush107attached to drum105may be rotated around the longitudinal axis of capsule100, along which spindles103are mounted.

According to embodiments of the invention, following insertion of capsule100into the patient's GI tract, capsule100may be magnetically maneuvered to a region of interest. Capsule100may, therefore, comprise a magnetic element (the capsule's maneuvering magnet is not shown) which may enable capsule100to be manipulated (e.g., steered) by an external magnet or by an external magnetic field to a region of interest, from the tissue of which the physician might want to acquire cells for later examination when the capsule exits from within the patient. Once the external magnet is distanced away from the patient's body, or the external magnetic field is deactivated or shut down, capsule100may continue to move in the GI system using peristaltic force.

Capsule100may comprise an internal magnet106positioned within drum105, which may enable drum105to be manipulated by an external magnet (the external magnet is not shown), such as to rotate drum105and cytology brush107, such that porthole104and cytology brush107are in alignment when capsule100is in contact with the surrounding tissue and cells acquisition is required. In the absence of an external magnetic field, magnet106and a biasing magnet108may be so arranged so that, in a resting position, cytology brush107is not in alignment with the porthole104, but rather a certain degrees, for example, 180 degrees, away from the porthole104, and porthole104may be effectively closed by drum105. By “resting position” is meant a non-sampling position, or a position in which no cells' harvesting/acquiring is performed.

Once the region of interest is reached, a sufficiently powerful external magnet (the external magnet is not shown) may be brought up or in proximity to the patient and maneuvered (e.g., rotated), in order to cause drum105to rotate so that brush107passes over and is in alignment with porthole104. Once brush107has passed across porthole104and brushes against the tissue at the region of interest, the external magnet may be withdrawn and distanced away from the patient to allow biasing magnet108to “park”, or lock, the brush107away from porthole104. For example, the brush107may be angularly displaced or moved, for example 180 degrees, away from porthole104. In some embodiments, if brush107is parked away from porthole104, drum105may effectively close porthole104, for example to prevent contaminants from entering cytology capsule100(e.g., drum105), and/or harvested cells from leaking out. In some applications the cytology capsule may reside in the GI system for hours, during which time harvested cells (or harvested tissue sample(s)) may deteriorate. In order to prevent deterioration, degradation or decaying of harvested cells or harvested tissue samples, the cytology capsule may include a container for storing a cell/tissue preservative, a material that has a desiccating and antibacterial effect, a Polyethylene glycol, an ethyl alcohol, etc. An injection or spraying mechanism may controllably be used to inject or to spray the cell/tissue preservative onto the harvested cells or tissue sample. In some embodiments, magnet106may be made of different magnetic materials or may be made of materials (e.g., iron) that are attractable to or can interact with magnets.

In some embodiments, cytology brush107may be used by rubbing the brush on or against the target lesion. Brush107may be removed from cytology capsule100after capsule100exits the patient's body. Brush107may then be stroked across a microscope slide to smear cells, preferably evenly across the slide so that individual cells may be examined. The microscope slide may then be fixed with a fixative and preservative, and may be stained so that the intracellular components thereon may be seen. Examples of cytology brushes that may be used are COOK™ cytology brushes, and Curaprox Interdental Brushes Regular White. In some embodiments, cytology capsule100may comprise a curved or flat surface on a plate that may be pulled out with the cells on it and then sent to the pathologist for analysis. The plate, which may be in or external to drum105, may be regarded as a cells collector. The plate, or cells collector, may be detachably connected, for example, to drum105to facilitate easy pull-out removal thereof.

According to some embodiments, biasing magnet108may be replaced by a non-magnetic element (e.g., spring, spring coil, etc.). This may allow magnets to be placed in capsule's end(s)102in such a way that the magnets may facilitate external maneuvering of cytology capsule100within the GI tract while drum105may be activated by rotating the external magnet. That is, the external magnet may have two functions: maneuvering capsule100to regions of interest, and rotating drum105so that brush107may contact the tissue and acquire cells through porthole104.

Reference is now made toFIGS. 3A-3D, which illustrate schematic side views and cross sections of cytology capsules in accordance with several embodiments of the present invention. In some embodiments, the body of cylindrically shaped capsules such as capsule301A, which has a round cross-section311A (shown inFIG. 3A) may rotate with the drum so that the brush may not pass across the porthole, and may not be able to contact the tissue and brush against it for cells acquisition. It is desirable that the drum be rotated relative to the capsule body. Several ways are possible to achieve this, for example, by changing the capsule's shape from a cylindrically-shaped capsule to an elliptically-shaped capsule301B, which also has a D-shaped cross-section311B (shown inFIG. 3B). In some embodiments, when an external magnet (not shown) is applied in close proximity to the patient, the capsule may tend to orientate itself so that the flat portion of the “D” shape is closest to the external magnet. In some embodiments, the porthole may be positioned at the flat back of the capsule. In such embodiments, it may be possible to use an external magnet (not shown) to position the porthole against the region of interest, so that tissue cells may be collected by the brush at a particular orientation with respect to the tubular GI section the cytology capsule is currently in. Other shapes that would resist the capsule body turning are an eye-shaped or “turtle” shaped capsule301C (shown inFIG. 3C) or a capsule comprising fins, as capsule301D (shown inFIG. 3D), or other non cylindrically shaped capsules. In some embodiments, capsule301D may comprise extendable fins. In this embodiment, when the capsule301D is swallowed by the patient, the fins are folded around the capsule, creating a cylindrically shaped capsule. However, when the capsule reaches a region of interest, the fins may extend outward from the cylindrically shaped capsule, thereby creating “stoppers” that may stop the capsule's outer body from turning along with the inner drum.

According to some embodiments, rather than a cylindrical drum105(as shown inFIG. 2), a spherically-shaped holder or an ellipsoidally-shaped holder for brush107and (brush) magnet106(like the ball in a ball point pen) may be used. This spherical brush and magnet holder may be mounted or built into the dome of the capsule100.

Reference is now made toFIGS. 4A-4Ewhich illustrate schematic side views of cytology capsules in accordance with several embodiments of the present invention.FIG. 4Aillustrates a schematic side view of a cytology capsule410connected to an imaging capsule401through a connector411. In some embodiments, connector411may be flexible while, in other embodiments, it may be rigid. Cytology capsule410may comprise a porthole404A through which cytology brush407A may collect cells from a region of interest. While cytology capsule410collects the cells, imaging capsule401may acquire images of the lumen. Thus, two operations may be done at once—cytology acquisition and image acquisition, both of which may provide information on the patient's condition.

With the increased miniaturisation of electronics it may be possible to incorporate both functionalities (cytology and imaging) into one capsule, as illustrated inFIG. 4B. Capsule420may comprise a porthole404B through which brush407B may acquire tissue cells, while further comprising an imaging end412, through which in-vivo images may be acquired. Imaging end412may include, for example, an image sensor413and an illumination source414. Capsule420may also comprise a control circuit, for example for controlling operation of image sensor413and illumination source414, and for processing images captured by image sensor413and/or data related to captured images and/or data related to, or derived, resulting or originating from other activities of, or processes executed by, capsule420. In other embodiments, for example as illustrated inFIG. 4C, imaging system422(which may comprise an imager423, illumination sources424and an optical system (not shown)) may be located such that it acquires images through the optically transparent side of capsule430and not from the front end of the capsule, as illustrated inFIG. 4B. In such embodiments, brush407C may acquire cells through porthole404C from a region of interest, while imaging system422may image that same region of interest. In some embodiments, it might be preferable to have a transparent partition between the imaging system and the cytology system, so that the imaging system may monitor the operation of the rotating drum or the brush, either from inside or outside the capsule.

In other embodiments, as illustrated inFIG. 4D, capsule440may comprise at least two imaging systems. In addition to brush407D, capsule440may comprise a first imaging system441, which may acquire images through the side of the capsule440, e.g., it may acquire images of the region of interest from which cytology is acquired. Capsule440may further comprise a second imaging system442, which may be located at one of the ends of capsule440, for example at the capsule's end opposite the end accommodating the first imaging system. Imaging system442may image the in-vivo lumen at a direction parallel to the direction of movement of the capsule (when no external magnet is applied). Imaging systems441and442may be similar to imaging system412or to imaging system422.

In yet other embodiments, as illustrated inFIG. 4E, capsule450may comprise a cytology brush (not shown) and an imaging system451, both mounted on the same/common drum in order to occupy less space in capsule450.

Reference is now made toFIG. 5, which schematically illustrates part of a cytology capsule in accordance with one embodiment of the present invention. In some embodiments, it may be possible to replace the magnet in the drum (e.g., magnet106ofFIG. 2) by a spring such as spring506, for example a torsion spring or a spiral clockwork spring, that may rotate the drum (e.g., drum501) or bias the drum against rotation. Spring506may be controllably triggered by, for example, a solenoid that may be operated wirelessly, for example by using an RF-activated switch. This may mean that the capsule may be magnetically maneuvered without the cytology function being affected or interfered with. Spring506may be initially wound so that when the capsule arrives at the site where cells need to be harvested/acquired, the potential energy stored in spring506may be controllably used to rotate drum105one or more revolutions, with brush507passing a porthole similar to, for example, porthole104), during each revolution. Alternatively, spring506may be wound so that drum501may be rotated only partially, with only part of brush507passing the porthole (e.g., porthole104) each time. The energy stored in spring506may be controllably released in portions, to facilitate cells' acquisition from different locations in the GI tract. Each energy portion, which is released from spring506, may rotate drum501at least part of a full revolution. Each individual or partial rotation may be separately triggered, where each trigger releases an energy portion. The capsule may include a control unit for locking drum501when no cells collection is not required, and for unlocking drum501when cells collection is required.

According to other embodiments, a cytology capsule with a spring activated brush does not include magnets. In such embodiments, an external magnet may activate the mechanism that triggers/operates the energy-loaded spring (e.g., spring506). Alternative triggering mechanisms may comprise an external RF link.

According to some embodiments, it may be necessary to apply, for example, onto the drum, some form of fixative in order to prevent the acquired cells from degrading within the capsule whilst the capsule passes through the GI tract after their acquisition. Also it may be possible to arrange the cytology so that harvested/acquired cells can be easily transferred onto a slide. Spring506may be connected to drum501by a rod508through which spring506can transfer a torque force to drum501.

Reference is now made toFIGS. 6A-6B, which illustrate schematic cross-sections of a cytology capsule in accordance with two embodiments of the present invention.FIG. 6Aillustrates a cross-section of a cytology capsule which comprises a cytology brush607. The cytology capsule illustrated inFIG. 6Amay be similar to any of cytology capsules100,301A-D,410,420,430,440or450as mentioned herein, i.e., wherein the capsule comprises a magnet606attached to, or associated with, a cytology brush for collecting cells from a region of interest. According to all of the above mentioned capsules, the magnet within the capsule may be manipulated by an external magnet, such that when the external magnet rotates (the external magnet is not shown), drum610, and therefore brush607, rotates with it or as a result of its rotation. However, the same mechanism may be used to take biopsies when brush607is replaced by a cutting edge or knife607′, as illustrated inFIG. 6B. In some embodiments, when drum620rotates (e.g., as a result of a rotation of magnet606by an external magnet), instead of brush607contacting tissue and collecting cells, knife607′ may contact the tissue through a porthole and may cut a piece of the tissue, i.e., a biopsy may be acquired. When drum620is further rotated, the harvested piece of tissue may be retained within the capsule until after the capsule exits the patient's body. A receiver receiving signals from the cytology capsule may use the signals to detect the time at which the capsule is excreted naturally out of the body. For example, if the capsule transmits images, images can be used to detect the capsule excretion time because ex-vivo environment is conspicuously visually different than in-vivo environment. The receiver may, then, indicate, for example, to the patient, that the capsule has exited his body.

The acquired/harvested cells (or piece of tissue, when a biopsy is acquired) may be analyzed in order to asses the patient's condition. Therefore, it is necessary that the capsule be safely retrieved in order to extract the harvested cells or tissue sample(s). In some embodiments, retrieval of the capsule may be achieved using a net over the lavatory or by using a magnet on a stick that may be inserted into the lavatory and attract the capsule to it. According to other embodiments, the capsule may be swallowed while attached to a thread or string, in order to increase the number and improve views of, for example, the cardio-esophageal junction. A threaded capsule that comprises cytology brush may be easily retrieved through the patient's mouth and the cytology may be examined by a pathologist.

Reference is now made toFIGS. 7-9which illustrate schematic cross-sections of cytology capsules in accordance with three embodiments of the present invention. The cytology capsules illustrated inFIGS. 7-9comprise multiple sampling cavities, each sampling cavity having a porthole and a cytology brush carrying drum.

FIG. 7illustrates a cross-section of a sampling wheel of a cytology capsule that comprises three sampling cavities, each sampling cavity containing a drum and a brush that is connected to the drum and rotatable through rotation of the drum, and a porthole through which the brush can scrape a tissue while the respective drum is rotated. Referring toFIG. 7, the sampling cavities have portholes704,704′ and704″, each sampling cavity having one porthole. Portholes704,704′ and704″ may be circumferentially positioned along the sampling wheel, or circumferentially positioned along the body of cytology capsule, at an angle of 120 degrees from one another along the circumference of the capsule. The capsule (e.g., the capsule's sampling wheel) may comprise three drums705,705′ and705″ that may be rotated about spindles703,703′, and703″, respectively, against portholes704,704′ and704″, respectively. In some embodiments, each drum may be located behind a respective porthole, such that drum705is located behind porthole704, drum705′ is located behind porthole704′, and drum705″ is located behind porthole704″. In some embodiments, every drum may have an attached cytology brush, such that brushes707,707′ and707″ are attached onto drums705,705′ and705″, respectively. In some embodiments, the brushes are attached onto their respective drums such that when the drums rotate, at least one brush is placed in front of (i.e., it is aligned with) its respective porthole at any time. This ensures that at any given time, there may be a cytology brush exposed to, and collecting cells from, the surrounding tissue. In some embodiments, rotating an external magnet may cause simultaneous rotation of all three drums (each drum typically comprising a magnet) at same speed and orientation. This method may be advantageous for cytology acquisition in the esophagus, where the esophagus surrounds and touches the capsule from all sides, such that every porthole may be in contact with esophageal tissue and three cytology samples may be acquired at once. The angular orientation of the cytology capsule may change, as shown at770.

Reference is now made toFIG. 8, which illustrates a schematic cross-section of a sampling wheel of a cytology capsule in accordance with another embodiment of the present invention. The capsule inFIG. 8comprises six sampling cavities, each sampling cavity containing a drum and a brush that is connected to the drum and rotatable through rotation of the drum, and a porthole through which the brush can scrape a tissue while the respective drum is rotated. Referring toFIG. 8, the sampling cavities have cytology brushes707,807,707′,807′,707″ and807″, which may be circumferentially located at an angle of 60 degrees from one to another along the circumference of the capsule/sampling wheel. In some embodiments, the brushes may be positioned and operated such that there will always be a cytology brush exposed to surrounding tissue at any given time. For example, cytology brush707is shown exposed to the outer environment through porthole704, while the other brushes are at various stages of rotation in the respective sampling cavities. That is, if all six drums are rotated at the same time and at the same speed, brush807″ will be the next brush to face its porthole, then brush707″, then brush807′, then brush707′, then brush807. Every brush that acquires cells or a tissue piece, when further rotated along with its respective drum, may be positioned such that it is contained within the capsule, as farther away from its respective porthole as possible, in order to avoid cells contamination or leakage. The angular orientation of the cytology capsule may change, as shown at870.

FIG. 9illustrates another embodiment where a cytology capsule comprises six cytology brushes, as illustrated inFIG. 8. However, unlike the capsule inFIG. 8wherein all six brushes are located along the same transverse or longitudinal axis, inFIG. 9the brushes are located along two different transverse or longitudinal axes. Other numbers of transverse axes along which the cytology brushes may be located at are possible. According to some embodiments, at any one time, there will always be a cytology brush collecting a sample from the surrounding tissue.

Reference is now made toFIG. 10, which depicts a method for harvesting cells or a piece of a tissue with a cytology capsule in accordance with one embodiment of the present invention. The method may comprise inserting, at step1010, into a patient a cytology capsule. The method may further comprise causing, at step1020, rotation of the cytology brush to scrape/rub against a GI lumen tissue, and thus acquiring, at step1030, cells, or tissue piece, from a GI lumen tissue. In some embodiments, causing rotation of the brush may be done by rotating an external magnet which may rotate an internal magnet that is attached to the drum and thus to the brush. In some embodiments, the method may further comprise rotating, at step1040, the cytology brush into the capsule such that the cells are contained within the capsule. The method may further comprise collecting, at step1050, cells from the cytology brush following capsule's exit from the patient.

FIG. 11shows a partial cross-section view of a spring-driven brush carrying drum according to an example embodiment. Cytology capsule1100may include a cytology part, section, or compartment,1102and an imaging part, section, or compartment,1180. Cytology section1102may include a rotatable (dynamic) sampling wheel1110, a cytology brush1120, a spring1130, a cam1140operable about a controllably rotatable hinge1150, a leak proof chamber1160, which is sealed by a sealing frame or gasket1170. The terms “drum” and “sampling wheel” are used herein interchangeably. One end of spring1130may be connected to a rod1132which is connected to sampling wheel1110. Rod1132is aligned with, and servers as, a rotation axis of sampling wheel1110. The other end of spring1130may be connected to sampling wheel1110, for example by a peripheral pin1134through which spring1130may transfer a rotation force to sampling wheel1110while spring1130is decompressing. Pin1134is referred to herein as a “peripheral pin” because it has to be decentred with respect to (rotation) rod1132to facilitate application of a rotation force on sampling wheel1110.

In general, device1100may be in a non-harvesting mode or in a harvesting mode. In the non-harvesting mode brush1120may be (concealed) in chamber1160, spring1130may be fully compressed to store potential energy, and sampling wheel1110may be locked by cam1140to inhibit rotation thereof. In addition, in the non-harvesting mode chamber1160may be tightly sealed by an impervious protruding part1162of the sampling wheel1110. Sampling wheel1110may be retained in position by cam1140that may sit in a retaining recess1142in sampling wheel1110. When cells harvesting is required, the mode of capsule1100can controllably be changed from non-harvesting to harvesting. In harvesting mode, rotatable hinge1150may be caused (e.g., by an actuating mechanism which is not shown inFIG. 11) to rotate a certain amount of degrees (e.g., 30 degrees) to cause cam1140to exit (i.e., to release it from) recess1142in sampling wheel1110, to thereby unlock sampling wheel1110and enable it to rotate about rotation rod1132. Unlocking sampling wheel1110may enable spring1130to release at least some of its stored energy, to thereby rotate sampling wheel1110(by pushing peripheral pin1134).

Sampling wheel1110may have multiple retaining recesses similar to retaining recess1142, and all the retaining recesses may be circumferentially located on the sampling wheel1110. The retaining recesses may be equidistantly located on sampling wheel1110, though other arrangements or setups can be used. Cam1140may be controlled such that sampling wheel1110rotates a certain amount of degrees (a certain angle) at a time (e.g., during each activation of cam1140), from one retaining recess to another. Sampling wheel1110may, but it does not have to, turn the same angle each time cam1140is activated. The amount of degrees rotated by sampling wheel1110each time generally depends on several parameters, for example the number of the circumferential retaining recesses and their angular arrangement on the circumference of sampling wheel1110, and these parameters may change according to application. When sampling wheel is unlocked, brush1120, when exposed to the porthole window of capsule1100, may scrape cells and may, by rotating sampling wheel1110further, discard of them in leak proof chamber1160. Capsule1100may include a motor, for example an electrical motor, for controllably rotating sampling wheel1110. Such a motor may obviate the need for spring1130and cam1140.

Imaging part, section, or compartment,1180may include an illumination source1182for illuminating the GI tract, and an imaging sensor1184for capturing images of areas of the GI tract illuminated by illumination source1182. Imaging part, section, or compartment,1180may also include a controller for controlling operation of illumination source1182and imaging sensor1184. The controller may also control the operation of cam1140, and, in general, the operation mode of the cytology part of capsule1100.

FIG. 12shows a partial cross-section view of a cytology capsule1200according to another example embodiment. Cytology capsule1200may include a rotatable (dynamic) sampling wheel1210that may reside in a leak proof chamber1250. Cytology capsule1200may also include a motor (the motor, which may be, for example, an off-the-shelf piezoelectric motor of Nanomotion Ltd., an Israeli company, is not shown inFIG. 12). Sampling wheel1210may be rotated about axis1230by the motor (and in some embodiments by using also a gear mechanism), for example in the counter clockwise direction1240. Sampling wheel1210may include a plurality of sampling cavities, similar to sampling cavity1250, on its circumference. Each circumferential sampling cavity may include a cavity and a porous or absorbing material (e.g., sponge, sponge-like material, etc.) that is contained in the cavity. In general, the porous or absorbing material in each cavity may be adapted to absorb various body fluids and/or to scrape cells off a body tissue. Cavity1220is shown empty for the sake of clarity, while the other cavities are shown containing a porous material (for example, sampling cavity1250is shown containing porous material1252). Since different body fluids may have different properties (e.g., viscosity, acidity, etc.), the porous material in the sampling cavities may be made of different materials and/or with different porosities to accommodate for different body samples and/or fluids.

Sampling wheel1210may be rotated in a stepwise manner corresponding, for example, to a predefined sampling plan or scheme. For example, at each step, sampling wheel1210may be rotated a predefined amount of degrees corresponding, for example, to a basic angle1232. Basic angle1232may be contingent on the number (s) of circumferential sampling cavities, for example basic angle1232may be equal to 360/s degrees. By way of example,FIG. 12shows eight sampling cavities (s=8), and angle1232may be equal to 360/8=45 degrees. In another example, at each step, sampling wheel1210may be rotated a predefined amount of degrees corresponding, for example, to n times (n>1, e.g., n may equal to 2, 3, etc.) that angle (e.g., n times basic angle1232). Currently, porous material1221is shown facing porthole window1202, through which it may scrape cells off a tissue, or absorb a body fluid. Assume that capsule1200is in a specific location of interest in the GI system and n=2 for that particular location. In response to a command to rotate sampling wheel1210under the above mentioned constraints (specific GI location and n=2), sampling wheel1210turns 90 (2×45) degrees CCW and, while it revolves, porous material1222goes past porthole window1202(while scraping cells off a tissue or absorbing body fluids, as the case may be), and then porous material1223takes the place of porous material1222against porthole window1202. Since the sampling wheel is brought to a stop position after it revolves 90 degrees (as per the example), porous material1223remains facing porthole window1202until a next command is issued (externally to capsule1200, or internally) to rotate sampling wheel1210further. Referring also toFIG. 13, sampling wheel1210, porthole window1202, and angle1232may be configured such that when sampling wheel1210completes an operation revolution (e.g., after all the sampling cavities have been used), the sampling wheel may be rotated further such that outer surface1310of sampling wheel1210tightly seals chamber1250. Alternatively, the sampling wheel may be brought to a resting position in which the outer surface1310of sampling wheel1210tightly seals chamber1250after each rotation step. The outer surface of the sampling wheel may be made of a bacteriostatic coating to prevent contamination between sampling cavities. The gasket between the porthole window and the sampling wheel may also be made of bacteria-deterring material.

FIG. 14shows a cytology capsule1400according to another example embodiment. Capsule1400may be similar to cytology capsule1200. Sampling wheel1410, an example dynamic sampling wheel, may have multiple sampling cavities that may be similar to sampling cavity1420. Capsule1400may also include an on-board cytology analysis system. The on-board cytology analysis system may include an excitation or stimulation source1430, a detector1440, and a controller for controlling the excitement/stimulation source1430, and for processing or interpreting the output of detector1440. Each of the sampling cavities (e.g., sampling cavity1420) may be soaked in a bio-sense or bio-marker agent so that when the agent contacts a certain type of tissue cells or body fluid, the cells, or fluid, may emit a visible light when exposed to an electromagnetic radiation, for example to an Ultraviolet light. Thus, detection of a visible light emitted from cells or fluid may enable the controller to detect the presence of the cells or body fluid.

Sampling cavity1420is shown in a test position, in which the tissue cells or body fluid scraped off or absorbed by the porous material of sampling cavity1420(and interact with the bio-sense or bio-marker agent) may be tested. During the test process, the sample in the sampling cavity1420is excited or stimulated by the excitation/stimulation source. The excitation/stimulation source may emit, for example, an Ultraviolet light onto the sample cells/fluid, and detector1440may detect the consequent visible light.

As explained above, for example, in connection withFIG. 12, a particular sampling cavity may be used to sample tissue cells or fluid in a particular location in the GI system. Therefore, after the sample content of a particular sampling cavity is tested in the way described above, it may be beneficial to associate the test results obtained for the particular sampling cavity with the particular location in the GI system.

In some embodiments some of the sampling cavities of a sampling wheel may be dedicated to a particular type of tissue cells, pathogen cells, or fluid(s) while other sampling cavities of the sampling wheel may be dedicated to other types of tissue cells, pathogen cells, or fluid(s). In another embodiment, a capsule may contain more than one sampling wheel (e.g., two sampling wheels), and each sampling wheel may be dedicated to different tissue cells, pathogen cells, or fluid(s). The sampling wheels may be adjacent to each other, and they may be controlled individually. For example, when a first sampling wheel is exhausted (fully used), another sampling wheel may be used, and so on. Using multiple sampling wheels enables increasing the total number of sampling cavities in a capsule. Sampling wheels such as, for example, sampling wheels1110,1210,1310, and1410, may replace sharp protruding tools such as needles, injectors and other sharp objects that may injure or tangle with, for example, tissues.

In order to use the cytology capsule efficiently (for example to ensure tissue cells and/or body fluids are taken from desired locations), a maneuvering module may be added to the capsule. Such a module may include permanent magnet(s) and eddy current manifold that are respectively sensitive to external direct current (“DC”) electromagnetic field and alternating current (“AC”) electromagnetic field. The external electromagnetic fields may exert force on the permanent magnets and on the eddy current manifold to thereby steer the cytology capsule to the desired locations, and to orient the capsule to the desired directions. The cytology capsule may also contain localization means sensitive to an external localization system. The localization means may include one or more electromagnetic field sensing coils, and the external localization system may generate an electromagnetic signal that may be sensed by the electromagnetic field sensing coils. The localization means and the localization system may facilitate determination, in real-time, of the location and orientation of the capsule, and consequent real-time localization data may be provided to the external system applying the external maneuvering forces on the capsule, in order to accurately maneuver the cytology capsule. Since magnetic maneuvering involves applying a magnetic force on permanent magnets in the maneuvered capsule, operating a sampling wheel by a driving mechanism that is unaffected by magnetic fields (e.g., a spring, as demonstrated byFIG. 11, or a motor, as explained, for example, in connection withFIG. 12) is preferable. An example of a maneuverable capsule and of a maneuvering system may be found in a U.S. patent application Ser. No. 12/963,502, entitled “MAGNETICALLY MANEUVERABLE IN-VIVO DEVICE”.

Due to strict space constraints (swallowable capsules have to be small enough for ingestion), adding maneuvering components (e.g., permanent magnets, eddy current manifold, sensing coils) to the capsule does not leave much space for a sampling wheel (or drum). Therefore, adding a sampling wheel or drum to a magnetically maneuvered capsule requires that various capsule's components, including the permanent magnets, eddy current manifold, sensing coils and the sampling wheel or drum, be meticulously designed, so that they can coexist both physically and operationally.

FIG. 15shows a magnetically maneuverable cytology in-vivo capsule1500according to an example embodiment. Capsule1500may include batteries1502, cylindrically shaped permanent magnets1520to transform an external electromagnetic field into a maneuvering force to steer capsule1500, eddy current manifold1510to restrain the movement of capsule1500, cylindrically shaped electromagnetic field sensing coil(s)1540to sense localization signals, image sensor1550for capturing images of the GI system, illumination source1560for illuminating the GI system, optical head1570, visually transparent dome1580, transmitter1590for transmitting the images captured by image sensor1550, sampling (cytology) module1530, and controller1592for controlling operation of capsule1500. Sampling module1530may include a sampling portion1532that may include a drum and a brush or sampling wheel that may be similar to any of the drum/brush/sampling wheels described above, and a driving mechanism1534that may be similar to any of the driving mechanism described above.

FIG. 16shows a cytology capsule1600with an example locking/unlocking mechanism according to another example embodiment. Cytology capsule1600may include a drum1620, which may be similar to any of the drums described above, and other components which are not shown inFIG. 16(e.g., an image sensor, a transceiver, a controller, a maneuvering module, etc.). Drum1620may include a recess1630to facilitate locking and unlocking drum1620. In order to lock drum1620(to inhibit inadvertent rotation thereof), a pin1640is pushed into recess1630. In order to unlock drum1620(to enable it to rotate), pin1640is pulled out of recess1630. Pin1640may be pushed in and pulled out by using, for example, a solenoid mechanism or a motor. When pin1640is pulled out of recess1630, drum1620may rotate about axle1610.

FIG. 17shows brush bristles according to some example embodiments. Brush bristle1710is a plain bristle; brush bristle1720includes a miniature adze-like cutting surface1722, and brush bristle1730includes small spikes1732on the tip of the bristle to improve gathering and adherence of tissue cells. A brush used by a cytology capsule may include any combination of brush bristles similar to1710, brush bristles similar to brush bristle1720, and brush bristles similar to brush bristle1730. Alternatively or additionally, other types of bristles may be used.

It will be appreciated that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined only by the claims which follow.